By Dr Benjamin Chua.
The incidence of locally advanced oropharyngeal squamous cell carcinoma (OPSCC) has increased in the last two decades in the Western world, largely due to the influence of human papilloma virus (HPV) infection.
Associated with this has been a shift in the demographics of patients affected, a dramatic improvement in prognosis and a change in focus of treatment and clinical trials towards achieving complication-free survivorship. Lessons from changing treatment paradigms of OPSCC are relevant for all oncologists.
In the past 2 decades radical surgery has played a limited role in treatment of OPSCC due to the proximity of tumour to structures critical for speech and swallowing, and the attendant challenges in achieving adequate margins, reconstruction and rehabilitation. Definitive radiotherapy (RT) is a key modality in the organ-preserving approach, aiming to eradicate the tumour while maintaining structure and function. The aim of this commentary is to review developments in RT and concurrent systemic therapy, to elucidate the changing biology of the disease, particularly with regard to HPV, and to outline current experimental approaches aiming to improve the therapeutic ratio.
Prior to the recognition of HPV as a causative agent of OPSCC, rates of locoregional cure with RT alone were around 50% for stage III-IV disease, hence a number of collaborative clinical trials in Australia and overseas were initiated in the 1990’s which explored intensification of treatment. There is now high-level evidence for use of altered fractionation schedules (1) and concurrent chemoradiotherapy (2) to improve locoregional control and survival in patients with locally advanced head & neck cancer. These intensified regimens have made their way into routine clinical practice, however with a significant acute and long-term toxicity burden for these patients. For example, the addition of concurrent platinum-based chemotherapy is estimated to result in a 300% increase in the burden of acute toxicity compared to RT alone (3), rising up to 500% when both altered fractionation and chemotherapy are combined. In a meta-analysis of three major phase III chemoRT studies, the rate of late severe pharyngeal dysfunction was 27%, with a 13% rate of long-term feeding tube dependence (4).
Improvements in staging, and treatment, such as PET-CT and intensity-modulated radiotherapy (IMRT), respectively, have improved the therapeutic ratio for most patients by allowing better localisation of disease and sparing of normal tissues. However there remain a proportion of patients who suffer significant late toxicity and for whom rehabilitation to premorbid function is challenging or impossible. At the same time organ-preserving treatment was being intensified, changes in the aetiology and demographic of OPSCC were taking place which have today permanently altered our perspective of this disease. In developed countries, numerous epidemiological studies have reported a dramatic increase in the rate of OPSCC compared to other head & neck subsites, driven by increased incidence of HPV infection (5).
HPV-associated OPSCC are now considered a distinct clinical entity, which tends to occur in younger patients with fewer co-morbidities, and associated with sexual behaviour (in particular, oral sex) and marijuana smoking rather than traditional risk factors such as tobacco smoking, alcohol intake and poor dentition (6).
Additionally, HPV-associated disease tends to present at a locally advanced stage with small primary tumour but early nodal spread, sometimes with characteristic cystic lymphadenopathy (figure 1). There is now ample evidence that patients with HPV-associated OPSCC benefit from superior locoregional control and survival after both surgery (7) and non-surgical treatment (8), indicating a greater sensitivity to therapy than non-HPV associated disease.
At present, however, patients with locally advanced OPSCC are treated in an identical fashion regardless of HPV status, in most cases receiving intensified approaches of altered fractionation or chemoRT. However, for some patients with HPV-associated OPSCC, such therapy probably represents overtreatment, causing greater toxicity than necessary in order to incrementally improve potentially already high rates of locoregional control and cure. In the area of HPV-associated OPSCC research, the focus is now firmly on treatment de-escalation rather than ongoing intensification, aiming to safely reduce toxicity without compromising hard-won gains in locoregional control.
Given the established efficacy of modern chemoRT in OPSCC, there is some reluctance to simply reduce current doses of definitive RT or chemotherapy. Instead, current studies of de-intensification have taken more novel approaches of using biological therapies, or employing novel combinations of systemic agents and surgery with RT.
Targeted therapies, in particular EGFR inhibitors such as cetuximab, are an attractive option for concurrent treatment because they increase locoregional control compared to RT alone, without a concomitant increase in in-field toxicity (9, 10). A large randomised trial in the United States which has recently closed after rapid accrual, compared the efficacy of concurrent cetuximab with weekly concurrent cisplatin for patients with HPV-associated OPSCC. A similar trial is being conducted in Australia led by the Trans-Tasman Radiation Oncology Group (TROG, 12.01), but with the endpoint being patient-reported outcomes of symptom severity and quality of life rather than efficacy. These complementary studies, when reported, may be practice-changing in supporting the routine use of concurrent biologic therapy as comparably effective and less toxic than concurrent cisplatin.
Another active area of research in HPV-associated disease is the use of induction chemotherapy as a means to stratify patients who may be eligible for de-intensified treatment depending on response; patients who are more sensitive to initial chemotherapy may benefit from de-escalation of subsequent RT. The current phase II ECOG 1308 study treats patients with HPV-positive OPSCC with upfront paclitaxel, cetuximab and cisplatin, followed by concurrent RT with concurrent cetuximab. The RT dose varies depending on response to induction chemotherapy with complete responders receiving a reduced dose compared to established regimens.
Surgical approaches to OPSCC have also evolved in the last 20 years. Trans-oral laser microsurgery and robotic-assisted endoscopic surgery are now feasible in a number of patients who would have previously required highly morbid open operations. By employing upfront surgery, patients have the benefit of being risk-stratified by pathology, with adjuvant treatment limited to patients with pathologic risk factors for locoregional recurrence. To explore this issue, two collaborative trials incorporating surgery into the organ-preserving approach for patients with HPV-associated OPSCC are underway in the United States. ECOG 3311 employs upfront transoral resection, with RT omitted in patients with pathologic low-risk disease (T1-2N0-1, negative margins). Patients with intermediate risk features are randomised into two different dose levels of adjuvant RT with concurrent cetuximab. The randomised phase II study RTOG 1221 takes a different approach, directly randomising patients to standard chemoRT, or upfront surgery followed by a risk-adapted approach to adjuvant radiotherapy depending on pathological findings.
While de-escalation based on HPV status is not yet in routine clinical practice, the level of interest and large number of patients enrolled on collaborative trials worldwide is highly encouraging. The focus has shifted from increasing locoregional control towards reducing acute and late toxicity for these patients who are often younger, with fewer competing co-morbidities and keen to return to premorbid function. Until data from current trials emerge, the temptation to de-escalate outside the context of a clinical trial should be resisted.
Dr Benjamin Chua (Benjamin.Chua@health.qld.gov.au) is a Radiation Oncology Fellow at the Princess Alexandra Hospital in Brisbane.
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