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Caroline J Voskens,
Duane Sewell,
Ronna Hertzano,
Jennifer Desanto,
Sandra Rollins,
Myounghee Lee,
Rodney Taylor,
Jeffrey Wolf,
Mohan Suntharalingam,
Brian Gastman,
John C Papadimitriou,
Changwan Lu,
Ming Tan,
Robert Morales, Kevin Cullen,
Esteban Celis,
Dean Mann,
Scott E Strome
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ABSTRACT: BACKGROUND: We performed a pilot study using Trojan vaccines in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). These vaccines are composed of HLA-I and HLA-II restricted melanoma antigen E (MAGE)-A3 or human papillomavirus (HPV)-16 derived peptides, joined by furin-cleavable linkers, and linked to a "penetrin" peptide sequence derived from HIV-TAT. Thirty-one patients with SCCHN were screened for the trial and 5 were enrolled. METHODS: Enrolled patients were treated with 300 μg of Trojan peptide supplemented with Montanide and granulocyte-macrophage colony-stimulating factor (GM-CSF) at 4-week intervals for up to 4 injections. RESULTS: Following vaccination, peripheral blood mononuclear cells (PBMCs) from 4 of 5 patients recognized both the full Trojan constructs and constituent HLA-II peptides, whereas responses to HLA-I restricted peptides were less pronounced. CONCLUSION: This treatment regimen seems to have acceptable toxicity and elicits measurable systemic immune responses against HLA-II restricted epitopes in a subset of patients with advanced SCCHN. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
Head & Neck 01/2012; · 2.40 Impact Factor
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ABSTRACT: At a minimum follow-up of 2 years, the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) versus cisplatin and fluorouracil (PF) in locally advanced head and neck cancer. We report the long-term results at 5 years' minimum follow-up.
TAX 324 was a randomised, open-label phase 3 trial comparing three cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2), followed by intravenous cisplatin 100 mg/m(2) and fluorouracil 1000 mg/m(2) per day, administered as a continuous 24-h infusion for 4 days) with three cycles of PF (intravenous cisplatin 100 mg/m(2), followed by fluorouracil 1000 mg/m(2) per day as a continuous 24-h infusion for 5 days) in patients with stage III or IV squamous-cell carcinoma of the head or neck. Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin. Randomisation was done centrally with the use of a biased-coin minimisation technique. At study entry, patients were stratified according to the site of the primary tumour, nodal status (N0 or N1 vs N2 or N3), and institution. For this long-term analysis, data as of Dec 1, 2008, were gathered retrospectively from patients' medical records. Overall and progression-free survival were the primary endpoints. Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity. The intention-to-treat analysis included data from all 501 patients (255 TPF, 246 PF); data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up. TAX 324 was registered at ClinicalTrials.gov, NCT00273546.
Median follow-up was 72·2 months (95% CI 68·8-75·5). Overall survival was significantly better after treatment with TPF versus PF (hazard ratio [HR] 0·74, 95% CI 0·58-0·94), with an estimated 5-year survival of 52% in patients treated with TPF and 42% in those receiving PF. Median survival was 70·6 months (95% CI 49·0-89·0) in the TPF group versus 34·8 months (22·6-48·0) in the PF group (p=0·014). Progression-free survival was also significantly better in patients treated with TPF (median 38·1 months, 95% CI 19·3-66·1, vs 13·2 months, 10·6-20·7; HR 0·75, 95% CI 0·60-0·94). We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups. In the TPF group, three (3%) of 91 patients remained feeding-tube dependent, compared with eight (11%) of 71 patients in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, versus eight (11%) of 71 in the PF group.
Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer. Patients who are candidates for induction chemotherapy should be treated with TPF.
Sanofi-Aventis.
The lancet oncology 02/2011; 12(2):153-9. · 14.47 Impact Factor
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ABSTRACT: Bisphosphonate-associated osteonecrosis (BON) is a recently recognized oral complication of bisphosphonate (BP) therapy. Currently, research into the pathogenesis of BON has been hampered by being deficient in studies capable of measuring the level of BP in saliva or at the bone-soft tissue interface. The objective of this current study was to develop a novel bioassay model representative of the oral levels of BPs in patients presenting with or at risk for BON.
Zoledronic acid (ZA) injectable was used to develop standardized MTS cell proliferation assay curves at concentrations of 0-10 microM, which were used either in a dilution in normal media, mimicking BP freed from bone or used to "spike" saliva individuals not taking BPs and mimicking BP levels being excreted. This bioassay was then used to estimate BP levels from samples of saliva and bone ex vivo from patients with and without BON.
Saliva and bone from patients with existing BON showed levels of BP ranging from 0.4 to 4.6 microM, while patients receiving IV infusion of BP and naïve to BON showed levels in saliva ranging from 0.4 to 5 microM. All control specimens and patients naïve to BP showed levels at 0 microM.
Given the fact that BPs are poor candidates for detection using standard methods (HPLC), this bioassay provides us with the ability to estimate clinically relevant concentrations of BP capable of producing apoptosis and the inhibition cell proliferation of oral mucosal cells based on previous studies. Subsequently, apoptosis and the inhibition of proliferation could lead to BON, secondary to the exposure of the bone in the unique microenvironment of the oral cavity.
