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Biomedical subjects

Marshall R Posner

Publications and source records attributed to Marshall R Posner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Paradigm shift in the treatment of head and neck cancer: the role of neoadjuvant chemotherapy.

Chemotherapy is an integral component of the management of patients with locally advanced head and neck cancer, though the optimal use of chemotherapy remains to be defined. The combination of a platinum agent and 5-fluorouracil has been used as the standard neoadjuvant treatment and has been shown to permit organ preservation in operable patients and improve long-term survival outcomes in operable and inoperable patients. Recently, the addition of a taxane, docetaxel or paclitaxel, to standard platinum plus 5-fluorouracil induction chemotherapy has been shown to further improve response rates and survival outcomes. Phase III data are emerging to support combinations of docetaxel or paclitaxel with a platinum plus 5-fluorouracil as a new, more effective and less toxic standard for neoadjuvant chemotherapy. Sequential treatment regimens, incorporating a combination of induction chemotherapy and chemoradiation, are also under study in efforts to further improve long-term survival outcomes. Induction regimens incorporating docetaxel or paclitaxel with a platinum plus 5-fluorouracil are under evaluation in this setting. Randomized trials comparing a sequential treatment approach with standard therapies are also being undertaken and will likely define a new treatment paradigm for patients with locally advanced head and neck cancer.

Antineoplastic Agents↗
PubMed2004

A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor.

PURPOSE: E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G(1) arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m(2) over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to immunohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation. RESULTS: Because none of the first 15 patients achieved progression-free survival > 4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49-73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1-5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment. CONCLUSIONS: At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.

Aged↗
PubMed2004

Positron emission tomography with 18F-fluorodeoxyglucose to predict pathologic response after induction chemotherapy and definitive chemoradiotherapy in head and neck cancer.

BACKGROUND: Conventional imaging is limited in identifying persistent disease after organ-preserving therapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). We studied the accuracy of positron emission tomography (PET) with (18)F-fluoro-2-deoxy-D-glucose (FDG-PET) in restaging disease in patients with SCCHN after they had undergone induction chemotherapy (ICT) followed by chemoradiotherapy (CRT). METHODS: Forty patients with advanced SCCHN were treated with ICT followed by CRT. FDG-PET imaging was performed to assess for residual cancer at the primary site and in nodal metastases. Two nuclear medicine physicians interpreted PET scans in random sequence. Test characteristics were calculated with pathologic analysis or clinical recurrence as the standard. RESULTS: After induction chemotherapy, PET imaging had a sensitivity of 100% and specificity of 65% for detecting persistent disease at the primary tumor site. After ICT and CRT were completed, the sensitivity and specificity of PET imaging were 67% and 53%, respectively, for detecting occult disease in cervical lymph nodes. CONCLUSIONS: FDG-PET imaging showed some correlation with pathologic response after ICT and CRT in patients with advanced SCCHN. The use of FDG-PET warrants further investigation in this setting.

Adult↗
PubMed2004

Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: evolution of the sequential treatment approach.

Cisplatin plus 5-fluorouracil (5-FU) (PF regimen) induction chemotherapy (IC) has been studied over the last two decades and has proven to be a durable and effective therapy for patients with locally advanced squamous cell cancer of the head and neck (SCCHN). Although randomized trials and meta-analyses have demonstrated that PF-based IC improves survival, reduces systemic metastases, and permits organ preservation, the effect on overall survival has been less robust than the results seen with cisplatin-based chemoradiotherapy (CRT) regimens. Differences in trial design, scheduling, and surgical interventions account for some of the variation in results. As studies have evolved, it has become evident that there are advantages to both approaches. This perception has led to the concept of sequential therapy (ST), the combination of IC, CRT, and surgery. ST programs are being studied intently in many centers. Phase II and III trials of ST regimens have reported unprecedented survival results in patients with locally advanced disease. In addition, the hypothesis that PF plus a taxane may result in an improved survival, compared to PF alone, for patients with locally advanced SCCHN on ST treatments is being tested in phase III trials. Although ST has not been compared head to head with CRT, early results support the use of this treatment paradigm in patients with poor prognosis SCCHN and should lead to definitive phase III trials in the near future. ST may represent the cutting edge of therapy for patients with curable, locally advanced SCCHN.

Carcinoma, Squamous Cell↗
PubMed2004

Prospective phase II trial of PFL-induction chemotherapy followed by definitive local treatment for advanced squamous cell carcinoma of the head and neck: 10-year follow-up.

Reported is an analysis of overall survival at 10 years of 102 patients with advanced squamous cell carcinoma of the head and neck (SCCHN) who were enrolled in a prospective phase II trial of high-dose cisplatin, 5-fluorouracil (5-FU), and high-dose leucovorin (PFL) induction chemotherapy followed by surgery and/or definitive radiation therapy (RT) between 1987 and 1991. Initially, 14 patients underwent primary site (PS) and neck surgery irrespective of the clinical response to PFL. The high rate of clinical and pathologic complete response (CR) to PFL prompted a switch from PS surgery to definitive RT. Of 102 patients, 18 (17.6%) who completed PFL and local-regional treatment for SCCHN between 1988 to 1991 were alive in December 2000. Among these, 1 of 14 patients (7%) who had undergone PS resection and 17 of 85 (20%) who were treated after PFL with definitive RT but without PS surgery were alive at 10 years. Median survival time was higher in the nonsurgical group (98.9 vs. 51.9 months). Subset analysis suggested that patients with oropharyngeal PS had the longest median survival (108.6 months). The oropharyngeal patients represented the 61% (11/18) of the long-term survivors with organ preservation. An organ preservation approach for patients with advanced SCCHN who demonstrated PS CR to chemotherapy demonstrated a trend to improved overall survival.

