21 results on '"Wirth, Lori J."'
Search Results
2. Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy.
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Kalchiem-Dekel, Or, Falcon, Christina J., Bestvina, Christine M., Liu, Dazhi, Kaplanis, Lauren A., Wilhelm, Clare, Eichholz, Jordan, Harada, Guilherme, Wirth, Lori J., Digumarthy, Subba R., Lee, Robert P., Kadosh, David, Mendelsohn, Robin B., Donington, Jessica, Gainor, Justin F., Drilon, Alexander, and Lin, Jessica J.
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- 2022
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3. Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization.
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Chu, Ying-Hsia, Wirth, Lori J., Farahani, Alexander A., Nosé, Vânia, Faquin, William C., Dias-Santagata, Dora, and Sadow, Peter M.
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- 2020
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4. 57 Local Control Following Combination Hypofractionated Radiotherapy and Pembrolizumab in a Phase II Trial of Recurrent or Metastatic Adenoid Cystic Carcinoma Patients
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Bang, Andrew, Mahmood, Umair, Chen, Yu-Hui, Mak, Raymond H., Lorch, Jochen H., Hanna, Glenn J., Sridharan, Vishwajith, Busse, Paul M., Willers, Henning, Mamon, Harvey J., Yoo, Hyung-Jin, Pai, Sara I., Wirth, Lori J., Haddad, Robert I., Chau, Nicole G., and Schoenfeld, Jonathan D.
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- 2019
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5. PARTNER: An open-label, randomized, phase 2 study of docetaxel/cisplatin chemotherapy with or without panitumumab as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck.
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Wirth, Lori J., Dakhil, Shaker, Kornek, Gabriela, Axelrod, Rita, Adkins, Douglas, Pant, Shubham, O’Brien, Paul, Debruyne, Philip R., Oliner, Kelly S., Dong, Jun, Murugappan, Swami, and O'Brien, Paul
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HEAD & neck cancer treatment , *DOCETAXEL , *CANCER chemotherapy , *CANCER treatment , *SQUAMOUS cell carcinoma , *CANCER relapse , *METASTASIS , *ANTINEOPLASTIC agents , *CISPLATIN , *CLINICAL trials , *COMPARATIVE studies , *HEAD tumors , *HYDROCARBONS , *RESEARCH methodology , *MEDICAL cooperation , *MONOCLONAL antibodies , *NECK tumors , *RESEARCH , *EVALUATION research , *RANDOMIZED controlled trials - Abstract
Objective: This phase 2 estimation study evaluated docetaxel/cisplatin with/without panitumumab, an anti-epidermal growth factor receptor monoclonal antibody, as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).Patients and Methods: Randomized patients received docetaxel/cisplatin (75mg/m(2) each) with/without panitumumab (9mg/kg) in 21-day cycles. Patients randomized to panitumumab+chemotherapy could continue panitumumab monotherapy after completing six chemotherapy cycles without progression; patients randomized to chemotherapy alone could receive second-line panitumumab after progression. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), overall response rate (ORR), time to response (TTR), duration of response (DOR), and safety. A protocol amendment limited enrollment to patients <70years owing to excess toxicity in older patients and added mandatory pegfilgrastim/filgrastim support. Outcomes were also analyzed by human papillomavirus status.Results: 103 of the 113 enrolled patients were evaluable and randomized to receive ⩾1 dose of first-line treatment. Median PFS for panitumumab+chemotherapy was 6.9 (95% CI=4.7-8.3) months versus 5.5 (95% CI=4.1-6.8) months for chemotherapy alone (hazard ratio [HR]=0.629; 95% CI=0.395-1.002; P=0.048). ORR for panitumumab+chemotherapy was 44% (95% CI=31-58%) versus 37% (95% CI=24-51%) for chemotherapy alone (odds ratio [OR]=1.37; 95% CI=0.57-3.33). Median OS for panitumumab+chemotherapy was 12.9 (95% CI=9.4-18.5) months versus 13.8 (95% CI=11.8-22.9) months for chemotherapy alone (HR=1.103; 95% CI=0.709-1.717). Median TTR for panitumumab+chemotherapy treatment was 6.9weeks versus 11.0weeks for chemotherapy alone. Median DOR was 8.0 (95% CI=5.7-11.1) months with panitumumab+chemotherapy versus 5.1 (95% CI=4.4-7.2) months with chemotherapy alone. Grade 3/4 adverse event incidence was 73% with panitumumab+chemotherapy versus 56% with chemotherapy alone. 41% and 55% of patients in the panitumumab+chemotherapy and chemotherapy-alone arms, respectively, received panitumumab monotherapy.Conclusion: The addition of panitumumab to docetaxel/cisplatin may improve PFS in recurrent/metastatic SCCHN and has the potential to improve outcomes in these fully, or mostly, active patients. [ABSTRACT FROM AUTHOR]- Published
- 2016
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6. DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity.
