Interventions for the treatment of oral cavity and oropharyngeal cancer: radiotherapy

Anne‐Marie Glenny; Susan Furness; Helen V Worthington; David I Conway; Richard Oliver; Jan E Clarkson; Michaelina Macluskey; Sue Pavitt; Kelvin KW Chan; Paul Brocklehurst; The CSROC Expert Panel

doi:10.1002/14651858.CD006387.pub2

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Figure 1

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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$Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Total mortality.$

Figure 2

Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Total mortality.

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$Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Locoregional control.$

Figure 3

Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Locoregional control.

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$Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Disease free survival.$

Figure 4

Forest plot of comparison: Summary analyses for altered fractionation versus conventional radiotherapy, outcome: Disease free survival.

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$Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 1 Total mortality (using IPD where available).$

Analysis 1.1

Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 1 Total mortality (using IPD where available).

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$Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 2 Locoregional control (using IPD where available).$

Analysis 1.2

Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 2 Locoregional control (using IPD where available).

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$Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 3 Disease free survival.$

Analysis 1.3

Comparison 1 Altered fractionation versus conventional radiotherapy, Outcome 3 Disease free survival.

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$Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 1 Total mortality.$

Analysis 2.1

Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 1 Total mortality.

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$Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 2 Locoregional control.$

Analysis 2.2

Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 2 Locoregional control.

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$Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 3 Disease free survival.$

Analysis 2.3

Comparison 2 Summary analyses for altered fractionation versus conventional radiotherapy, Outcome 3 Disease free survival.

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Analysis 3.1

Comparison 3 Neutron therapy, Outcome 1 Total mortality.

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Altered fractionation compared with conventional radiotherapy for the treatment of oral cavity and oropharyngeal cancer
Patient or population: people with oral cavity and oropharyngeal cancer Settings: hospital Intervention: altered fractionation Comparison: conventional
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional	Altered fractionation
Mortality (follow‐up: 5 years)	Low risk population		HR 0.86 (0.76 to 0.98)	[3751] (13)	+OOO very low^2,3,4	Analysis conducted on all included studies
	200 per 1000¹	175 per 1000 (156 to 196)
	Medium risk population
	500 per 1000	449 per 1000 (410 to 493)
	High risk population
	700 per 1000¹	645 per 1000 (599 to 693)
Mortality (follow‐up: 5 years)	Low risk population		HR 0.93 (0.80 to 1.07)	[1511] (5)	+++O moderate²	Analysis conducted for studies at low risk of bias
	200 per 1000¹	187 per 1000 (163 to 212)
	Medium risk population
	500 per 1000	475 per 1000 (426 to 524)
	High risk population
	700 per 1000¹	674 per 1000 (618 to 724)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Based on data presented by McGurk 2005 ²Studies included patients with other head and neck cancers ³Heterogeneity due to one study ⁴Assessed as unclear regarding allocation concealment, incomplete outcome data, selective reporting and/or other biases for 8 included trials

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Table 1. Percentage of patients with oral cavity (OC) or oropharyngeal (OP) cancer in studies included in this review

Trial ID	%OC	%OP	Total % OC/OP
Ang 2001*	49	51	100
Bergermann 1992	100	0	100
Horiot 1992	0	100	100
Inoue 2001	100	0	100
Marcial 1993	0	100	100
Olmi 2003	0	100	100
Pinto 1991	0	100	100
Sanguineti 2005*			100
Bourhis 2006	14	77	91
Bartelink 2002	33	47	80
Horiot 1997	16	64	80
Griffin 1989	27	52	79
Poulsen 2001	11	67	78
Maor 1986	26	51	77
Maor 1995	23	51	75
Hukku 1991	10	62	72
Dobrowsky 2000	30	41	71
Fu 2000	10	60	71
Lawrence 1974	45	26	71
Terz 1981	38	29	67
Ghoshal 2008	0	65	65
Cox 1990	20	44	64
Weissberg 1983	19	45	64
Fu 1995	11	51	61
MacDougall 1990	40	21	61
Marcial 1987	15	46	61
Griffin 1984	25	33	58
Ketcham 1969	56	unclear	>56
Bjarnason 2009	19	35	54
Skladowski 2006	22	28	50
*Data were available from the authors for those participants with cancer of the oral cavity or oropharynx only.

Table 1. Percentage of patients with oral cavity (OC) or oropharyngeal (OP) cancer in studies included in this review

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Table 2. Results from comparisons where there are data from a single study only

	Total mortality	Locoregional control		Disease free survival
Accelerated/split versus conventional
Marcial 1993	5 years RR 1.17 (95% CI 0.57 to 2.43)
Split course versus accelerated
Hukku 1991	2 years RR 1.00 (95% CI 0.82 to 1.22)		2 years RR 1.33 (95% CI 0.67 to 2.67)	2 years RR 0.83 (95% CI 0.29 to 2.42)
Variable total dose/duration of radiotherapy
Cox 1990	High versus standard HR 1.08 (95% CI 0.69 to 1.70)	High versus standard HR 0.78 (95% CI 0.55 to 1.11)
	Low versus standard HR 1.38 (95% CI 0.83 to 2.29)	Low versus standard HR 1.13 (95% CI 0.78 to 1.64)
Morning versus afternoon radiotherapy
Bjarnason 2009	2 years RR 1.09 (95% CI 0.74 to 1.59)	HR 0.92 (95% CI 0.60 to 1.42)
Mixed beam versus photon
Griffin 1989	HR 1.12 (95% CI 0.92 to 1.36)	HR 1.04 (95% CI 0.84 to 1.29)
Neutron versus photon
MacDougall 1990	5 years RR 1.15 (95% CI 0.95 to 1.40)	5 years RR 0.97 (95% CI 0.69 to 1.36)		5 years RR 0.63 (95% CI 0.36 to 1.09)
Pre‐operative radiotherapy versus surgery alone
Ketcham 1969		Timing unclear RR 0.63 (95% CI 0.28 to 1.46)
Terz 1981	HR 0.83 (95% CI 0.64 to 1.07)
Pre‐operative and post‐operative radiotherapy versus post‐operative radiotherapy alone
Bergermann 1992	HR 0.67 (95% CI 0.35 to 1.28)	HR 1.13 (95% CI 0.78 to 1.64)		HR 1.13 (95% CI 0.78 to 1.64)
Low dose rate interstitial radiotherapy versus high dose rate interstitial radiotherapy
Inoue 2001		HR 1.00 (95% CI 0.16 to 6.44)
CI = confidence interval; HR = hazard ratio; RR = risk ratio.

