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Cochrane Database of Systematic Reviews

Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy

Information

DOI:
https://doi.org/10.1002/14651858.CD010341.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 01 December 2015see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Oral Health Group

Copyright:
  1. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Kelvin KW Chan

    Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada

  • Anne‐Marie Glenny

    Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK

  • Jo C Weldon

    Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK

  • Susan Furness

    Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK

  • Helen V Worthington

    Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK

  • Helen Wakeford

    Correspondence to: Cochrane Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK

    [email protected]

Contributions of authors

Protocol

  • Background: Kelvin Chan (KC), Susan Furness (SF).

  • Methods: KC, SF, Anne‐Marie Glenny (AMG), Helen Worthington (HWo).

Review

  • Screening the search results and retrieving the papers: KC, SF, Helen Wakeford (HWa), Jo Weldon (JW).

  • Developing the background: KC, SF, HWa.

  • Data extraction and risk of bias assessment: SF, HWa, HWo, JW.

  • Developing the 'Methods' section: KC, SF, AMG, HWa, HWo, JW.

  • Analysing the data and interpreting the results: HWa, JW, AMG, HWo, SF, KC.

  • Writing the results, discussion, conclusions and abstract: HWa, KC, SF, JW.

Sources of support

Internal sources

  • School of Dentistry, The University of Manchester, UK.

  • Cochrane Oral Health Group, UK.

  • The University of Dundee, UK.

  • The University of Glasgow, UK.

  • MAHSC, UK.

    The Cochrane Oral Health Group is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre.

External sources

  • National Institutes of Health, National Institute of Dental and Craniofacial Research, USA.

  • Central Manchester & Manchester Children's University Hospitals NHS Trust, UK.

  • Cochrane Oral Health Group Global Alliance, Other.

    Through our Global Alliance (http://ohg.cochrane.org/partnerships‐alliances), the Cochrane Oral Health Group has received support from: British Association for the Study of Community Dentistry, UK; British Association of Oral Surgeons, UK; British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists Association, Canada; Mayo Clinic, USA; National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; and Royal College of Surgeons of Edinburgh, UK

  • National Institute for Health Research (NIHR), UK.

    This project was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Oral Health Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

  • Kelvin Chan: none to declare.

  • Jo Weldon: none to declare. Jo is a salaried member of staff with the Cochrane Oral Health Group.

  • Anne‐Marie Glenny: none to declare. Anne‐Marie is Deputy Co‐ordinating Editor of the Cochrane Oral Health Group.

  • Susan Furness: none to declare. Susan is an Editor with the Cochrane Oral Health Group.

  • Helen Worthington: none to declare. Helen is Co‐ordinating Editor of the Cochrane Oral Health Group.

  • Helen Wakeford: none to declare. Helen is a salaried member of staff with the Cochrane Oral Health Group.

Acknowledgements

Our thanks go to the Cochrane Oral Health Group editorial team and external referees (Anirudha Agnihotry, Rosa Rojo and Andrew Sikora) for their help in conducting this systematic review.

Our thanks go to Toru Naito for assisting with the translation of Fujii 2013, and to Chunjie Li who translated several papers from Chinese and contacted Chinese authors on our behalf.

Version history

Published

Title

Stage

Authors

Version

2015 Dec 01

Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy

Review

Kelvin KW Chan, Anne‐Marie Glenny, Jo C Weldon, Susan Furness, Helen V Worthington, Helen Wakeford

https://doi.org/10.1002/14651858.CD010341.pub2

2013 Feb 28

Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy

Protocol

Kelvin KW Chan, Anne‐Marie Glenny, Susan Furness, Helen V Worthington

https://doi.org/10.1002/14651858.CD010341

Differences between protocol and review

In the protocol, we did not specify the different comparisons by which we would group the trials. In the review, we grouped the trials by intervention type. We decided that this was the most biologically and clinically logical way to organise these trials as each intervention type (mAb, TKIs, immunotherapy) has a differing mode of action.

We did not specify the creation of subgroups based on standard therapy type (CRT, RT) in the protocol. However, we decided to create these subgroups in the review, given that these different standard therapies may well have differing effects on the efficacy of the targeted therapies and immunotherapies and vice versa (Dittmann 2005; Nakata 2004).

As we had not previously determined how continuous data would be addressed, an amendment has been included under the 'Methods' section (Measures of treatment effect).

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Review flow diagram
Figures and Tables -
Figure 1

Review flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Figures and Tables -
Figure 3

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

Comparison 1 Monoclonal antibodies (mAb), Outcome 1 Overall survival (5 years).
Figures and Tables -
Analysis 1.1

Comparison 1 Monoclonal antibodies (mAb), Outcome 1 Overall survival (5 years).

Comparison 1 Monoclonal antibodies (mAb), Outcome 2 Locoregional control.
Figures and Tables -
Analysis 1.2

Comparison 1 Monoclonal antibodies (mAb), Outcome 2 Locoregional control.

Comparison 1 Monoclonal antibodies (mAb), Outcome 3 Progression‐free survival.
Figures and Tables -
Analysis 1.3

Comparison 1 Monoclonal antibodies (mAb), Outcome 3 Progression‐free survival.

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 1 Overall survival.
Figures and Tables -
Analysis 2.1

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 1 Overall survival.

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 2 Locoregional control.
Figures and Tables -
Analysis 2.2

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 2 Locoregional control.

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 3 Disease‐free survival.
Figures and Tables -
Analysis 2.3

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 3 Disease‐free survival.

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 4 Progression‐free survival.
Figures and Tables -
Analysis 2.4

Comparison 2 Tyrosine kinase inhibitors (TKI), Outcome 4 Progression‐free survival.

Comparison 3 Immunotherapy, Outcome 1 Overall survival.
Figures and Tables -
Analysis 3.1

Comparison 3 Immunotherapy, Outcome 1 Overall survival.

Comparison 3 Immunotherapy, Outcome 2 Disease‐free survival.
Figures and Tables -
Analysis 3.2

Comparison 3 Immunotherapy, Outcome 2 Disease‐free survival.

