Head Neck Cancers Guidelines

EVIDENCE-BASED MANAGEMENT FOR
HEAD AND NECK CANCERS

General principles and outline of management.

• History & Clinical Examination, including complete head and
  neck examination.
• Clinical Staging with subsite involvement
• Assessment of Performance Status and Nutrition
• Investigations for histological diagnosis- Biopsy / FNAC / Slide
  Review

Surgery
It is used as a single modality in early disease (stage I & II). It is combined with radiotherapy in advanced disease (stage III & IV). Wide excision of tumour in all dimensions with microscopically negative margins is essential in local control of disease.

Radiotherapy
External beam radiotherapy and / or brachytherapy are used either as a single modality or as a part of multi-modality treatment. Radiotherapy is used in 3 different settings

• Radical curative radiotherapy (Alone or in combination with chemotherapy)
• Post-operative adjuvant radiotherapy
• Palliative radiotherapy

Chemotherapy:
It is usually used in combination with radiotherapy (sequential or concurrent). It has a role in organ / voice preservation (in laryngeal / hypopharyngeal cancers) and in oropharyngeal cancers. In select patients chemotherapy can be used for palliating symptoms.

General guidelines for selecting a treatment modality:

• Stage I / II disease- Single modality (Surgery or RT)
• Stage III & IV disease -- Combined modality
  • Surgery + Radiotherapy (In most patients),
  • Chemotherapy + radiotherapy (In selected patients)
• When different modalities are available, the modality that gives maximum chance of cure should be used.
• When different modalities have similar results, a modality that gives better quality of life, with organ / voice preservation, functional and cosmetic results is preferred.

Surgery is preferred over radiotherapy as a single modality in
1. Young patients -due to high incidence of second primary
2. Sub mucous fibrosis
3. Lesions involving or close to bone - to prevent radionecrosis.
4. Sites where surgery is not morbid (cosmetically and functionally)
RT is preferred over surgery as a single modality, where
1. Severe impairment of function / cosmesis with surgery.
2. Surgery has high morbidity and poor results e.g. nasopharyngeal carcinoma.
3. Patient refuses surgery / high risk of surgery

Criteria of Unresectability:

Primary disease: Adequate surgical clearance is not achievable

• Extensive InfraTemporal Fossa involvement
• Extensive involvement of base skull.
• Extensive soft tissue disease: skin oedema/ ulceration.

Nodal Disease:

• Clinically fixed nodes.
• Infiltration of Internal /Common carotid artery.
• Extensive infiltration of prevertebral muscles, skull base.

Reconstruction options:

• Mucosal defects:Small defect- local flap / SSG / leave raw
  Large defect- Free flap/Pedicled flap (PMMC)
• Skeletal defect- free fibula /cadaveric bone graft /silastic /plate
• Skin defect- local flap / free flap / deltopectoral flap / forehead flap / PMMC

Pathology report in Head & Neck specimens:
I. Gross Pathology:
1. Location of the tumour / lesion
2. Tumour dimensions ( including tumour depth)
3. Extent of the lesions.
4. Distance from the various margins of excision
5. Nodal dissection

II. Microscopy:
1. Histologic type
2. Grade
3. Extent of disease
4. Presence / absence of perineural invasion
5. Presence / Absence of lymphovascular invasion
6. Bone / cartilage / skin / soft tissue involvement
7. Margins of excision, submucosal spread
8. Nodal status- number and size of nodes, perinodal extension and level of nodes

III. Miscellaneous features
1. In RND /MND status of the internal jugular vein
2. Presence of predisposing factors - Solar elastosis, HPV, leukoplakia, Submucous fibrosis.
3. Dysplasia / insitu elements
4. In tongue specimens - microscopic tumour thickness.
5. Larynx - preepiglottic fat status
- paraglottic space status
- cartilage involvement

Indications for post operative radiotherapy

Primary:

• Large primary - T4 or T3 with soft tissue infiltration
• Close or positive margins of excision
• Deep infiltrative tumour
• High grade tumour
• Lympho-vascular and perineural invasion

Lymph nodes:

• Bulky nodal disease N2 / N3
• Extra nodal extension
• Multiple level involvement

Indications for Brachytherapy (BRT):

• Accessible lesions
• Small (preferably < 3cm) tumours
• Lesions away from bone
• N0 nodal status

Radical Radiotherapy:

Tumour suitable for brachytherapy

• T1-2 N0: Radical BRT: 60-70Gy Low Dose Rate 192Iridium
  Or equivalent doses with fractionated high dose rate.
• T1-3 N0-1: External RT: 56-60Gy/ 28-30#/ 6 wks
  Boost BRT: Low dose rate 192Iridium: 15-20Gy or
  High Dose Rate: 14Gy in 4 fractions over 2 days (4-3-3-4 Gy)

Tumours not suitable for brachytherapy:

• T1-4 N0-2: Concomitant Chemoradiation: 66-70Gy/33-35# /6-7 wks + concomitant weekly Cisplatinum, 30mg/m2 for 6-7 wks
  Or
• External RT: 66-70Gy/33-35# /6-7 wks (reducing fields)

Post-operative radiotherapy:

• Primary and nodal disease: 50 - 60 Gy/25-30 fr/5-6 weeks, using reducing fields.
• Site of residual disease, positive cut margins: 4-10 Gy Boost

Rehabilitation:

• Abstinence from tobacco/ alcohol
• Oral Hygiene
• Shoulder physiotherapy in all cases of neck dissections
• Bite guide prosthesis following mandibulectomy
• Jaw stretching exercises to prevent post-operative trismus
• Swallowing and speech rehabilitation

Follow up:

• Every two to three months for first 2 years.
• Six monthly for next 3 years.
• Annually thereafter.
• On every follow up thorough head and neck examination for locoregional control, second primary tumour and late sequelae of treatment. Investigation only if indicated by symptoms and positive clinical findings.
  
  Oral cavity and Oropharynx

Oral cavity Subsites:

• Buccal mucosa
• Lower alveolus
• Retro molar trigone
• Oral tongue
• Floor of mouth (FOM)
• Lip
• Upper alveolus
• Hard palate

Oropharynx Subsites:

• Base of tongue
• Tonsil
• Soft palate
• Pharyngeal wall

 

Specific Investigations before definitive treatment:

• OPG / Dental occlusal view for mandibular involvement.
• USG neck for clinically N0 neck when clinical suspicion is high and neck evaluation is difficult.
• CT scan if recent onset trismus (ITF involvement), suspected vascular / maxillary infiltration
• MRI in selected cases to evaluate soft tissue extent eg. Base tongue
• EUA for mapping of lesion.

TNM STAGING (UICC 1997)

Lip & Oral Cavity
Tx	Primary tumour cannot be assessed
T0	No evidence of primary tumour
Tis	Carcinoma in situ
T1	Tumour 2cm or less in the greatest diameter
T2	Tumour > 2cm but < 4 cm in the greatest diameter
T3	Tumour > 4cm in the greatest diameter
T4	Lip: tumour invade adjacent structures eg., through       cortical bone, inferior alveolar nerve, floor of mouth, skin of face.   Oral Cavity: tumour invades adjacent structures eg., through cortical bone, into deep (extrinsic) muscles of tongue, maxillary sinus, skin.(superficial erosion alone of bone /tooth socket by gingival primary is not icient  to classify a tumour as T4)

        
Oropharynx
T1          Tumour 2cm or less in the greatest diameter
T2          Tumour >2cm but <4cm in the greatest diameter
T3          Tumour > 4cm in the greatest diameter
T4          Tumour invades adjacent structures eg., pterygoid, muscles, mandible, hard               palate, deep muscles of tongue, larynx.

Neck Nodes
Nx          Regional LN cannot be assessed
N0          No regional LN metastasis
N1          Ipsilateral Single node < 3cm
N2a        Ipsilateral Single node >3cm and <6cm
N2b        Ipsilateral multiple nodes <6cm
N2c        Bilateral / Contralateral nodes < 6cm
N3          Lymph node > 6cm

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BUCCAL MUCOSA

T1, T2 Tumours:

Primary:
Surgery: wide excision +/- marginal mandibulectomy for margins.
Radiotherapy: Radical Radiotherapy / Brachytherapy.

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) à FS à MND
N+: MND / RND

Note: Post op RT as per earlier guidelines.

T3, T4 Tumours: Surgery + Post operative Radiotherapy

Primary:
Surgery: Composite resection of the buccal mucosa with mandible or upper alveolus or overlying skin with reconstruction

Nodes
N0: SOHD à FSà MND
N+: MND / RND

Note: Post op RT as per earlier guidelines.

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LOWER ALVEOLUS AND RETRO MOLAR TRIGONE

Mandible Uninvolved or minimally involved
Primary:
Surgery: Wide Excision with marginal mandibulectomy (avoided in RMT disease, edentulous mandible, paramandibular disease)

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) à FS à MND
N+: MND / RND

Note: Post op RT as per earlier guidelines.

Mandible grossly involved: Surgery + Post operative RT

Primary:
Surgery: Wide Excision (cheek flap) with segmental/ hemi-mandible resection

Nodes
N0: SOHD à FS à MND
N+: MND / RND.

Note:
Bilateral neck needs to be addressed if the primary disease is extending across midline (including middle third mandible).
Post op RT as per earlier guidelines.

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LIP

T1, T2 Tumours:

Primary:
Surgery: wide excision
Radiotherapy: Radical Radiotherapy / Brachytherapy.

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) à FS à MND
N+: MND / RND

Note: Post op RT as per earlier guidelines.

T3, T4 Tumours: Surgery + Post operative Radiotherapy

Primary:
Surgery: Wide excision with marginal/ segmental / hemimandible resection if required with reconstruction.

Nodes
N0: SOHD ? FS? MND
N+: MND / RND

Note:

• Bilateral neck needs to be addressed if the primary disease is extending across midline (including middle third mandible).
• Post op RT as per earlier guidelines.

ORAL TONGUE AND FLOOR OF MOUTH

T1, T2 Tumours:

Primary:
Surgery: Wide Excision Glossectomy / Hemiglossectomy
Radiotherapy: Radical Radiotherapy / Brachytherapy

Nodes
N0** Observe/ Elective MND (criteria listed below)#
N+ MND/ RND

Note: Post op RT as per earlier guidelines.

