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1.
Cancer Invest ; 24(3): 242-5, 2006.
Article in English | MEDLINE | ID: mdl-16809151

ABSTRACT

BACKGROUND: The purpose of this retrospective evaluation was to assess the palliative effect of oral etoposide in heavily pretreated patients with squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Between October 1995 and February 2003, a total of 26 patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with oral etoposide. Therapy consisted of etoposide at a total dose of 100 mg daily for 7 days and was repeated every 4 weeks until progression of disease or for a maximum of 8 courses. Eighteen patients underwent primary surgery of the tumour followed by adjuvant irradiation or surgery after neoadjuvant radiochemotherapy. Eight patients had primary irradiation with or without concomitant chemotherapy. All patients previously received at least one palliative chemotherapy with cisplatin/5-floururacil (5-FU) or cisplatin/taxotere. Patients did not routinely receive anti-emetic medication. RESULTS: All patients were eligible for toxicity and survival assessment, and 24 of 26 patients for response evaluation according to an intention-to-treat principle. Two patients had a partial response (8 percent); disease was stable in 9 patients (35 percent) and progressed in 13 patients (50 percent). The median time to progression for all patients was 3 months (range, 2-54), and median overall survival was 10 months (range, 2-52). Toxicity was in general mild and moderate (Grade 1 and 2), except three patients, who experienced Grade 3 anaemia, and one patient who had Grade 3 thrombocytopenia without bleeding complications. Severe nonhematologic adverse reactions were not seen, except for alopecia. CONCLUSION: Our data suggest that oral etoposid is markedly effective, in regard to stabilization of disease and survival, and an excellent tolerated therapy for pretreated patients with recurrent and/or metastatic head and neck carcinomas. Its advantage over other commonly used and more intensive regimens such as 5-fluorouracil (5-FU) + cisplatin or taxane-containing combinations is its superior tolerance, in particular the incidence of nausea and vomiting, complete alopecia, and/or hematologic complications.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Etoposide/therapeutic use , Head and Neck Neoplasms/drug therapy , Administration, Oral , Aged , Female , Humans , Male , Middle Aged , Neoplasm Metastasis/drug therapy , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Treatment Outcome
3.
Oncology ; 63(2): 145-50, 2002.
Article in English | MEDLINE | ID: mdl-12239449

ABSTRACT

PURPOSE: Since the combination of cisplatin and docetaxel have demonstrated activity in squamous cell carcinomas of the lung and oesophagus before, promising results in recurrent metastatic head and neck cancer were expected. PATIENTS AND METHODS: Between September 1998 and October 2000, 40 patients entered this trial, 38 of whom were evaluable. Six patients were previously untreated, 24 had surgery and/or radiotherapy and 13 had received chemoradiation and/or surgery. Therapy consisted of 75 mg/m(2) docetaxel (1-hour infusion) and 75 mg/m(2) cisplatin (90-min infusion) on day 1, repeated every three weeks for a maximum of 6 courses. All patients received corticosteroids routinely, 5-HT3-antagonists, and hydration. RESULTS: The overall response rate was 52.5% (95% confidence interval, 36.1 to 68.5%) including 7 complete (17.5% complete response; CR) and 14 partial remissions (35% partial response; PR). The overall response rate in patients who had no prior treatment (n = 6) was 100%, including 3 CR and 3 PR. In patients who had prior surgery and/or radiotherapy (n = 21) an overall response rate of 42.8% was observed, including 2 CR and 7 PR; 8 patients (38.1%) had stable disease, while disease progressed in 3 (14.3%). Six of 13 patients (46.2%) who had prior chemoradiation +/- surgery responded, including 2 CR (15.4%) and 4 PR (30.8%), no change was seen in 4 patients (30.8%) and tumour progressed in 2 (15.4%). The median response duration for all patients was 10 months (range, 3-20), the median overall survival was 11 months (range, 1-30). Myelosuppression was commonly observed; WHO grade 3 or 4 neutropenia occurred in 12 patients (30%) each, and was complicated by septicaemia in 5 cases. WHO grade 3 anaemia was observed in only 3 patients (7.5%). Severe non-hematologic toxicity except for alopecia was rarely observed, and included diarrhea in 2 (5%), nausea/vomiting in 2 patients (5%) and stomatitis in 1 patient (2.5%). CONCLUSION: Our data suggest that docetaxel and cisplatin in combination is an effective and fairly well tolerated regimen for the treatment of head and neck cancer with an excellent response rate in previously untreated patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Adult , Aged , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/secondary , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy , Disease-Free Survival , Docetaxel , Head and Neck Neoplasms/mortality , Humans , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Palliative Care , Recurrence , Survival Rate , Time Factors
5.
Br J Cancer ; 86(12): 1858-63, 2002 Jun 17.
Article in English | MEDLINE | ID: mdl-12085176

