Stuart J. Wong

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study

BACKGROUND Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. METHODS Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. FINDINGS In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. INTERPRETATION The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Phase II Study of Low-Dose Paclitaxel and Cisplatin in Combination With Split-Course Concomitant Twice-Daily Reirradiation in Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Protocol 9911

PURPOSE Recurrent squamous cell carcinoma of the head and neck (SCCHN) or new second primary tumor (SPT) in a previous radiation field, if not curable by surgery or radiation, is almost always fatal. Chemotherapy alone yields a median survival time (MST) of no more than 10 months and 1-year overall survival (OS) of 35% at best. Concurrent reirradiation and chemotherapy is an alternative strategy. PATIENTS AND METHODS Eligibility for Radiation Therapy Oncology Group (RTOG) protocol 9911 stipulated recurrent SCCHN or SPT in a previous radiation field. Patients received twice-daily radiation (1.5 Gy per fraction bid x 5 days every 2 weeks x4), plus cisplatin 15 mg/m2 intravenously (IV) daily x 5 and paclitaxel 20 mg/m2 IV daily x 5 every 2 weeks x4. Granulocyte colony-stimulated factor was administered days 6 through 13 of each 2-week cycle. RESULTS One hundred five patients were enrolled from March 2000 through June 2003; 23% had SPT. Oropharynx (40%) and oral cavity (27%) were the predominant primary sites. Median prior radiation dose was 65.4 Gy. Seventy-four percent of patients completed chemotherapy. Grade 4 or worse acute toxicity occurred in 28%, grade 4 or worse acute hematologic toxicity in 21%. Eight treatment-related deaths (8%) occurred: five in the acute setting, three late (including two carotid hemorrhages). MST was 12.1 months, with estimated 1- and 2-year OS rates of 50.2% and 25.9%. CONCLUSION Despite a high incidence of grade 5 toxicity, 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone.

Phase III Comparison of Prophylactic Cranial Irradiation Versus Observation in Patients With Locally Advanced Non–Small-Cell Lung Cancer: Primary Analysis of Radiation Therapy Oncology Group Study RTOG 0214

PURPOSE This study was conducted to determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS Patients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model. RESULTS Overall, 356 patients were accrued of the targeted 1,058. The study was closed early because of slow accrual; 340 of the 356 patients were eligible. The 1-year OS (P = .86; 75.6% v 76.9% for PCI v observation) and 1-year DFS (P = .11; 56.4% v 51.2% for PCI v observation) were not significantly different. The hazard ratio for observation versus PCI was 1.03 (95% CI, 0.77 to 1.36). The 1-year rates of BM were significantly different (P = .004; 7.7% v 18.0% for PCI v observation). Patients in the observation arm were 2.52 times more likely to develop BM than those in the PCI arm (unadjusted odds ratio, 2.52; 95% CI, 1.32 to 4.80). CONCLUSION In patients with stage III disease without progression of disease after therapy, PCI decreased the rate of BM but did not improve OS or DFS.

Locally Recurrent, Previously Irradiated Head and Neck Cancer: Concurrent Re-Irradiation and Chemotherapy, or Chemotherapy Alone?

Patients with locally recurrent head and neck cancer previously treated with radiation have a poor prognosis. Administration of a second course of radiation to tissues within a previous radiation portal, has been traditionally considered unsafe. Survival rates of highly selected patients treated with concurrent chemotherapy and re-irradiation may be as high as 25% at 2 years--exceeding the outcome of matched historical controls treated with chemotherapy alone (10%). However, many questions exist regarding the use of re-irradiation. Uncertainty exists over the criteria for selecting patients who are most appropriate for treatment with re-irradiation. Even greater concern exists regarding toxicity and functional sequelae associated with the use of re-irradiation. Whether the benefits of re-irradiation on locoregional disease control and survival outweigh its potentially severe and life-threatening adverse effects is not clear. In this review, we will discuss re-irradiation and other treatment options for squamous cell carcinoma patients with previously irradiated, locoregional recurrent or second primary tumors in the head and neck, and describe a recently initiated randomized trial comparing chemotherapy plus re-irradiation with chemotherapy.

A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer.

BACKGROUND: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts. PATIENTS AND METHODS: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours x 6 doses orally in the first 2 days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every 2 cycles (8 weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53, and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods. RESULTS: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival. CONCLUSIONS: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.