Summary of findings for the main comparison. Monoclonal antibodies plus standard therapy versus standard therapy alone for the treatment of people with oral cavity or oropharyngeal cancers

Monoclonal antibodies plus standard therapy versus standard therapy alone for the treatment of people with oral cavity and oropharyngeal cancers

Patient or population: people with oral cavity or oropharyngeal cancers
Settings: secondary care
Intervention: EGFR mAb (either cetuximab or nimotuzumab + either RT or CRT)

Comparison: RT or CRT alone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Standard therapy

Corresponding risk

mAb

Overall survival
Follow‐up: 24‐70 months

Low‐risk population*

HR 0.82
(0.69 to 0.97)

1421
(3 studies)

⊕⊕⊕⊝

moderate1

There was an 18% reduction in death (during the follow‐up period) in the participants treated with EGFR mAb therapies in addition to standard therapies

160 per 1000

133 per 1000 (113 to 156)

Moderate‐risk population*

405 per 1000

347 per 1000 (301 to 396)

High‐risk population*

650 per 1000

577 per 1000 (515 to 639)

Locoregional control
Follow‐up: 24‐70 months

Low‐risk population*

HR 0.68
(0.52 to 0.89)

424
(1 study)

⊕⊕⊕⊝
moderate2

There was a 32% reduction in recurrence of cancer (during the follow‐up period) in the participants treated with EGFR mAb therapies (cetuximab) in addition to standard therapies

160 per 1000

112 per 1000 (87 to 144)

Moderate‐risk population*

405 per 1000

297 per 1000 (237 to 370)

High‐risk population*

650 per 1000

510 per 1000 (421 to 607)

Progression‐free survival
Follow‐up: 24‐70 months

We formed 2 subgroups: mAb therapy + RT versus RT alone and mAb therapy + CRT versus CRT alone. There was a significant difference between these subgroups (P value = 0.008; I2 = 86%) and as a result we were unable to pool the data. The subgroup comparing mAb therapy + RT versus RT alone reported a 30% reduction in the number of people whose disease progresses if treated with EGFR mAb in addition to RT (HR 0.70; 95% CI 0.54 to 0.91; P value = 0.006). However, the subgroup comparing mAb therapy + CRT versus CRT alone reported no evidence of a difference in progression‐free survival (HR 1.08; 95% CI 0.89 to 1.32; P value = 0.76)

Adverse effects

A subgroup estimate shows evidence of an increase in skin toxicity/acneiform rash (all grades of adverse effects: RR 6.56, 95% CI 5.35 to 8.03; 1311 participants, 2 studies; adverse effects grades ≥ 3: RR 17.72, 95% CI 8.33 to 37.73; 1403 participants, 3 studies) in people treated with cetuximab in addition to standard therapy

CI: confidence interval; CRT: chemoradiotherapy; EGFR: epidermal growth factor receptor; mAb: monoclonal antibody; HR: hazard ratio; OIS: optimal information size; RR: risk ratio; RT: radiotherapy.

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.

* Assumed risk based on 5‐year survival data (Pulte 2010).

1 Downgraded once for reporting bias (potential publication bias and poor reporting of EGFR and biopsy data in one study).
2 Downgraded once due to this being a single study at unclear risk of performance bias.

Figures and Tables -
Summary of findings for the main comparison. Monoclonal antibodies plus standard therapy versus standard therapy alone for the treatment of people with oral cavity or oropharyngeal cancers
Summary of findings 2. Tyrosine kinase inhibitors plus standard therapy versus standard therapy alone for the treatment of people with oral cavity and oropharyngeal cancers

Tyrosine kinase inhibitors in addition to standard treatments for people with oral cavity and oropharyngeal cancers

Patient or population: people with oral cavity or oropharyngeal cancers
Settings: secondary care
Intervention: tyrosine kinase inhibitors (erlotinib, gefitinib or lapatinib) + standard therapy (either RT or CRT)

Comparison: standard therapy (either RT or CRT alone)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Standard therapy

Corresponding risk

Tyrosine kinase inhibitors

Overall survival
Follow‐up: 40‐60 months

Low‐risk population*

HR 0.99
(0.62 to 1.57)

271
(2 studies)

⊕⊝⊝⊝
very low1,2,3

There was no evidence of a difference in participant survival in people treated with tyrosine kinase inhibitors in addition to standard therapies

160 per 1000

159 per 1000 (102 to 239)

Moderate‐risk population*

405 per 1000

402 per 1000 (275 to 557)

High‐risk population*

650 per 1000

646 per 1000 (478 to 808)

Locoregional control
Follow‐up: 40‐60 months

Low‐risk population*

HR 0.89
(0.53 to 1.49)

271
(2 studies)

⊕⊝⊝⊝
very low1,2,3

There was no evidence of a difference in locoregional control in people treated with tyrosine kinase inhibitors in addition to standard therapies

160 per 1000

144 per 1000 (88 to 229)

Moderate‐risk population*

405 per 1000

370 per 1000 (241 to 539)

High‐risk population*

650 per 1000

607 per 1000 (429 to 791)

Disease‐free Survival
Follow‐up: 40‐60 months

Low‐risk population*

HR 1.51
(0.61 to 3.71)

60
(1 study)

⊕⊝⊝⊝
very low1,2,4

There was no evidence of a difference in the length of time that participants survived without signs or symptoms of oral cavity cancer when treated with tyrosine kinase inhibitors (gefitinib) in addition to standard therapies

160 per 1000

231 per 1000 (101 to 476)

Moderate‐risk population*

405 per 1000

543 per 1000 (271 to 854)

High‐risk population*

650 per 1000

795 per 1000 (473 to 980)

Progression‐free Survival
Follow‐up: 40‐60 months

Low‐risk population*

HR 0.8
(0.51 to 1.28)

271
(2 studies)

⊕⊝⊝⊝
very low1,2,3

There was no evidence of a difference in the length of time that participants stayed alive with stable disease when treated with tyrosine kinase inhibitors in addition to standard therapies

160 per 1000

130 per 1000 (85 to 200)

Moderate‐risk population*

405 per 1000

340 per 1000 (233 to 486)

High‐risk population*

650 per 1000

568 per 1000 (415 to 739)

Adverse effects

A subgroup estimate showed evidence of an increase in gastrointestinal complaints (all grades of adverse effects: RR 15.53, 95% CI 2.18 to 110.55; 67 participants, 1 study) in people treated with lapatinib in addition to standard therapy

CI: confidence interval; CRT: chemoradiotherapy; HR: hazard ratio; OIS: optimal information size; RR: risk ratio; RT: radiotherapy

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.

* Assumed risk based on 5‐year survival data (Pulte 2010).

1 Downgraded once due reporting bias (data from a large study (Gregoire 2011) was not available).

2 Downgraded once due to imprecision

3 Downgraded once due to unclear risk of bias across multiple domains.

4 Downgraded once for applicability ‐ only participants receiving RT as a standard therapy were included in this subgroup (no CRT).

