Elsevier

European Journal of Cancer

Volume 50, Issue 15, October 2014, Pages 2636-2648
European Journal of Cancer

Review
De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: A systematic review and meta-analysis of current clinical trials

https://doi.org/10.1016/j.ejca.2014.07.001Get rights and content

Abstract

Iatrogenic complications associated with current treatment protocols for oropharyngeal squamous cell carcinoma are noted to cause high rates of acute and chronic morbidity. The aims of this study are to provide an overview of the current de-escalation trials for human papillomavirus positive (HPV+) oropharyngeal carcinoma and to evaluate the evidence supporting improved response to treatment of patients within this viral cohort.

This study reviewed all completed or in progress randomised controlled trials (RCTs) assessing clinical interventions for human papillomavirus-associated locally advanced oropharyngeal squamous cell carcinoma. We utilised a validated ‘risk of bias’ tool to assess study quality.

We identified nine RCTs that met the full inclusion criteria for this review (all of which are currently on-going and will report from 2015 onwards). Five RCTs performed a post hoc analysis by HPV status, which allowed meta-analysis of 1130 patients. The data reveal a significant difference in overall survival (hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.35–0.69]), loco-regional failure (HR 0.43 [95% CI 0.17–1.11]) and disease specific survival (0.41 [95% 0.3–0.56]) in favour of the HPV+ category.

In considering de-escalation treatment protocols, nine studies are currently ongoing. Our meta-analysis provides strong evidence for an improved prognosis in the viral associated cohort when treated by platinum based chemotherapy in combination with radiotherapy or primary radiotherapy. So far, one trial (with moderate to high risk of bias) suggests a reduced survival outcome for the HPV+ population when using the epidermal growth factor receptor (EGFR) inhibitor cetuximab.

Introduction

Human papillomavirus (HPV) has a well described oncogenic role and epidemiological studies estimate a link to ∼5% of global cancers [1], [2]. HPV-associated oropharyngeal carcinomas are now established as a distinct biological entity, and this knowledge is significant because the associated prognosis is superior than HPV negative tumours (primarily associated with smoking or alcohol) [3], [4].

A recent meta-analysis of the published literature suggests that the proportion of oropharyngeal squamous cell carcinoma (SCC) associated with HPV has increased from 40.5% in studies recruiting before the year 2000 to 72.2% in studies reporting after 2005 [5].

The management of oropharyngeal squamous cell carcinoma (OPSCC) is dictated by the stage of the disease as well as patient and clinician preference. Early disease (T1 N0 and T2 N0) can be treated by a single modality (surgery or radiotherapy). Loco-regional advanced disease often necessitates primary chemoradiotherapy (+/− selective neck dissection) or primary surgical resection (+/− reconstruction) with postoperative chemo-radiotherapy [6].

Acute and late toxicities are both significant problems for these patients [7] and the possibility of de-escalating treatment intensity provides an opportunity to reduce morbidity from standard treatment protocols. Specifically, it has the potential to reduce gastric tube dependence, osteoradionecrosis, pain, scarring, fibrosis, dysphagia, xerostomia, dental decay, hypothyroidism, carotid stenosis and stroke. De-escalation of treatment could also lead to a reduction in second primary cancers as well as yet undetermined long-term consequences of radiation therapy that are dose dependent. Similarly, reducing the extent of surgery could decrease the risk of surgical morbidity and modifying chemotherapy ameliorates long-term neurotoxicity, nephrotoxicity and ototoxicity.

As patients with HPV-associated OPSCC are more likely to be younger and healthier, the long-term morbidity associated with current treatment will be longer lasting and have a larger social and economic impact [8], [9]. This scenario has resulted in interest in establishing safe de-escalation trials that attempt to maintain the enhanced disease free survival with HPV-associated locally advanced OPSCC while reducing acute and chronic treatment related morbidity.

At present, three main de-escalation treatment strategies are being investigated: (1) Exploring cetuximab as an alternative to cisplatin when given concurrently with radiation; (2) Reduction of radiation dose when given in combination with chemotherapy as primary treatment (guided by induction chemotherapy response) and (3) Reduction of adjuvant chemotherapy or radiotherapy dose following primary treatment with surgery (guided by histopathological features in the resected specimen).

These approaches raise many questions regarding clinical efficacy, safety, inclusion criteria of study patients and HPV diagnostic protocols. In this systematic review, we attempt to quantify the survival advantage conferred by HPV+ status, discuss the de-escalation trials currently in progress, their scientific background and suggest common goals for future therapeutic approaches.

Section snippets

Search methods

A systematic search was conducted for randomised controlled trials. No language, time period or publication status restrictions were in place. The date of the most recent search was 24th March 2014. Full details of the search and data analysis can be found in Appendix A.

Study criteria

Types of studies: Randomised controlled trials (RCTs) investigating treatments for HPV positive locally advanced (stage III/IV) OPSCC.

Types of participants: Patients with squamous cell carcinoma arising from the oropharynx

Results

Our search identified 615 references in total, which reduced to 503 after duplicate removal. Review of the titles and abstracts highlighted 40 studies as being potentially relevant. Fig. 1 shows a flow chart depicting the search history.

Nine studies met the full inclusion criteria and are currently in progress (Table 1). Five RCT studies demonstrated a post hoc analysis of HPV status allowing for a meta-analysis of available data (Table 2/Appendix B). We excluded 26 studies in total after a

Reducing toxicity by replacement of cisplatin with cetuximab

Cetuximab (and other epidermal growth factor receptor (EGFR) inhibitors) may be associated with less toxicity than cisplatin, although it remains unclear if it provides equivalent locoregional control in HPV+ OPSCC. Previous studies have suggested conflicting data in this regard [15], [16], [17], [18], [19].

Unlike cisplatin that decreases distant metastasis when given prior to or during radiation (RT), cetuximab + RT has not been shown to impact distant failure rates [15], [20]. Therefore, if the

Conclusion

The identification of the role of HPV in OPSCC presents an exciting opportunity to develop new therapeutic strategies to reduce morbidity associated with conventional treatments. There is evidence to believe that treatment de-escalation is a justifiable goal in selected HPV+ OPSCC patients; however, we recommend no change in current practice until conclusive data are available.

Our analysis would suggest that the most promising clinical trials address the concept of radiation dose reduction; the

Role of funding source

Cancer Research UK and Addenbrookes Charitable Trust provided external funding for this study. Each organisation played no role in study design; collection, analysis and interpretation of data; writing of the report or the decision to submit the article for publication.

Conflict of interest statement

None declared.

Acknowledgements

We acknowledge the very helpful contributions made by Richard Parker (Cambridge Centre for Health Services Research, University of Cambridge) for advice and guidance on statistical analysis. We also acknowledge the support of Cambridge Biomedical Research Campus.

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