T3, T4 Tumours: Surgery + Post operative Radiotherapy

Primary:
Surgery: Appropriate wide / total glossectomy with mandibular swing or pull through along with lingual plate / segmental / hemimandibular resection, if required (based on extent of involvement)

Nodes
N0: SOHD / MND / RND
N+: MND / RND

Note:

• Bilateral neck need to be addressed if the primary disease is extending across midline (including middle third mandible).
• Post op RT as per earlier guidelines.

** USG neck if decision to observe the N0 neck is made.

#Criteria for elective neck dissection
¨ Depth of infiltration > 3-4mm
¨ High grade tumour
¨ Expected poor follow up

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UPPER ALVEOLUS & HARD PALATE

Maxillary antrum not involved

• Upper alveolectomy or Partial maxillectomy
• Radical Radiotherapy / Brachytherapy for selected early T1-2 Hard palate lesions

• Orbital floor preserving total maxillectomy

Note:

• Neck need to be addressed if the neck is clinically positive, if there is extension of the primary disease to the buccal mucosa and there is soft tissue infiltration.
• Post operative RT as per guidelines mentioned earlier.

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OROPHARYNX

T1-2 N0

• Radical Radiotherapy: In most cases.
• Surgery: In selected cases eg. Lateralised lesion, infiltrative disease. (Criteria: Patient's preference, institutional practice and complexity of procedure).

T3-4, N0 / Any T, N+

Concomitant CT plus RT: In most cases.

·Surgery: (if low peri-op risk & reasonable functional outcome) Composite resection + appropriate neck dissection + Post-operative radiotherapy

Note: Post op RT as per earlier guidelines.

 

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LARYNX AND HYPOPHARYNX

Larynx

• Supra-glottis: Epiglottis, Ary-epiglottic folds, Arytenoids, False cords, Ventricles
• Glottis: True vocal cord with anterior & posterior commissures
• Subglottis:

Hypopharynx:

• Pyriform sinus
• Post-cricoid region
• Posterior pharyngeal wall

 

Specific Investigations before definitive treatment:

• Indirect laryngoscopy / Hopkins telescopy
• Ba swallow
• Direct laryngoscopy
• Microlaryngocsopy for early cord lesions
• CT scan / MRI mandatory before conservative laryngectomy / laryngeal preservation therapy

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TNM STAGING (UICC 1997)

Supraglottis
T1	Limited to one subsite of supraglottis, normal cord mobility
T2	Invades mucosa of >1 adjacent subsite of supraglottis or  glottis or region outside the supraglottis (eg., mucosa of base tongue, medial wall of PFS) without fixation of the larynx
T3	Limited to larynx with cord fixation and/or invades any of the following : PC, pre-epiglottic tissues, deep of base tongue
T4	Invades through thyroid cartilage, and/or extends into soft tissues of the neck, thyroid and/or oesophagus

Glottis
T1	Limited to vocal cord(s) (may involve anterior or posterior commissure) with normal mobilityT1a limited to one vocal cord; T1b: Involving both vocal cords
T2	Extends to supraglottis / subglottis, and or impaired cord mobility
T3	Limited to larynx with vocal cord fixation.
T4	Invades through thyorid cartilage, and/or extends to the tissues beyond larynx, eg. trachea, soft tissues of neck, thyroid, pharynx

        

Subglottis
T1	Limited to subglottis
T2	Extends to vocal cord(s) with normal or impaired mobility
T3	Limited to larynx with vocal cord fixation
T4	Invades through cricoid or thyroid cartilage and/or extends into other tissues beyond the larynx, eg. trachea, soft tissues of neck, thyroid, oesophagus

Hypopharynx
T1	Limited to one subsite of hypopharynx and 2cm or less in greatest diameter
T2	Invades more than one subsite of hypopharynx or adjacent site or, measures >2cm but <4cm in the greatest diameter without fixation of the hemilarynx
T3	>4cm in greatest diameter, or, with fixation of hemilarynx
T4	Invades adjacent structure eg, thyroid / cricoid cartilage, carotid artery, soft tissues of the neck, prevertebral fascia/muscles etc

Nodes
Nx          Regional LN cannot be assessed
N0          No regional LN metastasis
N1          Ipsilateral Single node < 3cm
N2a        Ipsilateral Single node >3cm and <6cm
N2b        Ipsilateral multiple nodes <6cm
N2c        Bilateral / Contralateral nodes < 6cm
N3         Lymph node > 6cm

SUPRAGLOTTIS:

Surgery is preferred over radiotherapy in cases with

• Large volume disease.
• Cartilage erosion.
• Bulky nodal disease.
• Gross pre epiglottic space involvement

Management of neck nodes
No	Bilateral neck nodes need to be addressed either with surgery lateral neck dissection (II-IV) or RT
N1	Bilateral Comprehensive/ anterolateral neck dissection (II-IV) + Post operative RT.
N2-3	Bilateral MND / RND (on side of greater disease) + Post operative RT.

  Small primary (radiocurableT1-2) with large resectable disease (N2-3) may be considered for neck dissection with RT to primary and neck.

Note:
Post operative RT as per guidelines mentioned earlier.

GLOTTIS

Aim of treatment: To maximise cure and to preserve voice

Radical Radiotherapy: Small, localised fields covering only the Larynx with margins, after appropriate immobilisation and planning.
Dose: 55Gy/16fr/3 weeks or 60Gy/24 fractions/5 weeks
Note:
Control rates: Radiotherapy = Endoscopic Laser Surgery = VPL
Voice Quality:Radiotherapy > Endoscopic Laser Surgery > VPL
Surgery preferred in: Young patient, Verrucous lesion, When quality of voice is not a major factor.

T3-4 tumors

• Surgery: Near-Total laryngectomy / Total laryngectomy + RT
• Concomitant CT+RT
• Radical radiotherapy in patients with low GC/poor performance status who might not tolerate CT+RT

N0-1 nodes are managed with RT if the primary is treated with RT. If surgery is the primary treatment modified neck dissection for N1 nodes is recommended.

N2-3 nodes need MND/RND with Post-operative radiotherapy. If radiotherapy is the primary treatment, neck dissection follows radiotherapy 4-6 weeks later if residual nodes persist

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PYRIFORM FOSSA

T1-2 N0,1

• Radical Radiotherapy
• Partial Laryngo-pharyngectomy

T1-2 N2-3

• Concurrent CT+RT.
• Radical Radiotherapy Salvage surgery (Low GC -unable to tolerate CT+RT).
• Split Therapy - Neck dissection + Radical Radiotherapy to primary and neck.

T3-4, Any N

• Near-Total Laryngectomy /Total laryngectomy + Post operative Radiotherapy.
• Concurrent CT + RT.
• Radical radiotherapy salvage surgery (Low GC -unable to tolerate CT+RT).

Note:

• Post operative RT as per guidelines mentioned earlier.
• Surgery is the treatment of choice in
• Large volume disease.
• Bulky neck nodes
• Cartilage erosion
• Extensive soft tissue involvement.

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POST CRICOID & POSTERIOR PHARYNGEAL WALL

T1-2 N0-1 :
Radical Radiotherapy

T3-4 Any N: Small volume disease

• Concurrent CT+RT.
• Radical Radiotherapy Salvage surgery (Low GC -unable to tolerate CT+RT

T3-4 Any N: Large volume disease

• Total laryngo-pharyngo-oesophagectomy with gastric pullup or Free jejunal flap or tube pectoralis myocutaneous flap and Post operative Radiotherapy.

Note:

1. Post operative RT as per guidelines mentioned earlier.
2. Surgery is the treatment of choice in
o Large volume disease.
o Bulky neck nodes
o Cartilage erosion
o Extensive soft tissue involvement.

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NASOPHARYNX

Specific Investigations before definitive treatment:

o Nasal endoscopy / Nasopharyngoscopy
o CT scan

TNM STAGING (UICC 1997)
T1	Tumour confined to the nasopharynx
T2	Tumour extends to soft tissue of oropharynx and or nasal fossa
T2a	without parapharyngeal extension
T2b	with parapharyngeal extension
T3	Tumour invades bony structure and/or paranasal sinuses
T4	Tumour with intracranial extension and./or involvement of cranialnerves, infratemporal fossa, hypopharynx, or orbit.

Nx	Regional LN cannot be assessed
N0	No Regional LN metastasis
N1	Unilateral metastasis in LN(s), 6 cm or less in greatest dimension above  Supraclavicular fossa
N2	Bilateral Metastasis in LN(s), 6cm or less in greatest dimensionabove  supraclavicular fossa
N3	Metastasis in LN(s)(a) greater than 6 cm in dimension(b) in the  supraclavicular fossa

Nasopharyngeal carcinoma differs from other head and neck squamous cell carcinomas in following aspects
o Classified into 3 types
a) WHO type I - Keratinising Sq. Ca
b) WHO type II - Non-keratinising Sq. Ca
c) WHO type III - Undiferrentiated carcinoma
o Radiosensitive tumours, even with large volume nodal disease respond well to radiotherapy.
o WHO type III (Undiferrentiated carcinoma) responds better than keratinising variety.
o Surgery has a very limited role as en bloc surgical resection of the tumour and the regional lymph nodes is difficult and severely morbid

Nasopharyngeal Carcinoma: Treatment options

T1 / Selected T2 N0:

• Radiotherapy alone with or without Intraluminal Brachytherapy

Bulky T2 & T3-4 N0 / Any T N+

• Neo Adjuvant CT 2 cycles + Concurrent CT + RT

Chemoradiotherapy Schedule for Undiferentiated Ca Nasopharynx: Cisplatinum (33mg / m2 / day x 3 days) + Ifosfamide (2gm /m2 / day x 3 days) - 2cycles + Mesna rescue followed by Concomitant weekly Cisplatinum (30 mg / m2) during radiotherapy(70Gy)

Note

• Role of surgery is minimal: No neck dissection upfront even for large nodes/ Neck dissection is reserved for palpable nodes persisting 8 weeks after radiotherapy and when the primary is controlled.
• Treatment of recurrence: Re-irradiation, surgery in selected cases.

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PARANASAL SINUSES / NASAL CAVITY

Maxillary Sinus
T1	Tumour limited to the antral mucosa with no erosion or destruction of bone.
T2	Tumour causing bone erosion or destruction, except for the posterior antral wall, including extension into hard palate and/or middle nasal meatus.
T3	Tumour invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, skin of cheek, floor or medial wall of orbit, infratemporal fossa, pterygoid plates, ethmoid sinuses.

