Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment

Richard Oliver; Jan E Clarkson; David Conway; Anne‐Marie Glenny; Michaelina Macluskey; Sue Pavitt; Philip Sloan; The CSROC Expert Panel; Helen V Worthington

doi:10.1002/14651858.CD006205.pub2

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Analysis 1.1

Comparison 1 Surgery 1 versus surgery 2, Outcome 1 Disease‐free survival.

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Analysis 1.2

Comparison 1 Surgery 1 versus surgery 2, Outcome 2 Total mortality.

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Analysis 1.3

Comparison 1 Surgery 1 versus surgery 2, Outcome 3 Disease‐related mortality.

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Analysis 1.4

Comparison 1 Surgery 1 versus surgery 2, Outcome 4 Recurrent disease.

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Analysis 1.5

Comparison 1 Surgery 1 versus surgery 2, Outcome 5 Recurrent disease ‐ neck nodes.

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Analysis 1.6

Comparison 1 Surgery 1 versus surgery 2, Outcome 6 Recurrent disease ‐ new primary site.

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Analysis 1.7

Comparison 1 Surgery 1 versus surgery 2, Outcome 7 Recurrent disease ‐ distant metastases.

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Analysis 2.1

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 1 Disease‐free survival.

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Analysis 2.2

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 2 Total mortality.

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Analysis 2.3

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 3 Total mortality.

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Analysis 2.4

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 4 Disease‐related mortality.

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Analysis 2.5

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 5 Harms: Operative deaths.

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Analysis 2.6

Comparison 2 Surgery plus radiotherapy versus surgery, Outcome 6 Harms: Post‐operative complications.

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Analysis 3.1

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 1 Total mortality (oral cavity and oropharynx).

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Analysis 3.2

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 2 Total mortality (oral cavity only).

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Analysis 3.3

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 3 Death or recurrent disease (oral cavity and oropharynx).

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Analysis 3.4

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 4 Death or recurrent disease (oral cavity only).

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Analysis 3.5

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 5 Death or recurrent disease ‐ primary site (oral cavity and oropharynx).

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Analysis 3.6

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 6 Death or recurrent disease ‐ neck nodes (oral cavity and oropharynx).

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Analysis 3.7

Comparison 3 Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation), Outcome 7 Death or recurrent disease ‐ distant metastases (oral cavity and oropharynx).

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Analysis 4.1

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 1 Disease‐free survival.

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Analysis 4.2

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 2 Death or recurrent disease.

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Analysis 4.3

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 3 Total mortality.

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Analysis 4.4

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 4 Recurrent disease ‐ total.

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Analysis 4.5

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 5 Recurrent disease ‐ locoregional (neck nodes and/or at primary site).

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Analysis 4.6

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 6 Recurrent disease ‐ distant metastases.

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Analysis 4.7

Comparison 4 Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy, Outcome 7 Harms: Death due to treatment.

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Analysis 5.1

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 1 Disease‐free survival.

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Analysis 5.2

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 2 Death or recurrent disease.

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Analysis 5.3

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 3 Total mortality.

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Analysis 5.4

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 4 Total mortality.

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Analysis 5.5

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 5 Recurrent disease ‐ total.

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Analysis 5.6

Comparison 5 Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation), Outcome 6 Recurrent disease.

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Analysis 7.1

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 1 Disease‐free survival.

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Analysis 7.2

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 2 Total mortality.

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Analysis 7.3

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 3 Total mortality.

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Analysis 7.4

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 4 Disease‐related mortality.

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Analysis 7.5

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 5 Recurrent disease ‐ locoregional.

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Analysis 7.6

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 6 Recurrent disease ‐ new primary site.

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Analysis 7.7

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 7 Recurrent disease ‐ distant metastases.

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Analysis 7.8

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 8 Harms: Morbidity ‐ post‐operative.

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Analysis 7.9

Comparison 7 Surgery plus chemotherapy versus surgery, Outcome 9 Harms: Mortality ‐ post‐operative.

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Analysis 8.1

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 1 Disease‐free survival.

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Analysis 8.2

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 2 Total mortality.

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Analysis 8.3

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 3 Total mortality.

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Analysis 8.4

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 4 Disease‐related mortality.

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Analysis 8.5

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 5 Recurrent disease ‐ total.

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Analysis 8.6

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 6 Recurrent disease ‐ at primary site.

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Analysis 8.7

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 7 Recurrent disease ‐ neck nodes (regional nodes).

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Analysis 8.8

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 8 Recurrent disease ‐ locoregional.

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Analysis 8.9

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 9 Recurrent disease ‐ distant metastases.

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Analysis 8.10

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 10 Harms: Morbidity ‐ post‐operative.

