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Biomedical subjects

Ralph R Weichselbaum

Publications and source records attributed to Ralph R Weichselbaum.

At least 37 records · Page 2Linked to original sources
PubMed2004

A Phase I trial of TNFerade biologic in patients with soft tissue sarcoma in the extremities.

PURPOSE: TNFerade is a second-generation replication-deficient adenovector carrying a transgene encoding human tumor necrosis factor alpha under control of a radiation- induced promoter. The objective of this study was to assess the tolerance of combining TNFerade and radiation therapy in patients with soft tissue sarcomas of the extremity. EXPERIMENTAL DESIGN: TNFerade was administered in combination with single-daily fractionated radiation therapy in 14 patients with soft tissue sarcoma of the extremities. Three escalating dose levels of TNFerade (4 x 10(9) -4 x 10(11) particle units) were planned, given in 1 log increments by intratumoral injections, twice weekly during week 1 and once weekly during weeks 2-5 of radiation therapy. RESULTS: TNFerade was well tolerated with no dose-limiting toxicities noted. Grade 1-2 chills (50.0%), fever (43.0%), fatigue (36.0%), and flu-like symptoms (21.0%) were the most common side effects. Serum-tumor necrosis factor alpha levels were low in all of the patients (<15 pg/mL). No patients had virus-detected blood, sputum, or urine cultures. Of the 13 evaluable patients, 11 received TNFerade preoperatively, and 2 received the treatment for palliation. Eleven patients (85%) showed objective or pathological tumor responses (2 complete and 9 partial), and 1 had stable disease. Partial responses were achieved despite some of these tumors being very large (up to 675 cm(2)). Of the 11 patients who underwent surgery, 10 (91%) showed a pathological complete response/partial response. CONCLUSION: TNFerade + radiation therapy was well tolerated in the treatment of patients with soft-tissue sarcoma of the extremity. The high number of objective responses observed warrants additional studies of this approach in a larger controlled prospective trial.

Adenoviridae↗
PubMed2004

Glioblastoma cells block radiation-induced programmed cell death of endothelial cells.

We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.

Apoptosis↗
PubMed2004

A hot spot for RAD51C interactions revealed by a peptide that sensitizes cells to cisplatin.

DNA repair via the homologous recombination pathway requires the recombinase RAD51 and, in vertabrates, five RAD51 paralogs. The paralogs form two complexes in solution, a XRCC3/RAD51C heterodimer and a RAD51B/RAD51C/RAD51D/XRCC2 heterotetramer. Mutation of any one of the five paralog genes prevents subnuclear assembly of recombinase at damaged sites and renders cells 30-100 fold sensitive to DNA cross-linking drugs. Phage display was used to isolate peptides that bind the paralog XRCC3. Sequences of binding peptides showed similarity to residues 14-25 of RAD51C protein. Point mutations in this region of RAD51C altered its interaction with both XRCC3 and RAD51B in a two-hybrid system. A synthetic peptide composed of residues 14-25 of RAD51C fused to a membrane transduction sequence [protein transduction domain 4 (PTD4)], inhibited subnuclear assembly of RAD51 recombinase, and sensitized Chinese hamster ovary cells to cisplatin when added to growth medium. These results suggest that residues 14-25 of RAD51C contribute to a "hot spot" used in both XRCC3-RAD51C and RAD51B-RAD51C interactions. Peptide-based inhibition of homologous recombination may prove useful for improving the efficacy of existing cancer therapies.

Amino Acid Sequence↗
PubMed2004

Endothelial cells co-cultured with wild-type and dominant/negative p53-transfected glioblastoma cells exhibit differential sensitivity to radiation-induced apoptosis.

We performed expressional profiling of isogenic glioblastoma cell lines U87-Lux8 and U87-175.4. These cell lines differ in that U87-Lux8 expresses wild-type p53 and U87-175.4 expresses a dominant-negative p53 (175(His) mutation). DNA array analysis and real-time PCR measurements demonstrated that basal expression and response to irradiation were different in these isogenic glioblastoma cell lines. These differences included genes involved in growth regulation and genes associated with cell-to-cell and cell/ECM communications. Co-cultivation of U87-175.4 and U87-Lux8 with HUVE cells demonstrated that U87-175.4 cells suppress the angiogenic phenotype of HUVEC and increase their sensitivity to radiation-induced apoptosis compared to co-culture of U87-Lux8/HUVEC. These data suggest that blockade of p53 function may alter the communication between tumor cells and endothelial cells such that endothelial cells exhibit an increase in radiosensitivity. These findings may have important implications for the treatment of glioblastoma tumors and other human cancers.