CLINICAL OUTCOMES OF PATIENTS RECEIVING INTEGRATED PET/CT-GUIDED RADIOTHERAPY FOR HEAD AND NECK CARCINOMA

PURPOSE We previously reported the advantages of (18)F-fluorodeoxyglucose-positron emission tomography (PET) fused with CT for radiotherapy planning over CT alone in head and neck carcinoma (HNC). The purpose of this study was to evaluate clinical outcomes and the predictive value of PET for patients receiving PET/CT-guided definitive radiotherapy with or without chemotherapy. METHODS AND MATERIALS From December 2002 to August 2006, 42 patients received PET/CT imaging as part of staging and radiotherapy planning. Clinical outcomes including locoregional recurrence, distant metastasis, death, and treatment-related toxicities were collected retrospectively and analyzed for disease-free and overall survival and cumulative incidence of recurrence. RESULTS Median follow-up from initiation of treatment was 32 months. Overall survival and disease-free survival were 82.8% and 71.0%, respectively, at 2 years, and 74.1% and 66.9% at 3 years. Of the 42 patients, seven recurrences were identified (three LR, one DM, three both LR and DM). Mean time to recurrence was 9.4 months. Cumulative risk of recurrence was 18.7%. The maximum standard uptake volume (SUV) of primary tumor, adenopathy, or both on PET did not correlate with recurrence, with mean values of 12.0 for treatment failures vs. 11.7 for all patients. Toxicities identified in those patients receiving intensity modulated radiation therapy were also evaluated. CONCLUSIONS A high level of disease control combined with favorable toxicity profiles was achieved in a cohort of HNC patients receiving PET/CT fusion guided radiotherapy plus/minus chemotherapy. Maximum SUV of primary tumor and/or adenopathy was not predictive of risk of disease recurrence.

A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.

Purpose: This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Experimental Design: This phase II multiinstitutional study enrolled patients with recurrent/metastatic SCCHN into two cohorts: those without (arm A) and those with (arm B) before exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1,500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (PFS; arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy. Results: Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, and 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34–159) and 17% of arm B subjects (median, 163 days, range, 135–195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62–374) and 155 (95% CI, 75–242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue. Conclusion: Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects. Clin Cancer Res; 18(8); 2336–43. ©2012 AACR.

Head and Neck Carcinoma in the United States First Comprehensive Report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN)

Detailed information about how patients with head and neck carcinoma (HNC) are treated across practice settings does not exist. The authors conducted a prospective, observational study to examine the patterns of care for a series of patients with newly diagnosed HNC in the United States and to test 2 hypotheses: 1) There is no difference in the pattern of care between community and academic settings; and 2) the results of major randomized clinical trials will change the pattern of care in both practice settings within 1 year of publication in peer‐reviewed journals.

Longitudinal oncology registry of head and neck carcinoma (LORHAN)

A study was undertaken to examine the patterns of systemic therapy use in conjunction with radiation therapy for patients with locally advanced head and neck squamous cell cancer.

Phase I study of epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and vascular endothelial growth factor monoclonal antibody, bevacizumab, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN)

5539 Background: Studies of EGFR inhibitors in SCCHN have demonstrated reproducible activity. Preclinical studies have implicated angiogenesis as a mechanism of resistance to these agents. Furthermore, angiogenesis has been linked with tumor progression and worse outcome in SCCHN. This phase I multi-institutional trial was undertaken to assess the feasibility and toxicity of adding bevacizumab, an anti-VEGF monoclonal antibody to erlotinib, an EGFR tyrosine kinase inhibitor. METHODS Eligible patients were required to have performance status 2 or better, measurable disease, intact organ function, no more than one prior therapy for recurrent/metastatic disease, and no prior EGFR or VEGF based therapy. Escalating doses of bevacizumab (5, 10, and 15 mg/kg IV q3 weeks) were administered with a fixed dose of erlotinib (150 mg PO QD) to consecutive patient cohorts to establish a phase II dose. Plasma VEGF and serum TGF-alpha levels were drawn prior to therapy, after 2 weeks, and after 8 weeks of therapy. RESULTS 10 patients have been enrolled with 4, 3, and 3 patients in each cohort. Grade 3 toxicity consisted of diarrhea (1 patient), skin rash (1 patient), lymphopenia (1 patient). One patient experienced grade 4 hemorrhage from a tongue tumor after 6 treatment cycles that was felt to be therapy related. Common grade 1/2 toxicities observed included dermatologic (70%), fatigue (70%), and diarrhea (50%). Dose limiting toxicity, as defined by the protocol, was not observed at any dose level. Of 9 patients evaluated after 2 cycles, we have observed 1 PR, 7 SD, and 1 PD. 6 patients have had stable disease for greater than 12 weeks. CONCLUSIONS Administration of bevacizumab 15mg/kg q3 weeks with erlotinib 150mg QD is feasible and well tolerated in recurrent/metastatic SCCHN. Assessment of regimen efficacy is underway in the phase II segment of this trial. Supported by NCI grant # N01-CM-17102. No significant financial relationships to disclose.