Ethmoid Sinus
T1          Tumour confined to ethmoid with or without bone erosion
T2          Tumour extends into nasal cavity
T3          Tumour extends to anterior orbit and/or maxillary sinus
T4          Tumour with intracranial extension including apex, involving sphenoid and/or frontal sinus andor skin of nose

Nodes:
Nx          Regional LN cannot be assessed
N0          No regional LN metastasis
N1          Ipsilateral Single node < 3cm
N2a        Ipsilateral Single node >3cm and <6cm
N2b        Ipsilateral multiple nodes <6cm
N2c        Bilateral / Contralateral nodes < 6cm
N3          Lymph node > 6cm

Ethmoid Sinus and Nasal Cavity Carcinoma.
Operable tumours: Surgical excision with post-operative RT
Primary: Approach either by midface degloving or lateral rhinotomy or by craniofacial approach for superior extent.

• Orbital exenteration should be done only if the peri-orbita and orbital apex is involved.
  Medial maxillectomy with ethmoidal clearance may be adequate for localised ethmoidal and nasal cavity tumors.
• For tumors extending to the adjoining regions (cribriform plate, orbits, maxillary sinuses): appropriate extended procedure
  Neck: N0: Observe; N+: Appropriate neck dissection + post-op RT.
  Inoperable tumours: Radiotherapy
  
  Maxillary Sinus
  Surgery with or without post-op RT is the treatment of choice in resectable lesions. If primary tumor is not resectable with clear margins, radiotherapy is to be considered

Extent of surgery: Depending upon the extent of the disease as described below. Obtain pre-op dental impression for post-op prosthesis.

Lesions of hard palate & upper alveolus (antral mucosa uninvolved): Infrastructure (Partial) maxillectomy

Maxillary antral mucosa involved:
· Orbital floor uninvolved: Orbital floor preserving total maxillectomy
· Orbital floor involved: Total Maxillectomy (TM).
· Peri-orbital tissue / Eye ball involved: TM + Orbital Exentration
· Ant / Middle ethmoidal air cells involved: TM + Ethmoid Clearance
· Cribriform plate involved (Extra-dural disease): TM + Cranio-facial resection

Neck:

• N0 necks are observed.
• N+ - Ipsilateral appropriate neck dissection and post-operative radiotherapy, if required.

Criteria of Unresectability

• Gross infiltration of infratemporal fossa.
• Involvement of dura and intra-cerebral extension of squamous carcinoma.
• Involvement of posterior ethmoids and sphenoid.
• Extensive soft tissue and skin infiltration.
• Bilateral neck nodes

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SALIVARY GLANDS:

Specific investigations prior to definitive treatment:
FNAC- recommended but not mandatory when other pathology suspected e.g. granulomatous pathology and in cases of malignancy when facial nerve may have to be sacrificed.
CT scan- to differentiate b/w deep lobe and parapharyngeal mass or MRI to visualise facial canal in facial nerve involvement

TNM STAGING (UICC 1997)
T1	Tumour 2cm or less in greatest dimension without extraparenchymal extension
T2	Tumour >2cm but < 4 cm in greatest dimension without extraparenchymal extension
T3	Tumour having extraparenchymal extension without Facial nerve involvement and/or more than 4cm but not more than 6 cm in greatest dimension
T4	Tumour invades base of skull, facial nerve, and/or exceeds 6cm in greatest dimension

Nodes
Nx Regional LN cannot be assessed
N0 No regional LN metastasis
N1 Ipsilateral Single node < 3cm
N2a Ipsilateral Single node >3cm and <6cm
N2b Ipsilateral multiple nodes <6cm
N2c Bilateral / Contralateral nodes < 6cm
N3 Lymph node > 6cm

Treatment: Primary Tumor:

• Superficial /Adequate parotidectomy :Minimal surgical procedure.
• Total parotidectomy for deep lobe involvement.
• Radical parotidectomy for involvement of nerve/adjacent structures
• Radiotherapy for unresectable primary.
  Note: Facial nerve is spared if there is clearly identifiable plane between it and the tumour, else sacrificed

Neck: N0 neck - Level II nodal sampling - FS - MND
N+ neck - MND/RND

Indications for Post Operative Radiotherapy:

• Close or positive margins
• Lymph node metastasis
• Adenoid cystic carcinoma
• High or intermediate grade tumours
• Deep lobe tumours
• Preop facial nerve paralysis
• Lymphatic or vascular invasion or perineural involvement
• Recurrent tumours

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THYROID CANCERS

Specific investigations prior to definitive treatment:
1. FNAC
2. Serum Calcitonin (In suspected case of Medullary thyroid carcinoma)
3. CT scan (if tracheal / vascular infiltration suspected).

TNM STAGING (UICC 1997)
T1	Tumour 1 cm or less in greatest dimension, limited to the thyroid
T2	Tumour more than 1 cm but not more than 4 cm in greatest dimension, limited to the thyroid
T3	Tumour more than 4 cm in greatest dimension, limited to the thyroid
T4	Tumour of any size extending beyond the thyroid capsule

Nodes
Nx Regional LN cannot assessed
N0 No regional LN metastasis
N1 Regional LN metastasis
N1a Metastasis in ipsilateral cervical LN (s)
N1b Metastasis in bilateral midline, or contralateral cervical or mediastinal LN(s)

Histological classification
Differentiated thyroid cancerso Papillary o Follicularo Hurthle cell
Medullary thyroid cancer (MTC)
Anaplastic carcinoma
Lymphoma

Treatment of Differentiated Thyroid Cancers:

Surgery forms the mainstay of treatment in all stages of differentiated thyroid cancers including metastatic cancer. The extent of surgery depends upon the risk categorisation of the patient.

Risk stratification by AMES criteria
Low Risk Patient
Low risk age without metastasis
High risk age without metastasis with low risk extent and size

High Risk Patients
Any patient with metastasis
High risk age with high risk extent or size

Hemithyroidectomy: Low risk patient with good expected follow-up

Total Thyroidectomy: High risk patient or expected poor follow-up

Management of lymph nodes:

• Central compartment clearance and ipsilateral nodal sampling ?FS?MND
• MND (Type II or III) for positive lymph nodes.
• RND (rarely required) if large nodes infiltrating surrounding structure

Treatment of Medullary Thyroid Carcinoma (MTC):

There are two types of MTC

• Sporadic type
• Familial type - associated with Multiple Endocrine Neoplasia (MEN) IIA, IIB and familial non-MEN MTC

Indications to investigate for familial MTC:

• Young age
• Bilateral / multicentric disease
• Clinical features of familial MTC
• Family history of MTC or other tumours associated with MEN

Investigations for suspected familial MTC:

• S. Ca, S. phosphate and S. PTH for parathyroid tumours
• USG abdomen, Urinary VMA

Metastatic work-up for all MTCs:

• Chest X-ray
• USG abdomen
• Bone scan

Treatment for MTC:

• Surgery: Total thyroidectomy with central compartment clearance +/- MND
• Radiotherapy used only for palliation in advanced unresectable disease.
• No role of chemotherapy.

Follow up: Clinical examination and Serum Calcitonin

Serum Calcitonin normal: Observe

Serum Calcitonin raised: Imaging to detect recurrence

• Operable recurrence detected: Surgery
• Inoperable Recurrence detected: If GC good debulking surgery else radiotherapy or symptomatic treatment.

Other treatment modalities:

• Surgery: For orthopaedic stabilisation / cord compression.
• External radiotherapy: Limited role, indications are
• Surgically unresectable disease not responding to 131I
• Gross residual disease, poor uptake on post-op scan.
• Chemotherapy - No role.

Follow up: Oral thyroxine (T4) supplementation to keep TSH low (0.5 - 5 mIU/ml if no residual disease and 0.1 mIU/ml if residual disease present); Oral calcium supplementation, S. Thyroglobulin, Diagnostic whole body scan.

Treatment of anaplastic thyroid carcinoma:

Operable (very uncommon):
Total Thyroidectomy

Inoperable:
Palliative RT

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Head Neck Cancers Abstracts

HEAD & NECK CANCERS Oral cancers

1 EBM

Surgery as a single modality therapy for squamous cell carcinoma of the oral tongue.
Hicks WL Jr, North JH Jr, Loree TR, et al. Am J Otolaryngol 1998: 19:24-8

PURPOSE: The treatment of squamous cell cancer of the oral tongue remains a challenging clinical problem. The efficacy of primary treatment with surgery versus radiation therapy for early stage disease and an adequate treatment paradigm for the clinically negative neck continues to be the subject of clinical debate. We have reviewed our experience in the treatment of oral tongue cancer with surgery as a single definitive treatment modality. PATIENTS AND METHODS: From 1971 to 1993, 79 patients with squamous cell carcinoma of the oral tongue were treated with surgery alone at Roswell Park Cancer Institute. RESULTS: Clinically, 69% of the patients presented with stage I/II disease and 31% presented with stage III/IV. Survival by pathological stage I to IV was 89%, 95%, 76%, and 65%, respectively. Surgical therapy ranged from partial to total glossectomy. There were no patients with positive margins. Local recurrence was observed in 15% of patients with close margins (< 1 cm) and 9% of patients with adequate margins (> or = 1 cm). The incidence of pathological node positive (N+) disease was 6%, 36%, 50%, and 67% for T1, T2, T3, and T4 tumors, respectively. Twenty-five percent of patients undergoing elective neck dissection were pathological N+. All pathological confirmed nodal disease was at level I or II. Of the 43 patients with clinical N0 disease, 16% subsequently developed regional recurrence, all of which were surgically salvaged. CONCLUSION: Locoregional control in patients with squamous cell carcinoma of the oral tongue can be achieved with primary surgical therapy. Adequate margins are crucial to local control. Salvage neck dissection may result in long-term survival for patients with regional relapse. Because of the high rate of occult disease (41%), we currently recommend prophylactic treatment of regional lymphatics for primary clinical disease of T2 or greater.