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Analysis 8.11

Comparison 8 Chemotherapy versus no chemotherapy (surgery received prior to randomisation), Outcome 11 Harms: Mortality ‐ post‐operative.

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Analysis 9.1

Comparison 9 Surgery plus radiotherapy versus radiotherapy, Outcome 1 Total mortality.

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Analysis 10.1

Comparison 10 Surgery plus chemotherapy versus surgery plus radiotherapy, Outcome 1 Total mortality.

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Analysis 11.1

Comparison 11 Surgery plus immunotherapy/biotherapy versus surgery, Outcome 1 Total mortality.

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Analysis 11.2

Comparison 11 Surgery plus immunotherapy/biotherapy versus surgery, Outcome 2 Total mortality.

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Analysis 11.3

Comparison 11 Surgery plus immunotherapy/biotherapy versus surgery, Outcome 3 Death or recurrent disease.

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Analysis 12.1

Comparison 12 Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy, Outcome 1 Disease‐free survival.

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Analysis 12.2

Comparison 12 Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy, Outcome 2 Total mortality.

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Analysis 12.3

Comparison 12 Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy, Outcome 3 Disease‐related mortality.

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Analysis 12.4

Comparison 12 Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy, Outcome 4 Recurrent disease ‐ total.

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Table 1. Summary of inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Patients with primary cancer of the oral cavity (ICD‐O: C01‐06) or oropharyngeal (ICD‐O: C9‐10 ‐ includes tonsil). Primary head & neck cancer patients where > 50% of cases had oral/oropharynx cancer. If separate oral/oropharynx data were available they were used to the exclusion of the combined head & neck cancer data.	Lip (ICD‐O: C00) cancers.
Squamous cell carcinoma (SCC).	Parotid gland (ICD‐O: C07), unspecified major salivary gland (ICD‐O: C08) and thyroid gland (ICD‐O: C73.9) cancers. Nasopharynx (ICD‐O: C11), hypopharynx (ICD‐O: C13), larynx (ICD‐O: C32), pyriform sinus (ICD‐O: C12.9), accessory sinuses (ICD‐O: C31), nasal cavity and middle ear (ICD‐O: C30) cancers. In combined head & neck trials, these cancers were permitted if they comprised < 50% of the total cancer patients.
Histological variants of SCC.	Recurrent cancer i.e. not treatment of the primary cancer.
Randomised controlled trials.	Sarcomas and lymphomas.
Primary outcomes included.	Odontogenic tumours.
Surgical treatment of the primary tumour (even if this procedure was given prior to randomisation but so long as given to all patients in all arms or presents data as +/‐ surgery).	Trials only on prophylactic antibiotic use in surgical treatment.
Surgical management of the cervical lymph nodes when combined with surgical management of the primary tumour.	Trials were the treatment modality was not for curative intent (i.e. palliative care trials, nutritional supplements).
	Trials using hyperbaric oxygen.
	Trials with insufficient reporting of data i.e. indication of numbers at risk and where the follow‐up time has not been taken into account in the analysis (including variable follow‐up time points).

Table 1. Summary of inclusion and exclusion criteria

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Table 2. Included trials sorted by tumour location (% of total head & neck cancer)

Percentage	OC & OP combined	OC alone	OP alone
100%	Bier 1994† De Stefani 2002 Fakih 1989a Kligerman 1994 Licitra 2003 Lubrionski 1985† Mohr 1994† Rao 1991/194 Richard 1991 Robertson 1998 Szabo 1999 Szpirglas 1978 Vandenbrouck 1980 Volling 1994 *i #	Bier 1994† Fakih 1989a Kligerman 1994 Licitra 2003 Lubrionski 1985† Rao 1991 Szabo 1999 Szpirglas 1978 Vandenbrouck 1980
91‐99%		Robertson 1998
81‐90%	Bier 1981*ii Maiplang 1995	Bier 1981*ii
71‐80%	Cooper 2004 Lawrence 1974 Paccagnella 1994	Lawrence 1974 Maiplang 1995
61‐70%	Ang 2001*i ii, iii Schuller 1988 Terz 1981	De Stefani 2002
51‐60%	Bernier 2004 Lam 2001† Martin 1990 Laramore 1992 Rentschler 1987 Weissler 1992†	Richard 1991	Paccagnella 1994
41‐50%	Hintz 1979b i Neifeld 1985ii	Neifeld 1985*ii	Cooper 2004 Richard 1991
31‐40%	Sanguineti 2005 *i and ii	Ang 2001*i Lam 2001† Rentschler 1987 Schuller 1988 Terz1981 Volling 1994	Ang 2001*i Bernier 2004 Martin 1990 Weissler 1992†
21‐30%		Bernier 2004 Cooper 2004 Laramore 1992 Sanguineti 2005 *i and ii	De Stefani 2002 Lam 2001† Laramore 1992 Rentschler 1987 Schuller 1988 Terz 1981
11‐20%		Paccagnella 1994 Martin 1990 Weissler 1992†	Sanguineti 2005 *i and ii
< 10%			Bier 1981 Maiplang 1995 Robertson 1998
Unavaliable			Lawrence 1974 Neifeld 1985*ii
*	OC and/or OP data available as a separate entity (in trial report or provided by author). i OC/OP combined. ii OC alone. iii OP alone.
†	Limited data available not in a useable form to include in 'Analyses' refer to 'Additional Table 07.'
#	Pignon 2000a data used combined head and neck data and not separate OC data (refer to Comparison 04 Outcome 03 ‐ Total mortality). It is unclear if Pignon's data for this a trial also included cancers of the hypopharynx.

