ArticlesCisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial
Introduction
Platinum-based combination chemotherapy regimens can be used to treat patients with incurable locoregionally recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN).1 Although these regimens lead to tumour responses in about 10–35% of patients, median survival is less than 1 year and the effects on patients' quality of life are unknown.2, 3, 4, 5, 6
Dysregulation of the EGFR signalling pathway plays a part in the development and progression of SCCHN.7, 8 Clinical trials6, 9 have shown that addition of anti-EGFR monoclonal antibodies to chemotherapy improves clinical outcomes in patients with recurrent or metastatic SCCHN. In a randomised phase 3 study in the USA,6 more patients in the group given cisplatin plus cetuximab responded than in the group receiving cisplatin plus placebo; and in a randomised phase 3 study (EXTREME) in Europe,9 addition of cetuximab to cisplatin and fluorouracil or to carboplatin and fluorouracil improved overall survival.
Human papillomavirus (HPV) DNA has been detected in up to two-thirds of oropharyngeal SCCHN tumours in patients presenting with locoregionally advanced disease.10, 11 Patients with locoregionally advanced HPV-positive oropharyngeal SCCHN who are treated with radiotherapy with or without chemotherapy have a better outlook than do HPV-negative patients.11, 12, 13, 14, 15, 16 However, the global prevalence and prognostic effect of HPV in patients with recurrent or metastatic SCCHN arising from the oropharynx, oral cavity, larynx, and hypopharynx is not well understood, particularly in the clinical trial setting. HPV-positive and HPV-negative SCCHN tumours differ in terms of biology, histology, genetic alterations, and prognosis.11, 13, 17, 18 HPV-positive SCCHN tumours are characterised by the presence of high-risk HPV DNA (most commonly HPV 16) and the coexpression of the viral oncoproteins E6 and E7, which modulate expression of key cellular proteins (such as the tumour suppressor p53 and retinoblastoma tumour-suppressor protein), leading to upregulated expression of the cyclin-dependent kinase inhibitor p16-INK4A (henceforth, p16).10, 18, 19 How HPV status affects the outlook of patients with recurrent or metastatic disease, or their response to treatment, is unknown. Some studies20, 21, 22, 23, 24 have suggested interactions between HPV and the EGFR signalling pathway. Therefore, HPV status (as assessed by p16 immunohistochemistry of formalin-fixed paraffin-embedded samples) might affect outcomes during anti-EGFR treatment.
Panitumumab is a fully human anti-EGFR monoclonal antibody that is used both as a single agent and combined with chemotherapy for treatment of metastatic colorectal cancer.25 Preclinical data for SCCHN cell lines and xenografts showed more antitumour activity with panitumumab plus radiotherapy than with radiotherapy alone,26 and phase 1 response data for panitumumab plus chemoradiotherapy have suggested that additional investigation of panitumumab in SCCHN is warranted.27 In the Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer (SPECTRUM), we compared panitumumab plus cisplatin and fluorouracil with chemotherapy alone as first-line treatment for recurrent or metastatic SCCHN. Additionally, we investigated the relative effect of treatment with panitumumab combined with chemotherapy in patients with recurrent or metastatic SCCHN who do (p16 positive) or do not (p16 negative) express p16.
Section snippets
Study design and participants
This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients who had received primary
Results
Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients to the two treatment groups (figure 1). Baseline characteristics were similar in the two groups (table 1). Seven patients did not receive treatment (figure 1); 325 patients in each group received at least one dose of panitumumab or chemotherapy and were included in safety analyses.
Of the 327 patients assigned to the panitumumab group, all discontinued chemotherapy (reasons given for discontinuation of each component;
Discussion
SPECTRUM was a global study of a geographically diverse population of patients with wide variation in previous treatment. The results show that the addition of panitumumab to a regimen of cisplatin and fluorouracil does not significantly improve overall survival of patients with recurrent or metastatic SCCHN. By contrast, both progression-free survival and frequency of objective response were significantly improved by the addition of panitumumab, confirming its antitumour activity in SCCHN.
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