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Willers, Henning, Gheorghiu, Liliana, Liu, Qi, Efstathiou, Jason A., Wirth, Lori J., Krause, Mechthild, and von Neubeck, Cläre
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Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anticancer agents. Genomic profiling of human cancers provides us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome produces biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (ie, foci) of proteins in the DNA damage response (DDR), such as gamma-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant end points such as tumor control probability. Therefore, preclinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future. [ABSTRACT FROM AUTHOR]
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- 2015
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7. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors.
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Chong, Curtis R., Wirth, Lori J., Nishino, Mizuki, Chen, Aileen B., Sholl, Lynette M., Kulke, Matthew H., McNamee, Ciaran J., Jänne, Pasi A., and Johnson, Bruce E.
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CARCINOID , *CANCER chemotherapy , *ADJUVANT treatment of cancer , *RETROSPECTIVE studies , *DIAGNOSIS , *THERAPEUTICS ,MEDICAL literature reviews - Abstract
Objectives The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined. Materials and methods A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012. Results 300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I–III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum–etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months). Conclusions These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy. [ABSTRACT FROM AUTHOR]
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- 2014
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8. Outcome of patients with pulmonary carcinoid tumors receiving chemotherapy or chemoradiotherapy
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Wirth, Lori J., Carter, Mark R., Jänne, Pasi A., and Johnson, Bruce E.
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Study objectives: To determine the outcome of patients with pulmonary typical and atypical carcinoid tumors treated with chemotherapy with or without radiotherapy. Methods: Patients with pulmonary neuroendocrine tumors treated at our institution from 1990 to 2001 were identified. The medical records of patients with diagnoses of typical or atypical pulmonary carcinoids were reviewed for the presence of evaluable disease, treatment with chemotherapy with or without radiotherapy, response to these treatments, survival and cause of death. Results: Eighteen patients with typical (
n=8 ) or atypical (n=10 ) pulmonary carcinoid tumors who were treated with chemotherapy with or without radiotherapy were identified. Of these, four received chemotherapy plus chest radiotherapy. Three of these had stable disease and one had a partial response. One of the patients with stable disease to chemoradiotherapy subsequently received chemotherapy alone, to which he had a complete response. Fourteen additional patients were treated with 18 chemotherapy regimens. There were two partial responses, eight stable disease, seven progressive disease and one allergic reaction precluding further treatment. The overall response rate to any chemotherapy was 3/15 (20%, 95% CI 0.07–0.45), and the best overall response rate to chemotherapy with or without chest radiotherapy was 4/18 (22%, 95% CI 0.09–0.45). Median overall survival was 20 months (95% CI 0–51 months). Conclusions: Patients with typical and atypical pulmonary carcinoid tumors can respond to chemotherapy with or without chest radiotherapy, though with response rates that appear less than those of small cell lung cancers. Further characterization of pulmonary carcinoid tumors and study of treatment alternatives for unresectable disease is warranted. [Copyright &y& Elsevier]- Published
- 2004
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9. O10-3 Selpercatinib (LOXO-292) in patients (pts) with RET-altered thyroid cancer.
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Wirth, Lori J., Sherman, Eric J., Robinson, Bruce, Solomon, Benjamin, Kang, Hyunseok, Lorch, Jochen H., Worden, Francis, Brose, Marcia S., Leboulleux, Sophie, Godbert, Yann, Meurer, Marie, Morris, John, Owonikoko, Taofeek K., Shao-Weng Tan, Daniel, Gautschi, Oliver, Patel, Jyoti, Yang, Luxi, Kherani, Jennifer, Cabanillas, Maria E., and Shah, Manisha H.