Table 2. Results from comparisons where there are data from a single study only

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Table 3. Sensitivity analyses: altered fractionation versus conventional radiotherapy

	All trials	Trials assessed as being at low risk of bias
Total mortality	HR 0.86 (95% CI 0.76 to 0.98) (13 trials)	HR 0.93 (95% CI 0.80 to 1.07) (5 trials)
Locoregional control	HR 0.79 (95% CI 0.70 to 0.89) (11 trials)	HR 0.79 (95% CI 0.68 to 0.91) (4 trials)
Disease free survival	HR 0.85 (95% CI 0.70 to 1.03) (8 trials)	HR 0.95 (95% CI 0.0.74 to 1.22)* (2 trials)
*Fixed‐effect model due to limited number of trials. CI = confidence interval; HR = hazard ratio.

Table 3. Sensitivity analyses: altered fractionation versus conventional radiotherapy

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Comparison 1. Altered fractionation versus conventional radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality (using IPD where available) Show forest plot	13		Hazard Ratio (Fixed, 95% CI)	0.88 [0.82, 0.95]

1.1 Hyperfractionated versus conventional	3		Hazard Ratio (Fixed, 95% CI)	0.78 [0.68, 0.90]
1.2 Hyperfractionated/accelerated versus conventional	4		Hazard Ratio (Fixed, 95% CI)	0.87 [0.75, 1.00]
1.3 Hyperfractionated/accelerated/split versus conventional	4		Hazard Ratio (Fixed, 95% CI)	1.02 [0.90, 1.17]
1.4 Accelerated versus conventional	1		Hazard Ratio (Fixed, 95% CI)	0.27 [0.16, 0.47]
1.5 Accelerated/boost versus conventional	3		Hazard Ratio (Fixed, 95% CI)	0.95 [0.80, 1.13]
2 Locoregional control (using IPD where available) Show forest plot	11		Hazard Ratio (Fixed, 95% CI)	0.80 [0.73, 0.87]

2.1 Hyperfractionated versus conventional	3		Hazard Ratio (Fixed, 95% CI)	0.74 [0.62, 0.89]
2.2 Hyperfractionated/accelerated versus conventional	4		Hazard Ratio (Fixed, 95% CI)	0.84 [0.72, 0.99]
2.3 Hyperfractionated/accelerated/split versus conventional	4		Hazard Ratio (Fixed, 95% CI)	0.86 [0.74, 1.01]
2.4 Accelerated versus conventional	1		Hazard Ratio (Fixed, 95% CI)	0.26 [0.14, 0.50]
2.5 Accelerated/boost versus conventional	1		Hazard Ratio (Fixed, 95% CI)	0.78 [0.62, 0.99]
3 Disease free survival Show forest plot	8		Hazard Ratio (Fixed, 95% CI)	0.88 [0.80, 0.96]

3.1 Hyperfractionated versus conventional	1		Hazard Ratio (Fixed, 95% CI)	0.88 [0.72, 1.07]
3.2 Hyperfractionated/accelerated versus conventional	1		Hazard Ratio (Fixed, 95% CI)	0.87 [0.66, 1.14]
3.3 Hyperfractionated/accelerated/split versus conventional	2		Hazard Ratio (Fixed, 95% CI)	1.04 [0.88, 1.24]
3.4 Accelerated versus conventional	2		Hazard Ratio (Fixed, 95% CI)	0.68 [0.51, 0.91]
3.5 Accelerated/boost versus conventional	4		Hazard Ratio (Fixed, 95% CI)	0.82 [0.69, 0.96]

Comparison 1. Altered fractionation versus conventional radiotherapy

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Comparison 2. Summary analyses for altered fractionation versus conventional radiotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality Show forest plot	13		Hazard Ratio (Random, 95% CI)	0.86 [0.76, 0.98]

2 Locoregional control Show forest plot	11		Hazard Ratio (Random, 95% CI)	0.79 [0.70, 0.89]

3 Disease free survival Show forest plot	8		Hazard Ratio (Random, 95% CI)	0.85 [0.70, 1.03]

Comparison 2. Summary analyses for altered fractionation versus conventional radiotherapy

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Comparison 3. Neutron therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total mortality Show forest plot	4		Hazard Ratio (Fixed, 95% CI)	1.11 [0.96, 1.27]

1.1 Mixed beam (neutron/photon) versus photon	1		Hazard Ratio (Fixed, 95% CI)	1.12 [0.92, 1.36]
1.2 Neutron versus photon	3		Hazard Ratio (Fixed, 95% CI)	1.10 [0.90, 1.34]

Comparison 3. Neutron therapy

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