Apoptosis↗
PubMed2004

STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells.

Nu61, a radiation-resistant human tumor xenograft, was selected from a parental radiosensitive tumor SCC-61 by eight serial cycles of passage in athymic nude mice and in vivo irradiation. Replicate DNA array experiments identified 52 genes differentially expressed in nu61 tumors compared with SCC-61 tumors. Of these, 19 genes were in the IFN-signaling pathway and moreover, 25 of the 52 genes were inducible by IFN in the nu61 cell line. Among the genes involved in IFN signaling, STAT1alpha and STAT1beta were the most highly overexpressed in nu61 compared to SCC-61. STAT1alpha and STAT1beta cDNAs were cloned and stably transfected into SCC-61 tumor cells. Clones of SCC-61 tumor cells transfected with vectors expressing STAT1alpha and STAT1beta demonstrated radioprotection after exposure to 3 Gy (P < 0.038). The results indicate that radioresistance acquired during radiotherapy treatment may account for some treatment failures and demonstrate an association of acquired tumor radioresistance with up-regulation of components of the IFN-related signaling pathway.

Animals↗
PubMed2004

Poloxamer 188 prevents acute necrosis of adult skeletal muscle cells following high-dose irradiation.

Acute cellular necrosis occurring minutes to hours after massive ionizing radiation exposure (IR) results from rapid membrane lipid peroxidation, blebbing and membrane breakdown. We have shown, previously, that certain polymer surfactants can restore structural integrity and transport barrier function of cell membranes following high-dose IR. We now investigate, specifically, the efficacy of the amphiphilic surfactant Poloxamer 188 (P188) in preventing acute necrosis of adult rat skeletal muscle cells after high-dose IR. Explanted cells were treated with 60Co IR doses of 10, 40 or 80Gy and their viability was determined using fluorometric probes at 4 and 18h post-IR. IR of 10Gy did not cause acute necrosis. Significant acute cell necrosis was observed after 40 and 80Gy doses in a dose-dependent manner. Post-IR treatment with P188 significantly enhanced the cells' viability post-IR treatment. By comparison 10kDa neutral dextran, a hydrophilic polymer, was found to be ineffective. Despite progressive cell death over 18h after high-dose IR, cells treated with P188 manifested greater survival than media or dextran-treated cells. It appears that use of P188 or similar multi-block copolymers to prolong viability of irradiated cells in vitro through membrane sealing is an important step in development of effective interventional therapy for extreme IR exposure. Not only can repairing the membrane prevent acute necrosis, but it also can provide a critical time opportunity to address other mechanisms of cell death, such as apoptosis or mitotic arrest, which manifest over a longer time frame.

Animals↗
PubMed2004

Control of gene therapy by MDR1 and EGR1 promoter sequences in transcriptional targeting by chemotherapy (Review).

The promising benefits of cancer gene therapy have been limited by the inability to deliver therapeutic genes homogeneously throughout the tumor mass and to control gene expression within the tumor cells. Transcriptional targeting, the use of DNA regulatory promoter sequences to localize transgene expression, has been employed as a solution to circumvent these limitations. TNF-alpha is a cytokine that exhibits potent anticancer properties, but its utility following systemic administration is limited by toxicity. We review a strategy whereby ligating TNF-alpha to segments of the chemo-inducible EGR1 or MDR1 promoters activates expression of TNF-alpha cDNA and enhances effectiveness of gene therapy and chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Impact of radioimmunoscintigraphy on definition of clinical target volume for radiotherapy after prostatectomy.