Adolescent↗
PubMed2004

Endoscopic management of hypopharyngeal stenosis after organ sparing therapy for head and neck cancer.

OBJECTIVES: The objective of this study was to describe and evaluate the efficacy of an endoscopic technique for the management of postchemoradiation hypopharyngeal stenosis in head and neck cancer patients. STUDY DESIGN: Retrospective review. METHODS: Patients with postchemoradiation hypopharyngeal stenoses were identified from the Dana Farber Cancer Institute head and neck database. Patients who had undergone extirpative surgery and reconstruction were excluded. All patients underwent either anterograde dilatation (AD) by the lead author (C.A.S.) or transgastric retrograde esophagoscopy with anterograde dilatation (TREAD) (C.A.S., M.T.J.). Chemoradiation records, clinic notes, operative reports, and swallowing test data were reviewed. Removal of the gastric feeding tube was considered the endpoint of rehabilitation. RESULTS: Seventeen patients had postcricoid stenoses identified by modified barium swallow. Endoscopy confirmed 15 postcricoid stenoses and 2 proximal esophageal stenoses. Nine (53%) patients had partial stenoses, and eight (47%) had complete stenoses. Eight partial stenosis patients underwent 10 AD procedures and 3 TREAD procedures. Eight complete stenosis patients underwent 9 TREAD procedures and 26 subsequent AD procedures. Fifteen of 16 (93%) patients resumed swallowing after dilatation. Thirteen (81%) patients maintained their weight on an oral diet and had their gastric feeding tubes removed. Complications included hypopharyngeal perforation (13%), abdominal wall infection (6%), stomach wall dehiscence (6%), and chondroradionecrosis of the cricoid cartilage (6%). CONCLUSIONS: Postcricoid hypopharyngeal stenosis may be partial or complete after organ sparing chemoradiation for head and neck cancer. Using the TREAD technique, successful rehabilitation of swallowing can be achieved with a low incidence of complications.

Adult↗
PubMed2003

Binding and neutralization activity of human IgG1 and IgG3 from serum of HIV-infected individuals.

The IgG1 and IgG3 subclasses represent the predominant antibody response to viral infections, including HIV. IgG subclasses differ in their interaction with antigen and functional effects due to specific physiochemical features. With an elongated hinge, IgG3 antibodies tend to have more segmental flexibility, which can render the antibody more effective at interacting with antigen. We have previously shown that the change of the human anti-CD4-binding site monoclonal antibody F105 from IgG1 to IgG3 results in neutralization of a T cell line-adapted isolate (TCLA) resistant to neutralization by the parental IgG1. In the studies presented here, we have purified IgG1 and IgG3 subclasses from the sera of HIV-infected individuals and tested for immunoreactivity with and neutralization of HIV. Purified total IgG3 tended to have less relative reactivity and mediated relatively poorer neutralization of either laboratory or primary isolates. IgG3 also tended to react relatively less well with gp160 and gp120 and more robustly with gp41 and p24. The contrasting results with serum, as opposed to F105, may result from the polyclonal nature of serum antibodies. There is also a failure to make a robust IgG3 response to neutralizing epitopes on envelope glycoproteins during natural infection. These studies suggest that the investigation of isotype effects on neutralization will require isotype-switched human monoclonal antibodies. Understanding isotype and neutralization will provide important data necessary for designing the most effective possible vaccines.

Antibodies, Monoclonal↗
PubMed2003

Integration of chemotherapy in the curative treatment of locally advanced head and neck cancer.

The role of chemotherapy for locoregionally advanced head and neck cancer continues to evolve. Chemotherapy can be given as induction therapy, concomitant with radiation or occasionally in an adjuvant form following definitive local therapy. Timing and sequence of chemotherapy varies between institutions. The recent advances in the treatment of head and neck cancer will be reviewed, with focus on the recent application of sequential chemoradiotherapy regimens, which combines high-dose induction chemotherapy with concomitant chemoradiation. Surgery is reserved for advanced nodal-stage disease and for salvage at the primary site. This novel approach has resulted in a higher rate of organ preservation and is ultimately expected to improve survival in this patient population.

Animals↗
PubMed2003

Progress and perspectives in chemoprevention of head and neck cancer.