ABSTRACT

A phase II trial was performed to determine the antitumour efficacy and tolerance of combined paclitaxel and cisplatin with or without hematopoetic growth factor support in patients with advanced gastric cancer. Forty-five patients with histologically confirmed metastatic gastric cancer were entered in this trial. Treatment consisted of 2-weekly courses of paclitaxel 160 mg per m2 and cisplatin 60 mg per m2 both given on day 1. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1000-2000 per microl), a 5-day course of human granulocyte colony-stimulating factor 5 microg x kg(-1) per day was given subcutaneously; in addition, if haemoglobin was <12.0 mg dl(-1), erythropoietin 10 000 IU was administered subcutaneously three times per week. The confirmed overall response rate (intent-to-treat) was 44%, including five complete (11%) and 15 partial remissions (33%). Twelve patients had stable disease (27%), 11 (24%) progressed while on chemotherapy, and two patients were not evaluable. The median time to response was 3 months, the median time to progression 7.0 months, and the median survival time was 11.2 months with 12 patients currently alive. Haematologic toxicity was common, though WHO grade 4 neutropenia occurred in only five patients (11%). Apart from total alopecia in 16 patients (36%), severe non-haematologic adverse reactions included grade 3 peripheral neuropathy in six (13%) and anaphylaxis in two patients. In addition, there was one patient each who experienced grade 3 emesis, diarrhea, and infection, respectively. Our data suggest that the combination of paclitaxel and cisplatin with or without G-CSF and/or erythropoietin has promising therapeutic activity in patients with advanced gastric cancer.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Erythropoietin/administration & dosage , Granulocyte Colony-Stimulating Factor/administration & dosage , Stomach Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Erythropoietin/adverse effects , Female , Granulocyte Colony-Stimulating Factor/adverse effects , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate , Treatment Outcome
6.
Scand J Gastroenterol ; 37(2): 222-5, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11843061

ABSTRACT

BACKGROUND: Carcinoma of the biliary system is a rare tumour entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for advanced biliary carcinoma and reports of expression of receptors for somatostatin (SST), we performed a phase II study to evaluate the clinical potential of the long-acting SST analogue lanreotide (LAN) for treatment of this disease. METHODS: Twenty consecutive patients with histologically verified primary hepatic cholangiocellular cancer or primary adenocarcinoma of the gallbladder were enrolled in the study. Before initiation of therapy, SST-receptor scintigraphy using 111In-DOTA-LAN was carried out in eight patients to check for in vivo expression of SST receptors. Thirty milligrams of a slow-release formulation of LAN was administered by deep intramuscular injection every 2 weeks until progression or patients wished to withdraw. Restaging by means of computed tomography was performed every 8 weeks, and response was assessed according to World Health Organisation standard criteria. In addition, weight, performance status, analgesic intake and subjective pain perception were recorded every 4 weeks, along with evaluation of tumour markers CEA and Ca 19-9. RESULTS: Tumour sites were visualized by means of 111In-DOTA-LAN in all 8 patients. A total of 161 injections were administered, the median number per patient being 5 (range 2-36). Side effects were generally mild, only two patients complained of mild nausea and one patient had meteorism attributed to therapy. Therapeutic results, however, were disappointing, with only one patient demonstrating complete remission (CR), which lasted for 18 months before diagnosis of recurrence. Four patients had stable disease (SD) lasting between 3.5 and 9+ months accompanied by weight gain and improvement in performance status in 2 cases, while the remaining 15 patients progressed during therapy. The median time to progression was 2.5 months (range 1-18), and the median survival was 4.5 months (range 1.5-18+ months). No clear-cut correlation between scan result and therapeutic outcome could be demonstrated, as not only the patient with CR and two with SD, but also five patients with progressive disease had a positive scan result. CONCLUSION: Our data show that adenocarcinomas of the gallbladder and hepatic cholangiocellular carcinomas express SST receptors in vivo as judged by 111In-DOTA-LAN scintigraphy. Despite this fact, LAN did not display therapeutic activity in this study.