Analysis of treatment results for oral tongue cancer.
Sessions DG, Spector GJ, Lenox J, et al. Laryngoscope 2002;112:616-25

OBJECTIVE: The study reports the results of treatment of oral tongue cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 332 patients with oral tongue cancer treated in the Departments of Otolaryngology-Head and Neck Surgery and Radiation Therapy at Washington University School of Medicine (St. Louis, MO) from 1957 to 1996. METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral tongue who were previously untreated and were treated with curative intent by one of five modalities and who were eligible for 5-year follow-up were included. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival rate (DSS) was 57% with death due to tumor in 43%. The 5-year cumulative disease-specific survival probability (CDSS) was 0.61 (Kaplan-Meier) with a mean of 17.5 years and a median of 30.1 years. The DSS by treatment modality included local resection (73%), composite resection (61%), radiation therapy (46%), local resection and radiation therapy (65%), and composite resection with radiation therapy (CR/RT) (44%). Overall, local resection had a significantly improved DSS and CR/RT had a decreased DSS that was related to the stage of disease being treated. In treating stage IV disease, CR/RT produced a more significantly improved CDSS than the other treatment modalities. Recurrence at the primary site was as common as recurrence in the neck. Eighty-nine percent of recurrences occurred within the first 60 months. Recurrence significantly decreased survival. DSS was significantly improved in patients with clear margins of resection. Metastasis to a distant site occurred in 9.6% of patients. Twenty-one percent of patients had second primary cancers, and 54% of these patients died of their second primary cancer. CONCLUSIONS: Significant improvement in DSS was seen in patients with clear margins, early stage grouping and clinical (pretreatment) tumor stage, and negative nodes. Significant decrease in DSS was seen in patients with close or involved margins, advanced stage grouping and clinical (pretreatment) tumor staging, positive clinical (pretreatment) node staging, and tumor recurrence. Obtaining clear margins of resection is crucial because it significantly affects survival. A minimum of 5 years of close monitoring is recommended because of the high incidence of second primary cancers.

Analysis of treatment results for floor-of-mouth cancer.
Sessions DG, Spector GJ, Lenox J, et al. Laryngoscope 2000;110:1764-72

OBJECTIVE: This study reports the results of treating floor-of-mouth cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 280 patients with floor-of-mouth cancer treated in the Department of Otolaryngology-Head and Neck Surgery at Washington University Medical School (St. Louis, MO) from 1960 to 1994. METHODS: Patients with biopsy-proven squamous cell carcinoma of the floor of mouth who were previously untreated were treated with curative intent by one of five modalities and were all eligible for 5-year follow-up. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival (DSS) was 56% with death due to tumor in 44% of patients. The 5-year cumulative disease-specific survival (CDSS) was 0.61 (Kaplan-Meier probability) with a mean of 8.3 years and a median of 9.7 years. The DSS by treatment modality included local resection (76%), composite resection (63%), radiation therapy (43%), local resection with radiation therapy (61%), and composite resection with radiation therapy (55%). Overall, there was no significant difference in DSS by treatment modality. Recurrence at the primary site (41%) was the most common site of treatment failure. Nineteen percent of patients had recurrence in the neck. Eighty-eight percent of initial recurrences occurred within 60 months after the onset of treatment. Metastasis to a distant site occurred in 30% of patients. Twenty percent of these patients had second primary cancers, and 53% of these patients died of their second primary cancers. CONCLUSIONS: Significantly improved 5-year DSS was seen in the patients with clear margins, early clinical tumor stage, and negative nodes. Significantly decreased 5-year survival was seen in the patients with involved margins, advanced clinical tumor stage, positive nodes, and tumor recurrence. Patients with no clinically positive nodes (cNO) can be observed safely for regional nodal disease and subsequent positive nodes can be treated as they occur with no adverse affect on survival. Because of high recurrence rates at the primary site and neck, and an increased rate of both distant metastasis and the development of second primary cancers, patients should be monitored closely for a minimum of at least 5 years.

Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection.
Haddadin KJ, Soutar D, Oliver R, et al. Head Neck 1999;21:517-25

BACKGROUND: Prophylactic surgical treatment of the neck in "early tongue tumors" is a controversial issue. METHODS: From a database of 226 patients with squamous cell carcinoma of the tongue treated at Canniesburn Hospital, Glasgow, U.K., between 1980 and 1996, a total of 137 patients with a minimum follow up of 24 months or until death were clinically identified as being T1/T2, N0 (UICC) when first seen. These patients were divided into three groups according to the management of the neck; 53 patients did not have a neck dissection at any time (NKD0), 47 patients underwent a synchronous neck dissection at the time of treatment of the primary (NKDS), and 37 patients subsequently required a metachronous neck dissection when lymph node metastasis became clinically apparent (NKDM). These three groups were compared with respect to age, sex, site, duration of symptoms, previous treatment (if any), initial treatment protocol, resection margin, type of neck dissection (if any), loco-regional recurrence, systemic escape, number of positive lymph nodes, and presence of extracapsular spread. Disease-related survival was calculated using Kaplan-Meier survival curves with logrank test and chi-square statistical analysis. RESULTS: The pT stage was upgraded to T3/4 in 3/53 patients (6%) of the NKD0 group, 11/47 patients (23%) of the NKDS group, and 2/37 patients (5%) of the NKDM group (p < 0.001). The 5-year determinate survival rates for the three groups were: NKD0 59.7%, NKDS 80.5%, NKDM 44.8%, and (NKD0 + NKDM) 53.6% with a statistically significant improvement in survival for NKDS vs NKDM (logrank 10.58, p = 0.001) and for NKDS vs (NKD0 + NKDM) (logrank 6.06, p = 0.014). The incidences of positive nodes in the NKDS and NKDM groups were 18/47 patients (38%) and 32/37 patients (86%) respectively. Neck positive patients in the NKDM group had a significantly greater number of positive nodes in comparison with N positive patients in the NKDS group (chi trend, p = 0.001), a higher incidence of extracapsular spread, 30/32 vs 9/18 (chi test, p < 0. 0001), and decreased survival. The incidence of occult cervical metastasis for the whole group was 41%. CONCLUSION: Patients with clinical T1/2, N0 tongue tumors who underwent a synchronous neck dissection had an improved survival outcome even though as a group they had a higher incidence of occult metastasis, relatively more T2 lesions, a worse pT stage, and had more posterior third lesions requiring more difficult initial surgery. Tongue tumors have a high incidence of subclinical nodal disease, which is less curable when it presents clinically. The information gleaned from the nodal status allows a more informed plan of adjuvant therapy.

Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity.
Kligerman J, Lima RA, Soares JR, et al. Am J Surg 1994;168:391-4

BACKGROUND: Recent studies in patients with previously untreated T1 and T2 squamous cell carcinoma (SCC) of the tongue and floor of the mouth have shown a relationship between tumor thickness, neck metastasis, and survival. Our study was conducted to determine the indication of elective neck dissection in patients with early oral cavity SCC. PATIENTS AND METHODS: Sixty-seven patients were stratified by stage (T1 and T2 NO), and those in each stage were randomized to receive one of two types of treatment; resection alone (RA) or resection plus elective supraomohyoid neck dissection (RSOND). Fifty-two patients (78%) were men and 15 (22%) were women. The median age was 57 years old (range 34 to 95). RESULTS: Twenty-six (39%) patients had tumor in the floor of the mouth and 41 (61%), in the tongue. Using the criteria of the Union Internationale Contre le Cancer (UICC), 1987, we classified 31 tumors (46%) as T1 lesions and 36 (54%) as T2 lesions. Thirty patients had a tumor thickness < or = 4 mm and 37 had a tumor thickness > 4 mm. Thirty-three (49%) patients were treated with RA, and 34 patients (51%) were treated with RSOND. Seven (21%) patients of the RSOND group had occult cervical metastasis. There were recurrences in 14 (42%) patients of the RA group and 8 (24%) patients of the RSOND group. The disease-free survival rates at 3.5 years for RA and RSOND patients were 49%, and 72%, respectively. The impact of sex, age, site, cancer stage, and tumor thickness was assessed by the Mantel-Haenszel chi-square procedure. Later stage (P = 0.05) and increased tumor thickness
(P = 0.005) were significantly associated with treatment failures. CONCLUSION: Neck dissection remains mandatory in the early stage of oral SCC, because of better survival rates compared to RA and the poor salvage rate. In particular, patients with tumor thickness > 4 mm treated with RSOND had significant benefit on disease-free survival.

Elective versus therapeutic neck dissection in early carcinoma of the oral tongue.
Fakih AR, Rao RS, Borges AM, et al. Am J Surg 1989;158:309-13

A prospective, randomized trial was carried out to assess the value of elective versus therapeutic neck dissection in early squamous cell carcinoma of the oral tongue. Disease-free survival (median follow-up 20 months) was 52 percent versus 63 percent in patients who underwent hemiglossectomy alone and those who underwent hemiglossectomy and radical neck dissection, respectively (difference not statistically significant). Patients with a tumor depth of less than 4 mm did significantly better than those with a tumor depth of greater than 4 mm; they were also more likely to have uninvolved nodes at elective radical neck dissection compared with those with a tumor depth of greater than 4 mm. However, when the survival rates of patients in the two treatment groups were compared with respect to a tumor depth of 4 mm, there was no significant difference between the hemiglossectomy and the hemiglossectomy and radical neck dissection groups. A policy of interval elective radical neck dissection only in those with a tumor depth of greater than 4 mm may optimize cure rates and avoid neck dissection in those unlikely to develop neck recurrence.

Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: results of a randomized clinical trial.
Vandenbrouck C, Sancho-Garnier H, Chassagne D, et al. Cancer 1980;46:386-90

This study concerns 75 patients with squamous cell carcinoma of the oral cavity who were patients at the Gustave-Roussy Institute between December 1966 and July 1973. These patients were divided into two groups. The first group was comprised of 39 patients who underwent elective radical neck dissection; nodal involvement was present in 49% with capsular rupture in 13%. In the second group of 36, neck disease appeared during follow up in 19 cases. Therapeutic radical neck dissection was carried out in 17; the nodes were histologically positive in 15, 9 of which had a capsular rupture. In 2 cases, local or general conditions did not permit operative intervention. In this group, the involvement rate was 47% with a 25% capsular rupture rate. However, the comparison of the survival curves by the log-rank test did not reveal any differences, even though histologic prognostic factors were taken into account. These findings led to the conclusion that in squamous cell carcinoma of the oral cavity staged T1N0, T2N0, or T3N0 (from AJC's and UICC's clinical staging system), it seems possible, without risk, to delay neck dissection until a node is detectable, although it is reasonable to perform elective neck dissection in those cases in which the patient is unavailable for regular followup.

