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De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma

  1. Liam Masterson1,*,
  2. Daniel Moualed2,
  3. Ajmal Masood3,
  4. Raghav C Dwivedi1,
  5. Richard Benson4,
  6. Jane C Sterling5,
  7. Kirsty M Rhodes6,
  8. Holger Sudhoff7,
  9. Piyush Jani1,
  10. Peter Goon8

Editorial Group: Cochrane ENT Group

Published Online: 15 FEB 2014

Assessed as up-to-date: 25 JUN 2013

DOI: 10.1002/14651858.CD010271.pub2


How to Cite

Masterson L, Moualed D, Masood A, Dwivedi RC, Benson R, Sterling JC, Rhodes KM, Sudhoff H, Jani P, Goon P. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010271. DOI: 10.1002/14651858.CD010271.pub2.

Author Information

  1. 1

    Cambridge University Hospitals NHS Foundation Trust, ENT Department, Cambridge, UK

  2. 2

    Great Western Hospitals NHS Foundation Trust, ENT Department, Swindon, UK

  3. 3

    Norfolk and Norwich University Hospital, ENT Department, Norwich, UK

  4. 4

    Addenbrooke's Hospital, Oncology Centre, Cambridge, UK

  5. 5

    Addenbrooke's Hospital, Department of Dermatology, Cambridge, UK

  6. 6

    University of Cambridge, MRC Biostatistics Unit, Cambridge, Cambridgeshire, UK

  7. 7

    Bielefeld Academic Teaching Hospital, Department of Otolaryngology, Head and Neck Surgery, Bielefeld, Germany

  8. 8

    University of Cambridge, Department of Pathology, Cambridge, UK

*Liam Masterson, ENT Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK. lmm398@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 15 FEB 2014

SEARCH

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Argiris 2011ALLOCATION:

Not a randomised controlled trial

Chen 2013ALLOCATION:

Not a randomised controlled trial

Chera 2012ALLOCATION:

Not a randomised controlled trial

DAHANCA 5ALLOCATION:

Randomised
PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

DAHANCA 6 & 7ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

Eisbruch 2012ALLOCATION:

Not a randomised controlled trial

Fakhry 2008ALLOCATION:

Not a randomised controlled trial

Gilbert 2012ALLOCATION:

Not a randomised controlled trial

Huang 2012ALLOCATION:

Not a randomised controlled trial

Kies 2010ALLOCATION:

Not a randomised controlled trial

Le 2012ALLOCATION:

Not a randomised controlled trial

Mehrotra 2012ALLOCATION:

Not a randomised controlled trial

Merlano 2013ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples (study not yet completed)

O'Sullivan 2012ALLOCATION:

Not a randomised controlled trial

Psyrri 2011ALLOCATION:

Not a randomised controlled trial

Quon 2012ALLOCATION:

Not a randomised controlled trial

REALISTIC 2012ALLOCATION:

Not a randomised controlled trial

RTOG 0129ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

RTOG 0522ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

RTOG 9003ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

Seiwert 2011ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples (study not yet completed)

Semrau 2012ALLOCATION:

Not a randomised controlled trial

Siu 2009ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples (study not yet completed)

Snietura 2011ALLOCATION:

Not a randomised controlled trial

Takenaka 2013ALLOCATION:

Not a randomised controlled trial

TAX 324ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

Teknos 2010ALLOCATION:

Not a randomised controlled trial

Thibaudeau 2011ALLOCATION:

Not a randomised controlled trial

TROG 02.02ALLOCATION:

Randomised

PARTICIPANTS:
Patients recruited to this RCT were subjected to a post hoc analysis by investigating HPV status in pre-treatment biopsy samples

Yao 2013ALLOCATION:

Not a randomised controlled trial

 
Characteristics of ongoing studies [ordered by study ID]
Cohen 2010

Trial name or title'Selection of chemoradiotherapy based on response to induction chemotherapy - a randomised phase II study in locally advanced squamous cell carcinoma of the head and neck'