Table 2. Included trials sorted by tumour location (% of total head & neck cancer)

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Table 3. Summary of included trials with limited data & not included in 'Data and analyses'

Trial	Comparison	Treatment details	Cancer type(%OC/OP)	Summary of data*	Notes
Bier 1994	Comparison 1: Surgery 1 versus surgery 2.	Radical surgery + radical neck dissection versus radical surgery + conservative neck dissection.	100% oral cavity.	Figure 3 ‐ Life table analysis in complete remission. Figure 4 ‐ Life table analysis for patients alive. Authors reported in text: "The relative mortality 'at the moment' is 23% for both groups. The life table analyses in Figures 3 and 4 show no differences between the 2 groups."	Statistical analysis unclear.
Lam 2001	Comparison 8: Chemotherapy versus no chemotherapy (surgery received prior to randomisation).	Surgery plus chemotherapy (pre‐operative levamisole and adjuvant post‐operative chemotherapy with levamisole and UFT) versus surgery.	H&N cancer with 32% of sample with oral cavity, 21% oropharynx, combined OC/OP = 53%.	Figure 1 ‐ Actuarial survival data for 5 years. The overall 5‐year survival rate was 47%. The 5‐year survival rate of patients with chemotherapy and without chemotherapy were 57% and 39% respectively (Kalplan‐Meier method, log rank statistics P = 0.207). The subgroup analysis of survival with respect to different stages, differentiation and tumour site were all not statistically significant (Kalplan‐Meier method, log rank statistics, all with P > 0.1).	Radiotherapy was either administered pre‐operative, postoperative or omitted.
Luboinski 1985	Comparison 7: Surgery plus chemotherapy versus surgery. (May also be classified as Comparison 6: Surgery plus radiotherapy plus chemotherapy versus surgery or Comparison 4: Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy.)	Surgery plus pre‐operative intra‐arterial chemotherapy (bleomycin and vincristine) versus surgery. Optional radiotherapy administered to both arms post‐operatively ‐ determined by the quality of the margins and extension to cervical nodes.	100% oral cavity.	Figure1 ‐ Survival curve up to 5 years (interim report not all patients have completed necessary follow up). No statistical significant results reported favouring surgery plus chemotherapy group compared to surgery alone P = 0.076.	Interim analysis no numbers at risk.
Mohr 1994	Comparison 6: Surgery plus radiotherapy plus chemotherapy versus surgery.	Surgery plus pre‐operative radiotherapy plus pre‐operative chemotherapy (cisplatin) versus surgery.	100% oral cavity/oropharynx.	Figure 9 ‐ Survival life table analysis. Significant difference between the trial arms in favour of surgery plus immunotherapy treatment (P < 0.05). Authors report improvement of survival rates of 4.5% after 1 year and 8.3% after 2 years in favour of surgery plus chemotherapy treatment. A difference of more than 20% after 3 years also reported but founded on smaller number of patients and has to be considered with reservation.	Part of the Dosak study.
Weissler 1992	Comparison 5: Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation).	No surgery multiple dose/day radiation therapy plus cisplatin and 5‐FU versus no surgery with radiation alone versus surgery plus multiple dose/day radiation therapy plus cisplatin and 5‐FU versus surgery plus radiation alone.	H&N cancer with 16% of sample with oral cavity, 39% oropharynx, combined 55%.	Figure 2 ‐ In patients with resectable, high risk tumours, the addition of chemotherapy prolongs the mean time to death from disease by a factor of 1.13 (95% CI 0.38 to 3.3). This is not a significant increase in survival (P = 0.83). Figure 3 ‐ The addition of chemotherapy prolongs the time to progression in patients with resectable, high‐risk tumours by a factor of 1.11 (95% CI, 0.33 to 3.69). Again not a significant increase (P = 0.86).

