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Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.
Jimeno, A, Machiels, JP, Wirth, L, Specenier, P, Seiwert, TY, Mardjuadi, F, Wang, X, Kapp, AV, Royer-Joo, S, Penuel, E, et al
Cancer. 2016;(24):3803-3811
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Abstract
BACKGROUND This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck. METHODS On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m2 and 5-fluorouracil at a dose of 1000 mg/m2 /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m2 ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred. RESULTS Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses). CONCLUSIONS Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.
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A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.
Chen, AC, Martin, AJ, Dalziell, RA, McKenzie, CA, Lowe, PM, Eris, JM, Scolyer, RA, Dhillon, HM, Vardy, JL, Bielski, VA, et al
The British journal of dermatology. 2016;(5):1073-1075
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Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT).
Chiu, JW, Chan, K, Chen, EX, Siu, LL, Abdul Razak, AR
Investigational new drugs. 2015;(4):895-900
Abstract
BACKGROUND Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided). METHODS Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. RESULTS Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. CONCLUSION Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.
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Detection of superficial esophageal squamous cell neoplasia by chromoendoscopy-guided confocal laser endomicroscopy.
Huang, J, Yang, YS, Lu, ZS, Wang, SF, Yang, J, Yuan, J
World journal of gastroenterology. 2015;(22):6974-81
Abstract
AIM: To evaluate the diagnostic potential of Lugol's chromoendoscopy-guided confocal laser endomicroscopy (CLE) in detecting superficial esophageal squamous cell neoplasia (ESCN). METHODS Between December 2008 and September 2010, a total of 52 patients were enrolled at the Chinese PLA General Hospital in Beijing, China. First, Lugol's chromoendoscopy-guided CLE was performed in these patients and the CLE in vivo histological diagnosis was recorded. Then, chromoendoscopy-guided biopsy was performed in the same patients by another endoscopist who was blinded to the CLE findings. Based on the biopsy and CLE diagnosis, en bloc endoscopic resection was performed. The CLE in vivo diagnosis and the histological diagnosis of biopsy of ESCN were compared, using a histological examination of the endoscopic resection specimens as the standard reference. RESULTS A total of 152 chromoendoscopy-guided biopsies were obtained from 56 lesions. In the 56 lesions of 52 patients, a total of 679 CLE images were obtained vs 152 corresponding biopsies. The sensitivity, specificity, negative predictive value and positive predictive value of chromoendoscopy-guided CLE compared with biopsy were 95.7% vs 82% (P < 0.05), 90% vs 70% (P < 0.05), 81.8% vs 46.7% (P < 0.05), and 97.8% vs 92.7% (P > 0.05), respectively. There was a significant improvement in sensitivity, specificity, negative predictive value, and accuracy when comparing chromoendoscopy-guided CLE with biopsy. CONCLUSION Lugol's chromoendoscopy-guided CLE is a real-time, non-invasive endoscopic diagnostic technology; the accuracy of the detection of superficial ESCN is equivalent to or may be superior to biopsy histology.
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Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
Machiels, JP, Haddad, RI, Fayette, J, Licitra, LF, Tahara, M, Vermorken, JB, Clement, PM, Gauler, T, Cupissol, D, Grau, JJ, et al
The Lancet. Oncology. 2015;(5):583-94
Abstract
BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. METHODS In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. FINDINGS Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. INTERPRETATION Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING Boehringer Ingelheim.
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Management of inoperable malignant oesophageal strictures with fully covered WallFlex(®) stent: a multicentre prospective study.
Repici, A, Jovani, M, Hassan, C, Solito, B, Di Mitri, R, Buffoli, F, Macrì, G, Fregonese, D, Cennamo, V, De Bellis, M, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2014;(12):1093-8
Abstract
BACKGROUND The majority of currently available oesophageal metal stents are partially covered to reduce migration risk. Preliminary experiences with fully covered stents seem to indicate an increased risk of migration in patients treated for malignant dysphagia. The aim of our study was to determine, in this setting, the safety and efficacy of a new, recently introduced stent with anti-migration proprieties. METHODS We designed a prospective, multicentre, non-randomized, follow-up study in nine tertiary referral centres. Eighty-two patients with dysphagia due to inoperable or metastatic oesophageal cancer were included. In all of them the fully covered WallFlex(®) stent was placed. Main outcome measurements included functional outcome, recurrent dysphagia, complications, and mortality. RESULTS Dysphagia score improved from a median of 3, before stenting, to 1 at 4 weeks after stent placement (P<0.001). Perforation occurred in 1 patient after 39 days, while bleeding was reported in 3. In total, 19 patients (23.1%) developed recurrent dysphagia because of stent migration (N=10, 12.2%), tissue overgrowth (N=7; 8.5%), and food impaction (N=2; 2.4%). CONCLUSIONS Placement of the fully covered WallFlex(®) stent resulted in safe and effective palliation of malignant dysphagia, with migration and tissue overgrowth rates comparable to previously reported data on partially covered stents.
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A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.
Ho, AL, Lipson, BL, Sherman, EJ, Xiao, H, Fury, MG, Apollo, A, Seetharamu, N, Sima, CS, Haque, S, Lyo, JK, et al
Investigational new drugs. 2014;(3):549-54
Abstract
BACKGROUND Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). PATIENTS AND METHODS This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. RESULTS Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. CONCLUSIONS Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.
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Phase I trial of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma - GORTEC 2004-02.