MethodsInterventional, multicentre, phase II trial, randomised, double-blind

Participants80 adult patients with local advanced stage III-IV head and neck squamous cell carcinoma. HPV status ascertained at baseline

InterventionsDrug: everolimus escalating dose
Phase I portion (2 21-day cycles): cisplatin (100 mg/m2 day 1), paclitaxel (175 mg/m2, day 1), cetuximab (400 mg/m2 loading dose day 1 then 250 mg/m2 weekly), everolimus escalating dose

Drug: everolimus or placebo
Phase II portion (2 28-day cycles): cisplatin (100 mg/m2 day 1), paclitaxel (175 mg/m2, day 1), cetuximab (400 mg/m2 loading dose day 1 then 250 mg/m2 weekly), everolimus dose determined in phase I

HPV-positive patients who have a positive response to induction chemotherapy will undergo an attenuated radiation field

OutcomesPrimary: response rates to induction chemotherapy consisting of cisplatin/paclitaxel/cetuximab +/- everolimus

Secondary: study will determine the maximum administered dose (MAD), maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and safety of everolimus with cisplatin/paclitaxel/cetuximab induction chemotherapy

Starting dateMay 2010

Contact informationDr Ezra Cohen, University of Chicago (ecohen@medicine.bsd.uchicago.edu)

NotesPrimary data collection due for completion in May 2016

De-ESCALaTE 2012

Trial name or title'Determination of epidermal growth factor receptor-inhibitor (cetuximab) versus standard chemotherapy (cisplatin) early and late toxicity events in human papillomavirus-positive oropharyngeal squamous cell carcinoma: a randomised controlled trial'

MethodsInterventional, multicentre, phase III trial, randomised, open-label

Participants1. 304 adult patients with stage III-IVa oropharyngeal squamous cell carcinoma
2. Clinical multidisciplinary team decision to treat with primary curative chemoradiotherapy
3. Medically fit Eastern Co-operative Oncology Group (ECOG) 0, 1 or 2
4. Adequate cardiovascular, haematological, renal and hepatic function
5. Using adequate contraception (male and female participants); must take contraceptive measures during and for at least 3 months after treatment

InterventionsExperimental group: cetuximab initial dose of 400 mg/m2, administered intravenously, 1 week before start of radiotherapy followed by 7 weekly doses of 250 mg/m2, administered intravenously during radiotherapy

Control group: 3 doses of cisplatin 100 mg/m2, administered intravenously, on days 1, 22 and 43 of radiotherapy

OutcomesPrimary outcome:
Early and late toxicity (grade 3-5 CTCAE 2009); time point(s): 2 years from end of treatment
Secondary outcomes:

1. Acute severe toxicity; time point(s): 3 months from end of treatment
2. Late severe toxicity; time point(s): 2 years from end of treatment
3. Quality of life; time point(s): 2 years from end of treatment
4. Dysphagia; time point(s): 2 years from end of treatment
5. Cost effectiveness; time point(s): 2 years from end of treatment
6. Overall survival, recurrence and metastasis; time point(s): 2 years from end of treatment

Starting date9 October 2012

Contact informationh.mehanna@bham.nhs.uk and m.t.fulton-lieuw@warwick.ac.uk

NotesPrimary data collection due for completion in February 2015

DFCI 2010

Trial name or title'Paclitaxel, carboplatin and cetuximab (PCC) versus cetuximab, docetaxel, cisplatin and fluorouracil (C-TPF) in previously untreated patients with locally advanced head and neck squamous cell carcinoma (HNSCC)'

MethodsInterventional, phase II RCT, dual-site, open-label

ParticipantsThe study will enrol 128 patients diagnosed with stage III-IV locally advanced HNSCC with HPV status ascertained at baseline

InterventionsPatients will be allocated to 1 of 2 induction therapy groups: paclitaxel/carboplatin/cetuximab (PCC) or cetuximab/docetaxel/cisplatin/fluorouracil (C-TPF). The groups will then undergo further randomisation to receive radiotherapy or concurrent chemoradiotherapy