	* Data as reported in the manuscript. N.B. Figure and Table numbers refer to those used in manuscript.

Table 3. Summary of included trials with limited data & not included in 'Data and analyses'

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Table 4. Factors influencing later quality of life post‐operatively

Quality of life	Gr 1 ‐ chemotherapy	Gr 2 ‐ radiotherapy
Reported in Szabo 1999 KEY: ‐ = No essential difference + = Minor difference ++ = Moderate difference
OBJECTIVE FACTORS
Mastication, speech	‐	‐
Limitation of movement	‐	+
Insensitive areas	‐	‐
Dryness of mouth	‐	++
Secondary factors (teeth, operations etc)	‐	+
SUBJECTIVE FACTORS
Pain	‐	+
Psychic disturbances	‐	‐
EXTERNAL ENVIRONMENT
Distortion	‐	+
Workplace	+	+
Family	+	+

Table 4. Factors influencing later quality of life post‐operatively

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Table 5. Complications of treatment: toxicity/adverse events ‐ severe acute side effects

Adverse event	Bernier 2004	Cooper 2004	Licitra 2003	Robertson 1998	Sanguineti 2005 c	Terz 1981
	Gr 1: n = 167; Gr 2: n =167	Gr 1: n = 206; Gr 2: n = 209	Gr 1: n = 96; Gr 2: n = 95	Gr 1: n = 17; Gr 2: n = 18	Gr 1: n = 110; Gr 2: n = 111	Gr 1: n = 126; Gr 2: n = 122
OROFACIAL
Mucositis	Gr 1: 41%; Gr 2: 21%	Gr 1: 62%; Gr 2: 37%
Mucositis fibrosis	Gr 1: 10%; Gr 2: 5%			Gr 1: 29%; Gr 2: 13%
Mucosal dehiscence			Gr 1: 12%; Gr 2: 18%
Mucosal necrosis	Gr 1: 1%; Gr 2: 2%
Xerostomia/salivary gland	Gr 1: 14%; Gr 2: 20%	a Gr 1:4%; Gr 2: 2% b Gr 1: 32%; Gr 2: 6%		Gr 1: 59%; Gr 2: 60%	Gr 1: 66%; Gr 2: 59%	Gr 1: 23%; Gr 2: 18%
Trismus				Gr 1: 18%; Gr 2: 0%
FUNCTIONAL
Dysphagia	Gr 1: 12%; Gr 2: 10%
Shoulder syndrome	Gr 1: 8%; Gr 2: 5%
Impaired lymphatic drainage	Gr 1: 7%; Gr 2: 2%
SKIN
Skin and connective tissue fibrosis/necrosis	Gr 1: 1%; Gr 2: 2%	Gr 1: 21%; Gr 2: 14%	Gr 1: 5%; Gr 2: 7%		Gr 1: 96%; Gr 2: 98%	Gr 1: 10%; Gr 2: 4%
Transposed flap necrosis			Gr 1: 13%; Gr 2: 19%
HAEMATOLOGICAL
Leukopaenia/haematologic		Gr 1: 78%; Gr 2: 2%
Anaemia		Gr 1: 6%; Gr 2: 0%
OTHER
Nausea & vomiting
Regional infection			Gr 1: 7%; Gr 2: 4%
Oedema				Gr 1: 24%; Gr 2: 40%

KEY: a Salivary gland b Upper GI tract c Based on H&N cancer patient data

Table 5. Complications of treatment: toxicity/adverse events ‐ severe acute side effects

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Table 6. Quality assessment of trials