UNLABELLED: The goal of this study was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen in modifying postprostatectomy prostate fossa clinical target volume (CTV) definition. METHODS: The records of 25 postprostatectomy patients who received external-beam radiotherapy after prostatectomy and who underwent vessel-based RIS/planning CT registration were reviewed. For each patient, the CTV that would have been treated (CTV(pre)) before this registration was compared with that defined after the registration (CTV(post)). In addition, using a standard dose of 66 Gy in 2-Gy fractions, the corresponding bladder and rectum dose volume histograms were compared using 2 endpoints: volume receiving > or =60 Gy (V60) and area under the curve (AUC). RESULTS: The mean CTV(pre) vs. CTV(post) volumes were 24.4 vs. 35.0 cm(3), respectively (P = 0.032). The V60 results for CTV(pre) and CTV(post) were 32.7 vs. 41.0 cm(3), respectively, for the rectum (P = 0.168) and 33.9 vs. 46.6 cm(3), respectively, for the bladder (P = 0.015). The AUC results for CTV(pre) and CTV(post) were 4,027 vs. 4,516 Gy x cm(3), respectively, for the rectum (P = 0.396) and 4,782 vs. 5,561, respectively, for the bladder (P = 0.119). No Radiation Therapy Oncology Group grade 3, 4, or 5 (acute or late, gastrointestinal, or genitourinary) toxicity was observed. Two-year biochemical failure-free survival (with failure defined as 2 consecutive prostate-specific antigen rises above 0.2ng/mL) was 87% for the cohort. CONCLUSION: Incorporating RIS uptake resulted in significant modifications in CTV definition. The consequences of these modifications on the rectum V60 or AUC or on the bladder AUC were not significant, although the bladder V60 did increase. However, observed toxicity was low, with acceptable short-term biochemical control, suggesting that treatment to the modified CTV was tolerable.

Humans↗
PubMed2004

Influence of radioimmunoscintigraphy on postprostatectomy radiotherapy treatment decision making.

UNLABELLED: The aim of this study was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen (PSMA) in influencing postradical retropubic prostatectomy (RRP) radiotherapy (RT) decision making. METHODS: The records of consecutive patients who underwent RRP, who were referred for consideration of RT, and for whom an RIS scan was obtained were reviewed. The RT decisions, with regard to (a) the decision to offer RT and (b) the general volume to be treated [prostate fossa (PF) only versus PF + pelvis (P)] before knowledge of the RIS findings were charted. The RIS findings, with regard to uptake in the PF, uptake in the P, or extrapelvic (EP) uptake were tabulated. Then, the RT treatment decisions based on the RIS knowledge were evaluated and compared with the pre-RIS RT treatment decisions. RESULTS: Of the 54 patients originally referred for post-RRP RT, the initial decision was to recommend RT to the PF only in 52 cases and to PF+P in 2 cases. The RIS findings were as follows: PF only, 43 patients; PF+P, 8 patients; PF+EP, 2 patients; PF+P+EP, 1 patient. After knowledge of these RIS results, the decision to offer RT was withdrawn in 4 of 54 patients (7.4%; P = 0.046). Furthermore, RIS changed the general treatment volume (PF only to PF+P) in 6 of 54 patients (11.1%; P = 0.015). In total, RIS altered the RT decision in 10 of 54 patients (18.5%; P = 0.0067). Three-year biochemical failure-free survival (with failure defined as 2 consecutive prostate-specific antigen [PSA] rises above 0.2 ng/mL after PSA nadir) was 78%; no patient, disease, or treatment factor reached statistical significance on univariate or multivariate analysis. CONCLUSION: RIS was found to influence post-RRP RT decision making for the identification of patients not likely to benefit from RT and for guiding general target volume definition.

Aged↗
PubMed2004

Radioimmunoscintigraphy for postprostatectomy radiotherapy: analysis of toxicity and biochemical control.