OutcomesPrimary outcome: 2-year progression-free survival
Secondary outcomes: acute/late toxicity and quality of life

Starting dateThe primary data collection date is July 2015

Contact informationDr Vali A. Papadimitrakopulou (vpapadim@mdanderson.org)

NotesPrimary data collection due for completion in July 2015

ECOG 1308

Trial name or title'A phase II trial of induction chemotherapy followed by cetuximab with low dose versus standard dose IMRT in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx'

MethodsOpen-label randomised controlled trial

Participants90 adult patients diagnosed to have local advanced oropharyngeal carcinoma (stage III/IV). HPV status ascertained at baseline by both p16 immunohistochemistry and HPV16 in situ hybridisation

InterventionsExperimental group: patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1 to 2 hours once weekly for 6 weeks

OutcomesPrimary outcome: 2-year progression-free survival
Secondary outcome: toxicity, overall survival, objective response of primary tumour and nodal disease, quality of life (assessed at baseline,1, 6, 12 and 24 months after treatment)

Starting date17 March 2010

Contact informationDr Shanthi Marur, Eastern Co-operative Oncology Group (smarur1@jhmi.edu)

NotesPrimary data collection due for completion in January 2014

Quarterback 2012

Trial name or title'The Quarterback Trial: a randomized phase III clinical trial comparing reduced and standard radiation therapy doses for locally advanced HPV16 positive oropharynx cancer'

MethodsInterventional, multicentre, phase III trial, randomised, single-blinded (outcomes assessor)

Participants365 patients with stage III-IV oropharyngeal/nasopharyngeal/unknown primary SCC. HPV status ascertained at baseline by both p16 immunohistochemistry and HPV consensus PCR

InterventionsEligible, consented and registered patients will receive 3 cycles of docetaxel cisplatin and 5-FU (TPF) induction chemotherapy. After 3 cycles, the patients will be assessed for clinical, radiographic and pathological response to TPF. Patients with a clinical or radiographic complete or partial remission will be randomised in the second phase of this study, where patients will undergo a 2:1 randomisation to reduced (56 Gy) or standard (70 Gy) dose radiotherapy with weekly carboplatin and cetuximab (Erbitux) or carboplatin only, respectively. Patients not meeting the response criteria will be treated with standard-dose CRT. Patients not completing 3 cycles of TPF for reasons of toxicity, progressive disease, choice or other medical necessity will be treated with standard-dose CRT or surgery depending on their primary site and overall medical condition and will be followed for survival

OutcomesToxicity will be assessed by symptom scores, quality of life and serious adverse event monitoring. The primary endpoint of the trial is equivalent local regional control and PFS at 3 years

Starting dateSeptember 2012

Contact informationDr Marshal Posner (marshall.posner@mssm.edu)

NotesPrimary data collection due for completion in June 2019

RTOG 1016

Trial name or title'Phase III trial of radiotherapy plus cetuximab versus chemoradiotherapy in HPV-associated oropharynx cancer (RTOG-1016)'

MethodsInterventional, multicentre, phase III trial, randomised, open-label

Participants706 adult patients with early or late-stage oropharyngeal carcinoma. HPV status ascertained at baseline by both p16 immunohistochemistry and HPV16 in situ hybridisation. Patients are stratified according to T stage (T1-2 versus T 3-4), N stage (N0-2a versus N2b-3), Zubrod performance status (0 versus 1) and smoking history (≤ 10 pack-years versus > 10 pack-years). Patients are randomised to 1 of 2 treatment arms

InterventionsExperimental group: 1 week prior to radiotherapy, patients receive cetuximab IV over 2 hours (400 mg/m2). Patients then receive cetuximab IV over 1 hour once weekly (250 mg/m2) for 7 weeks. Patients undergo IMRT once daily on days 1 to 4 and twice daily on day 5 weekly for 6 weeks (70Gy 35 fractions).