Figures and Tables -
Summary of findings 2. Tyrosine kinase inhibitors plus standard therapy versus standard therapy alone for the treatment of people with oral cavity and oropharyngeal cancers
Summary of findings 3. Immunotherapy plus standard therapy versus standard therapy alone for the treatment of people with oral and oropharyngeal cancers

Recombinant Interleukin (rIL‐2) in addition to surgery for the treatment of people with oral and oropharyngeal cancers

Patient or population: people with oral cavity or oropharyngeal cancers
Settings: secondary care
Intervention: recombinant Interleukin (rIL‐2) + standard therapy (surgery)

Comparison: standard therapy (surgery) alone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Standard therapy

Corresponding risk

rIL‐2

Overall survival
Follow‐up: 24‐70 months

Low‐risk population*

HR 0.52

(0.31 to 0.87)

201
(1 study)

⊕⊝⊝⊝
very low1,2

There was an 48% reduction in death in the groups treated with rIL‐2 in addition to standard therapy

160 per 1000

87 per 1000
(53 to 141)

Moderate‐risk population*

405 per 1000

237 per 1000

(149 to 363)

High‐risk population*

650 per 1000

421 per 1000

(278 to 599)

Disease‐free survival
Follow‐up: 24‐70 months

Low‐risk population*

HR 0.66
(0.43 to 1.02)

201
(1 study)

⊕⊝⊝⊝
very low1,2

There is no evidence of a difference in the length of time that participants survived without signs or symptoms of cancer when treated with rIL‐2 in addition to standard therapies

160 per 1000

109 per 1000

(72 to 163)

Moderate‐risk population*

405 per 1000

290 per 1000

(200 to 411)

High‐risk population*

650 per 1000

500 per 1000

(363 to 657)

Adverse effects

There was no evidence of an increase or reduction of nausea/vomiting, stomatitis or leukopenia in participants treated with rIL‐2 in addition to standard therapy (1 study, 30 participants)

CI: confidence interval; HR: hazard ratio; OIS: optimal information size

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.

* Assumed risk based on 5‐year survival data (Pulte 2010)

1 Downgraded twice due to high/unclear risk of bias across domains.
2 Downgraded once due to this being a single study and due to applicability (only participants receiving surgery as a standard therapy were included in this subgroup (no RT/CRT).

Figures and Tables -
Summary of findings 3. Immunotherapy plus standard therapy versus standard therapy alone for the treatment of people with oral and oropharyngeal cancers
Table 1. Summary of inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

Location of cancer

People with primary cancer of the oral cavity (ICD‐O: C01‐06) or oropharynx (ICD‐O: C09‐10 ‐ includes tonsil)
People with primary cancer of the head and neck where > 50% of cases had oral/oropharynx cancer. If separate oral/oropharynx data are available they will be used to the exclusion of the combined head and neck cancer data

Lip (ICD‐O: C00) cancers

Type of cancer

Squamous cell carcinoma

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 and neck trials, these cancers will be included if they comprise < 50% of the total cancer diagnoses of participants

ICD‐O: International Classification of Diseases for Oncology.

Figures and Tables -
Table 1. Summary of inclusion and exclusion criteria
Table 2. Outcome data from Koh 2013

ITT analysis

Docetaxel + cisplatin + cetuximab (n = 48)

Docetaxel + cisplatin (n = 44)

OS (3 years)

88% (n = 42)

74% (n = 33)

PFS (3 years)

70% (n = 34)

56% (n = 25)

ITT: intention to treat; n: number of participants; OS: overall survival; PFS: progression‐free survival.

Figures and Tables -
Table 2. Outcome data from Koh 2013
Table 3. Adverse event outcomes: comparison 1: monoclonal antibodies

Outcome

Grade

No. of studies

No. of patients

Risk ratio (MH, 95% CI, P value)

Heterogeneity (P value; I2)

1.6 Mucositis

All grades

3

1417

Not estimable due to high heterogeneity (P value = 0.0009; I2 = 86%) between subgroups (cetuximab; nimotuzumab), and within the cetuximab subgroup (P value = 0.0002) I2 = 93%)

Grades ≥ 3

4

1495

1.20 (0.96 to 1.51) (random effects) P value = 0.12

P value = 0.07; I2 = 58%

1.7 Dysphagia

All grades

3

1403

0.97 (0.92 to 1.03) (fixed effect) P value = 0.37

P value = 0.60; I2 = 0%

Grades ≥ 3

3

1403

0.93 (0.83 to 1.04) (fixed effect) P value = 0.19

P value = 0.26; I2 = 26%

1.8 Xerostomia

All grades

3

1417

0.97 (0.91 to 1.04) (fixed effect) P value = 0.46

P value = 0.61; I2 = 0%

Grades ≥ 3

2

1311

1.36 (0.80 to 2.31) (fixed effect) P value = 0.25

P value = 0.60; I2 = 0%

1.9 Skin toxicity/ acneiform rash

All grades

3

1403

Not estimable due to significant difference between subgroups (P value < 0.00001; I2 = 99.3%)

2 (cetuximab)

1311

6.56 (5.35 to 8.03) (fixed effect) P value < 0.00001

P value = 0.080; I2 = 66%

1 (nimotuzumab)

92

1.06 (0.85 to 1.31) P value = 0.61

Not applicable

Grades ≥ 3

4

1495

Not estimable due to significant difference between subgroups (P value = 0.005; I2 = 87.5%)

3 (cetuximab)

1403

17.72 (8.33 to 37.73) (fixed effect) P value < 0.00001

P value = 0.56; I2 = 0%

1 (nimotuzumab)

92

0.20 (0.01 to 4.05) P value = 0.29

Not applicable

CI: confidence interval; MH: Mantel‐Haenszel.

Figures and Tables -
Table 3. Adverse event outcomes: comparison 1: monoclonal antibodies
Table 4. Adverse event outcomes: comparison 2: tyrosine kinase inhibitors

Outcome

Grade

No. of studies

No. of participants

Risk ratio (MH, 95% CI, P value)

Heterogeneity (P value; I2)

2.5 Mucositis

All grades

2

286

1.03 (0.94 to 1.11) (fixed effect) P value = 0.55

P value = 0.44; I2 = 0%

Grades ≥ 3

2

286

1.22 (0.96 to 1.56) (fixed effect) P value = 0.10

P value = 0.53; I2 = 0%

2.6 Skin toxicity

All grades

4

544

Not estimable due to significant difference between subgroups (P value < 0.00001; I2 = 95.5%)

2 (gefitinib)

286

1.03 (0.82 to 1.28) (fixed effect) P value = 0.82

P value = 0.42; I2 = 0%

1 (lapatinib)

67

2.02 (1.23 to 3.32) P value = 0.005

Not applicable

1 (erlotinib)

191

6.57 (3.60 to 12.00) P value < 0.00001

Not applicable

Grades ≥ 3

4

544

1.25 (0.54 to 2.88) (random effects) P value = 0.61

P value = 0.09; I2 = 54%

2.7 Gastrointestinal

All grades

2

293

Not estimable due to significant difference between subgroups (P value = 0.007; I2 = 86.2%)

1 (gefitinib)

226

1.04 (0.98 to 1.11) P value = 0.18

Not applicable

1 (lapatinib)

67

15.53 (2.18 to 110.55) P value = 0.006

Not applicable

Grades ≥ 3

3

484

1.11 (0.83 to 1.49) (fixed effect) P value = 0.47

P value = 0.53; I2 = 0%

CI: confidence interval; MH: Mantel‐Haenszel.