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THYROID cancer , *ANTINEOPLASTIC agents - Published
- 2021
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10. SY33-2 New perspectives on the treatment of thyroid cancer: novel drugs for medullary thyroid cancer.
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Wirth, Lori J.
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THYROID cancer treatment , *PROTO-oncogenes , *KINASE inhibitors - Published
- 2021
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11. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer.
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Tahara, Makoto, Brose, Marcia S., Wirth, Lori J., Suzuki, Takuya, Miyagishi, Hideaki, Fujino, Katsuki, Dutcus, Corina E., and Gianoukakis, Andrew
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CONFIDENCE intervals , *METASTASIS , *MULTIVARIATE analysis , *STATISTICS , *DATA analysis , *THYROID gland tumors , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *TREATMENT duration , *ODDS ratio , *PROTEIN kinase inhibitors , *IODINE radioisotopes , *PROGNOSIS , *THERAPEUTICS - Abstract
Abstract Background In the phase 3 S tudy of (E 7080) Le nvatinib in D ifferentiated C ancer of the T hyroid (SELECT), lenvatinib significantly improved efficacy outcomes versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Lenvatinib-treated patients had more adverse events (AEs), which were generally managed with dose modifications, including dose interruption. This exploratory post hoc analysis investigated the impact of dose interruption on lenvatinib efficacy. Methods Dose modifications were required for grade 3 or intolerable grade 2 AEs in SELECT. Lenvatinib-treated patients were dichotomised based on the duration of dose interruption relative to total treatment duration: shorter dose interruption (<10% of total treatment duration) and longer dose interruption (≥10%). Results At the time of primary data cut-off (November 15, 2013; median follow-up, 17.1 months), the median progression-free survival (PFS) for the shorter dose-interruption group had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% confidence interval [CI], 9.3–16.5). Compared with placebo, the hazard ratios for PFS in the shorter and longer dose-interruption groups were 0.14 (95% CI, 0.09–0.20) and 0.31 (95% CI, 0.22–0.43), respectively. In a multivariate model, dose interruption was significantly associated with lenvatinib efficacy, even after adjustment for patient characteristics. Conclusions Lenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions. This analysis highlights the importance of timely management of lenvatinib toxicities to minimise dose interruptions and maximise lenvatinib efficacy in patients with RR-DTC. ClinicalTrials.gov number NCT01321554 Highlights • Lenvatinib significantly improved progression-free survival (PFS) versus placebo, regardless of dose interruption. • Shorter duration of lenvatinib dose interruption is associated with longer PFS. • Proactive management of lenvatinib toxicities may maximise efficacy. [ABSTRACT FROM AUTHOR]
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- 2019
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12. Seeking alternative biological therapies: The future of targeted molecular treatment
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Lorch, Jochen H., Posner, Marshall R., Wirth, Lori J., and Haddad, Robert I.
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ALTERNATIVE medicine , *SQUAMOUS cell carcinoma , *HEAD & neck cancer patients , *TARGETED drug delivery , *CANCER treatment , *PATIENTS - Abstract
Summary: In recent years targeted therapies have expanded treatment options for patients with squamous cell cancer of the head and neck (SCCHN) considerably and have led to clinically significant benefit. However, the multitude of new targeted drugs that have emerged and are in development also represent a challenge and many years of carefully conducted clinical studies will be needed to explore their full potential. This article summarizes the most important recent developments in the targeted treatment of SCCHN and provides an overview of pathways and promising potential targets that could impact the treatment of patients with SCCHN in the future. [Copyright &y& Elsevier]
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- 2009
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13. Screening and Validation of Molecular Targeted Radiosensitizers.
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Willers, Henning, Pan, Xiao, Borgeaud, Nathalie, Korovina, Irina, Koi, Lydia, Egan, Regina, Greninger, Patricia, Rosenkranz, Aliza, Kung, Jong, Liss, Andrew S., Parsels, Leslie A., Morgan, Meredith A., Lawrence, Theodore S., Lin, Steven H., Hong, Theodore S., Yeap, Beow Y., Wirth, Lori J., Hata, Aaron N., Ott, Christopher J., and Benes, Cyril H.