Study	Randomisation	Concealed allocation	Explanation drop out	Risk of bias	Assessor blinded	Data available
Ang 2001	Adequate	Adequate	Yes	Low	Not reported	Additional data provided by authors by cancer location. Data included in comparisons and data analyses.
Bernier 2004	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Bier 1981	Unclear	Unclear	Yes ‐ no drop outs	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Cooper 2004	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
DeStefani 2002	Adequate	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Fakih 1989a	Adequate	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Hintz 1979b	Adequate	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Kligerman 1994	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Laramore 1992	Adequate	Adequate	Yes ‐ no drop outs	Low	Not reported	Data included in comparisons and data analyses. Pignon 2000a data used ‐ Total mortality IPD.
Lawrence 1974	Unclear	Unclear	Yes ‐ no drop outs	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Licitra 2003	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Maipang 1995	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses. Only Pignon 2000a data used, remaining data in manuscript inadequate for further analysis.
Martin 1990	Unclear	Unclear	Yes ‐ no drop outs	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Neifeld 1985	Adequate	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Paccagnella 1994	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Rao 1991	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses. Pignon 2000a data used ‐ Total mortality IPD.
Rentschler 1987	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Richard 1991	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses. Only Pignon 2000a data used, remaining data in manuscript inadequate for further analysis.
Robertson 1998	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Sanguineti 2005	Adequate	Adequate	Yes	Low	Not reported	Additional data provided by authors by cancer location. Data included in comparisons and data analyses.
Schuller 1988	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Szabo 1999	Adequate	Adequate	Yes	Low	Not reported	Data included in comparisons and data analyses.
Szpirglas 1978	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses. Only Pignon 2000a data used, remaining data in manuscript inadequate for further analysis.
Terz 1981	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Vandenbrouck 1980	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses.
Volling 1994	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Data included in comparisons and data analyses. Pignon 2000a data used ‐ Total mortality IPD.
Bier 1994†	Adequate	Unclear	No	Moderate‐>High	Not reported	Limited data available. Not presented in useable form. Data not included in comparisons and data analyses.
Lam 2001†	Unclear	Adequate	Yes	Moderate‐>High	Not reported	Limited data available. Not presented in useable form. Data not included in comparisons and data analyses.
Lubroinski 1985†	Unclear	Unclear	Yes ‐ no drop outs	Moderate‐>High	Not reported	Limited data available. Not presented in useable form. Data not included in comparisons and data analyses.
Mohr 1994†	Adequate	Unclear	Yes	Moderate‐>High	Not reported	Limited data available.Not presented in useable form. Data not included in comparisons and data analyses.
Weissler 1992†	Unclear	Unclear	Yes	Moderate‐>High	Not reported	Limited data available. not presented in useable form. Data not included in comparisons and data analyses. Pignon 2000a additional data available but not appropriate for this review.
†Refer to 'Additional Table 07'

Table 6. Quality assessment of trials

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Table 7. Complications of treatment: toxicity/adverse events ‐ severe late side effects

Adverse event	Cooper 2004	Laramore 1992	Lawrence 1974	Sanguineti 2005	Terz 1981
	Gr 1: n = 206; Gr 2: n = 209	a Gr 1: n = 223; Gr 2: n = 225	Gr 1: n = 69; Gr 2: n = 74	b Gr 1: n = 110; Gr 2: n = 111	Gr 1: n = 126; Gr 2: n = 122
OROFACIAL	Gr 1: 4%; Gr 2: 5%
Mucositis
Mucositis fibrosis/mucosa				Gr 1: 11%; Gr 2: 9%
Mucosal necrosis			Gr 1: 12%; Gr 2: 5%
Xerostomia/salivary gland	Gr 1: 7%; Gr 2: 5%	Gr 1: 3%; Gr 2: 1%	Gr 1: 14%; Gr 2: 12%	Gr 1: 15%; Gr 2: 13%
Upper GI tract/pharynx/larynx	Gr 1: 3%; Gr 2: 1%	Gr 1: 5%; Gr 2: 12%
SKIN
Skin & connective tissue fibrosis	Gr 1: 5%; Gr 2: 2%	Gr 1: 2%; Gr 2: 2%		c Gr 1: 14%; Gr 2: 12% d Gr 1: 39%; Gr 2: 33%
HAEMATOLOGICAL
Leukopaenia/haematologic	Gr 1: 3%; Gr 2: 2%	Gr 1: 1%; Gr 2: 0%
Anaemia		Gr 1: 0%; Gr 2: 1%
OTHER
Carotid exposure ‐ ligation required			Gr 1: 3%; Gr 2: 4%		Gr 1: 3%; Gr 2: 2%
Bone/prosthesis exposure					Gr 1: 17%; Gr 2: 4%
Nausea & vomiting	Gr 1: 0%; Gr 2: 0%	Gr 1: 0%; Gr 2: 1%

KEY: a Late toxicities based on Gr 1 n = 215; Gr2 n = +215 a b Based on H&N cancer patient data c Skin d Connective tissue

Table 7. Complications of treatment: toxicity/adverse events ‐ severe late side effects

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Table 8. Summary statistics on adverse events

Adverse event	Cooper 2004
	Gr 1: n = 206; Gr 2: n = 209
Acute adverse event > grade 3	Gr 1: 77%; Gr 2: 34%
Severe late adverse event	Gr 1: 21%; Gr 2: 17%
Combined ‐ any late adverse event	Gr 1: 78%; Gr 2: 46%

Table 8. Summary statistics on adverse events

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Table 9. Treatment specific: severe adverse events ‐ chemotherapy