Figures and Tables -
Table 4. Adverse event outcomes: comparison 2: tyrosine kinase inhibitors
Table 5. Outcome data from Bier 1981

Outcome

BCG‐cell wall preparation + surgery

Surgery alone

Overall survival (3 years)

10/10

9/10

Recurrence (3 years)

3/10

4/10

BCG: Bacillus Calmette‐Guérin.

Figures and Tables -
Table 5. Outcome data from Bier 1981
Table 6. Outcome data from Mantovani 1998

Outcome

Neoadjuvant chemotherapy (n = 17)

Neoadjuvant chemotherapy + rIL‐2 (n = 16)

Locoregional control

Complete response

3/15

4/13

Locoregional control

Partial response

9/15

6/13

rIL‐2: recombinant interleukin.

Figures and Tables -
Table 6. Outcome data from Mantovani 1998
Table 7. Adverse event outcomes: comparison 3: immunotherapies

Outcome

Grade

No. of studies

No. of participants

Risk ratio (MH, 95% CI, P value)

Heterogeneity (P value; I2)

3.3 Nausea/vomiting

All grades

1

30

1.24 (0.90 to 1.70) P value = 0.19

Not applicable

Grades ≥ 3

1

30

3.40 (0.15 to 77.34) P value = 0.44

Not applicable

3.4 Stomatitis

All grades

1

30

1.47 (0.75 to 2.90) P value = 0.27

Not applicable

Grades ≥ 3

1

30

1.71 (0.33 to 8.83) P value = 0.52

Not applicable

3.5 Leukopenia

All grades

1

30

0.57 (0.22 to 1.50) P value = 0.25

Not applicable

Grades ≥ 3

1

30

0.38 (0.04 to 3.26) P value = 0.38

Not applicable

3.6 Increased temperature

All grades

1

24

0.67 (0.13 to 3.30) P value = 0.62

Not applicable

3.7 Moderate‐severe chills

All grades

1

24

11.00 (0.67 to 179.29) P value = 0.09

Not applicable

3.8 Gastrointestinal

All grades

1

24

5.00 (0.27 to 94.34) P value = 0.28

Not applicable

CI: confidence interval; MH: Mantel‐Haenszel.

Figures and Tables -
Table 7. Adverse event outcomes: comparison 3: immunotherapies
Comparison 1. Monoclonal antibodies (mAb)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival (5 years) Show forest plot

3

1421

Hazard Ratio (Fixed, 95% CI)

0.82 [0.69, 0.97]

1.1 mAb therapy + radiotherapy (RT) vs. RT alone

2

530

Hazard Ratio (Fixed, 95% CI)

0.73 [0.58, 0.91]

1.2 mAb therapy + chemoradiotherapy (CRT) vs. CRT alone

1

891

Hazard Ratio (Fixed, 95% CI)

0.95 [0.74, 1.23]

2 Locoregional control Show forest plot

1

Hazard Ratio (Fixed, 95% CI)

Subtotals only

2.1 mAb therapy + RT vs. RT alone

1

424

Hazard Ratio (Fixed, 95% CI)

0.68 [0.52, 0.89]

3 Progression‐free survival Show forest plot

2

Hazard Ratio (Fixed, 95% CI)

Subtotals only

3.1 mAb therapy + RT vs. RT alone

1

424

Hazard Ratio (Fixed, 95% CI)

0.70 [0.54, 0.91]

3.2 mAb therapy + CRT vs. CRT alone

1

891

Hazard Ratio (Fixed, 95% CI)

1.08 [0.89, 1.32]

Figures and Tables -
Comparison 1. Monoclonal antibodies (mAb)
Comparison 2. Tyrosine kinase inhibitors (TKI)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

2

271

Hazard Ratio (Fixed, 95% CI)

0.99 [0.62, 1.57]

1.1 TKI + chemoradiotherapy (CRT) vs. CRT alone

2

271

Hazard Ratio (Fixed, 95% CI)

0.99 [0.62, 1.57]

2 Locoregional control Show forest plot

2

271

Hazard Ratio (Fixed, 95% CI)

0.89 [0.53, 1.49]

2.1 TKI + CRT vs. CRT alone

2

271

Hazard Ratio (Fixed, 95% CI)

0.89 [0.53, 1.49]

3 Disease‐free survival Show forest plot

1

Hazard Ratio (Fixed, 95% CI)

Subtotals only

3.1 TKI + radiotherapy (RT) vs. RT alone

1

60

Hazard Ratio (Fixed, 95% CI)

1.51 [0.61, 3.71]

4 Progression‐free survival Show forest plot

2

271

Hazard Ratio (Fixed, 95% CI)

0.80 [0.51, 1.28]

4.1 TKI + CRT vs. CRT alone

2

271

Hazard Ratio (Fixed, 95% CI)

0.80 [0.51, 1.28]

Figures and Tables -
Comparison 2. Tyrosine kinase inhibitors (TKI)
Comparison 3. Immunotherapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

1

Hazard Ratio (Fixed, 95% CI)

Subtotals only

1.1 Surgery ± radiotherapy (RT) + rIL‐2 vs. surgery ± RT alone

1

201

Hazard Ratio (Fixed, 95% CI)

0.52 [0.31, 0.87]

2 Disease‐free survival Show forest plot

1

Hazard Ratio (Fixed, 95% CI)

Subtotals only

2.1 Surgery ± RT + rIL‐2 vs. surgery ± RT alone

1

201

Hazard Ratio (Fixed, 95% CI)

0.66 [0.43, 1.02]

Figures and Tables -
Comparison 3. Immunotherapy
Table 8. Adverse events: monoclonal antibodies

Study ID

Specified adverse effect

Intervention arm

Control arm

Ang 2014

Comparison: mAb

(CRT + cetuximab vs. CRT (no placebo))

Acute period : ≤ 90 days from start of RT (Gp A n = 444; Gp B n = 447)

Any event

All grades: n = 431 (97%);
Grades 3‐4: n = 395 (89%)

All grades: n = 434 (97%);
Grades 3‐4: n = 389 (87%)

Dysphagia

All grades: n = 364 (82%);
Grades 3‐4: n = 235 (53%)

All grades: n = 384 (86%);
Grades 3‐4: n = 255 (57%)

Mucositis

All grades: n = 364 (82%);
Grades 3‐4: n = 191 (43%)

All grades: n = 322 (72%);
Grades 3‐4: n = 147 (33%)

Skin reaction outside portal (pruritus; dermatitis exfoliative NOS; acne NOS; nail disorder NOS)

