Reduced-dose radiotherapy/chemotherapy compared to standard-dose treatment after keyhole surgery for throat cancer caused by human papillomavirus

Review question

What are the effects of reduced-dose radiotherapy/chemotherapy treatment compared to standard-dose treatment after keyhole surgery for throat cancer caused by human papillomavirus (HPV)?

Background

More than 400,000 cases of cancer of the throat are diagnosed each year and this is increasing, with HPV being a significant factor. Throat cancer caused by this virus often affects younger patients but has a better prognosis than non-viral throat cancer. Traditional treatment for throat cancer is with radiotherapy and chemotherapy as this had been shown to have similar survival outcomes to surgery but with fewer side effects. However, treatments have evolved, such as computerised planning and improvements in radiotherapy, and the development of keyhole surgery, which have the potential for fewer side effects. Chemotherapy and radiotherapy do have long-term negative effects on quality of life. With younger patients being affected, any way of reducing these side effects should be investigated.

Study characteristics

In April 2018, we searched for randomised controlled trials (RCTs) that had compared reduced-dose radiotherapy/chemotherapy treatment with standard-dose treatment. We were interested in the outcomes of overall survival and disease-free survival, as well as the effects on swallowing ability and voice. Our searches did not identify any completed RCTs, however three relevant studies are ongoing and the first results are expected between 2021 and 2023.

Key results

Currently there is no high-quality evidence comparing these two treatments, however such trials are in progress.

Authors' conclusions: 

This review highlights the current lack of high-quality randomised controlled trials studying treatment de-escalation after minimally invasive surgery in patients with HPV-positive OPSCC. However, trials that will meet the inclusion criteria for this review are in progress with results expected between 2021 and 2023.

Read the full abstract...
Background: 

More than 400,000 cases of oropharyngeal squamous cell cancer (OPSCC) are diagnosed every year worldwide and this is rising. Much of the increase has been attributed to human papillomavirus (HPV). HPV-positive OPSCC patients are often younger and have significantly improved survival relative to HPV-negative patients. Traditional management of OPSCC has been with radiotherapy with or without chemotherapy, as this was shown to have similar survival to open surgery but with significantly lower morbidity. Techniques have evolved, however, with the development of computerised planning and intensity-modulated radiotherapy, and of minimally invasive surgical techniques. Acute and late toxicities associated with chemoradiotherapy are a significant burden for OPSCC patients and with an ever-younger cohort, any strategies that could decrease treatment-associated morbidity should be investigated.

Objectives: 

To assess the effects of de-intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV-positive oropharyngeal squamous cell carcinoma.

Search strategy: 

The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 26 April 2018.

Selection criteria: 

Randomised controlled trials (RCTs) in patients with carcinoma of the oropharynx (as defined by the World Health Organization classification C09, C10). Cancers included were primary HPV-positive squamous cell tumours originating from the oropharyngeal mucosa. Tumours were classified as T1-4a with or without nodal spread and with no evidence of distant metastatic spread. The intervention was minimally invasive transoral surgery followed by de-intensified adjuvant therapy (either omission of chemotherapy or reduced-dose radiotherapy). The comparator was minimally invasive transoral surgery followed by standard concurrent chemoradiotherapy or standard-dose radiotherapy. The treatments received were of curative intent and patients had not undergone any prior intervention, other than diagnostic biopsy.

Data collection and analysis: 

We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related survival was to be studied where possible) and disease-free survival, measured at one, two, three and five years. Our secondary outcomes included assessment of swallowing ability and voice, measured at one, six, 12 and 24 months. We planned to use GRADE to assess the quality of evidence for each outcome.

Main results: 

We did not identify any completed RCTs that met our inclusion criteria. However, three eligible studies are in progress:

ADEPT is a phase III trial comparing postoperative radiotherapy with or without cisplatin in HPV-positive T1-4a OPSCC patients. Included patients must have received minimally invasive surgery and demonstrated extra-capsular spread from disease in the neck.

ECOG-E3311 is a phase II trial of treatment for HPV-positive locally advanced OPSCC (stages III-IVa + IVb without distant metastasis). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy.

PATHOS is a phase III trial of treatment for HPV-positive OPSCC (T1-3, N0-2b). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. High-risk patients are randomised to radiotherapy with or without concurrent cisplatin.

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