Patients with HPV-positive oropharynx cancer should receive chemoradiation

Munich, Germany, 22 October 2018 - Patients with human papilloma virus (HPV)-positive throat cancer should receive chemoradiotherapy rather than cetuximab with radiotherapy, according to late-breaking research reported at the ESMO 2018 Congress in Munich. (1)

"Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused less side effects but there has been no head-to-head comparison of the two treatments," said study author Prof Hisham Mehanna, Chair, Head and Neck Surgery, Institute of Cancer and Genomic Sciences, University of Birmingham, UK.

Throat cancer is rapidly becoming more common in Western countries. For example in the UK, incidence was unchanged in 1970 to 1995, then doubled in 1996 to 2006, and doubled again in 2006 to 2010.The rise has been attributed to HPV, a sexually transmitted infection. Most throat cancer was previously caused by smoking and alcohol and affected 65-70 year-old working class men. Today HPV is the main cause and patients are around 55, middle class, working, and have young children.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30-40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate chemotherapy, for example because of poor kidney function or older age, receive cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, and radiotherapy.

This study compared side effects and survival with the two treatments in 334 patients with HPV-positive throat cancer enrolled from 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

During the two-year study there were ten recurrences and six deaths with cisplatin compared to 29 recurrences and 20 deaths with cetuximab. Patients on cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%; p=0.001, hazard ratio [HR] 4.99, 95% confidence interval [CI] 1.70-14.67). Cancer was over three times more likely to recur in two years with cetuximab compared to cisplatin, with recurrence rates of 16.1% versus 6.0%, respectively (p=0.0007, HR 3.39, 95% CI 1.61-7.19).

There were no differences between groups in the overall number of side effects, or of acute or late severe (grade 3-5) toxic events including dry mouth and difficulty swallowing. There were significantly more serious adverse events such as renal and haematological problems with cisplatin than with cetuximab.

Mehanna said: "Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise - we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible."

Commenting on the study for ESMO, Dr Branislav Bystricky, Head, Medical and Radiation Oncology Department, University Hospital Trencin, Slovakia, said: "It was believed that cetuximab causes less side effects and was therefore a good option for HPV-positive throat cancer patients who are young and expected to survive for several decades, as well as those less able to tolerate chemotherapy. This study shows that the best treatment choice for patients with HPV-positive throat cancer is cisplatin and radiotherapy. This combination gives 'double' the benefit since it is more effective in terms of survival and does not worsen all grade toxicity compared to cetuximab with radiotherapy."

Bystricky noted that the results were in agreement with interim findings of the US National Cancer Institute's RTOG 1016 trial, which is scheduled to report this month.(2) He said: "We now have two studies showing that these patients should not be given cetuximab. Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy."

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References

1. Abstract LBA9_PR 'Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy' will be presented by Hisham Mehanna during the Presidential Symposium 3 on Monday, 22 October, 16:30 to 18:00 (CEST) in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
2. Full results presented at the plenary session at the American Society for Radiation Oncology (ASTRO) annual meeting on 22 October: https://www.astro.org/Meetings-and-Education/Live-Meetings/2018/2018-Annual-Meeting

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LBA9_PR - Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy

H. Mehanna1, A. Kong1, A. Hartley2, P. Mistry3, M. Dalby3, T. Fulton-Lieuw1, M. Robinson4, A. Gray5, B. Foran6, M. Sen7, L. O'Toole8, K. Dyker9, H. Al Booz10, R. Moleron11, S. Brennan12, E. Aynsley13, A. Chan14, D. Srinivasan15, J. Buter16, J. Dunn3

1Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK, 2Oncology, Queen Elizabeth Hospital Birmingham, Birmingham, UK, 3Warwick Clinical Trials Unit, University of Warwick, Coventry, UK, 4Centre for Oral Health Research, Newcastle University, Newcastle-upon-Tyne, UK, 5Department of Population Health, University of Oxford, Oxford, UK, 6Oncology, Weston Park Hospital, Sheffield, UK, 7Oncology, St James's Institute of Oncology, Leeds, UK, 8Oncology, Castle Hill Hospital, Cottingham, UK, 9Oncology, Bradford Institute for Health Research, Bradford, UK, 10Oncology, Bristol Haematology and Oncology Centre, Bristol, UK, 11Oncology, NHS Grampian, Aberdeen, UK, 12Radiation Oncology, Saint Luke's Radiation Oncology Network, Dublin, Ireland, 13Oncology, South Tees Hospitals, Middlesborough, UK, 14Oncology, University Hospitals Coventry & Warwickshire, Coventry, UK, 15Oncology, Western General Hospital, Edinburgh, UK, 16Medical Oncology, VU University Medical Center, Amsterdam, Netherlands

Background: The incidence of Human papillomavirus-positive oropharyngeal cancer (HPV+OPSCC) is rapidly rising. It is a distinct disease entity, affecting younger patients, with much better outcomes. However, standard treatment (cisplatin+radiotherapy) causes significant toxicity, which these young patients have to endure for decades. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation to reduce toxicity of standard (cisplatin) treatment, but no randomised trials exist.

Methods: In this international, multi-centre, randomised, controlled trial, patients with low-risk HPV+OPSCC were randomised to receive radiotherapy (70G in 35F) and either cisplatin (3 doses of 100 mg/m2) or cetuximab (400 mg/m2 loading dose followed by weekly 250 mg/m2). Outcomes were total number of severe (Grades 3-5) toxicity events, overall survival, and quality of life.

Results: We recruited 334 patients (166 in cisplatin arm and 168 in cetuximab arm) between November 2012 through October 2016 at 32 head and neck treatment centres in 3 countries: UK, Ireland and the Netherlands. Of patients randomised, 80% are male, mean age 57 years. The arms were well balanced. There were 10 recurrences and 6 deaths in cisplatin arm, compared to 29 recurrences and 20 deaths in cetuximab arm. There was a significant difference in the 2-year overall survival between cisplatin and cetuximab (97.5% vs 89.4% respectively, p=0.001, HR=4.99, 95% CI 1.70-14.67) and in 2-year recurrence rate (6.0% vs 16.1% respectively, p=0.0007, HR=3.39, 95% CI 1.61-7.19). There were no differences between the cisplatin and cetuximab arms in the reported mean number of overall (5.37 vs 5.45 events per patient respectively), acute or late severe (grade 3-5) toxicity events per patient or all grade toxicity (overall 29.15 vs 30.05 event per patients respectively). There were significantly more serious adverse events (162 vs 95) in the cisplatin arm compared to the cetuximab arm.

Conclusions: There was significant detriment from the use of cetuximab instead of cisplatin in terms of tumour control, and no benefit in terms of reduced toxicity. Cisplatin and radiotherapy remains the standard of care in this setting.

Clinical trial identification: ISRCTN33522080

Legal entity responsible for the study: University of Warwick

Funding: Cancer Research UK

Disclosure: H. Mehanna: Honoraria: AstraZeneca. Speakers' Bureau: MSD, Sanofi Pasteur, Merck. Research Funding: GSK Biologicals, MSD, Sanofi Pasteur, Silence Therapeutics, GSK Plc, AZ. Travel Accommodation Expenses: Sanofi Pasteur, MSD, Merck.

A. Kong: I have received research grants from PUMA and AstraZeneca. I have received payments as a speaker, consultant or in an advisory role for the following companies: PUMA, Merck, BMS, MSD and Avvinity Therapeutics Limited.

M. Robinson: Consultancy for Leica Biosystems.

B. Foran: I have received payments from MSD and Merck for speaker engagements.

L. O'Toole: Merck sponsored my trip to ICHNO 2015.

R. Moleron: I hereby declare the receipt of consultation fees from Bristol-Myers-Squibb and MSD.

All other authors have declared no conflicts of interest.

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