All grades: n = 364 (82%);
Grades 3‐4: n = 89 (20%)

All grades: n = 63 (14%);
Grades 3‐4: n = 4 (1%)

Skin reaction inside portal (radiation dermatitis NOS; radiation recall syndrome)

All grades: n = 346 (78%);
Grades 3‐4: n = 111 (25%)

All grades: n = 353 (79%);
Grades 3‐4: n = 67 (15%)

Fatigue

All grades: n = 289 (65%);
Grades 3‐4: n = 62 (14%)

All grades: n = 268 (60%);
Grades 3‐4: n = 40 (9%)

Late period : > 90 days from start of RT (Gp A n = 415; Gp B n = 432)

Any event

All grades: n = 403 (97%);

Grades 3‐4: n = 249 (60%)

All grades: n = 419 (97%);

Grades 3‐4: n = 233 (54%)

Dysphagia

All grades: n = 357 (86%);

Grades 3‐4: n = 154 (37%)

All grades: n = 359 (83%);

Grades 3‐4: n = 156 (36%)

Dry mouth

All grades: n = 311 (75%);

Grades 3‐4: n = 21 (5%)

All grades: n = 324 (75%);

Grades 3‐4: n = 17 (4%)

Skin fibrosis

All grades: n = 311 (46%);

Grades 3‐4: n = 8 (2%)

All grades: n = 190 (44%);

Grades 3‐4: n = 4 (1%)

Fatigue

All grades: n = 170 (41%);

Grades 3‐4: n = 12 (3%)

All grades: n = 194 (45%);

Grades 3‐4: n = 13 (3%)

Laryngeal oedema

All grades: n = 166 (40%);

Grades 3‐4: n = 17 (4%)

All grades: n = 181 (42%);

Grades 3‐4: n = 13 (3%)

Bonner 2006

Comparison: mAb

RT + cetuximab vs. RT (no placebo)

(Gp A n = 208; Gp B n = 212)

Mucositis

All grades: n = 193 (93%);

Grades 3‐5: n = 116 (56%)

All grades: n = 199 (94%);

Grades 3‐5: n = 110 (52%)

Acneiform rash

All grades: n = 181 (87%);

Grades 3‐5: n = 35 (17%)

All grades: n = 21 (10%);

Grades 3‐5: n = 2 (1%)

Radiation dermatitis

All grades: n = 179 (86%);

Grades 3‐5: n = 48 (23%)

All grades: n = 191 (90%);

Grades 3‐5: n = 38 (18%)

Weight loss

All grades: n = 175 (84%);

Grades 3‐5: n = 23 (11%)

All grades: n = 153 (72%);

Grades 3‐5: n = 15 (7%)

Xerostomia

All grades: n = 150 (72%);

Grades 3‐5: n = 10 (5%)

All grades: n = 151 (71%);

Grades 3‐5: n = 6 (3%)

Dysphagia

All grades: n = 135 (65%);

Grades 3‐5: n = 54 (26%)

All grades: n = 134 (63%);

Grades 3‐5: n = 64 (30%)

Koh 2013

Comparison: mAb

(CRT + cetuximab vs. CRT (no placebo))

Gp A n = 48; Gp B n = 44

Partial narrative reporting for Gp A toxicities relating to attrition rationale in abstract:

"Reason for incompletion in CDP arm included hypersensitivity (1), septic shock (1), skin rash (1), seizure (1), arterial thrombosis (1), unexplained death (1), unsatisfactory response (1), and withdrawal of informed consent (1)". No detail reported for Gp B. However, poster presented alongside abstract indicates similar frequency of Grade 3‐4 toxicities in both Gps

Neutropenia

CRT induction

Concurrent CRT

Grades 3‐4: n = 13 (27%)

Grades 3‐4: n = 5 (10%)

Grades 3‐4: n = 5 (11%)

Grades 3‐4: n = 4 (9%)

Anorexia

CRT induction

Concurrent CRT

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 6 (13%)

Grades 3‐4: n = 4 (9%)

Grades 3‐4: n = 4 (9%)

Mucositis

CRT induction

Concurrent CRT

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 9 (19%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 3 (7%)

Febrile neutropenia

CRT induction

Concurrent CRT

Grades 3‐4: n = 7 (%)

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 4 (9%)

Grades 3‐4: n = 0 (0%)

Skin toxicity

CRT induction

Concurrent CRT

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 1 (2%)

Diarrhoea

CRT induction

Concurrent CRT

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 3 (7%)

Grades 3‐4: n = 0 (0%)

Reddy 2014

Comparison: mAb

CRT + nimotuzumab vs. CRT vs. RT + nimotuzumab vs. RT

(Gp A n = 23; Gp B n = 23; Gp C n = 23; Gp D n = 23)

**Note: control arm mucositis events Gp D n = 27 (+4 than Gp n), therefore, all grade mucositis data not used in analysis

Mucositis

All grades: n = 44 (96%);

Grade 3: n = 21 (46%)

All grades: n = 49 (106%)** ;

Grade 3: n = 21 (46%)

Skin reaction

All grades: n = 37 (80%);

Grade 3: n = 0 (0%)

All grades: n = 35 (76%);

Grade 3: n = 2 (4%)

Nausea/vomiting

All grades: n = 34 (74%);

Grade 3: n = 1 (2%)

All grades: n = 30 (65%);

Grade 3: n = 0 (0%)

Salivary gland disorder

All grades: n = 27 (59%);

Grade 3: n = 0 (0%)

All grades: n = 29 (63%);

Grade 3: n = 2 (4%)

Dysphagia

All grades: n = 16 (35%);

Grade 3: n = 5 (%)

All grades: n = 16 (35%);

Grade 3: n = 1 (2%)

Candidiasis

All grades: n = 13 (28%);

Grade 3: n = 5 (11%)

All grades: n = 19 (41%);

Grade 3: n = 7 (15%)

Rodriguez 2010

Comparison: mAb

RT + nimotuzumab vs. RT + placebo

(Gp A n = 54; Gp B n = 52)

Any adverse event

n = 38 (70%)

n = 30 (58%)

Mucositis

n = 11 (20%)

n = 9 (17%)

Dry mouth

n = 9 (17%)

n = 12 (23%)

Dry radio‐dermatitis

n = 6 (11%)

n = 6 (12%)

Odynophagia

n = 4 (7%)

n = 6 (12%)

CRT: chemoradiotherapy; Gp: group; mAb: monoclonal antibody; NOS: not otherwise specify; RT: radiotherapy.

Figures and Tables -
Table 8. Adverse events: monoclonal antibodies
Table 9. Adverse events: immunotherapies

Study ID

Specified adverse effect

Intervention arm

Control arm

De Stefani 2002

Comparison: interleukin

rIL‐2 + RT + surgery vs. RT + surgery (no placebo)

(Gp A n = 100; Gp B n = 101)

Narrative commentary only:

"Complication and toxicity rates for the surgery arm and the surgery plus radiotherapy arm were the same in the control group and in the rIL‐2 group.