Controlling advanced neck disease: efficacy of neck dissection and radiotherapy.
Richards BL, Spiro JD. Laryngoscope 2000;110:1124-7

OBJECTIVE: Neck dissection remains the standard method of treating cervical metastasis from head and neck squamous cell carcinoma. In light of recent trends to modify the classic radical neck dissection (RND) for early neck disease, we reviewed our experience with radical and modified RND (MRND) plus radiotherapy as treatment for N2/N3 neck disease in head and neck squamous cell carcinoma. METHODS: We retrospectively reviewed our clinical records from July 1989 to June 1996 to identify 43 neck dissections in 39 patients who were found to have pathologically N2 or N3 neck disease treated primarily by neck dissection and
postoperative radiotherapy. All patients had head and neck squamous cell carcinoma with a minimum follow-up of 24 months. RESULTS: Nine percent (4/43) of the dissected necks were pathologically N2a, 72% (31/43) were N2b, 7% (3/43) were N2c, and 12% (5/43) were N3. Of these, 28% (12/43) underwent a RND and 72% (31/43) underwent a MRND. The most common modification of RND was preservation of the spinal accessory nerve. All patients underwent postoperative radiotherapy with a mean dose of 55 Gy. Only 4 of 43 dissected necks had isolated treatment failure, for a regional control rate of 91%. CONCLUSIONS: The combination of RND or MRND and radiotherapy is highly effective in controlling neck disease in the absence of persistent or recurrent local disease. Also, in our experience, MRND appears to be as effective as RND in controlling even advanced neck disease, which supports preservation of the spinal accessory nerve whenever oncologically feasible.

A comparison of results after radiotherapy and surgery for stage I squamous cell carcinoma of the lower lip.
de Visscher JG, Botke G, Schakenraad JA, et al. Head Neck 1999;21:526-30

BACKGROUND: Controversy still exists as to whether radiotherapy or surgery is the preferable therapeutic modality for stage I squamous cell carcinoma of the lower lip. Therefore, a retrospective study was undertaken to compare the results of both treatment modalities. METHODS: The results of 90 patients who received radiotherapy and 166 patients who underwent surgery as the primary form of treatment for their stage I primary squamous cell carcinoma of the lower lip were evaluated. Tumor size and histological grade of differentiation were assessed. RESULTS: Local control rates were the same with radiotherapy or surgery. Overall survival rates for both groups of patients were similar as well. Disease-free survival rates in the patients who underwent radiotherapy were significantly lower compared with the surgically treated group. This was due to a higher occurrence of regional metastases in the patients who received radiotherapy. Univariate analysis showed that irradiated patients had a statistically significant greater tumor size. The difference of histological differentiation between the groups was also statistically significant, the analysis showed that only tumor size carried significant independent prognostic information. CONCLUSIONS: The cure rates of stage I squamous cell carcinoma of the lower lip are favorable whether treated by radiotherapy or surgery, and local control rates are similar. The radiotherapeutic treated group showed an increased incidence of cervical metastases, which was due to the more advanced tumor size in these patients.

Stage I and II are treated with surgery or radiotherapy as a single modality. There are no randomized control trials comparing surgery with radiotherapy in early stage disease. Combined modality in the form of surgery with post-operative radiotherapy is used in operable stage III & IV disease. There is a controversy regarding management of N0 neck in oral cancers.

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HEAD & NECK CANCERS Oropharyngeal carcinoma

2 EBM

Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tete et du Cou (GETTEC).
Domenge C, Hill C, Lefebvre JL, De Raucourt D, et al. Br J Cancer 2000;83:1594-8

The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2-3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d'Etude des Tumeurs de la Tete Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy.

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma.
Calais G, Alfonsi M, Bardet E, et al. J Natl Cancer Inst 1999;91:2081-6

BACKGROUND: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

 

Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma.
Pinto LH, Canary PC, Araujo CM, et al. Int J Radiat Oncol Biol Phys 1991;21:557-62

From April 1986 to May 1989, 112 patients seen at a single institution with previously untreated squamous cell oropharynx carcinoma, Stages III and IV, were randomly assigned to 66 Gy in 33 fractions of 2 Gy each (conventional RT) versus 70.4 Gy in 64 fractions of 1.1 Gy given twice a day with a minimal interfraction interval of 6 hours (hyperfractionated RT). The overall time for both arms was 6 1/2 weeks. Patients were stratified by site (base of the tongue vs others), T stage (T1/T2 vs T3 vs T4), N stage (N0/N1 vs N2 vs N3), and lymphnode size (less than 6 cm vs greater than 6 cm). As of January 1990, an analysis was performed in 98 patients (8 patients in the conventional arm and 6 in the hyperfractionation not included). The groups were balanced by age, performance status, stage, and site of the primary disease. The median follow-up time was 25 months. The probability of complete loco-regional response was 62% in the hyperfractionation arm and 52% for the conventional fractionation (p = 0.28). There was no difference in the control of lymphnodal disease (hyperfractionated = 55%, conventional = 57%; p = 0.92), but the disease control in the oropharynx only was significantly improved in the hyperfractionation arm (84% vs 64%, p = 0.02). Overall survival rate at 42 months was 27% for the hyperfractionation arm and 8% for the conventional (p = 0.03). Survival rates for hyperfractionated versus conventional RT were 40% versus 18% (p = 0.06), respectively, for Stage III patients and 16% versus 0% (p = 0.15), respectively, for Stage IV. There was significant improvement in survival in favor of the hyperfractionation arm in patients with lesions outside the base of the tongue (31% vs 15%, p = 0.02), for those with a 50-70% Karnofsky status (19% vs 0%, p = 0.006) and for patients with N0/N1 disease (38% vs 15%, p = 0.03). Acute toxicities were of similar magnitude, although both skin and mucosal reactions appeared earlier on the hyperfractionation scheme. To date, no differences in late toxicity have been observed. We conclude that in a subset group of patients with locally advanced carcinoma of the oropharynx, hyperfractionated radiotherapy appears to provide improved survival without adding to increased toxicity.

 

Is radiation therapy a preferred alternative to surgery for squamous cell carcinoma of the base of tongue?
Mendenhall WM, Stringer SP, Amdur RJ, et al. J Clin Oncol 2000;18:35-42

PURPOSE: To evaluate irradiation alone for treatment of base-of-tongue cancer. PATIENTS AND METHODS: Two hundred seventeen patients with squamous cell carcinoma of the base of tongue were treated with radiation alone and had follow-up for >/= 2 years. RESULTS: Local control rates at 5 years were as follows: T1, 96%; T2, 91%; T3, 81%; and T4, 38%. Multivariate analysis revealed that T stage (P =.0001) and overall treatment time (P =.0006) significantly influenced local control. The 5-year rates of local-regional control were as follows: I, 100%; II, 100%; III, 83%; IVA, 64%; and IVB, 65%. Multivariate analysis revealed that the following parameters significantly affect the probability of this end point: T stage (P =.0001), overall treatment time (P =.0001), overall stage (P =.0131), and addition of a neck dissection (P =.0021). The rates of absolute and cause-specific survival at 5 years were as follows: I, 50% and 100%; II, 81% and 100%; III, 65% and 76%; IVA, 42% and 56%; and IVB, 44% and 52%. Severe radiation complications developed in eight patients (4%). CONCLUSION: The likelihood of cure after external-beam irradiation was related to stage, overall treatment time, and addition of a planned neck dissection. The local-regional control rates and survival rates after radiation therapy were comparable to those after surgery, and the morbidity associated with irradiation was less.

OTHER SELECT PUBLICATIONS:
Tiwari RM, van Ardenne A, Leemans CR, et al. Advanced squamous cell carcinoma of the base of the tongue treated with surgery and post-operative radiotherapy. Eur J Surg Oncol. 2000; 26:556-60.

Gourin CG, Johnson JT. Surgical treatment of squamous cell carcinoma of the base of tongue. Head Neck. 2001;23(8):653-60.

Robertson ML, Gleich LL, Barrett WL, et al. Base-of-tongue cancer: survival, function, and quality of life after external-beam irradiation and brachytherapy. Laryngoscope. 2001;111:1362-5.

The treatment of oropharyngeal carcinoma is aimed at maximizing cure with minimal functional morbidity. Radical radiotherapy is the treatment of choice in early T1, T2 tumors and chemoradiotherapy is the treatment of choice in advanced T3, T4 tumors. Surgery is preferred in select early cases where surgical resection is associated with reasonable functional outcome. It is also preferred with postoperative radiotherapy in select advance cases eg. Infiltrative lesions of base tongue, tonsil and lesions involving the mandible and as a salvage procedure for residual neck nodes following chemoradiotherapy.

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HEAD & NECK CANCERS Nasopharyngeal Carcinoma

3 EBM

Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials.
Huncharek M, Kupelnick B. Am J Clin Oncol 2002;25:219-23

It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.

Combined radiotherapy and chemotherapy for nasopharyngeal carcinoma. Fu KK. Semin Radiat Oncol 1998;8:247-53

Among squamous cell carcinomas of the head and neck, nasopharyngeal carcinoma is probably the most radiosensitive and chemosensitive. It also has the highest incidence of distant metastasis. This article reviews the results of randomized trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma to date. Induction chemotherapy with bleomycin, epirubicin, and cisplatin was shown to increase disease-free survival but not overall survival in a trial by the International Nasopharyngeal Cancer Study Group. Concurrent radiotherapy and cisplatin followed by adjuvant cisplatin and 5-fluorouracil infusion significantly decreased local, nodal, and distant failures and increased progression-free and overall survival in the Head and Neck Intergroup Trial. The toxicity of combined chemotherapy and radiotherapy, however, primarily acute toxicity, was significantly greater than that of radiotherapy alone. Further clinical trials using novel drugs, altered fractionation radiotherapy and chemotherapy dose schedules, new radiotherapy techniques, and other treatment modifiers are needed to further improve the therapeutic ratio.

Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial.
Int J Radiat Oncol Biol Phys 1996;35:463-9

PURPOSE: Our Phase II trial using bleomycin, epirubicin, and cisplatin (BEC) protocol in the treatment of loco-regionally advanced undifferentiated nasopharyngeal carcinoma (UCNT) patients has shown encouraging results with high objective response, disease-free survival, and overall survival rates. To establish the value of this BEC regimen as neoadjuvant chemotherapy, we initiated in 1989 a large international Phase III trial. It compares three cycles of BEC followed by radiotherapy to radiotherapy alone. METHODS AND
MATERIALS: From November 1989 to October 1993, 339 patients with negative metastases workup, stratified by accrual center have been randomized, 168 to radiotherapy alone and 171 to chemotherapy plus radiotherapy. All patients characteristics were well balanced in both arms. There was a quality control/data verification by specialist panel (radiology, histology, radiotherapy, chemotherapy) and external policy board expert every 60-80 patients having completed treatment. RESULTS: With a median follow-up of 49 months (range: 23-70), despite an excess of treatment-related deaths in the neoadjuvant chemotherapy arm (8 vs. 1%), there is a significant difference in disease free survival favoring the chemotherapy arm (p < 0.01). The proportion of local and/or regional metastases was comparable in both arms. No difference in overall survival is seen but the numbers of events needed for analysis has not yet been reached. CONCLUSIONS: BEC type neoadjuvant chemotherapy has a significant impact in the natural history of UCNT. Further follow-up is needed to establish an eventual overall survival difference.

Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngealcancer: phase III randomized Intergroup study 0099.
Al-Sarraf M, LeBlanc M, Giri PG,et al. J Clin Oncol 1998;16:1310-7

PURPOSE: The Southwest Oncology Group (SWOG) coordinated an Intergroup studywith the participation of Radiation Therapy Oncology Group (RTOG), and EasternCooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS: Radiotherapy was administered in both arms: 1.8-to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total doseof 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

Nasophary Nasopharyngeal carcinomas are relatively radio and chemosensitive tumours. Radiotherapy forms the mainstay of treatment of nasopharyngeal carcinomas. Surgery has a very limited role to play in management of nasopharyngeal carcinomas. It is shown that chemotherapy plus radiotherapy improves disease free and progression free survival compared to radiotherapy alone in advanced nasopharyngeal carcinomas. But, it is controversial whether addition of chemotherapy to radiotherapy improves overall survival. Recently published meta-analysis has shown that it does improve overall survival.

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HEAD & NECK CANCERS Hypopharyngeal cancer

4 EBM

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group.
Lefebvre JL, Chevalier D, Luboinski B, et al. J Natl Cancer Inst 1996;88:890-9

BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.

 

 

 

Surgery and radiotherapy as a single modality have similar results in Stage I & II disease (level III evidence). However, Radiotherapy is preferred over surgery due to its low morbidity and voice preservation. In stage III & IV disease, Surgery + Post-operative radiotherapy and Chemo-radiotherapy have shown equal results regarding survival. Due to higher chance of laryngeal preservation, Chemo-radiotherapy should be offered to patients with low volume disease and good follow up

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HEAD & NECK CANCERS Early Glottic Carcinoma

5 EBM

Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control/complications.
Dinshaw KA, Sharma V, Agarwal JP, Ghosh S, Havaldar R. Int J Radiat Oncol Biol Phys 2000;48:723-35

PURPOSE: To evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. METHODS AND MATERIALS: Between 1975 and 1989, 676 patients with early glottic carcinoma (460 T1 and 216 T2) received curative radiation with three different treatment regimens, as follows: Regimen 1-50 Gy/15 Fr/3 weeks (3.33 Gy/daily) for 192 patients; Regimen 2-60-62.5 Gy/24-25 Fr/5 weeks (2.5 Gy/daily) for 352 patients; and Regimen 3-55-60 Gy/25-30 Fr/5-6 weeks (2-2.25 Gy/daily) for 132 patients. RESULTS: The local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p = 0.0). For the T1N0M0 group, field size had significant impact on local control with both univariate (p = 0.05) and multivariate (p = 0.03) analysis. For T2N0M0, group field size (p = 0.03) as well as registration year (p = 0.016) were significant in univariate analysis whereas only field size remained significant on multivariate analysis. Persistent radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p = 0.000) but not related to different treatment regimens. CONCLUSION: The shorter fractionation schedule had comparable local control, without increased complications in comparison to the protracted schedule and is best suited for a busy department.

Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer.
Dey P, Arnold D, Wight R, et al.
Cochrane Database Syst Rev 2002;(2):CD002027

BACKGROUND: Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early stage glottic cancer. Case series suggest that they confer similar survival advantage. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES: To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer SEARCH STRATEGY: Electronic search of MEDLINE (from 1966 to October 2000), EMBASE (from 1980 to October 2000), CINAHL (from 1982 to October 2000) and CancerLit (from 1963 to October 2000) databases and the Cochrane Controlled Trials Register. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing open surgery, endolaryngeal resection and/or radiotherapy DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed RCTs identified from the electronic searches for eligibility and methodological quality. All authors of the review discussed the results of these assessments. MAIN RESULTS: Only one RCT was identified which compared open surgery and radiotherapy among a substantial number of patients with early glottic laryngeal cancer. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence to guide management decisions on the most effective treatment. Interpretation of the only large scale RCT comparing open surgery and radiotherapy in patients with early glottic cancer is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis. Endolaryngeal resection of early glottic tumours is becoming more common and a well designed multicentre RCT is warranted.

Cure rates are similar in early glottic cancers with radiation therapy and surgical modalities like transoral laser surgery and open partial laryngectomy. There is no conclusive evidence to support any particular modality and at this instance the treatment is still based on patient and physician preference. The possibility of running a trial to demonstrate the superiority of a particular modality is difficult

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HEAD & NECK CANCERS Organ preservation protocol

6 EBM

Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group.
N Engl J Med 1991;324:1685-90

BACKGROUND. We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. METHODS. Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. RESULTS. After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. CONCLUSIONS. These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

 

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group
Lefebvre JL, Chevalier D, Luboinski B, et al. J Natl Cancer Inst; 88:890-9 1996 UI: 8656441

Abstract: BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.

META-ANALYSIS OF CHEMOTHERAPY IN HEAD AND NECK CANCER (MACH-NC): (2) LARYNX PRESERVATION USING NEOADJUVANT CHEMOTHERAPY (CT) IN LARYNGEAL AND HYPOPHARYNGEAL CARCINOMA (Meeting abstract).
Lefebvre JL, Wolf G, Luboinski B, et al. Proc Annu Meet Am Soc Clin Oncol; 17:A1473 1998 UI: 98701471

Abstract: The MACH-NC group performed a meta-analysis using updated individual patient data from all 3 randomized trials (1985--1993) comparing immediate surgery + radiotherapy (RT) to CT followed by RT in responders or by surgery + RT in non responders in laryngeal & hypopharyngeal carcinoma. Overall survival (OS) was the main end-point. The logrank-test, stratified by trial, and the relative risk (RR) were calculated. The American (n = 332) and French (n = 68) trials included laryngeal tumors and the European (n = 202), pharyngeal & epilaryngeal tumors. OS and disease-free survival (DFS) results are given below for the 602 patients: [EMBEDDED TABLE] The types of first events were different in the two arms with twice as many loco-regional recurrences in the CT arm as in the control arm, 35% vs 20%, less metastases/second primaries, 38% vs 54%, and similar rates of deaths not due to cancer, 27% vs 26%. In the CT group, the proportion of patients with a functional larynx was 67% and 58% among patients alive at 3 and 5 years respectively. In conclusion, no significant differences in OS or DFS were observed between the CT arm and the control arm. The larynx was preserved in 58% of patients alive at 5 years. However, organ preservation should remain experimental because of the non significant trend observed in favor of the control arm.

 

 

Organ preservation in laryngeal / hypopharynngeal cancers seemed a reality with the landmark VA trial, However the meta analysis of the various organ preservation trials does not seem to warrant concurrent chemoradiation as a standard treatment as of now. Outside clinical trials surgery followed by radiation therapy remains the standard of care in advanced operable laryngeal and hypopharynngeal cancers and concurrent chemoradiation is to be followed only in a controlled trial setting.

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HEAD & NECK CANCERS Salivary Gland Neoplasm

7 EBM

Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Spiro RH. Head and Neck Surgery 1986;8:177-184.
We have reviewed a 35-year experience with 2,807 patients treated for salivary tumors which arose in the parotid gland (1,695 patients; 70%), submandibular gland (235 patients; 8%), and seromucinous glands of the upper aerodigestive tract (607 patients; 22%). Pleomorphic adenomas comprised 45% of the total, most of which occurred in the parotid gland. The clinical findings and the distribution of patients according to the histology and the site of origin are summarized. Treatment was surgical and the resection was conservative when possible, depending upon the extent of the tumor. The impact of site, histology, grade, and tumor stage on the results is shown.

Malignant parotid tumors: prognostic factors and optimum treatment. Theriault C, Fitzpatrick PJ. American Journal of Clinical Oncology 1986;9: 510-516.

A retrospective study of 271 patients with parotid carcinoma seen between 1958 and 1980 is reported. Among these were 64 (24%) mucoepidermoid tumors (all degrees of differentiation), 50 (18%) adenocarcinomas, 40 (15%) malignant mixed tumors, 39 (14%) adenoid cystic carcinomas, 37 (14%) undifferentiated, 21 (8%) acinic, and 20 (7%) squamous cell carcinomas. The proportion of advanced (T3T4) to early (T1T2) tumors was 1.7:1. At diagnosis, 42 (15%) patients had regional metastases. An analysis for prognostic factors showed that the histology, tumor stage, regional metastases (No vs. N+), age, and damage to the facial nerve all influence cause-specific survival. After multivariate analysis the tumor size and the presence of regional metastases were the two most significant factors (p less than 0.0001 and 0.004). The prognostic characteristics were similar for the 67 (25%) patients treated by surgery and for the 169 (62%) patients treated with surgery and postoperative radiotherapy. Patients treated with combined therapy had a 10-year relapse-free rate of 62% compared to 22% for those treated by surgery alone (p = 0.0005).

HEAD & NECK CANCERS Thyroid cancer

8 EBM

An expanded view of risk-group definition in differentiated thyroid carcinoma.
Cady B, Rossi R. Surgery 1988;104:947-53

There continues to be controversy about every aspect of management of differentiated thyroid carcinoma. In an age-based risk group previously described, low-risk patients made up 62% of cases and had a death rate of only 1%. Recent reports from the Mayo Clinic have expanded the concept of the low-risk group to include 86% of all cases with a 2% death rate by utilizing several anatomic and pathologic criteria of risk. We offer here another multifactorial system for the identification of low-risk patients who made up 89.4% of all patient seen between 1961 and 1980 and who have a death rate of only 1.8%. The resultant high-risk group constitutes 11% of cases but carries a 46% mortality rate. The risk-group definition is completely clinical and is based on age, presence of distant metastases, and the size and extent of primary cancer. It can be used confidently at the operating table to select conservative succeeding decades analyzed, from 1941 to 1980, the effectiveness of this clinical categorization has increased substantially in separating patients at high and low risk, so that a mortality rate ratio of 26:1 now exists between high- and low-risk groups, respectively.

Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system.
Hay ID, Grant CS, Taylor WF, et al. Surgery 1987;102:1088-95

From a multivariate analysis of more than 14,200 patient-years' experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system can identify patients at increased risk of PTC mortality and was employed as an adjustment variable for analyzing the role of different types of surgical treatment in 860 PTC patients. Cancer mortality at 25 years in patients with an AGES score of 3.99 or less was 1% after ipsilateral lobectomy (n = 131) and 2% after bilateral resection (n = 603), whether subtotal or total (p = 0.15). Of patients with an AGES score of 4 or more, those who underwent lobectomy alone (n = 30) had a mortality rate from PTC at 25 years of 65%, while those undergoing bilateral resection (n = 86) had a lower rate of 35% (p = 0.06). For patients at minimal risk (score of 3.99 or less) of PTC death, no improvement in survival was demonstrable when patients underwent more than ipsilateral lobectomy. However, in a subgroup (score of 4 or more) identified to be at significant risk of PTC death, the survival after bilateral resection was much higher than after ipsilateral lobectomy alone. In neither the "minimal" nor the "higher" risk subgroup was PTC survival significantly improved by the performance of total thyroidectomy.

Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer.
Pasieka JL, Zedenius J, Auer G, et al. Surgery 1992;112:1154-9

BACKGROUND. The purpose of this study was to prospectively assess whether nuclear DNA content added prognostic value to existing risk factors in patients with papillary thyroid cancer. METHODS. Nuclear DNA content was measured both on the fine needle aspiration material and the surgical specimen in 73 patients with primary or recurrent papillary thyroid cancer. We modified the existing age of patient, presence of distant metastases, extent and size of the tumor (AMES) risk-group classification to include DNA ploidy with AMES (DAMES). Patients with euploid tumors that were AMES low risk were considered to be DAMES low risk; patients with euploid tumors that were AMES high risk became intermediate risk, and patients with aneuploid tumors that were AMES high risk became DAMES high risk. RESULTS. Forty-eight patients were in the DAMES low-risk group. Recurrences and/or distant metastases developed in only four (8%) of these patients. Twenty-two patients were in the DAMES intermediate-risk group. Twelve (55%) of the intermediate-risk group had residual, recurrent, or distant metastatic disease, with one death from cancer at 120 months. Three patients were in the DAMES high-risk group. Distant metastases developed in all three patients, who died within 24 months from thyroid cancer. A statistically significant difference existed in the development of recurrence/metastases or death from cancer in the DAMES high-risk group compared with the other risk groups combined. CONCLUSIONS. Nuclear DNA content adds prognostic value to the existing AMES risk-group classification. Because DNA analysis on fine needle aspiration correlated well with the surgical specimen DNA analysis, this modified classification can be used perioperatively to further individualize the treatment of patients with papillary thyroid cancer.

Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989.
Hay ID, Bergstralh EJ, Goellner JR, et al. Surgery 1993;114:1050-7

BACKGROUND. Multivariate analyses in papillary thyroid carcinoma (PTC) have shown that age, tumor size, local invasion and distant metastasis are independent predictive variables. This study attempted to define a reliable prognostic scoring system for predicting PTC mortality rates with 15 candidate variables that included completeness of primary tumor resection but excluded histologic grade and DNA ploidy. METHODS. The study group comprised 1779 patients with PTC (followed up for > 26,000 patient-years), divided by treatment dates into 1940 to 1964 (n = 764) and 1965 to 1989 (n = 1015). Cox model analysis and stepwise variable selection led to a prognostic model initially derived from the training set (n = 764). The initial prognostic score was thereafter validated externally with the later (1965 to 1989) "test" data set. RESULTS. The final model included five variables abbreviated by metastasis, age, completeness of resection, invasion, and size (MACIS). The final prognostic score was defined as MACIS = 3.1 (if aged < or = 39 years) or 0.08 x age (if aged > or = 40 years), + 0.3 x tumor size (in centimeters), +1 (if incompletely resected), +1 (if locally invasive), +3 (if distant metastases present). Twenty-year cause-specific survival rates for patients with MACIS less than 6, 6 to 6.99, 7 to 7.99, and 8+ were 99%, 89%, 56%, and 24%, respectively (p < 0.0001). CONCLUSIONS. Because the five variables needed for MACIS scoring are readily available after primary operation, such a prognostic system could have widespread applicability in assessment of PTC.

Low-risk differentiated thyroid cancer: the need for selective treatment.
Shaha AR, Shah JP, Loree TR. Ann Surg Oncol 1997;4:328-33

BACKGROUND: The well recognized prognostic factors in differentiated carcinoma of the thyroid are age, grade, extracapsular extension, distant metastasis, and size of the tumor. Based on these prognostic factors, we have divided patients into low-, intermediate-, and high-risk categories. Clearly, there are significant differences in these three groups. This article analyzes in depth our data on low-risk thyroid cancer patients. METHODS: A retrospective review of 1,038 patients with differentiated carcinoma of the thyroid was undertaken. Various prognostic factors and risk groups were analyzed. Univariate and multivariate analyses were performed, and the survival curves were plotted by the Kaplan-Meier method. The inclusion criteria for the low-risk group were age younger than 45 years, tumors < 4 cm in size, low-grade histology, absence of distant metastasis, and absence of extrathyroidal extension. There were 465 patients in the low-risk group. Four hundred three patients had papillary and 62 patients had follicular thyroid cancer. There were 120 male and 354 female patients. Two hundred seventy-eight patients (60%) presented with clinically apparent lymph node metastasis. RESULTS: With a median follow-up of 20 years, the 10- and 20-year survival in this select group was 99%. The local, regional, and distant recurrence rates were 5, 9, and 2% in this series. The analysis of the data showed statistical difference in local recurrence rate between partial lobectomy and total lobectomy (27 vs. 4%; p = 0.005). There was no statistical difference in local recurrence rate between total lobectomy compared with total thyroidectomy (4 vs. 1%; p = 0.10). The overall failure rate between partial lobectomy and total thyroidectomy (27 vs. 8%) was statistically significant (p = 0.04). There was no statistical difference in the overall failure rate between total lobectomy and total thyroidectomy (13 vs. 8%; p = 0.06). There was no survival difference between various histologies or nodal status. CONCLUSIONS: Patients with low-risk tumors have excellent long-term survival. Nodulectomy or partial lobectomy should be avoided. The intraoperative decisions regarding the extent of thyroidectomy should be based on gross clinical findings and risk group analysis.

Current approaches and perspectives in the therapy of medullary thyroid carcinoma.
Vitale G, Caraglia M, Ciccarelli A, et al. Cancer 2001;91:1797-808

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells. At present, surgery is the most important treatment for MTC. METHODS: We describe the current approaches of MTC treatment (surgery, chemotherapy, radiation therapy, and biologic therapy). RESULTS: MTC is currently approached surgically in the main part through total thyroidectomy and compartment-oriented microdissection of cervicomediastinal lymph nodes. Substitutive l-thyroxine administration together with close clinical monitoring and the measurement of basal and stimulated serum calcitonin are subsequently performed. Radiotherapy and chemotherapy play a marginal role in advanced MTC. Recently, it has been found that somatostatin analogs and type I interferon are able to control the neuroendocrine symptoms induced by advanced MTC and that they provide clinical benefit by improving the lifestyle of these patients. CONCLUSION: Although these agents are poorly active in inducing a shrinkage in tumor mass, the combined use of different biologic agents and cytotoxic drugs needs to be explored in advanced MTC. However, at present, surgery is the only curative treatment for MTC. Copyright 2001 American Cancer Society.

OTHER SELECT PUBLICATIONS:

Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995 Dec;118:1131-6; discussion 1136-8

Steinmuller T, Klupp J, Rayes N, Ulrich F, Jonas S, Graf KJ, Neuhaus P. Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg 2000;166:29-33

Thyroid cancers are a heterogenous group of disorders. The treatment is based on evidence available from retrospective studies as there are no prospective trials available. It is impossible to perform a prospective randomised trial as the number of cases required will be enormous and considering the indolent nature of the disease a prolonged follow up is required. For differentiated cancers the treatment is guided by risk stratification criteria. Loboisthumectomy for the low-risk group, and total/near-total thyroidectomy for the high-risk, intermidiate risk and for cases with lymph node metastases is recommended. No role of prophylactic neck dissection or anterolateral neck dissection MND is recommended for clinically palpable nodal metastasis. Post - operative 131I is mandatory in the high and intermidiate risk group where complete removal of the thyroid gland is achieved. Surgery is the mainstay in the treatment of medullary cancers and external radiotherapy is reserved for palliation in advanced and unresectable recurrent cases. Anaplastic cancers are treated with palliative intent.

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HEAD & NECK CANCERSNose & Paranasal Sinus

9 EBM

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review.
Dulguerov P, Jacobsen MS, Allal S, et al. Cancer 2001;92:3012-29

BACKGROUND: The authors reviewed treatment results in patients with nasal and paranasal sinus carcinoma from a large retrospective cohort and conducted a systematic literature review. METHODS: Two hundred twenty patients who were treated between 1975 and 1994 with a minimum follow-up of 4 years were reviewed retrospectively. A systematic review of published articles on patients with malignancies of the nasal and paranasal sinuses during the preceding 40 years was performed. RESULTS: The 5-year survival rate was 40%, and the local control rate was 59%. The 5-year actuarial survival rate was 63%, and the local control rate was 57%. Factors that were associated statistically with a worse prognosis, with results expressed as 5-year actuarial specific survival rates, included the following:
1) histology, with rates of 79% for patients with glandular carcinoma, 78% for patients with adenocarcinoma, 60% for patients with squamous cell carcinoma, and 40% for patients with undifferentiated carcinoma;
2) T classification, with rates of 91%, 64%, 72%, and 49% for patients with T1, T2, T3, and T4 tumors, respectively;
3) localization, with rates of 77% for patients with tumors of the nasal cavity, 62% for patients with tumors of the maxillary sinus, and 48% for patients with tumors of the ethmoid sinus;
4) treatment, with rates of 79% for patients who underwent surgery alone, 66% for patients who were treated with a combination of surgery and radiation, and 57% for patients who were treated exclusively with radiotherapy.