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HEAD & neck cancer , *FOCAL adhesion kinase , *EPIDERMAL growth factor receptors , *RADIATION-sensitizing agents , *HIGH throughput screening (Drug development) , *TREATMENT effectiveness , *RESEARCH funding - Abstract
The development of molecular targeted drugs with radiation and chemotherapy is critically important for improving the outcomes of patients with hard-to-treat, potentially curable cancers. However, too many preclinical studies have not translated into successful radiation oncology trials. Major contributing factors to this insufficiency include poor reproducibility of preclinical data, inadequate preclinical modeling of intertumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and a reliance on tumor growth delay instead of local control (TCD50) endpoints. There exists an urgent need to overcome these barriers to facilitate successful clinical translation of targeted radiosensitizers. To this end, we have used 3-dimensional (3D) cell culture assays to better model tumor behavior in vivo. Examples of successful prediction of in vivo effects with these 3D assays include radiosensitization of head and neck cancers by inhibiting epidermal growth factor receptor or focal adhesion kinase signaling, and radioresistance associated with oncogenic mutation of KRAS. To address the issue of tumor heterogeneity, we leveraged institutional resources that allow high-throughput 3D screening of radiation combinations with small-molecule inhibitors across genomically characterized cell lines from lung, head and neck, and pancreatic cancers. This high-throughput screen is expected to uncover genomic biomarkers that will inform the successful clinical translation of targeted agents from the National Cancer Institute Cancer Therapy Evaluation Program portfolio and other sources. Screening "hits" need to be subjected to refinement studies that include clonogenic assays, addition of disease-specific chemotherapeutics, target/biomarker validation, and integration of patient-derived tumor models. The chemoradiosensitizing activities of the most promising drugs should be confirmed in TCD50 assays in xenograft models with or without relevant biomarker and using clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts of being successfully incorporated into the standard management of hard-to-treat tumors. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer.
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Tahara, Makoto, Kiyota, Naomi, Hoff, Ana O., Badiu, Corin, Owonikoko, Taofeek K., Dutcus, Corina E., Suzuki, Takuya, Ren, Min, and Wirth, Lori J.
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CONFIDENCE intervals , *THYROID gland tumors , *LUNG tumors , *METASTASIS , *PROTEIN-tyrosine kinase inhibitors , *TREATMENT effectiveness , *CANCER patients , *RANDOMIZED controlled trials , *DESCRIPTIVE statistics , *STATISTICAL sampling , *CROSSOVER trials - Abstract
Lung metastases may worsen overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). We investigated (post hoc) the impact of lung metastases on survival in SELECT (a phase 3 study). 392 patients with RR-DTC were randomised 2:1 to lenvatinib 24 mg daily (n = 261) or placebo (n = 131). Placebo-treated patients could crossover to open-label lenvatinib following progression. Patients were grouped by size of baseline lung metastases. Safety/efficacy outcomes, collated by these lung-metastases subgroups, were generated. Lenvatinib-treated population distributions per baseline lung metastases subgroup were any lung metastases (target/nontarget lesions; n = 226), and by maximum size of target lung lesions ≥1.0 cm (n = 199), ≥1.5 cm (n = 150), ≥2.0 cm (n = 94) and <2.0 cm (n = 105). In patients with any lung metastases, no statistically significant difference in OS was observed between treatment arms (HR: 0.76; 95% CI: 0.57–1.01; P = 0.0549). Median OS for lung metastases of ≥1.0 cm was 44.7 months (lenvatinib) versus 33.1 months (placebo) (HR: 0.63; 95% CI: 0.47–0.85; P = 0.0025). OS was significantly prolonged with lenvatinib versus placebo among patients with lung metastases of ≥1.0 cm, ≥1.5 cm, ≥2.0 cm and <2.0 cm; median OS was shorter in the ≥2.0 cm subgroup (lenvatinib: 34.7 months) versus other subgroups (lenvatinib: 44.1–49.2 months). Multivariate analysis demonstrated lenvatinib significantly prolonged OS in patients with lung metastases of ≥1.0 cm after adjustment for baseline characteristics. Lenvatinib treatment resulted in longer OS in patients with lung metastases of ≥1.0 cm versus placebo (even with the 89% crossover rate). Early initiation of lenvatinib may improve outcomes in patients with RR-DTC and lung metastases of ≥1.0 cm. ClinicalTrials.Gov Identifier: NCT01321554. • The survival benefit of LEN was assessed in pts with lung metastases from SELECT. • Groups comprised: any lung metastases, ≥1.0 cm, ≥1.5 cm, ≥2.0 cm, or <2.0 cm. • OS and PFS: significantly longer with LEN vs placebo in all 4 groups. [ABSTRACT FROM AUTHOR]
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- 2021
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15. A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma.