Postoperative radiotherapy originates well‐known side effects, but they were independent of the preoperative rIL‐2 treatment. [...]

Neoadjuvant rIL‐2 injections did not complicate the surgical treatment, and adjuvant rIL‐2 injections did not increase distant side effects due to previous surgery or radiotherapy"

Mantovani 1998

Comparison: interleukin

rIL‐2 + CRT ± surgery vs. CRT ± surgery (no placebo)

(Gp A n = 14; Gp B n = 16)

Nausea/vomiting

All grades: n = 13 (93%);

Grades 3‐4: n = 1 (7%)

All grades: n = 12 (75%);

Grades 3‐4: n = 0 (0%)

Stomatitis

All grades: n = 9 (64%);

Grades 3‐4: n = 3 (21%)

All grades: n = 7 (44%);

Grades 3‐4: n = 2 (13%)

Leukopenia

All grades: n = 4 (29%);

Grades 3‐4: n = 1 (7%)

All grades: n = 8 (50%);

Grades 3‐4: n = 3 (19%)

Fever

All grades: n = 6 (43%);

Grades 3‐4: n = 0 (0%)

All grades: n = 0 (0%);

Grades 3‐4: n = 0 (0%)

Diarrhoea

All grades: n = 2 (14%);

Grades 3‐4: n = 1 (7%)

All grades: n = 3 (19%);

Grades 3‐4: n = 1 (6%)

Anaemia

All grades: n = 3 (21%);

Grades 3‐4: n = 1 (7%)

All grades: n = 2 (13%);

Grades 3‐4: n = 0 (0%)

Bier 1981

Comparison:

BCG‐CWP + surgery vs. surgery (no placebo)

(Gp A n = 12; Gp B n = 12)

Increased temperature
(> 3 to ≤ 14 days post treatment)

n = 2 (17%)

n = 3 (25%)

Moderate‐severe chills

n = 5 (42%)

n = 0 (0%)

Gastrointestinal complaints (including nausea/vomiting)

n = 2 (17%)

n = 0 (0%)

BCG‐CWP: Bacillus Calmette‐Guérin ‐ cell wall preparation; Gp: group; n: number of participants; rIL‐2: recombinant interleukin; RT: radiotherapy.

Figures and Tables -
Table 9. Adverse events: immunotherapies
Table 10. Adverse events: tyrosine kinase inhibitors

Study ID

Specified adverse effect

Intervention arm

Control arm

Gregoire 2011

Comparison: TKI

(CRT + gefitinib (250/500 mg) vs.
CRT + placebo) (concomitant phase
only: Gp A n = 110 (Gps B+C+D+E);

Gp B n = 116 (Gps A+F+G))

Mucositis

All grades: n = 96 (87%);

Grades 3‐5: n = 51 (%)

All grades: n = 98 (84%);

Grades 3‐5: n = 42 (36%)

Nausea

All grades: n = 50 (45%);

Grades 3‐5: n = 4 (4%)

All grades: n = 55 (47%);

Grades 3‐5: n = 3 (3%)

Vomiting

All grades: n = 56 (51%);

Grades 3‐5: n = 6 (5%)

All grades: n = 52 (45%);

Grades 3‐5: n = 9 (8%)

Dysphagia

All grades: n = 29 (26%);

Grades 3‐5: n = 5 (5%)

All grades: n = 43 (37%);

Grades 3‐5: n = 13 (11%)

Dry mouth (xerostomia)

All grades: n = 33 (30%);
Grades 3‐5: n = 1 (1%)

All grades: n = 30 (26%);

Grades 3‐5: n = 2 (2%)

Radiation skin injury

All grades: n = 29 (26%);

Grades 3‐4: n = 2 (2%)

All grades: n = 29 (25%);

Grades 3‐5: n = 4 (3%)

Harrington 2013

Comparison: TKI

(CRT + lapatinib vs. CRT + placebo)

Gp A n = 34; Gp B n = 33

Diarrhoea

All grades: n = 16 (46%);

Grade 3: n = 2 (6%)

All grades: n = 1 (3%);

Grade 3: n = 0 (0%)

Rash

All grades: n = 10 (29%);

Grade 3: n = 3 (9%)

All grades: n = 5 (16%);

Grade 3: n = 1 (3%)

Other skin reactions

All grades: n = 15 (43%);

Grade 3: n = 2 (6%)

All grades: n = 7 (23%);

Grade 3: n = 5 (16%)

Martins 2013
Comparison: TKI (CRT + erlotinib vs.
CRT (no placebo))

(Gp A n = 95; Gp B n = 96)

Pain

All grades: n = 50 (53%);

Grades 3‐4: n = 18 (19%)

All grades: n = 54 (56%);

Grades 3‐4: n = 18 (19%)

Gastrointestinal

Grades 3‐4: n = 46 (48%)

Grades 3‐4: n = 41 (43%)

Rash

All grades: n = 65 (68%);

Grade 3: n = 12 (13%)

All grades: n = 10 (10%);

Grade 3: n = 2 (2%)

Serious adverse events*

n = 38 (40%)

n = 32 (33%)

Haematological

Grades 3‐4: n = 15 (16%)

Grades 3‐4: n = 25 (26%)

Metabolic

Grades 3‐4: n = 7 (7%)

Grades 3‐4: n = 5 (5%)

Singh 2013

Comparison TKI

RT + gefitinib vs. RT (no placebo)

(Gp A n = 30; Gp B n = 30)

Mucositis

All grades: n = 30 (100%);

Grades 3‐4: n = 21 (70%)

All grades: n = 30 (100%);

Grades 3‐4: n = 19 (63%)

Skin reaction

All grades: n = 30 (100%);

Grades 3‐4: n = 12 (40%)

All grades: n = 30 (100%);

Grades 3‐4: n = 11 (36%)

CRT: chemoradiotherapy; Gp: group; n: number of participants; TKI: tyrosine kinase inhibitor.