Head and neck squamous cell carcinoma is ideally suited for chemoprevention efforts. Elucidation of molecular events underlying head and neck cancer has facilitated the development of preventive strategies. Landmark trials of 13-cis retinoic acid demonstrated that chemoprevention of head and neck cancer is indeed possible. New agents targeting specific molecular abnormalities contributing to the multifocal and multistep process of carcinogenesis have been identified. Innovative approaches to the study of chemoprevention, such as the use of biomarker intermediate end points, can select agents with particular promise for more definitive trials. However, barriers to progress in chemoprevention remain, including the validation of surrogate end point biomarkers and identification of safe and well-tolerated agents with the ability to delay carcinogenesis.

Animals↗
PubMed2003

Docetaxel, cisplatin, 5-fluorouracil (TPF)-based induction chemotherapy for head and neck cancer and the case for sequential, combined-modality treatment.

Since the publication of the Veterans Affairs study in the early 1990s, much has been learned regarding the role of chemotherapy, radiation therapy, and more importantly, the role of combined-modality treatment with chemoradiation in the therapy of locally advanced head and neck cancer. There continues to be widespread variation and controversy in the timing, schedule, and intensity of chemotherapy and chemoradiation. Herein, we present the various approaches currently used in the year 2003 with a specific emphasis on the role of sequential combined-modality therapy combining chemotherapy, chemoradiotherapy, and surgery in the treatment of these malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Palliative chemotherapy in patients with salivary gland neoplasms and preliminary reports of 2 recent phase II studies with trastuzumab and gemcitabine.

Salivary gland malignancies are a diverse group of neoplasms. Patients are usually treated with surgery followed by adjuvant radiation therapy. Those presenting with recurrent or metastatic disease have limited treatment options for these patients and discuss the results of 2 recent studies that used trastuzumab and gemcitabine as single agents in patients with incurable disease.

Antibodies, Monoclonal↗
PubMed2002

Interactions of human antibodies, epitope exposure, antibody binding and neutralization of primary isolate HIV-1 virions.

OBJECTIVE: Development of an effective HIV vaccine has been limited because of the inherent structural properties of the HIV envelope on native virions and the failure of the immune system to respond in an effective manner. Identification of the interactions of human antibodies with virions resulting in neutralization will facilitate vaccine design. DESIGN: Combinations of human monoclonal antibodies (hMAb) were studied for binding to and neutralization of primary isolate virions. METHODS: Virion binding and neutralization were measured using primary isolate virions. RESULTS: Antibodies and combinations of antibodies to epitopes exposed upon CD4 binding (CD4i) and V3 loop antibodies resulted in additive binding and neutralization of R5X4 virus. Antibodies did not bind to or neutralize R5 virus as well. The combination of V3 loop antibody with 2G12 resulted in enhanced neutralization and binding to the R5X4 isolate but not the R5 isolate. Preincubation of the R5X4 isolate with F240, a non-neutralizing anti-gp41 antibody, significantly enhanced binding and neutralization by CD4i hMAb and 2F5. F240 also enhanced the binding of 2F5 to the R5 isolate and the neutralization of the R5 isolate mediated by 2G12. CONCLUSIONS: Neutralizing epitopes are obscured on intact primary isolate virions and are dynamically exposed upon ligand (CD4) interactions. Interestingly, a non-neutralizing antibody to gp41 also increased binding and neutralizing activity of some hMAb that poorly neutralized R5 virus. These data suggest that non-neutralizing epitopes may be appropriate targets for vaccine design and epitope exposure should be considered in the development of immunotherapeutic strategies for HIV.

Antibodies, Monoclonal↗
PubMed2002

A Phase I/II trial of concurrent docetaxel and radiation after induction chemotherapy in patients with poor prognosis squamous cell carcinoma of the head and neck.

BACKGROUND: The authors conducted a Phase I/II study in patients with a poor prognosis who had locally advanced squamous cell carcinoma of the head and neck (SCCHN) and who were treated initially with induction chemotherapy. Patients were treated with weekly docetaxel and concurrent daily fractionated radiation therapy to determine the maximum tolerated dose (MTD) of docetaxel and the efficacy of the regimen. METHODS: Twenty-two patients were enrolled, and 21 patients were treated. Eight patients had Stage III SCCHN, and 13 patients had Stage IV SCCHN without distant metastases and were treated first with 2-3 cycles of induction chemotherapy, which consisted of cisplatin plus 5-fluorouracil with or without leucovorin. Patients with a poor prognosis were identified as those who achieved a partial response to induction treatment, achieved a complete response with a positive biopsy, or were at high risk for developing recurrent disease. Patients were treated subsequently with concurrent, escalating doses of docetaxel (given weekly x 6) and once daily 200-centigray radiation fractions. RESULTS: Three patients were treated with a weekly docetaxel dose of 20 mg/m(2) without dose-limiting toxicity (DLT). Both patients who were treated at the next dose level of 30 mg/m(2) experienced DLT. A dose of 25 mg/m(2) was studied without DLT in the 16 patients who were treated, establishing this as the MTD. Sixty-seven percent of the patients are alive without disease at a median follow-up of 35 months (range, 12-59 months) after the initiation of chemoradiotherapy. CONCLUSIONS: The MTD of weekly docetaxel with concurrent daily radiation therapy in the postinduction setting was 25 mg/m(2). Disease free survival data from this study were good and indicated that this regimen was effective in the treatment of patients with SCCHN who had a poor prognosis.

Adult↗