RTOG 0920: A Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-advanced Resected Head and Neck Cancer

Official Title

RTOG 0920: A Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-advanced Resected Head and Neck Cancer

Summary:

The adjuvant management of completely resected SCCHN is somewhat more controversial. In general, postoperative radiotherapy (PORT) is a standard of care for most stage III/IV and selected stage II resected cases. In the last several years, several high-profile randomized trials have shown that the addition of concurrent chemotherapy to PORT improves outcomes for selected patients. The RTOG led a North American Intergroup trial comparing standard PORT with or without three cycles of high dose concurrent cisplatin. The patient population consisted of individuals who underwent complete resection but had positive resection margins at the primary tumour site, multiple pathologically positive lymph nodes in the neck, or one or more lymph nodes in the neck with extracapsular extension. This study showed the chemo radiotherapy had significantly improved local-regional control (LRC) and disease-free survival (DFS) but not overall survival, compared with PORT alone. The EORTC performed a very similar study of PORT +/- chemotherapy, showing that chemo radiotherapy improved overall survival in addition to LRC and DFS (Bernier 2004).

Bernier, et al. (2005) subsequently performed a meta-analysis of the RTOG and EORTC trials. In this exploratory analysis, the primary subgroups of patients who benefited significantly from the addition of chemotherapy were those with positive resection margins and/or nodal extracapsular extension. Other patients did not have a significant benefit from high dose concurrent cisplatin. Specifically in RTOG 95-01, this refers to patients with multiple positive nodes (pN2) without extracapsular spread (ECS). In the EORTC study, this refers to a potpourri of patients, including: pathologic T3-4, N0 cancers (except T3, N0 larynx cancer), perineural and/or vascular invasion irrespective of T-stage, or oral/oropharynx cancer with lymph node involvement at Level IV or V. The failure of cisplatin to significantly improve survival or other clinical outcomes does not, however, mean that these patients have a very good or excellent prognosis. As shown below in Table 1, multiple series of data report a rate of local-regional failure between 15 and 35% for these patients, despite adjuvant RT. Most patients who suffer local-regional failure cannot be salvaged with additional anti-cancer treatment and proceed to die from their cancer. The exact rate of local-regional failure probably depends upon multiple factors, including the number of clinical risk factors present (as described by the University of Florida), treatment related factors (such as the quality of surgery and/or RT, as well as the amount of time required to deliver treatment), and currently poorly understood biological/molecular features of patients' tumours. These complex factors make it very difficult to compare one study to another, particularly retrospective experiences harvested at different institutions over several decades. A relatively large prospective trial would thus provide valuable information to help physicians and patients more precisely identify the risk factors for local-regional recurrence (and other clinical outcomes) after surgery + RT.

Trial Description

Primary Objective

  • Test whether the addition of cetuximab to radiation therapy will improve overall survival (OS) in postoperative patients with intermediate risk following surgery

Secondary Objectives

  • Assess the impact of the addition of cetuximab to postoperative radiation therapy on the following:
  • Disease-free survival (DFS);
  • Acute dysphagia, dry mouth, skin toxicity, and other toxicities (CTEP's Active Version CTCAE) and their relationships to patient-reported outcomes at 3 months;
  • Late dysphagia, dry mouth, skin toxicity, and other toxicities (Active Version CTCAE) and their relationships to patient-reported outcomes at 12 and 24 months.
  • Tumou analysis of EGFR, specifically extent of EGFR over expression by immunohistochemical (IHC) and FISH analysis, EGFRvIII expression, as well as association of these assay data with OS and DFS;
  • Tumor analysis of HPV infection (as defined by in situ hybridization), specifically, within the cohort of patients with oropharynx cancer, to perform an exploratory analysis of the impact of HPV on DFS and OS in this patient subset;
  • Tumour DNA analyses of TP53 mutations for response prediction to cetuximab and prognosis;
  • Germline DNA analyses of polymorphic variants in EGFR intron repeat for response prediction to cetuximab.

Tertiary Objectives (Exploratory)

  • Assess the impact of the addition of cetuximab to postoperative radiation therapy on the following:
  • Local-regional control;
  • Patient-reported quality of life (QOL), swallowing, xerostomia, and skin toxicity based on head and neck specific instruments, including: the Performance Status Scale for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), and the Dermatology Life Quality Index (DLQI);
  • Cost-utility analysis using the EuroQol (EQ-5D).
  • To evaluate the utility of IGRT as a means of enhancing the efficacy (i.e., local-regional control) of IMRT while reducing the acute and/or late toxicity (particularly xerostomia) and improving patient-reported outcomes (particularly scores with the XeQOLS);
  • To retrospectively compare the local regional control rate for patients treated with IMRT alone (no IGRT or cetuximab) with similar patients treated with external beam radiation alone in the postoperative trial, RTOG 95-01.

Patient Population:

Pathologically proven diagnosis of squamous cell carcinoma (including variants such as verrucous carcinoma, spindle cell carcinoma, carcinoma NOS, etc.) of the head/neck (oral cavity, oropharynx or larynx); clinical stage T2-3, N0-2, M0 or T1, N1-2, M0.

View this trial on ClinicalTrials.gov

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Resources

Canadian Cancer Society

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