Adverse event	Bernier 2004	Laramore 1992	Licitra 2003	Maipang 1995	Martin 1990	Richard 1991
	Gr 1: n = 167; Gr 2: n = 167	a Gr 1: n = 223; Gr 2: n = 225	Gr 1: n = 96; Gr 2: n = 95	b Gr 1: n = 30; Gr 2: n = 24	Gr 1: n = 38; Gr 2: n = 37	Gr 1: n = 112; Gr 2: n = 110 FM n = 64 and POC n = 48
OROFACIAL
Mucositis			Gr 1: 19%		Gr 1: 3%
Stomatitis		Gr 1: 6%		Gr 1: 33%
HAEMATOLOGICAL				Gr 1: 100%
Leukopaenia	Gr 1: 16%	Gr 1: 13%	Gr 1: 33%		Gr 1: 13%	1 patient died from methotrexate, haematological toxicity in the POC group
Granulocytopaenia/neutrapaenia	Gr 1: 13%	Gr 1: 24%	Gr 1: 63%
Thrombocytopaenia					Gr 1: 8%
OTHER
Nausea & vomiting	Gr 1: 12%	Gr 1: 8%	Gr 1: 67%	Gr 1: 86%	Gr 1: 63%
Diarrhoea		Gr 1: 2%			Gr 1: 11%
Total: Total % patients recorded with adverse event to chemotherapy			Gr 1: 96% Grade 1: 24% Grade 2: 35% Grade 3: 26% Grade 4: 11%			Gr 1: 24% (27/112) experienced toxicity: 28% in FM subgroup 19% in POC subgroup

KEY: a Late toxicities based on Gr 1 n = 215; Gr 2 n = +215; chemotherapy toxicity n = 169 b Based on 21 patients receiving chemotherapy using ECOG criteria (Eastern Co‐operative Oncology Group)

Table 9. Treatment specific: severe adverse events ‐ chemotherapy

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Table 10. Treatment specific: severe adverse events ‐ radiotherapy

Adverse event	Laramore 1992
	a Gr 1: n = 223; Gr 2: n = 225
OROFACIAL
Mucositis	Gr 1: 7%; Gr 2: 4%
Stomatitis	Gr 1: 7%; Gr 2: 5%
Xerostomia/salivary gland	Gr 1: 5%; Gr 2: 4%
HAEMATOLOGICAL
SKIN
Skin	Gr 1: 4%; Gr 2: 4%
OTHER
Pharynx	Gr 1: 4%; Gr 2: 5%

KEY: a Late toxicities based on Gr 1 n = 215; Gr 2 n = +215; radiotherapy toxicity Gr 1: n = 175; Gr 2 n = 207

Table 10. Treatment specific: severe adverse events ‐ radiotherapy

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Table 11. Treatment specific: severe adverse events ‐ immunotherapy

Adverse event	Bier 1981
	Gr 1: n = 12; Gr 2: n = 12
REACTION ON TUMOUR
Severe	50%
Moderate	8%
None	42%
REACTION ON LYMPH NODE
Severe	33%
Moderate	25%
None	42%

Table 11. Treatment specific: severe adverse events ‐ immunotherapy

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Comparison 1. Surgery 1 versus surgery 2

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Hemiglossectomy plus ipsilateral radical neck dissection versus hemiglossectomy (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Resection plus elective supraomohyoid dissection versus resection alone (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Hemiglossectomy plus ipsilateral radical neck dissection versus hemiglossectomy (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Resection plus elective supraomohyoid dissection versus resection alone (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Disease‐related mortality Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Hemiglossectomy plus ipsilateral radical neck dissection versus hemiglossectomy (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Resection plus elective supraomohyoid dissection versus resection alone (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Recurrent disease Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Hemiglossectomy plus ipsilateral radical neck dissection versus hemiglossectomy (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Resection plus elective supraomohyoid dissection versus resection alone (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Recurrent disease ‐ neck nodes Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent disease ‐ new primary site Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Recurrent disease ‐ distant metastases Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Elective radical neck dissection versus therapeutic (delayed) radical neck dissection (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Surgery 1 versus surgery 2

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Comparison 2. Surgery plus radiotherapy versus surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus pre‐operative radiotherapy versus surgery (6 months)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Surgery plus pre‐operative radiotherapy versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Surgery plus pre‐operative radiotherapy versus surgery (1.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.4 Surgery plus pre‐operative radiotherapy versus surgery (2 years)	2		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.5 Surgery plus pre‐operative radiotherapy versus surgery (2.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.6 Surgery plus pre‐operative radiotherapy versus surgery (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.7 Surgery plus pre‐operative radiotherapy versus surgery (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.8 Surgery plus pre‐operative radiotherapy versus surgery (4 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Surgery (mixed surgical procedures) plus pre‐operative radiotherapy versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Total mortality Show forest plot	2		Hazard ratio (Random, 95% CI)	0.87 [0.67, 1.12]

