Miriam N. Lango

Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting

Purpose: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. Experimental Design: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. Results: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. Conclusions: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

Impact of neck dissection on long-term feeding tube dependence in patients with head and neck cancer treated with primary radiation or chemoradiation.

The impact of posttreatment neck dissection on prolonged feeding tube dependence in patients with head and neck squamous cell cancer (HNSCC) treated with primary radiation or chemoradiation remains unknown.

p16 status, pathologic and clinical characteristics, biomolecular signature, and long‐term outcomes in head and neck squamous cell carcinomas of unknown primary

The purpose of this study was to report associations between p16 status, clinicopathologic characteristics, and outcomes for head and neck squamous cell carcinoma of unknown primary (CUP).

Controversies in Surgical Management of the Node-Positive Neck After Chemoradiation

The addition of chemotherapy to radiation in the treatment of advanced-staged head and neck cancer has improved local-regional control and increased complete clinical and pathologic response rates in the neck. However, for those patients with residual neck disease on a posttreatment computed tomography (CT) scan, there remains significant controversy as to how to further assess the neck for the presence of a viable tumor and when to perform a neck dissection. Recently, investigators from Australia have assembled level I evidence to support the use of positron-emission tomography (PET) scanning to assess treatment response and have shown a very high negative predictive value for patients with a negative PET at 12 weeks after the completion of therapy. These data support the practice of observing PET-negative necks and intervening with neck dissection in PET-positive necks. However, not all investigators, practitioners, and patients are comfortable with delaying intervention for such a long time interval after treatment. The authors favor assessment of the neck with a CT scan at 6 weeks after the completion of chemoradiotherapy and recommend neck dissection for patients with radiographic residual disease at this time point. One rationale is that 6 weeks is an optimal window for operative intervention after acute treatment effects have subsided and before extensive fibrosis and scarring, which translates to less morbidity for the patient who is treated surgically. Another rationale is that those who develop regional recurrence can be hard to salvage surgically, and waiting an additional 6 weeks could allow for the expansion of resistant clones. The significance of this is unclear, however, because patients with residual disease are at a higher risk for local and distant as well as regional failure. Thus, further prospective studies of the role of postchemoradiotherapy PET scanning and neck dissection are needed.

Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis.

For patients with head and neck cancer who were treated using primary radiotherapeutic approaches, the pattern of pathologic residual carcinoma in the neck dissection specimen and its effect on clinical outcome remains unknown.

Initial results of a Phase I dose-escalation trial of concurrent and maintenance erlotinib and reirradiation for recurrent and new primary head-and-neck cancer.

PURPOSE To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). METHODS AND MATERIALS Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. RESULTS Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. CONCLUSIONS Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.

Multimodal Treatment for Head and Neck Cancer

Head and neck cancers are relatively less common tumors, but with complex anatomic and physiologic relationships to the structures from which they arise. Multimodal management is required for advanced stage disease, while single modality treatment is usually sufficient for early lesions. Treatment paradigms have shifted toward more functional preservation of speech and swallowing, when possible. Increased use of radiation, systemic/targeted therapies and function-preserving surgical approaches have allowed for organ preservation without compromising oncologic outcomes in properly selected patients.

Quantification of excision repair cross-complementing group 1 and survival in p16-negative squamous cell head and neck cancers.

Purpose: Multimodality treatment of squamous cell carcinoma of the head and neck (SCCHN) often involves radiotherapy and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined excision repair cross-complementing group 1 (ERCC1) expression in human papillomavirus (HPV)-negative SCCHN treated with surgery [±adjuvant radiotherapy/chemoradiation (CRT)]. Experimental Design: We assessed ERCC1 protein expression in archival tumors using immunofluorescence staining and automatic quantitative analysis (AQUA) with three antibodies to ERCC1 (8F1, FL297, and HPA029773). Analysis with Classification and Regression Tree (CART) methods ascertained the cutoff points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T, and N stage. Kaplan–Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed. Results: ERCC1 low/high groups were defined on the basis of AQUA analysis with 8F1/2009, FL297, and HPA029773. Among patients treated with surgery plus adjuvant radiotherapy/CRT, longer median survival was observed in ERCC1-low versus ERCC1-high tumors (64 vs. 29 months; P = 0.02; HPA029773). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody. Conclusions: Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low-ERCC1 tumors from patients treated with surgery and adjuvant radiotherapy. Clin Cancer Res; 19(23); 6633–43. ©2013 AACR.

Baseline health perceptions, dysphagia, and survival in patients with head and neck cancer

In head and neck cancer patients prior to treatment, dysphagia noted by patients is more common than aspiration on formal swallow studies. The authors hypothesized that patient‐reported dysphagia impacts multiple domains of quality of life (QOL) and predicts disease recurrence and disease‐related death.

Head and Neck Sarcomas: A Comprehensive Cancer Center Experience

Head/neck sarcomas are rare, accounting for about 1% of head/neck malignancies and 5% of sarcomas. Outcomes have historically been worse in this group, due to anatomic constraints leading to difficulty in completely excising tumors, with high rates of local recurrence. We retrospectively analyzed cases of head/neck soft tissue sarcomas (STS) and osteogenic sarcomas managed in a multi-disciplinary setting at Fox Chase Cancer Center from 1999–2009 to describe clinicopathologic characteristics, treatment, outcomes, and prognostic factors for disease control and survival. Thirty patients with STS and seven patients with osteogenic sarcoma were identified. Most STS were high grade (23) and almost all were localized at presentation (28). Common histologies were synovial cell (6), rhabdomyosarcoma (5), angiosarcoma (4), liposarcoma (4) and leiomyosarcoma (3). The type of primary therapy and disease outcomes were analyzed. Cox proportional hazards regression analysis was performed to identify predictors of disease-free survival (DFS) and overall survival (OS). The HR and 95% CI for Cox model and median DFS/OS analyzed by Kaplan-Meier curves were calculated.