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Mahmood, Umair, Bang, Andrew, Chen, Yu-Hui, Mak, Raymond H., Lorch, Jochen H., Hanna, Glenn J., Nishino, Mizuki, Manuszak, Claire, Thrash, Emily M., Severgnini, Mariano, Sanborn, Matthew, Sridharan, Vishwajith, Margalit, Danielle N., Tishler, Roy B., Busse, Paul M., Willers, Henning, Mamon, Harvey J., Yoo, Hyung-Jin, Pai, Sara I., and Wirth, Lori J.
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ADENOID cystic carcinoma , *PROGRAMMED death-ligand 1 , *METASTASIS , *LIVER enzymes , *PEMBROLIZUMAB , *PROGRESSION-free survival , *THERAPEUTIC use of monoclonal antibodies , *RESEARCH , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *TREATMENT effectiveness , *DISEASE relapse , *COMPARATIVE studies , *RANDOMIZED controlled trials , *SURVIVAL analysis (Biometry) , *COMBINED modality therapy - Abstract
Purpose: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC).Methods and Materials: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses.Results: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT.Conclusions: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response. [ABSTRACT FROM AUTHOR]- Published
- 2021
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16. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.
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Brose, Marcia S, Cabanillas, Maria E, Cohen, Ezra E W, Wirth, Lori J, Riehl, Todd, Yue, Huibin, Sherman, Steven I, and Sherman, Eric J
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PHARMACODYNAMICS , *THYROID cancer , *IODINE isotopes , *KINASE inhibitors , *GENETIC mutation , *ANTINEOPLASTIC agents , *INDOLE compounds , *SULFONAMIDES , *CLINICAL trials , *COMPARATIVE studies , *IMMUNOENZYME technique , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *METASTASIS , *PROGNOSIS , *RADIATION , *RESEARCH , *RESEARCH funding , *SURVIVAL , *THYROID gland tumors , *TRANSFERASES , *TUMOR classification , *EVALUATION research , *PAPILLARY carcinoma , *SALVAGE therapy , *IODINE radioisotopes , *THERAPEUTICS - Abstract
Background: About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer.Methods: We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753.Findings: Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2-26·0) in cohort 1 and 12·0 months (6·7-20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2-59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2.Interpretation: Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]- Published
- 2016
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17. Long-term survival after distant metastasis in patients with oropharyngeal cancer.
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McBride, Sean M., Busse, Paul M., Clark, John R., Wirth, Lori J., Ancukiewicz, Marek, and Chan, Annie W.
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OROPHARYNGEAL cancer , *CANCER invasiveness , *SQUAMOUS cell carcinoma , *HEALTH outcome assessment , *LONG-term care facilities , *REGRESSION analysis , *PATIENTS - Abstract
Summary: Objectives: For patients with oropharyngeal squamous cell carcinoma (OPSCC), especially for those with HPV-positive tumors, locoregional control is excellent. Distant metastasis, however, remains a substantial problem. The purpose of our study was to evaluate outcomes and predictors of survival after distant metastasis in OPSCC. Materials and methods: Between June 2002 and January 2011, 25 OPSCC patients treated with curative intent subsequently developed distant metastasis. The primary end-points evaluated were time-to-distant metastasis and overall survival after development of distant metastasis. Predictors of outcome were evaluated with median regression analysis or Cox regression. Best subset models were chosen to minimize the Bayesian Information Criterion (BIC). A prognostic index for survival after distant failure was created based on the selected model. Results: Median time-to-distant metastasis after completion of radiation was 7.9months (range, 1.6–25.4). Median overall survival from distant metastasis was 18.3months (95% CI, 14.3–39.8). The overall survival rates at 1- and 2-year after development of distant metastasis were 72.0% (95% confidence interval [CI], 53.4–89.6) and 40.8% (95% CI, 20.6–61.0), respectively. In multivariate analysis, Karnofsky Performance Status score (KPS)⩾80 (p =0.01, hazard ratio [HR] 0.15, 95% CI, 0.04–0.52) and limited, single-organ disease (p =0.003, HR 0.13, 95% CI 0.03–0.61) predicted for increased survival from distant metastasis. Patients with both limited disease and good KPS formed the most favorable risk group with a 2-year survival of 100%. Two patients with human papilloma virus (HPV)-positive tumors were alive without any evidence of disease at 64.6 and 60.4months, respectively, after aggressive local treatment of solitary metastasis. Conclusion: For OPSCC patients with limited, single-organ disease and good KPS, long-term survival can be achieved. [ABSTRACT FROM AUTHOR]
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- 2014
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18. Efficacy and Toxicity of Chemoradiotherapy Using Intensity-Modulated Radiotherapy for Unknown Primary of Head and Neck
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Sher, David J., Balboni, Tracy A., Haddad, Robert I., Norris, Charles M., Posner, Marshall R., Wirth, Lori J., Goguen, Laura A., Annino, Donald, and Tishler, Roy B.