3.1 Surgery plus pre‐operative radiotherapy versus surgery (Pignon 2000a)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Surgery plus pre‐operative radiotherapy versus surgery (4 years)	1		Hazard ratio (Random, 95% CI)	0.87 [0.67, 1.12]
4 Disease‐related mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Surgery plus pre‐operative radiotherapy versus surgery (6 months)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Surgery plus pre‐operative radiotherapy versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Surgery plus pre‐operative radiotherapy versus surgery (1.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Surgery plus pre‐operative radiotherapy versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.5 Surgery plus pre‐operative radiotherapy versus surgery (2.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.6 Surgery plus pre‐operative radiotherapy versus surgery (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.7 Surgery plus pre‐operative radiotherapy versus surgery (3.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.8 Surgery plus pre‐operative radiotherapy versus surgery (4 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Harms: Operative deaths Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Surgery plus pre‐operative radiotherapy versus surgery	2		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Harms: Post‐operative complications Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Surgery plus pre‐operative radiotherapy versus surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Surgery plus radiotherapy versus surgery

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Comparison 3. Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality (oral cavity and oropharynx) Show forest plot	2		Hazard ratio (Random, 95% CI)	Totals not selected

1.1 Surgery plus post‐operative accelerated radiotherapy versus surgery plus conventional radiotherapy (10 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Surgery plus accelerated radiotherapy (5 wks) versus surgery plus conventional radiotherapy (7 wks) (2 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality (oral cavity only) Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

2.1 Surgery plus post‐operative accelerated radiotherapy versus surgery plus conventional radiotherapy (10 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3 Death or recurrent disease (oral cavity and oropharynx) Show forest plot	2		Hazard ratio (Random, 95% CI)	Totals not selected

3.1 Surgery plus post‐operative accelerated radiotherapy versus surgery plus conventional radiotherapy (10 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Surgery plus accelerated radiotherapy (5 wks) versus surgery plus conventional radiotherapy (7 wks) (2 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4 Death or recurrent disease (oral cavity only) Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

4.1 Surgery plus post‐operative accelerated radiotherapy versus surgery plus conventional radiotherapy (10 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
5 Death or recurrent disease ‐ primary site (oral cavity and oropharynx) Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

5.1 Surgery plus accelerated radiotherapy (5 wks) versus surgery plus conventional radiotherapy (7 wks) (2 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
6 Death or recurrent disease ‐ neck nodes (oral cavity and oropharynx) Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

6.1 Surgery plus accelerated radiotherapy (5 wks) versus surgery plus conventional radiotherapy (7 wks) (2 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
7 Death or recurrent disease ‐ distant metastases (oral cavity and oropharynx) Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

7.1 Surgery plus accelerated radiotherapy (5 wks) versus surgery plus conventional radiotherapy (7 wks) (2 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Radiotherapy 1 versus radiotherapy 2 (surgery received prior to randomisation)

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Comparison 4. Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Death or recurrent disease Show forest plot	3		Hazard ratio (Random, 95% CI)	Totals not selected

2.1 Surgery plus radiotherapy plus cisplatin versus surgery plus radiotherapy (5 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Surgery plus post‐operative radiotherapy plus adjuvant MTX versus surgery plus radiotherapy (5 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Surgery plus radiotherapy plus neoadjuvant/induction carboplatin/5‐FU versus surgery plus radiotherapy (7 yrs)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3 Total mortality Show forest plot	5		Hazard ratio (Random, 95% CI)	Totals not selected

3.1 Surgery plus radio plus induction chemo (cisplatin, bleomycin, MTX) versus surgery plus radio (Pignon 2000a)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Surgery plus radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (5 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Surgery plus post‐operative radiotherapy plus adjuvant MTX versus surgery plus radiotherapy (6 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Surgery plus post‐op radio plus pre‐op cisplatin/MTX/bleomycin/vincristine vs surgery plus radio (Pignon2000a)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Surgery plus radiotherapy plus neoadjuvant/induction carboplatin/5‐FU versus surgery plus radiotherapy (7 yrs)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4 Recurrent disease ‐ total Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Surgery plus radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Recurrent disease ‐ locoregional (neck nodes and/or at primary site) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Surgery plus radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent disease ‐ distant metastases Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Surgery plus radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Harms: Death due to treatment Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Surgery plus post‐op radio plus pre‐op cisplatin/MTX/bleomycin/vincristine versus surgery plus radio (5 yrs)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy

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Comparison 5. Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus post‐operative radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (4 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Death or recurrent disease Show forest plot	2		Hazard ratio (Random, 95% CI)	0.77 [0.65, 0.91]