Figures and Tables -
Table 10. Adverse events: tyrosine kinase inhibitors
Table 8. Adverse events: monoclonal antibodies

Study ID

Specified adverse effect

Intervention arm

Control arm

Ang 2014

Comparison: mAb

(CRT + cetuximab vs. CRT (no placebo))

Acute period : ≤ 90 days from start of RT (Gp A n = 444; Gp B n = 447)

Any event

All grades: n = 431 (97%);
Grades 3‐4: n = 395 (89%)

All grades: n = 434 (97%);
Grades 3‐4: n = 389 (87%)

Dysphagia

All grades: n = 364 (82%);
Grades 3‐4: n = 235 (53%)

All grades: n = 384 (86%);
Grades 3‐4: n = 255 (57%)

Mucositis

All grades: n = 364 (82%);
Grades 3‐4: n = 191 (43%)

All grades: n = 322 (72%);
Grades 3‐4: n = 147 (33%)

Skin reaction outside portal (pruritus; dermatitis exfoliative NOS; acne NOS; nail disorder NOS)

All grades: n = 364 (82%);
Grades 3‐4: n = 89 (20%)

All grades: n = 63 (14%);
Grades 3‐4: n = 4 (1%)

Skin reaction inside portal (radiation dermatitis NOS; radiation recall syndrome)

All grades: n = 346 (78%);
Grades 3‐4: n = 111 (25%)

All grades: n = 353 (79%);
Grades 3‐4: n = 67 (15%)

Fatigue

All grades: n = 289 (65%);
Grades 3‐4: n = 62 (14%)

All grades: n = 268 (60%);
Grades 3‐4: n = 40 (9%)

Late period : > 90 days from start of RT (Gp A n = 415; Gp B n = 432)

Any event

All grades: n = 403 (97%);

Grades 3‐4: n = 249 (60%)

All grades: n = 419 (97%);

Grades 3‐4: n = 233 (54%)

Dysphagia

All grades: n = 357 (86%);

Grades 3‐4: n = 154 (37%)

All grades: n = 359 (83%);

Grades 3‐4: n = 156 (36%)

Dry mouth

All grades: n = 311 (75%);

Grades 3‐4: n = 21 (5%)

All grades: n = 324 (75%);

Grades 3‐4: n = 17 (4%)

Skin fibrosis

All grades: n = 311 (46%);

Grades 3‐4: n = 8 (2%)

All grades: n = 190 (44%);

Grades 3‐4: n = 4 (1%)

Fatigue

All grades: n = 170 (41%);

Grades 3‐4: n = 12 (3%)

All grades: n = 194 (45%);

Grades 3‐4: n = 13 (3%)

Laryngeal oedema

All grades: n = 166 (40%);

Grades 3‐4: n = 17 (4%)

All grades: n = 181 (42%);

Grades 3‐4: n = 13 (3%)

Bonner 2006

Comparison: mAb

RT + cetuximab vs. RT (no placebo)

(Gp A n = 208; Gp B n = 212)

Mucositis

All grades: n = 193 (93%);

Grades 3‐5: n = 116 (56%)

All grades: n = 199 (94%);

Grades 3‐5: n = 110 (52%)

Acneiform rash

All grades: n = 181 (87%);

Grades 3‐5: n = 35 (17%)

All grades: n = 21 (10%);

Grades 3‐5: n = 2 (1%)

Radiation dermatitis

All grades: n = 179 (86%);

Grades 3‐5: n = 48 (23%)

All grades: n = 191 (90%);

Grades 3‐5: n = 38 (18%)

Weight loss

All grades: n = 175 (84%);

Grades 3‐5: n = 23 (11%)

All grades: n = 153 (72%);

Grades 3‐5: n = 15 (7%)

Xerostomia

All grades: n = 150 (72%);

Grades 3‐5: n = 10 (5%)

All grades: n = 151 (71%);

Grades 3‐5: n = 6 (3%)

Dysphagia

All grades: n = 135 (65%);

Grades 3‐5: n = 54 (26%)

All grades: n = 134 (63%);

Grades 3‐5: n = 64 (30%)

Koh 2013

Comparison: mAb

(CRT + cetuximab vs. CRT (no placebo))

Gp A n = 48; Gp B n = 44

Partial narrative reporting for Gp A toxicities relating to attrition rationale in abstract:

"Reason for incompletion in CDP arm included hypersensitivity (1), septic shock (1), skin rash (1), seizure (1), arterial thrombosis (1), unexplained death (1), unsatisfactory response (1), and withdrawal of informed consent (1)". No detail reported for Gp B. However, poster presented alongside abstract indicates similar frequency of Grade 3‐4 toxicities in both Gps

Neutropenia

CRT induction

Concurrent CRT

Grades 3‐4: n = 13 (27%)

Grades 3‐4: n = 5 (10%)

Grades 3‐4: n = 5 (11%)

Grades 3‐4: n = 4 (9%)

Anorexia

CRT induction

Concurrent CRT

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 6 (13%)

Grades 3‐4: n = 4 (9%)

Grades 3‐4: n = 4 (9%)

Mucositis

CRT induction

Concurrent CRT

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 9 (19%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 3 (7%)

Febrile neutropenia

CRT induction

Concurrent CRT

Grades 3‐4: n = 7 (%)

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 4 (9%)

Grades 3‐4: n = 0 (0%)

Skin toxicity

CRT induction

Concurrent CRT

Grades 3‐4: n = 3 (6%)

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 1 (2%)

Diarrhoea

CRT induction

Concurrent CRT

Grades 3‐4: n = 4 (8%)

Grades 3‐4: n = 0 (0%)

Grades 3‐4: n = 3 (7%)

Grades 3‐4: n = 0 (0%)

Reddy 2014

Comparison: mAb

CRT + nimotuzumab vs. CRT vs. RT + nimotuzumab vs. RT

(Gp A n = 23; Gp B n = 23; Gp C n = 23; Gp D n = 23)

**Note: control arm mucositis events Gp D n = 27 (+4 than Gp n), therefore, all grade mucositis data not used in analysis

Mucositis

All grades: n = 44 (96%);

Grade 3: n = 21 (46%)

All grades: n = 49 (106%)** ;

Grade 3: n = 21 (46%)

Skin reaction

All grades: n = 37 (80%);

Grade 3: n = 0 (0%)

All grades: n = 35 (76%);

Grade 3: n = 2 (4%)

Nausea/vomiting

All grades: n = 34 (74%);

Grade 3: n = 1 (2%)

All grades: n = 30 (65%);

Grade 3: n = 0 (0%)

Salivary gland disorder

All grades: n = 27 (59%);

Grade 3: n = 0 (0%)

All grades: n = 29 (63%);

Grade 3: n = 2 (4%)

Dysphagia

All grades: n = 16 (35%);

Grade 3: n = 5 (%)

All grades: n = 16 (35%);

Grade 3: n = 1 (2%)

Candidiasis

All grades: n = 13 (28%);

Grade 3: n = 5 (11%)

All grades: n = 19 (41%);

Grade 3: n = 7 (15%)

Rodriguez 2010

Comparison: mAb

RT + nimotuzumab vs. RT + placebo

(Gp A n = 54; Gp B n = 52)

Any adverse event

n = 38 (70%)

n = 30 (58%)

Mucositis

n = 11 (20%)

n = 9 (17%)

Dry mouth

n = 9 (17%)

n = 12 (23%)

Dry radio‐dermatitis

n = 6 (11%)

n = 6 (12%)

Odynophagia

n = 4 (7%)

n = 6 (12%)

CRT: chemoradiotherapy; Gp: group; mAb: monoclonal antibody; NOS: not otherwise specify; RT: radiotherapy.