Tao, Y, Bardet, E, Rosine, D, Rolland, F, Bompas, E, Daly-Schveitzer, N, Lusinchi, A, Bourhis, J
Radiation oncology (London, England). 2013;:40
Abstract
PURPOSE This study sought to determine the maximum tolerated dose (MTD) of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. Patients with locally advanced HNSCC were enrolled onto cohorts of escalating dose of etoposide. Oral etoposide was administered on five consecutive days every week for 7 weeks (7 treatment cycles) in combination with daily radiotherapy (70 Gy /35 fractions). Two dose levels (25 mg/day and 50 mg/day) of etoposide were planned and three to six patients were to be enrolled at each level according to the potential DLTs. RESULTS Fourteen patients were allocated to two dose levels: 25 mg/day (3) and 50 mg/day (11). Cisplatin was contra-indicated in all the patients included. Only one patient (50 mg/day) presents a grade 4 neutropenia (DLT), no other DLTs were observed. The most frequently adverse events (AEs) were radiomucositis. Two deaths before 3 months of end of treatment were not related to treatment. Seven patients were still alive with a median follow-up of 30 months (12-58 months). Nine patients had a complete response (CR) at 3 months after the radiotherapy; Among the 9 patients, 3 patients had a local relapse; one patient with local and distant relapse. CONCLUSION Due to only one DLT experienced, it is possible to a dose of 50 mg/day for phase II studies, however this should be considered with caution.
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Initial experiences of an enhanced recovery protocol in esophageal surgery.
Blom, RL, van Heijl, M, Bemelman, WA, Hollmann, MW, Klinkenbijl, JH, Busch, OR, van Berge Henegouwen, MI
World journal of surgery. 2013;(10):2372-8
Abstract
BACKGROUND A recent development in gastrointestinal surgery is the implementation of enhanced recovery after surgery (ERAS) programs. Evidence regarding the benefit of these programs in patients undergoing esophageal surgery is scarce. We investigated the feasibility and possible benefit of a perioperative ERAS program in patients undergoing esophagectomy for malignant disease. METHODS The ERAS program was initiated in 2009. Patients who underwent esophagectomy and were treated according to the ERAS program were included. Items of ERAS included preoperative nutrition, early extubation, early removal of nasogastric tube, and early mobilization. Primary outcome parameters were hospital stay and the incidence of postoperative complications. Outcome parameters in the ERAS cohort were compared to a cohort of patients who underwent surgical resection in the year prior to the implementation of the ERAS protocol. A feasibility analysis was performed among a sample of ERAS patients to determine the number of achieved items per patient. RESULTS Between 2008 and August 2010, 181 patients in our department underwent esophagectomy. Of these, 103 patients were included in the ERAS program (ERAS+ group) and were compared to 78 patients who had undergone an esophagectomy in 2008 (ERAS- group). Overall hospital stay was 14 days versus 15 days (ERAS+ and ERAS-, respectively; p = 0.013). There were no significant differences in the incidence of postoperative complications in either group. The percentage of achieved items varied between 42 and 93 % per item. CONCLUSIONS The implementation of an ERAS program in esophageal surgery was feasible and resulted in a small but significant reduction in overall hospital stay, whereas overall morbidity was not affected.
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[Adjunctive therapy of hypopharyngeal carcinoma by Qingliu Lianghou Recipe].
Chen, WJ, Wang, B, Han, XL
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2012;(7):892-5
Abstract
OBJECTIVE To study the adjunctive roles of Qingliu Lianghou Recipe (QLR) in treatment of hypopharyngeal carcinoma. METHODS A total of 156 patients with hypopharyngeal squamous cell carcinoma were recruited, including 21 cases of stage I, 34 in stage II, 55 in stage III, and 46 in stage IV. Of them, 31 patients (Group A) were managed with operation and post-operative radiotherapy, 40 patients (Group B) with operation, post-operative radiotherapy, and QLR, 45 patients (Group C) were managed with concomitant chemoradiotherapy, 40 patients (Group D)with concomitant chemoradiation and QLR. QLR was given for 12 weeks. The radio- and chemotoxic reactions, quality of life (KPS score), and long-term efficacy (the recurrence time and the survival time) were observed. RESULTS The toxicity levels were significantly lower in Group B than in Group A, manifested as radioactive dermatitis, mucositis, dysphagia, changes in body weight, and lymphatic edema (P < 0.05, P < 0.01). The toxicity levels were significantly lower in Group D than in Group C, manifested as radioactive dermatitis, mucositis, dysphagia, marrow depression, changes in body weight, and gastrointestinal reactions (P < 0.05, P < 0.01). After treatment the KPS scores of all patients obviously decreased (P < 0.05, P < 0.01). But the KPS scores were significantly higher in Group B than in Group A (P < 0.05), and they were significantly higher in Group D than in Group C (P < 0.05). The 3-year recurrence rate of patients in Group A was 41.94%, 20.00% in Group B, 60.00% in Group C, and 37.50% in Group D (P < 0.05). The 5-year survival rate of patients in Group A was 38.71%, 62.50% in Group B, 22.22% in Group C, and 42.50% in Group D (P < 0.05). CONCLUSIONS QLR could effectively prevent and reduce the toxicity response caused by operation, radiotherapy and chemotherapy. The combination therapy of integrative medicine could postpone the recurrence and prolong the lifespan of patients. Therefore, we must not neglect the adjunctive therapy of QLR in treating hypopharyngeal carcinoma.