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CANCER chemotherapy , *CANCER radiotherapy , *DRUG toxicity , *HEAD & neck cancer treatment , *SQUAMOUS cell carcinoma , *RETROSPECTIVE studies , *CANCER tomography , *COMBINED modality therapy - Abstract
Purpose: No single standard treatment paradigm is available for head-and-neck squamous cell carcinoma of an unknown primary (HNCUP). Bilateral neck radiotherapy with mucosal axis irradiation is widely used, with or without chemotherapy and/or surgical resection. Intensity-modulated radiotherapy (IMRT) is a highly conformal method for delivering radiation that is becoming the standard of care and might reduce the long-term treatment-related sequelae. We report the Dana-Farber Cancer Institute experience with IMRT-based treatment for HNCUP. Patients and Materials: A retrospective study of all patients treated at the Dana-Farber Cancer Institute for HNCUP with IMRT between August 2004 and January 2009. The primary endpoint was overall survival; the secondary endpoints were locoregional and distant control, and acute and chronic toxicity. Results: A total of 24 patients with HNCUP were included. Of these patients, 22 had Stage N2 disease or greater. All patients underwent neck computed tomography, positron emission tomography-computed tomography, and examination under anesthesia with directed biopsies. Of the 24 patients, 22 received concurrent chemotherapy, and 7 (29%) also underwent induction chemotherapy. The median involved nodal dose was 70 Gy, and the median mucosal dose was 60 Gy. With a median follow-up of 2.1 years, the 2-year actuarial overall survival and locoregional control rate was 92% and 100%, respectively. Only 25% of the patients had Grade 2 xerostomia, although 11 patients (46%) required esophageal dilation for stricture. Conclusion: In a single-institution series, IMRT-based chemoradiotherapy for HNCUP was associated with superb overall survival and locoregional control. The xerostomia rates were promising, but the aggressive therapy was associated with significant rates of esophageal stenosis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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19. Dose to Larynx Predicts for Swallowing Complications After Intensity-Modulated Radiotherapy
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Caglar, Hale B., Tishler, Roy B., Othus, Megan, Burke, Elaine, Li, Yi, Goguen, Laura, Wirth, Lori J., Haddad, Robert I., Norris, Carl M., Court, Laurence E., Aninno, Donald J., Posner, Marshall R., and Allen, Aaron M.
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LARYNGEAL cancer , *RADIOTHERAPY , *DRUG therapy , *QUALITY of life - Abstract
Purpose: To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. Methods and Materials: Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Women''s Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. Results: A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose–volume metrics, including the volume of the larynx receiving ≥50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving ≥50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. Conclusion: Aspiration and stricture are common side effects after intensity-modulated radiotherapy for head-and-neck squamous cell carcinoma. The dose given to the larynx and inferior constrictors correlated with these side effects. [Copyright &y& Elsevier]
- Published
- 2008
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20. Concurrent weekly docetaxel and concomitant boost radiation therapy in the treatment of locally advanced squamous cell cancer of the head and neck
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Tishler, Roy B., Posner, Marshall R., Norris, Charles M., Mahadevan, Anand, Sullivan, Christopher, Goguen, Laura, Wirth, Lori J., Costello, Rosemary, Case, MaryAnn, Stowell, Sara, Sammartino, Dan, Busse, Paul M., and Haddad, Robert I.