Figures and Tables -
Table 8. Adverse events: monoclonal antibodies
Table 9. Adverse events: immunotherapies

Study ID

Specified adverse effect

Intervention arm

Control arm

De Stefani 2002

Comparison: interleukin

rIL‐2 + RT + surgery vs. RT + surgery (no placebo)

(Gp A n = 100; Gp B n = 101)

Narrative commentary only:

"Complication and toxicity rates for the surgery arm and the surgery plus radiotherapy arm were the same in the control group and in the rIL‐2 group.

Postoperative radiotherapy originates well‐known side effects, but they were independent of the preoperative rIL‐2 treatment. [...]

Neoadjuvant rIL‐2 injections did not complicate the surgical treatment, and adjuvant rIL‐2 injections did not increase distant side effects due to previous surgery or radiotherapy"

Mantovani 1998

Comparison: interleukin

rIL‐2 + CRT ± surgery vs. CRT ± surgery (no placebo)

(Gp A n = 14; Gp B n = 16)

Nausea/vomiting

All grades: n = 13 (93%);

Grades 3‐4: n = 1 (7%)

All grades: n = 12 (75%);

Grades 3‐4: n = 0 (0%)

Stomatitis

All grades: n = 9 (64%);

Grades 3‐4: n = 3 (21%)

All grades: n = 7 (44%);

Grades 3‐4: n = 2 (13%)

Leukopenia

All grades: n = 4 (29%);

Grades 3‐4: n = 1 (7%)

All grades: n = 8 (50%);

Grades 3‐4: n = 3 (19%)

Fever

All grades: n = 6 (43%);

Grades 3‐4: n = 0 (0%)

All grades: n = 0 (0%);

Grades 3‐4: n = 0 (0%)

Diarrhoea

All grades: n = 2 (14%);

Grades 3‐4: n = 1 (7%)

All grades: n = 3 (19%);

Grades 3‐4: n = 1 (6%)

Anaemia

All grades: n = 3 (21%);

Grades 3‐4: n = 1 (7%)

All grades: n = 2 (13%);

Grades 3‐4: n = 0 (0%)

Bier 1981

Comparison:

BCG‐CWP + surgery vs. surgery (no placebo)

(Gp A n = 12; Gp B n = 12)

Increased temperature
(> 3 to ≤ 14 days post treatment)

n = 2 (17%)

n = 3 (25%)

Moderate‐severe chills

n = 5 (42%)

n = 0 (0%)

Gastrointestinal complaints (including nausea/vomiting)

n = 2 (17%)

n = 0 (0%)

BCG‐CWP: Bacillus Calmette‐Guérin ‐ cell wall preparation; Gp: group; n: number of participants; rIL‐2: recombinant interleukin; RT: radiotherapy.

Figures and Tables -
Table 9. Adverse events: immunotherapies
Table 10. Adverse events: tyrosine kinase inhibitors

Study ID

Specified adverse effect

Intervention arm

Control arm

Gregoire 2011

Comparison: TKI

(CRT + gefitinib (250/500 mg) vs.
CRT + placebo) (concomitant phase
only: Gp A n = 110 (Gps B+C+D+E);

Gp B n = 116 (Gps A+F+G))

Mucositis

All grades: n = 96 (87%);

Grades 3‐5: n = 51 (%)

All grades: n = 98 (84%);

Grades 3‐5: n = 42 (36%)

Nausea

All grades: n = 50 (45%);

Grades 3‐5: n = 4 (4%)

All grades: n = 55 (47%);

Grades 3‐5: n = 3 (3%)

Vomiting

All grades: n = 56 (51%);

Grades 3‐5: n = 6 (5%)

All grades: n = 52 (45%);

Grades 3‐5: n = 9 (8%)

Dysphagia

All grades: n = 29 (26%);

Grades 3‐5: n = 5 (5%)

All grades: n = 43 (37%);

Grades 3‐5: n = 13 (11%)

Dry mouth (xerostomia)

All grades: n = 33 (30%);
Grades 3‐5: n = 1 (1%)

All grades: n = 30 (26%);

Grades 3‐5: n = 2 (2%)

Radiation skin injury

All grades: n = 29 (26%);

Grades 3‐4: n = 2 (2%)

All grades: n = 29 (25%);

Grades 3‐5: n = 4 (3%)

Harrington 2013

Comparison: TKI

(CRT + lapatinib vs. CRT + placebo)

Gp A n = 34; Gp B n = 33

Diarrhoea

All grades: n = 16 (46%);

Grade 3: n = 2 (6%)

All grades: n = 1 (3%);

Grade 3: n = 0 (0%)

Rash

All grades: n = 10 (29%);

Grade 3: n = 3 (9%)

All grades: n = 5 (16%);

Grade 3: n = 1 (3%)

Other skin reactions

All grades: n = 15 (43%);

Grade 3: n = 2 (6%)

All grades: n = 7 (23%);

Grade 3: n = 5 (16%)

Martins 2013
Comparison: TKI (CRT + erlotinib vs.
CRT (no placebo))

(Gp A n = 95; Gp B n = 96)

Pain

All grades: n = 50 (53%);

Grades 3‐4: n = 18 (19%)

All grades: n = 54 (56%);

Grades 3‐4: n = 18 (19%)

Gastrointestinal

Grades 3‐4: n = 46 (48%)

Grades 3‐4: n = 41 (43%)

Rash

All grades: n = 65 (68%);

Grade 3: n = 12 (13%)

All grades: n = 10 (10%);

Grade 3: n = 2 (2%)

Serious adverse events*

n = 38 (40%)

n = 32 (33%)

Haematological

Grades 3‐4: n = 15 (16%)

Grades 3‐4: n = 25 (26%)

Metabolic

Grades 3‐4: n = 7 (7%)

Grades 3‐4: n = 5 (5%)

Singh 2013

Comparison TKI

RT + gefitinib vs. RT (no placebo)

(Gp A n = 30; Gp B n = 30)

Mucositis

All grades: n = 30 (100%);

Grades 3‐4: n = 21 (70%)

All grades: n = 30 (100%);

Grades 3‐4: n = 19 (63%)

Skin reaction

All grades: n = 30 (100%);

Grades 3‐4: n = 12 (40%)

All grades: n = 30 (100%);

Grades 3‐4: n = 11 (36%)

CRT: chemoradiotherapy; Gp: group; n: number of participants; TKI: tyrosine kinase inhibitor.

Figures and Tables -
Table 10. Adverse events: tyrosine kinase inhibitors