Kerstin M. Stenson

Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

PURPOSE The epidermal growth factor receptor (EGFR) is a mediator of squamous cell carcinoma of the head and neck (SCCHN) development. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor. This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN. PATIENTS AND METHODS Patients with recurrent or metastatic SCCHN were enrolled through the University of Chicago Phase II Consortium. Patients were allowed no more than one prior therapy for recurrent or metastatic disease and were treated with single-agent ZD1839 500 mg/d. Patient tumor biopsies were obtained and stained immunohistochemically for EGFR, extracellular signal-regulated kinase 1 (ERK1), and phosphorylated ERK1 (p-ERK). Study end points included response rate, time to progression, median survival, and inhibition of p-ERK. RESULTS Fifty-two patients were enrolled (40 male and 12 female) with a median age of 59 years (range, 34 to 84 years). Fourteen patients received ZD1839 through a feeding tube. Half the cohort received ZD1839 as second-line therapy. Forty-seven patients were assessable for response, with an observed response rate of 10.6% and a disease control rate of 53%. Median time to progression and survival were 3.4 and 8.1 months, respectively. The only grade 3 toxicity encountered was diarrhea in three patients. Performance status and development of skin toxicity were found to be strong predictors of response, progression, and survival. Ten biopsy samples were assessable and revealed no significant change in EGFR or p-ERK expression with ZD1839 therapy. CONCLUSION ZD1839 has single-agent activity and is well tolerated in refractory SCCHN. In contrast to other reports, development of skin toxicity was a statistically significant predictor of response and improved outcome.

Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer

PURPOSE The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. PATIENTS AND METHODS Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. RESULTS Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. CONCLUSION Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.

Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas

Purpose: The genetic differences between human papilloma virus (HPV)–positive and –negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC. Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method. Results: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified. Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. Clin Cancer Res; 21(3); 632–41. ©2014 AACR. See related commentary by Krigsfeld and Chung, p. 495

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.

Quality of Life and Performance in Advanced Head and Neck Cancer Patients on Concomitant Chemoradiotherapy: A Prospective Examination

PURPOSE To prospectively evaluate performance and quality of life (QOL) in advanced-stage head and neck cancer (HNC) patients on a curative-intent, concomitant-chemoradiotherapy (CT/XRT) (twice-daily radiation, fluorouracil, hydroxyurea, and cisplatin) regimen aimed at improving locoregional control, survival, and QOL. PATIENTS AND METHODS Sixty-four patients were assessed before, during, and at 3-month intervals after treatment. Standardized measures of QOL (Functional Assessment of Cancer Therapy-Head and Neck), performance (Performance Status Scale for Head and Neck Cancer Patients and Karnofsky Performance Status Rating Scale), and patient-reported symptoms (McMaster University Head and Neck Radiotherapy Questionnaire) were administered. RESULTS Acute treatment toxicities were severe, with declines in virtually all QOL and functional domains. Marked improvement was seen by 12 months; general functional and physical measures returned to baseline levels of good to excellent. Although up to a third of the patients continued to report problems with swallowing, hoarseness, and mouth pain, these difficulties were present in similar magnitudes before treatment. The following symptoms were more frequent at 12 months: dry mouth (58% v 17%), difficulties tasting (32% v 8%), and soft food diet (82% v 42%). Twelve-month diet was not related to pretreatment functioning, disease, treatment, or patient characteristics. Twelve-month QOL was best predicted by pretreatment QOL, with very little relationship to residual side effects or functional impairments. Small numbers of patients in four of the five disease sites precluded examination of outcome by site. CONCLUSION These data support the feasibility of intense CT/XRT as primary treatment for advanced HNC. Results confirm acute toxicity but indicate that many of the treatment-related performance and QOL declines resolve by 12 months. The persistent inability to eat a full range of foods warrants further attention and monitoring.

Concomitant Chemoradiotherapy as Primary Therapy for Locoregionally Advanced Head and Neck Cancer

PURPOSE To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, </= 75 Gy). Adjuvant chemoprevention with retinoic acid and interferon alfa-2A was offered. RESULTS Seventy-six patients were treated (stage IV, 93%; N2, 54%; N3, 21%). At a median follow-up of 38 months, the 3-year progression-free survival is 72%, locoregional control 92%, systemic control 83%, and overall survival 55%. Toxicities included mucositis (grade 3, 45%; grade 4, 12%), neutropenia (grade 4, 39%), and thrombocytopenia (grade 4, 53%). Surgery at the primary site was performed in 13 patients, and 39 had neck dissection. A majority of patients declined adjuvant chemoprevention. Pharmacokinetic parameters were not prognostic of tumor control. Quality of life declined during treatment but returned from good to excellent by 12 months after treatment. CONCLUSION Intensive concomitant chemoradiotherapy leads to high locoregional control and survival rates with organ preservation and a reversal of the historical pattern of failure (distant > locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.

Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer

PURPOSE To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

Phase I Study of Bevacizumab Added to Fluorouracil- and Hydroxyurea-Based Concomitant Chemoradiotherapy for Poor-Prognosis Head and Neck Cancer

PURPOSE We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients. PATIENTS AND METHODS Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m(2) (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded. RESULTS Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m(2), HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/(2), HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5). CONCLUSION Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m(2) every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

Neck dissection in the combined-modality therapy of patients with locoregionally advanced head and neck cancer

The purpose of this study was to evaluate the role of neck lymph node (ND) in the combined dissection modality therapy for locoregionally advanced head and neck.

Competing causes of death and second primary tumors in patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy.

Purpose: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. Experimental Design: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. Results: Median follow-up of surviving patients was 5.2 years (2–10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) Conclusions: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.