UNLABELLED: Our goal was to evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate-specific membrane antigen (PSMA) in influencing postprostatectomy radiotherapy (RT) toxicity and biochemical control. METHODS: The records of 107 postprostatectomy RT patients were reviewed. The group for whom no RIS scan was obtained (group A, n = 54) was identified as was the group for whom a RIS scan was obtained (group B, n = 53). Group B was further subdivided into those who had a RIS and CT-scan correlation to aid in treatment planning (subgroup B1, n = 40) versus those who did not (subgroup B2, n = 13). Gastrointestinal (GI) and genitourinary (GU) toxicities were reviewed for each of these groups and subgroups and compared. Biochemical failures (defined as 2 successive PSA rises after a nadir of >or=0.2 ng/mL) were identified to generate biochemical failure-free survival (BFFS) curves for each of the groups and subgroups. RESULTS: No significant differences in late toxicity were observed between any group or subgroup. However, acute GI toxicity was higher in group B versus group A (P = 0.026), and acute GU toxicity was higher in subgroup B2 versus subgroup B1 (P = 0.050). Overall, most toxicity was grade 1 or 2; only one case of grade 3 toxicity and no cases of grade 4 or 5 toxicity were observed. Three-year BFFS was higher for group B versus group A (80.7% vs. 75.5%) and for subgroup B1 versus subgroup B2 (84.5% vs. 71.6%). On multivariate analysis of pretreatment (age, race), surgical/staging (stage, grade, margin status, extracapsular extension, lymph node status, seminal vesicle invasion, post-radical retropubic prostatectomy [RRP] prostate-specific antigen [PSA] nadir, maximum post-RRP PSA, and RRP-to-RT interval), and treatment (hormone therapy, RT dose, RT technique, RIS scan, and RIS/CT correlation) factors on BFFS, the only covariate reaching significance was RIS/CT correlation (P = 0.042). CONCLUSION: A small BFFS advantage was observed in patients for whom RIS was used to guide RT decision making and treatment planning; however, this advantage only reached significance in this study for those for whom the RIS/CT correlation was used to guide target definition. The improved PSA control using RIS was achieved with a small increase in acute toxicity but with no observed change in late toxicity. These findings can serve as the basis for prospective studies in this area of investigation.

Cohort Studies↗
PubMed2004

Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity.

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.

Acetylcysteine↗
PubMed2004

Analysis of further disease progression in metastatic non-small cell lung cancer: implications for locoregional treatment.

To determine whether in the natural history of metastatic non-small cell lung cancer (NSCLC) a time interval exists when metastases are limited in number and/or destination organs. Thirty-eight stage IIIB (pleural effusion)/IV NSCLC patients were treated on a phase II trial of oxaliplatin and paclitaxel. Patients' charts were reviewed and all sites of disease at initial presentation and at subsequent follow-ups were recorded, including the number of organs involved and the number of individual metastatic sites. At presentation, 74% of patients had metastases confined to one or two organs (including the lung primary). Fifty percent had < or =3 metastatic sites in addition to the lung primary. At last follow-up, 17 patients developed new lesions, 14 in a new organ and 3 in a previously involved organ. Nineteen (50%) had stable (n=12) or progressive (n=7) disease in initially involved sites without developing any new metastatic tumors. Among the 17 patients who presented with < or =4 metastatic sites and no pleural effusion, 11 (65%) had stable or progressive disease in initially involved sites without developing new metastases. These results suggest that a subset of patients who present with metastatic NSCLC may not have widely disseminated disease and that some form of local treatment combined with systemic therapy might be beneficial in these patients. Our data support the feasibility of a clinical trial that incorporates local therapies to sterilize metastases in patients with NSCLC.

Adult↗
PubMed2003

Induction chemotherapy followed by concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and neck cancer.

PURPOSE: Induction chemotherapy with carboplatin and paclitaxel followed by concomitant TFHX (paclitaxel, infusional 5-fluorouracil, hydroxyurea, and twice-daily radiation therapy administered every other week) has resulted in 70% 3-year survival in stage IV patients. Locoregional and distant control rates were 94 and 93%, respectively. In an attempt to decrease toxicity without compromising local control, a second cohort of patients was treated with a lower dose of radiation to sites of potential microscopic disease. EXPERIMENTAL DESIGN: Sixty-four patients were entered on study. Patients received six weekly doses of carboplatin (area under the curve 2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. The radiation dose to gross disease was 75 Gy as in the previous trial. The radiation dose to high-risk microscopic disease was reduced from 60 to 54 Gy, and the dose to low-risk microscopic disease was reduced from 45 to 39 Gy. RESULTS: Ninety-seven percent of patients had stage IV disease. The response rate to induction chemotherapy was 82% with a complete response rate of 42%. At the completion of therapy the clinical complete response rate rose to 100% with a median follow-up of 29 months. The actuarial 2 and 3-year survival was 77 and 70%, respectively. Five patients developed progressive disease for an overall 3-year progression-free survival of 90%. Two patients failed in locoregional sites alone, resulting in a 3-year locoregional control of 97%. The 3-year systemic control was 95%. Four patients were completely feeding tube dependent at the time of analysis. Only 1 of these patients had normal swallowing function before treatment. CONCLUSIONS: In this second trial, induction chemotherapy with carboplatin and paclitaxel followed by TFHX chemoradiotherapy results in high survival and progression-free survival. The reduction in radiation dose did not compromise survival or disease control compared with our prior study using higher radiation doses. Data continues to support definitive evaluation of this approach.