Supportive Care in Cancer 09/2009; 17(12):1553-7. · 2.09 Impact Factor
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ABSTRACT: The role of adjuvant neck dissection in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who obtain complete clinical and radiologic response following definitive chemoradiation treatment is controversial.
Patterns of failure among 120 patients with locally advanced SCCHN, all with node-positive disease, treated with concurrent chemoradiation, were analyzed.
Ninety-one of the patients achieved a complete response and were observed without undergoing neck dissection. Isolated failure in the neck occurred in 2 patients. The most common site of failure was metastatic disease (17 patients). Six patients had recurrence at the primary only, and 1 experienced failure in the neck and at the primary. Partial responders with resectable disease underwent neck dissection following chemoradiation. This group had worse local control and overall survival compared with complete responders.
We recommend observation after definitive chemoradiation for complete responders. Further research is needed to improve outcomes among partial responders.
Head & Neck 06/2009; 32(1):46-52. · 2.40 Impact Factor
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ABSTRACT: The purpose of this study was to determine the impact of race on outcome in patients with stage III/IV squamous cell carcinoma of the head and neck (SCCHN) who have completed concurrent chemoradiotherapy.
The authors performed a retrospective analysis of 202 patients with stage III/IV SCCHN who were treated at the University of Maryland. Patients received daily radiation to a total dose of 70.2 Gray (Gy) (1.8 Gy/day), concurrently with weekly carboplatin (area under the curve [AUC] = 2) and paclitaxel (45 mg/m(2)) chemotherapy.
There were 108 Caucasian (CA) and 94 African American (AA) patients. The median age was 56 years, and 81% were stage IV. The median follow-up was 33 months. The median overall survival (OS) and disease-free survival (DFS) were 33 months and 19 months, respectively. When analyzed by race, the median DFS was 33 months (CA) versus 12 months (AA) (P = .028). The median OS was 44 months (CA) versus 24 months (AA) (P = .071). The 3-year DFS for stage IV AA versus stage IV CA was 29% versus 50% (P = .031). The 3-year DFS for N2 disease in AA versus CA was 32% versus 51% (P = .046). The 3-year DFS for AA versus CA with oropharyngeal tumors was 30% versus 60% (P = .006).
This analysis documents the inferior outcome for AA patients. They had inferior DFS and a trend toward worse OS. When stratified by several prognostic variables, the mediocre DFS in the AA patients remains. These data suggest that further investigation into the genetic characteristics of SCCHN in AA patients is warranted.
Cancer 03/2009; 115(8):1744-52. · 4.77 Impact Factor
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Marshall R Posner,
Diane M Hershock,
Cesar R Blajman,
Elizabeth Mickiewicz,
Eric Winquist,
Vera Gorbounova,
Sergei Tjulandin,
Dong M Shin, Kevin Cullen,
Thomas J Ervin, [......],
Sanjiv Agarwala,
K William Harter,
Matthew Dugan,
Anthony Cmelak,
Arnold M Markoe,
Paul W Read,
Lynn Steinbrenner,
A Dimitrios Colevas,
Charles M Norris,
Robert I Haddad
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ABSTRACT: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy.
We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival.
With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group.
Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).
New England Journal of Medicine 10/2007; 357(17):1705-15. · 53.30 Impact Factor
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ABSTRACT: Existing HER-2 targeted therapies for human head and neck cancers, usually administered in combination with chemotherapeutic drugs or irradiation, include monoclonal antibodies to HER-2, receptor tyrosine kinase inhibitors and HER-2 specific immunotoxins. Instead of targeting the existing protein, interference with HER-2 mRNA translation by antisense oligonucleotides may be a more efficient method to downregulate levels of HER-2 protein for combination therapy. To test this hypothesis we have used a phosphorothioate pentadecamer, complementary to the HER-2 mRNA initiation codon region (AS HER-2 ODN), to increase sensitivity to four chemotherapeutic agents in human head and neck cancer cell lines, all of which express low levels of the HER-2 protein. To improve delivery into tumor cells, the AS HER-2 ODN was complexed with our previously established folate-liposome delivery system. Cell survival assays and Western blot analysis data demonstrated that folate-liposome mediated AS HER-2 oligonucleotide treatment inhibited cell growth and HER-2 expression, and induced apoptosis in SCC-25CP cells. Moreover, there was a synergistic effect on the percent of apoptotic cells. Additionally, the combination of folate-liposome-AS HER-2 ODN and CDDP had a synergistic effect on the induction of apoptosis. Using confocal microscopy, FITC labeled ODN (FITC-ODN) in complex with folate-liganded, rhodamine (Rh) labeled, cationic liposomes was observed to enter SCC-25CP head and neck tumor cells within 3 to 6 h. Intracellularly, the FITC-ODN separated from the Rh-folate-liposomes, and FITC-ODN accumulated in the nucleus while Rh-liposomes remained in punctate cytoplasmic structures. Thus, folate-liposome-mediated delivery of AS HER-2 ODN has potential as a new means of increasing the responsiveness of head and neck cancer to conventional chemotherapy.
Annals of the New York Academy of Sciences 01/2004; 1002:78-89. · 3.15 Impact Factor