Control group: patients undergo IMRT as above and also receive cisplatin (100 mg/m2) IV over 1 to 2 hours on days 1 and 22

OutcomesPrimary: 5-year overall survival

Secondary: progression-free survival, local-regional failure, distant metastasis, acute toxicities (CTCAE 2009) and overall toxicity burden at end of treatment and at 1, 3 and 6 months after completion of treatment; late toxicities at 1, 2 and 5 years

Starting dateJune 2011

Contact informationandy.trotti@moffitt.org

NotesPrimary data collection due for completion in June 2020

TROG-12.01

Trial name or title'A randomised trial of weekly cetuximab and radiation versus weekly cisplatin and radiation in good prognosis locoregionally advanced HPV-associated oropharyngeal squamous cell carcinoma (TROG12.01)'

MethodsInterventional, multicentre, phase III trial, randomised, open-label

Participants200 adult patients with locally advanced oropharyngeal carcinoma. HPV status ascertained at baseline

1. Adequate haematological, renal and hepatic function
2. ECOG performance status score of 0 to 1
3. Participants capable of childbearing are using adequate contraception and intend to continue use of contraception for at least 6 months following completion of treatment

InterventionsExperimental group: IMRT (70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly cetuximab (400 mg/m2 loading dose IV prior to radiation, followed by weekly cetuximab 250 mg/m2 for the duration of the radiotherapy)

Control group: IMRT (70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly cisplatin (40 mg/m2 IV for the duration of the radiotherapy)

OutcomesPrimary outcome: early symptom severity as measured by M.D. Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) from baseline to week 20

Secondary outcomes (time point from 2 to 5 years after treatment):

1. Clinician-assessed acute and late toxicity (CTCAE 2009)
2. Late symptom severity
3. Quality of life
4. Dysphagia
5. Cost-effectiveness
6. Overall survival, recurrence and metastasis

Starting dateMay 2013

Contact informationjanani.sivasuthan@petermac.org

NotesPrimary data collection due for completion in May 2019

 
Table 1. Description of excluded studies (non-randomised studies)

TrialDescription

Argiris 2011A prospective clinical trial without randomisation investigating serum/tissue biomarkers, which may determine the success or failure of cetuximab therapy in 16 patients with locally advanced oropharyngeal SCC. HPV status was noted at baseline

Chen 2013A case-control study evaluating the responsiveness of HPV-positive and HPV-negative oropharyngeal cancer to intensity-modulated radiotherapy (IMRT), using axial imaging obtained daily during the course of image-guided radiotherapy (IGRT). HPV status was noted at baseline

Fakhry 2008A prospective study without randomisation investigating 62 patients with locally advanced oropharyngeal SCC who were treated by induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

Gilbert 2012A prospective study without randomisation, which evaluated the tolerability and clinical efficacy of combined oxaliplatin and pemetrexed as an induction chemotherapy regimen in 27 patients with locally advanced oropharyngeal SCC. A minority of patients consented to HPV status determination by a post hoc analysis

Kies 2010A prospective trial without randomisation investigating the efficacy of combining cetuximab with chemotherapy in 41 patients with locally advanced oropharyngeal SCC. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

Le 2012A prospective study without randomisation, which investigated biomarkers in 274 patients with locally advanced oropharyngeal SCC. The patients were recruited from an existing randomised trial comparing radiotherapy/cisplatin with tirapazamine/cisplatin. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples is an ongoing phase II trial that is open-label and non-randomised). The study has so far enrolled 7 patients diagnosed as having stage III-IV primary oropharyngeal SCC with HPV status ascertained at baseline. Patients will undergo an attenuated chemoradiotherapy regimen with the first results due in September 2015

O'Sullivan 2012A prospective study without randomisation, which investigated 358 patients with locally advanced oropharyngeal SCC. The patients were recruited from an existing randomised trial comparing altered fractionation radiotherapy with chemoradiotherapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 status (a post hoc analysis from pre-treatment biopsy samples)