Adult↗
PubMed2003

Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy.

Based on the role of phosphorylation of the histone H2A variant H2AX in recruitment of DNA repair and checkpoint proteins to the sites of DNA damage, we have investigated gammaH2AX as a reporter of tumor radiosensitivity and a potential target to enhance the effectiveness of radiation therapy. Clinically relevant ionizing radiation (IR) doses induced similar patterns of gammaH2AX focus formation or immunoreactivity in radiosensitive and radioresistant human tumor cell lines and xenografted tumors. However, radiosensitive tumor cells and xenografts retained gammaH2AX for a greater duration than radioresistant cells and tumors. These results suggest that persistence of gammaH2AX after IR may predict tumor response to radiotherapy. We synthesized peptide mimics of the H2AX carboxyl-terminal tail to test whether antagonizing H2AX function affects tumor cell survival following IR. The peptides did not alter the viability of unirradiated tumor cells, but both blocked induction of gammaH2AX foci by IR and enhanced cell death in irradiated radioresistant tumor cells. These results suggest that H2AX is a potential molecular target to enhance the effects of radiotherapy.

Animals↗
PubMed2003

Herpes simplex virus 1 activates cdc2 to recruit topoisomerase II alpha for post-DNA synthesis expression of late genes.

A subset (gamma(2)) of late herpes simplex virus 1 genes depends on viral DNA synthesis for its expression. For optimal expression, a small number of these genes, exemplified by U(S)11, also requires two viral proteins, the alpha protein infected cell protein (ICP) 22 and the protein kinase U(L)13. Earlier we showed that U(L)13 and ICP22 mediate the stabilization of cdc2 and the replacement of its cellular partner, cyclin B, with the viral DNA polymerase processivity factor U(L)42. Here we report that cdc2 and its new partner, U(L)42, bind a phosphorylated form of topoisomerase II alpha. The posttranslational modification of topoisomerase II alpha and its interaction with cdc2-U(L)42 proteins depend on ICP22 in infected cells. Although topoisomerase II is required for viral DNA synthesis, ICP22 is not, indicating a second function for topoisomerase II alpha. The intricate manner in which the virus recruits topoisomerase II alpha for post-DNA synthesis expression of viral genes suggests that topoisomerase II alpha also is required for untangling concatemeric DNA progeny for optimal transcription of late genes.

Antigens, Neoplasm↗
PubMed2003

Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells.

Tumour angiogenesis is a complex process based upon a sequence of interactions between tumour cells and endothelial cells. To model tumour/endothelial-cell interactions, we co-cultured U87 human glioma cells with human umbilical vein endothelial cells (HUVECs). U87 cells induced an 'activated' phenotype in HUVECs, including an increase in proliferation, migration and net-like formation. Activation was observed in co-cultures where cells were in direct contact and physically separated, suggesting an important role for soluble factor(s) in the phenotypic and genotypic changes observed. Expressional profiling of tumour-activated endothelial cells was evaluated using cDNA arrays and confirmed by quantitative PCR. Matching pairs of receptors/ligands were found to be coordinately expressed, including TGFbetaRII with TGFbeta3, FGFRII and cysteine-rich fibroblast growth factor receptor (CRF-1) with FGF7 and FGF12, CCR1, CCR3, CCR5 with RANTES and calcitronin receptor-like gene (CALCRL) with adrenomedullin. Consistent with cDNA array data, immunohistochemical staining of expressed proteins revealed the upregulation of Tie-2 receptor in vitro and in vivo. Our data suggest that tumour-induced activation of quiescent endothelial cells involves the expression of angiogenesis-related receptors and the induction of autocrine growth loops. We suggest that tumour cells release growth factors that induce endothelial cells to express specific ligands and their cognate receptors coordinately.

Angiogenesis Inhibitors↗
PubMed2003

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.

Adult↗