2.1 Surgery plus post‐operative radiotherapy plus cisplatin versus surgery plus post‐operative radiotherapy	2		Hazard ratio (Random, 95% CI)	0.77 [0.65, 0.91]
3 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Surgery plus post‐operative radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (4 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Total mortality Show forest plot	3		Hazard ratio (Random, 95% CI)	Subtotals only

4.1 Surgery plus post‐operative radiotherapy plus cisplatin versus surgery plus post‐operative radiotherapy	2		Hazard ratio (Random, 95% CI)	0.79 [0.65, 0.95]
4.2 Surgery plus post‐operative radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (Pignon 2000a)	1		Hazard ratio (Random, 95% CI)	0.91 [0.74, 1.13]
5 Recurrent disease ‐ total Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Surgery plus post‐operative radiotherapy plus cisplatin/5‐FU versus surgery plus radiotherapy (4 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent disease Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

6.1 Surgery plus post‐operative radio plus cisplatin versus surgery plus post‐operative radio (5 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Radiotherapy plus chemotherapy versus radiotherapy (surgery received prior to randomisation)

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Comparison 7. Surgery plus chemotherapy versus surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Total mortality Show forest plot	1		Hazard ratio (Fixed, 95% CI)	Totals not selected

3.1 Surgery plus intra‐arterial chemotherapy (vincristine and bleomycin) versus surgery (Pignon 2000a)	1		Hazard ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Disease‐related mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Recurrent disease ‐ locoregional Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent disease ‐ new primary site Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Recurrent disease ‐ distant metastases Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Surgery plus cisplatin and fluorouracil versus surgery alone (5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Harms: Morbidity ‐ post‐operative Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

8.1 Surgery plus cisplatin and fluorouracil versus surgery alone	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Harms: Mortality ‐ post‐operative Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

9.1 Surgery plus cisplatin and fluorouracil versus surgery alone	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 7. Surgery plus chemotherapy versus surgery

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Comparison 8. Chemotherapy versus no chemotherapy (surgery received prior to randomisation)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Total mortality Show forest plot	2		Hazard ratio (Random, 95% CI)	Totals not selected

3.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (Pignon 2000a)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Locoregional+chemotherapy(methotrexate/citrvorum factor/bleomycin) vs locoregional no chemo (Pignon 2000a)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4 Disease‐related mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Recurrent disease ‐ total Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Recurrent disease ‐ at primary site Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Recurrent disease ‐ neck nodes (regional nodes) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Recurrent disease ‐ locoregional Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

8.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Recurrent disease ‐ distant metastases Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

9.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (1 year)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9.2 Surgery plus perioperative chemotherapy (methotrexate) versus surgery (2 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10 Harms: Morbidity ‐ post‐operative Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

10.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11 Harms: Mortality ‐ post‐operative Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

11.1 Surgery plus perioperative chemotherapy (methotrexate) versus surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 8. Chemotherapy versus no chemotherapy (surgery received prior to randomisation)

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Comparison 9. Surgery plus radiotherapy versus radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

1.1 Surgery plus post‐operative radiotherapy versus radiotherapy (3 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 9. Surgery plus radiotherapy versus radiotherapy

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Comparison 10. Surgery plus chemotherapy versus surgery plus radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

1.1 Radical surgery plus pre‐op chemo (cisplatin plus epirubicin) versus radical surgery plus pre‐op radio (5 yrs)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 10. Surgery plus chemotherapy versus surgery plus radiotherapy

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Comparison 11. Surgery plus immunotherapy/biotherapy versus surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus intratumoural immuno/biotherapy (Corynebacterium parvum) versus surgery (1 yr)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Surgery plus intratumoural immuno/biotherapy (Corynebacterium parvum) versus surgery (2 yrs)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

2.1 Intratumoural BCG‐cell wall preparation plus surgery versus surgery alone (2.53 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3 Death or recurrent disease Show forest plot	1		Hazard ratio (Random, 95% CI)	Totals not selected

3.1 Intratumoural BCG‐cell wall preparation plus surgery versus surgery alone (2.53 years)	1		Hazard ratio (Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 11. Surgery plus immunotherapy/biotherapy versus surgery

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Comparison 12. Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Disease‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Surgery plus radiotherapy plus interleukin‐2 (IL‐2) versus surgery plus radiotherapy (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Total mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Surgery plus radiotherapy plus interleukin‐2 (IL‐2) versus surgery plus radiotherapy (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Disease‐related mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Surgery plus radiotherapy plus interleukin‐2 (IL‐2) versus surgery plus radiotherapy (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Recurrent disease ‐ total Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Surgery plus radiotherapy plus interleukin‐2 (IL‐2) versus surgery plus radiotherapy (3 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 12. Surgery plus radiotherapy plus immunotherapy/biotherapy versus surgery plus radiotherapy

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