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DRUG therapy , *THERAPEUTICS , *CANCER treatment , *CANCER radiotherapy - Abstract
Purpose: In a Phase I/II trial, we investigated concurrent weekly docetaxel and concomitant boost radiation in patients with locally advanced squamous cell cancer of the head and neck (SCCHN) after induction chemotherapy. Patients and Methods: Patients presented with American Joint Committee on Cancer Stage III/IV and were treated initially with induction chemotherapy using cisplatinum/5-fluorouracil (PF), carboplatinum-5-FU, or docetaxel-PF. Patients then received docetaxel four times weekly with concomitant boost (CB) radiation (1.8 Gy once-daily X20, 1.8/1.5 Gy twice a day). Fifteen patients each received 20 mg/M2 and 25 mg/M2. Results: Thirty-one patients were enrolled and 30 were evaluable for response and toxicity. Median follow-up was 42 months (range, 27–63 months). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, and unknown primary 4. Eighty-seven percent of patients had N2/N3 disease; 60% had T3/T4 disease. Twenty percent of patients had a complete response (CR) to induction chemotherapy. After chemoradiotherapy, 21 of 30 patients had a CR, 2 had progressive disease, and 7 had partial response (PR). Nineteen of 26 patients presenting with neck disease had neck dissections, and 7 of 19 were positive. Ninety-three percent of all patients were rendered disease-free after all planned therapy. Treatment failed in 8 patients, and 7 have died of disease. An additional patient died with no evidence of disease. Twenty-one patients (70%) are currently alive with no evidence of disease. No acute dose-limiting toxicity was observed at either dose level. Conclusions: This intensive treatment regimen of concurrent docetaxel/concomitant boost radiation and surgery after induction chemotherapy in poor prognosis patients yields good local regional control and survival. Docetaxel/CB chemoradiotherapy represents an aggressive alternative regimen to platinum-based chemoradiotherapy or surgery in patients who have a poor response to induction chemotherapy. [Copyright &y& Elsevier]
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- 2006
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21. A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma.
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Hanna, Glenn J., ONeill, Anne, Cutler, Jennifer M., Flynn, Michelle, Vijaykumar, Tushara, Clark, John R., Wirth, Lori J., Lorch, Jochen H., Park, Jong C., Mito, Jeffrey K., Lohr, Jens G., Kaufman, Jeffrey, Burr, Nicole Spardy, Zon, Leonard I., and Haddad, Robert I.
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ADENOID cystic carcinoma , *TRETINOIN , *DRUG dosage , *DRUG toxicity , *PROTEIN expression - Abstract
Background: Effective therapies are lacking for recurrent, metastatic adenoid cystic carcinoma (R/M ACC) and preclinical models suggest retinoic acid agonists inhibit ACC growth. This phase II trial evaluated all-trans retinoic acid (ATRA) as a novel therapy for ACC.Methods: Patients with R/M ACC (any site) with clinical and/or radiographic progression ≤12 months prior to study entry were eligible. Cohort 1 (CH1) received ATRA 45 mg/m2 split oral daily dosing on days 1-14 of a 28-day cycle; Cohort 2 (CH2) received the same dosing continuously. Primary endpoint was best overall response rate (CR + PR) (RECIST v1.1). Secondary endpoints: safety and progression-free survival (PFS). Exploratory analyses: ATRA impact on MYB expression and genomic predictors of response.Results: Eighteen patients enrolled. There were no responses, but 61% (11/18) had stable disease (SD) and 28% (5/18) progression as best response; 11% (2/18) unevaluable. Median duration of stability: 3.7 months (95%CI, 1.9-3.9). One patient (CH1) remains on drug with SD approaching 1 year. Half of those who received prior VEGFR therapy achieved SD (4/8). At median follow up of 7.9 months, median PFS was 3.2 months (95%CI, 1.8-3.9). N = 1 required dose adjustment; N = 1 came off drug for toxicity. There were no grade 3-4 adverse events. NOTCH1 and PI3K pathway alterations were most frequent. Low MYB protein expression was associated with longer duration of stability on ATRA (P < 0.01).Conclusion(s): While the trial did not meet its prespecified response endpoint, ATRA alone or in combination may be a low toxicity treatment for disease growth stabilization in R/M ACC. [ABSTRACT FROM AUTHOR]- Published
- 2021
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