Local extension factors that were associated with a worse prognosis included extension to the pterygomaxillary fossa, extension to the frontal and sphenoid sinuses, the erosion of the cribriform plate, and invasion of the dura. In the presence of an intraorbital invasion, enucleation was associated with better survival. In multivariate analysis, tumor histology, extension to the pterygomaxillary fossa, and invasion of the dura remained significant. Systematic review data demonstrated a progressive improvement of results for patients with squamous cell and glandularcarcinoma, maxillary and ethmoid sinus primary tumors, and most treatment modalities. CONCLUSIONS: Progress in outcome for patients with nasal and paranasal carcinoma has been made during the last 40 years. These data may be used to make baseline comparisons for evaluating newer treatment strategies.

Malignant tumors of the nasal cavity and paranasal sinuses.
Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB. Head Neck 2002;24:821-9.

PURPOSE: To evaluate the role of radiation therapy in patients with nasal cavity and paranasal sinus tumors. MATERIALS AND METHODS: Between October 1964 and July 1998, 78 patients with malignant tumors of the nasal cavity (48 patients), ethmoid sinus (24 patients), sphenoid sinus (5 patients), or frontal sinus (1 patient) were treated with curative intent by radiation therapy alone or in the adjuvant setting. There were 25 squamous cell carcinomas, 14 undifferentiated carcinomas, 31 minor salivary gland tumors (adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma), 8 esthesioneuroblastomas, and 1 transitional cell carcinoma. Forty-seven patients were treated with irradiation alone, 25 with surgery and postoperative irradiation, 2 with preoperative irradiation and surgery, and 4 with chemotherapy in combination with irradiation with or without surgery. RESULTS: The 5-year actuarial local control rate for stage I (limited to the site of origin; 22 patients) was 86%; for stage II(extension to adjacent sites (eg, adjacent sinuses, orbit, pterygomaxillary fossa, nasopharynx; 21 patients) was 65%; and for stage III (destruction of skull base or pterygoid plates, or intracranial extension; 35 patients) was 34%. The 5-year actuarial local control rate for patients receiving postoperative irradiation was 79% and for patients receiving irradiation alone was 49% (p =.05). The 5-, 10-, 15-, and 20-year ultimate local control rates for all 78 patients were 60%, 56%, 48%, and 48%, respectively. The 5-, 10-, 15-, and 20-year cause-specific survival rates for all 78 patients were 56%, 45%, 39%, and 39%, respectively. The 5-, 10-, 15-, and 20-year absolute survival rates for all 78 patients were 50%, 31%, 21%, and 16%, respectively. Of the 67 (86%) patients who were initially seen with node-negative disease, 39 (58%) received no elective neck treatment, and 28 (42%) received elective neck irradiation. Of the 39 patients who received no elective neck treatment, 33 (85%) did not experience recurrence in the neck compared with 25 (89%) of 28 patients who received elective neck irradiation. Most patients who received elective neck irradiation (57%) had stage III disease. Twenty-one (27%) of 78 patients had unilateral blindness develop secondary to radiation retinopathy or optic neuropathy; the complication was anticipated in most of these patients, because the ipsilateral eye was irradiated to a high dose. Four patients (5%) unexpectedly had bilateral blindness develop because of optic neuropathy. All four of these patients received irradiation alone. CONCLUSION: Surgery and postoperative radiation therapy may result in improved local control, absolute survival, and complications when compared with radiation therapy alone. Elective neck irradiation is probably unnecessary for patients with early-stage disease.

Surgical salvage after failed radiation for paranasal sinus malignancy.
Curran AJ, Gullane PJ, Waldron J, et al. Laryngoscope 1998;108:1618-22

OBJECTIVE: To comment on the role of surgical salvage following failed initial treatment for paranasal sinus malignancy. DESIGN: A retrospective analysis of one hundred eighty patients treated at The Princess Margaret Hospital, Toronto, from 1976 to 1993. MATERIALS AND METHODS: Thirty-four of 95 patients (36%) whofailed initial treatment underwent surgical salvage. Initial therapy in this group was radiation only (n = 27) and combined therapy (n = 7). Patient, tumor, and surgical data were recorded. There were 23 T4, three T3, six T2, and two T1 carcinomas. Survival, recurrence rates, and the influence of a variety of variables on outcome were analyzed. RESULTS: Two- and 5-year overall actuarial survival calculated from the date of diagnosis was 54% and 35%, respectively. Two- and 5-year overall actuarial survival calculated from the date of salvage surgery was 44% and 22%, respectively. Advanced age (P < .004), patients with T4 category disease (P < .04), and squamous cell carcinomas (P < .049) correlated with poorer outcome on univariate analysis. Local failure was the most common cause of death (n = 13; 65%). CONCLUSION: Salvage surgery has a limited role in the management of persistent or progressive disease following failure of initial treatment. Careful postradiation surveillance with endoscopic biopsy under General anesthesia and immediate surgical resection when appropriate may improve the salvage rate.

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HEAD & NECK CANCERS Role of radiotherapy

10 EBM

POST-OPERATIVE RADIOTHERAPY:

Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial
Peters LJ, Goepfert H, Ang KK, et al. Int J Radiat Oncol Biol Phys 1993;26:3-11

PURPOSE: This study was designed to determine in a prospective randomized trial the optimal dose of conventionally fractionated postoperative radiotherapy for advanced head and neck cancer in relation to clinical and pathologic risk factors. METHODS AND MATERIALS: Between January 1983 and March 1991, 302 patients were enrolled on the study. This analysis is based on the first 240 patients entered through September 1989, of whom 221 (92%) had AJC Stage III or IV cancers of the oral cavity, oropharynx, hypopharynx, or larynx. The patients were stratified by postulated risk factors and randomized to one of three dose levels ranging between 52.2 Gy and 68.4 Gy, all given in daily doses of 1.8 Gy. Patients receiving > 57.6 Gy had a field reduction at this dose level such that boosts were only given to sites of increased risk. RESULTS: The overall crude and actuarial 2-year local-regional recurrence rates were 25.4% and 26%, respectively. Patients who received a dose of < or = 54 Gy had a significantly higher primary failure rate than those receiving > or = 57.6 Gy (p = 0.02). No significant dose response could be demonstrated above 57.6 Gy except for patients with extracapsular nodal disease in the neck in whom the recurrence rate was significantly higher at 57.6 Gy than at > or = 63 Gy. Analysis of prognostic factors predictive of local-regional recurrence showed that the only variable of independent significance was extracapsular nodal disease. However, clusters of two or more of the following risk factors were associated with a progressively increased risk of recurrence: oral cavity primary, mucosal margins close or positive, nerve invasion, > or = 2 positive lymph nodes, largest node > 3 cm, treatment delay greater than 6 weeks, and Zubrod performance status > or = 2. Moderate to severe complications of combined treatment occurred in 7.1% of patients; these were more frequent in patients who received > or = 63 Gy. CONCLUSION: With daily fractions of 1.7 Gy, a minimum tumor dose of 57.6 Gy to the whole operative bed should be delivered with a boost of 63 Gy being given to sites of increased risk, especially regions of the neck where extracapsular nodal disease is present. Treatment should be started as soon as possible after surgery. Dose escalation above 63 Gy at 1.8 Gy per day does not appear to improve the therapeutic ratio.

Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx, and pharynx: preliminary report of a prospective randomized trial.
Kokal WA, Neifeld JP, Eisert D, et al. J Surg Oncol 1988;38:71-6

A prospective randomized trial was performed in patients with advanced squamous cell carcinomas (SCC) of the oral cavity, larynx, and pharynx to examine the effect of adjuvant postoperative radiation therapy on locoregional recurrence and survival following "curative" resection. Fifty-one patients with stage III or IV SCC treated from 1981 through 1984 were randomized to receive either surgery alone (n = 27) or surgery with postoperative radiation (n = 24). Five patients were excluded from the study after randomization because of ineligibility or protocol violations. Overall recurrence rates of 55.6% and 36.8% were noted in the surgery and surgery with adjuvant radiotherapy arms, respectively (p = NS). This trend towards a higher recurrence rate in the surgery only arm was in part due to the development of lymph node metastases in the contralateral, nonoperated neck. Thus far, no significant differences in either locoregional or overall survival have been noted between the two treatment arms. In this preliminary analysis, adjuvant postoperative radiotherapy does not appear to improve disease-free or overall survival.

Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03.
Tupchong L, Scott CB, Blitzer PH, et al. Int J Radiat Oncol Biol Phys 1991;20:21-8

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

OTHER SELECT PUBLICATIONS:
Robertson AG, Soutar DS, Paul J, et al. Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours. Clin Oncol (R Coll Radiol) 1998;10:155-60.

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HEAD & NECK CANCERS Role of chemotherapy-

EBM 11

Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.
Pignon J, Bourhis J, Domenge C, et al. Lancet 2000 18;355:949-55
BACKGROUND: Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment. METHODS: We updated data on all patients in randomized trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. FINDINGS: The main meta-analysis of 63 trials (10,741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI 0.85-0.94, p<0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trials (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1.19 (0.97-1.46). INTERPRETATION: Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis.
Browman GP, Hodson DI, et al. Head Neck 2001;23:579-89

BACKGROUND: A systematic review was conducted to develop clinical recommendations for concomitant chemotherapy (CT) and radiotherapy (RT) in patients with locally advanced squamous cell head and neck cancer (SCHNC). METHODS: Results of published randomized controlled trials (RCTs) were pooled using Meta-analyst(0.988) software. RESULTS: A pooled analysis of 18 RCTs (20 comparisons) involving 3,192 patients detected a reduction in mortality for concomitant therapy compared with RT alone (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.52-0.74; relative risk, 0.83; risk reduction, 11%; p < .00001). Platinum-based regimens involving 1,514 patients from nine trials (10 comparisons) were most effective (OR, 0.57; 95% CI, 0.46-0.71; p < .00001; risk reduction, 12%). Concomitant therapy produced more acute adverse effects than RT alone. CONCLUSION: Platinum-based concomitant CT and RT is superior to conventional RT alone in improving survival in locally advanced SCHNC. Subgroup analyses can be used to help in choosing the most appropriate concomitant regimen.

Concomitant chemo-radiotherapy improves survival compared to radiotherapy alone in locally advanced head & neck cancers. Neo-adjuvant & adjuvant chemotherapy does not improve survival. Neo-adjuvant chemotherapy helps in laryngeal preservation in laryngeal & hypopharyngeal cancers