Phase III Trial of PET/CT vs. CTSurveilance for Head and Neck Cancer
Phase III Trial of PET/CT vs. CTSurveilance for Head and Neck Cancer
The null hypothesis is that patients screened by PET/CT will not have detection of disease
 recurrence any earlier than those screened by CT alone. The alternative hypothesis is that
 PET/CT surveillance will lead to detection of disease recurrence 3 months earlier than CT
 surveillance. Furthermore, to reject the null hypothesis, earlier detection must be
 associated with a cause-specific survival improvement of 10%. Primary endpoints will include
 time from the completion of definitive therapy to diagnosis of recurrent disease, and
 absolute survival within 3 years after completion of initial therapy. Duration of survival
 between diagnosis of recurrence and subsequent death will not be a primary endpoint because
 the investigators expect that PET/CT will offer an opportunity for earlier recognition of
 recurrence and be subject to lead-time bias. Duration of survival will be measured from
 completion of primary treatment until death. Note: the presence of residual disease at
 surgical consolidation does not constitute a recurrence event.
Head and neck cancer (HNC) is the sixth leading incident cancer worldwide with 600,000 cases
 expected in 2012.1 The vast majority of cases are head and neck squamous cell carcinoma
 (HNSCC), comprising > 90% of histologies. Despite advances in multimodality therapy for
 HNSCC, 5-year overall survival (OS) is 40-60%, and has increased only incrementally in the
 past two decades.2 Improved prognosis is largely attributable to the emerging epidemic of
 oral human papillomavirus infection (HPV). An increasing proportion of oropharyngeal HNC is
 driven by oncogenic HPV, rather than the classic risk factors of tobacco and alcohol; HPV
 etiology is associated with improved survival after conventional treatments.3,4 Most patients
 with HNC present with locally advanced disease (stage III-IVb), and have associated anatomic
 deformity due to the primary tumor or neck adenopathy. Intensive multi-modality therapy
 including surgery, chemotherapy, and radiotherapy is routinely required. The current standard
 of care for primary nonsurgical management of previously untreated locally advanced (PULA)
 HNSCC is concurrent cisplatin-radiotherapy (RT), as administered in the sentinel Intergroup
 trial 0126 5,6. Likewise, the standard of care in the adjuvant management of high risk
 disease is cisplatin-RT as proven in the Radiation Therapy Oncology Group (RTOG) 95-01 and
 European Organization for Research and Treatment of Cancer (EORTC) 22931 trials.7,8 Despite
 curative-intent surgical or non-surgical therapy, approximately half of people will relapse.
 Unlike most other epithelial malignancies, the dominant pattern of relapse and the driver of
 HNC-related mortality is locoregional recurrence.9 The vast majority of recurrences occur
 within the first two years following definitive therapy.

 Patient evaluation following completion of definitive therapy for HNC is confounded by
 anatomic deformity which began with the primary tumor and nodal metastatic disease, and is
 further compounded by treatment-related effects such as scarring, flap reconstruction, and
 edema. There currently does not exist an ideal method for surveillance. National
 Comprehensive Cancer Center Network (NCCN) guidelines call for physical examination and
 intermittent imaging as required. Clinical trial designs incorporating definitive
 chemoradiotherapy typically employ a diagnostic, contrast-enhanced CT of the neck every 3
 months for 1 year, followed by every 6 months for 1 year, followed by annual evaluations (eg.
 ECOG 1308; UPCI 07-021). Single-arm prospective studies have suggested that positron emission
 tomography (PET) with fluorodeoxyglucose (FDG) is more sensitive than CT or physical
 examination alone for residual or recurrent disease, particularly when conducted with
 integrated diagnostic CT scan. In these studies, negative PET/CT scans correlated with lower
 likelihood of residual nodal pathology and improved DFS.12,13 The current practice at the
 University of Pittsburgh is to employ PET/CT surveillance, in particular following definitive
 chemoradiotherapy. However, prior investigations have not demonstrated improved salvage or
 survival outcomes with use of PET/CT surveillance, which is clearly more costly than CT
 surveillance and may carry morbidity related to increased diagnostic procedures for
 false-positive findings.