Psyrri 2011A prospective study without randomisation, which investigated the clinical outcomes of 38 patients with stage III-IV HNSCC. Patients were recruited from an existing phase II trial (Eastern Cooperative Oncology Group 2303) of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with weekly cetuximab. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples)

Semrau 2012A prospective study without randomisation, which investigated 52 patients with locally advanced oropharyngeal SCC. The patients received either concomitant boost (69.2 Gy) or conventionally fractionated (70 Gy) radiotherapy, with concurrent paclitaxel/carboplatin. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

Snietura 2011A prospective study without randomisation, which investigated 66 patients with oropharyngeal SCC. The purpose of the study was to analyse the influence of HPV infection on the outcome of a randomised clinical trial (p-CAIR) of conventional versus 7 days per week postoperative radiotherapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

Thibaudeau 2011A prospective cohort study of 169 patients with locally advanced oropharyngeal SCC treated with chemoradiation therapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

 HNSCC: head and neck squamous cell carcinoma
HPV: human papillomavirus
IHC: immunohistochemistry
SCC: squamous cell carcinoma
 
Table 2. Description of excluded studies (RCTs with post hoc analysis by HPV status)

TrialDescription

DAHANCA 5This double-blind, placebo-controlled study investigated the clinical outcomes of 331 patients with early and late-stage HNSCC. Participants were recruited from an existing nationwide cohort (Danish Head and Neck Cancer Group). All participants were treated by conventional radiotherapy +/- nimorazole. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples)

DAHANCA 6 & 7This trial investigated the clinical outcomes of 794 patients with early and late-stage HNSCC. Participants were recruited from an existing nationwide cohort (Danish Head and Neck Cancer Group) who were all treated by either conventional or accelerated radiotherapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples)

RTOG 0129323 patients with locally advanced oropharyngeal SCC were included in this study. The patients were recruited from an existing randomised trial comparing standard fractionation radiotherapy with accelerated fractionation radiotherapy. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples)

RTOG 0522This study investigated the concurrent use of cetuximab with cisplatin and radiation in 895 patients with locally advanced HNSCC. The study was terminated early at the third interim analysis because there was a less than 10% chance the study would be positive for the primary endpoint (only data from the experimental arm were available for analysis). Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 status (a post hoc analysis from pre-treatment biopsy samples)

RTOG 9003190 patients with locally advanced oropharyngeal SCC were included in this study. The patients were recruited from an existing randomised trial comparing 4 different radiotherapy protocols. Statistical models were used to compare the risk of death or recurrence among patients stratified by p16 IHC status (a post hoc analysis from pre-treatment biopsy samples)

TAX 324111 patients with locally advanced stage oropharyngeal SCC. The patients were recruited from an existing randomised trial (TAX 324) comparing induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

TROG 02.02185 patients with stage III-IV oropharyngeal SCC. The patients were recruited from an existing phase III randomised trial (Trans-Tasman Radiation Oncology Group 02.02) comparing concurrent radiotherapy and cisplatin with or without tirapazamine. Statistical models were used to compare the risk of death or recurrence among patients stratified by HPV status (a post hoc analysis from pre-treatment biopsy samples)

 HNSCC: head and neck squamous cell carcinoma
HPV: human papillomavirus
IHC: immunohistochemistry
SCC: squamous cell carcinoma
 
Table 3. Description of excluded studies (trials still ongoing)

TrialDescription

Chera 2012A phase I prospective trial investigating de-intensification chemoradiation protocols in 40 patients with either early or late-stage oropharyngeal SCC. HPV-positive status formed part of the inclusion criteria. The study design is not appropriate for inclusion as it was not randomised and incorporated a planned surgical intervention (neck dissection) 1 to 3 months after completion of medical therapy

Eisbruch 2012A phase II trial that is open-label and non-randomised. The study will enrol 36 patients diagnosed as having stage III-IV oropharyngeal SCC with HPV status ascertained at baseline. Patients will undergo an attenuated chemoradiotherapy regimen with the first results due in January 2021

Huang 2012A prospective study without randomisation, which analysed the temporal regression of cervical lymph nodes following primary radiotherapy or chemoradiation therapy (CRT) in 317 patients with N2-N3 oropharyngeal SCC. Statistical models will be used to compare the risk of death or recurrence among patients stratified by p16 status (a post hoc analysis from pre-treatment biopsy samples)

Mehrotra 2012A phase II trial that is open-label and non-randomised. The study has so far enrolled 2 patients diagnosed with stage III-IV primary oropharyngeal SCC with HPV status ascertained at baseline. Patients who respond to induction chemotherapy will undergo an attenuated radiotherapy dose schedule

Merlano 2013A phase III study comparing chemoradiation against induction chemotherapy followed by bioradiation (radiotherapy + cetuximab). The main outcome of the trial is overall survival and secondary endpoints are response rate, progression-free survival, role of biomolecular prognostic factors (EGFR, HPV) and toxicity. Initial results will be available in 2014. DNA PCR and p16 IHC will determine HPV status but there is no stratification on this basis (as reported by the lead author)

Quon 2012A prospective trial without randomisation evaluating de-escalation treatment in early and late-stage SCC of the oropharynx. HPV status will be established at baseline for 60 patients. Treatment is dictated by the staging of disease at presentation and will consist of de-escalated daily fractionated radiation therapy alone (63 Gy) or concurrent weekly cisplatin de-escalated chemoradiation therapy. Nodal metastases will receive 70 Gy in 35 fractions

REALISTIC 2012A phase I dose escalation trial of a Listeria monocytogenes based vaccine in patients with oropharyngeal SCC. The study is non-randomised and aims to recruit 161 patients who have recently completed standard-protocol chemoradiotherapy or surgery and have confirmed HPV16 status

Seiwert 2011Patients with locoregionally advanced head and neck cancer were treated with cetuximab, carboplatin, paclitaxel induction chemotherapy for 2 cycles. Patients were then randomised to A: cetuximab, 5-FU, hydroxyurea and hyperfractionated week-on, week-off radiotherapy (72 to 74 Gy) (CetuxFHX), or B: cetuximab, cisplatin, accelerated radiation with concomitant boost (72 Gy) (CetuxPX). Primary endpoints were 1- and 2-year progression-free and overall survival. The lead author has reported that HPV status will be determined by post hoc analysis

Siu 2009A phase III trial (NCIC-CTG) that is multicentre, randomised and open-label in design. The study will enrol 320 patients with locally advanced HNSCC who will be randomised to standard fractionation radiotherapy (70 Gy in 7 weeks) with concurrent cisplatin chemotherapy or accelerated fractionation radiotherapy (70 Gy in 6 weeks) with the molecular targeting agent panitumumab (similar in activity spectrum to cetuximab but with a reduced dermatological/allergy profile). The primary outcome will be progression-free survival. Primary data collection is due to be completed in March 2015. The lead author has reported that HPV status will be determined by post hoc analysis (p16 IHC/HPV DNA PCR)

Takenaka 2013A phase II trial that is open-label and non-randomised. The study will enrol 39 patients diagnosed to have stage III-IV oropharyngeal SCC with HPV status ascertained at baseline by PCR +/- p16 immunohistochemistry. All enrolled patients will undergo an attenuated radiotherapy treatment dose

Teknos 2010A phase I, prospective, non-randomised trial involving 38 participants with locally advanced oropharyngeal SCC. The study will investigate the side effects and optimal dose range for vorinostat when given together with cisplatin and radiation therapy. HPV status established at baseline

Yao 2013A phase II prospective trial without randomisation involving 37 participants with stage III-IV HNSCC. The study will investigate the effect of erlotinib combined with docetaxel and radiotherapy. HPV status established at baseline

 EGFR: epidermal growth factor receptor
HNSCC: head and neck squamous cell carcinoma
HPV: human papillomavirus
IHC: immunohistochemistry
PCR: polymerase chain reaction
SCC: squamous cell carcinoma