 The investigators propose a prospective, randomized phase III trial in patients undergoing
 definitive therapy for locally advanced Stage III-IVb carcinoma involving the head and neck.
 This includes primary tumors of the oral cavity, pharynx, and larynx, as well as cancer of
 the salivary glands and squamous cell carcinoma of the skin. Patients who have realized a
 clinical complete response to definitive therapy will be randomized to PET/CT vs. CT
 surveillance, to test the hypothesis that PET/CT surveillance is superior to CT surveillance
 due to earlier diagnosis of recurrence, more timely and effective salvage, and consequent
 reduction in HNC mortality. The study intervention will solely be the imaging modality
 assigned for surveillance. All study patients will otherwise be monitored strictly according
 to NCCN guidelines, including history and physical examination (and endoscopy where
 appropriate). Assigned imaging will be conducted at identical intervals. Areas suspicious for
 recurrence on the basis of history and physical examination, endoscopy or imaging will be
 biopsied. Therapeutic interventions will be determined by the treatment team, which will
 include at least one member from medical oncology, radiation oncology, and
 otolaryngology/head and neck surgery. Patients with recurrent locoregional disease will be
 offered salvage treatment as indicated by the clinical situation.
Inclusion Criteria:

 -  Histopathologically confirmed carcinoma arising in the head and neck. Histologies may
 include squamous cell carcinoma, poorly differentiated carcinoma, carcinoma NOS,
 basaloid carcinoma, or salivary gland carcinoma (including mucoepidermoid carcinoma,
 salivary duct carcinoma, adenocarcinoma, and adenoid cystic carcinoma).

 2. Primary site of origin must be one of the following: a) the oral cavity, pharynx,
 or larynx; b) major or minor salivary gland; c) skin; d) unknown primary site is
 acceptable in patients with squamous cell carcinoma metastatic to cervical lymph
 nodes.

 3. Stage III-IVb based upon AJCC 7th edition staging criteria. 4. Serum creatinine ≤
 1.5 mg/dL (most recent within the last three months) 5. The treating multidisciplinary
 team agrees that the patient has no evidence of disease (NED) after definitive
 therapy.

 1. Patients who have undergone primary surgery with R0 or R1 resection are eligible
 to enter the protocol for 6 weeks after the date of definitive surgery. Note:
 Patients treated with primary surgery will undergo first study surveillance 3
 months (+/- 30 days) after the date of definitive surgery.

 2. Patients who have undergone primary radiotherapy (including chemoradiotherapy)
 must have completed first response assessment 6-14 weeks after completion of
 radiotherapy. To be eligible, patients must be determined by the
 multidisciplinary team to without clear evidence of residual disease, without
 need of surgical consolidation, and appropriate to enter surveillance. Such
 patients are eligible to enter the surveillance protocol for 6 weeks after the
 date of first response assessment. Patients requiring surgical consolidation of
 the primary site and/or neck are eligible following the consolidative surgery,
 provided benign findings or negative margins were attained. Such patients are
 eligible to enter the surveillance protocol for 6 weeks after the date of
 consolidative surgery.

 Note: Patients treated with primary radiotherapy will undergo first study
 surveillance 6 months (+/-30 days) after completing radiotherapy.

 6. In the case of oropharyngeal primary squamous cell carcinomas, HPV status must
 be classified per standard of care. HPV(+) disease will be those cases which
 demonstrate diffuse nuclear and cytoplasmic staining in ≥ 70% tumor cells by p16
 immunohistochemistry (IHC).

 7. Age ≥ 18 years 8. Able to provide written, informed consent 9. ECOG
 Performance Status 0-2

 Exclusion Criteria:

 -  Severe allergy to iodinated contrast, despite appropriate premedications 2. Presence
 of gross residual disease after surgical resection 3. Serum creatinine > 1.5 mg/dL 4.
 Who Type II or III non-keratinizing squamous cell carcinoma of the nasopharynx