Subject(s)
Antineoplastic Agents/therapeutic use , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic , Cholangiocarcinoma/drug therapy , Peptides, Cyclic/therapeutic use , Receptors, Somatostatin/metabolism , Somatostatin/therapeutic use , Aged , Bile Duct Neoplasms/diagnostic imaging , Bile Ducts, Intrahepatic/diagnostic imaging , Cholangiocarcinoma/diagnostic imaging , Female , Gallbladder Neoplasms/diagnostic imaging , Gallbladder Neoplasms/drug therapy , Heterocyclic Compounds , Humans , Male , Prospective Studies , Radionuclide Imaging , Radiopharmaceuticals , Somatostatin/analogs & derivatives
7.
Ann Oncol ; 12(9): 1269-72, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11697839

ABSTRACT

BACKGROUND: A multicenter phase II trial was initiated to investigate the efficacy and tolerance of a dose-fractionated administration schedule of irinotecan in patients with advanced colorectal cancer pre-treated with fluoropyrimidine/ oxaliplatin-based first-line combination chemotherapy. PATIENTS AND METHODS: 38 patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding systemic chemotherapy with oxaliplatin in combination with 5-fluorouracil/leucovorin or the specific thymidilate synthase inhibitor raltitrexed were enrolled in this study. Treatment consisted of irinotecan 175 mg/m2 given on days 1 and 10. Courses were repeated every three weeks for a total of six courses unless prior evidence of progressive disease. RESULTS: The overall objective response rate was 21% for all 38 patients (95% confidence interval (95% CI): 9.6% to 37.4%). Stable disease was noted in 19 patients (50%), whereas the tumour progressed in 11 (29%). The median progression-free survival was 4.8 months (range 1.5 to 10.5). After a median follow-up time of 10 months, 21 patients (55%) are still alive. Treatment was fairly well tolerated with only 9 of 38 patients (24%) experiencing grade 3 or 4 neutropenia. Similarly, nonhaematologic adverse reactions were generally mild; grade 3 toxicities included late-onset diarrhoea in 2 (5%), alopecia in 5 (13%), and infection in 1 case (3%), respectively. CONCLUSIONS: Our data suggest that this dose-fractionated irinotecan monotherapy schedule has substantial antitumour activity in patients with flupropyrimidine/oxaliplatin-based pre-treated colorectal cancer. Because of its favourable toxicity profile when compared to previous experiences with the European standard schedule of 350 mg/m2 every three weeks, further evaluation of this modified regimen seems warranted.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Colorectal Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Camptothecin/administration & dosage , Camptothecin/adverse effects , Colorectal Neoplasms/pathology , Disease Progression , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Fluorouracil/pharmacology , Humans , Irinotecan , Leucovorin/pharmacology , Male , Middle Aged , Neutropenia/chemically induced , Organoplatinum Compounds/pharmacology , Oxaliplatin
8.
Alcohol Clin Exp Res ; 25(4): 496-501, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11329487

ABSTRACT

BACKGROUND: Alcohol increases the risk of cancers of the upper aerodigestive tract, but the biological mechanisms of this ethanol effect are still unclear. We recently reported that ethanol is able to induce in vitro proliferation accompanied by an increased number of cells in the S phase of the cell cycle in squamous cell carcinoma cell lines of the head and neck (SCCHN). In the current study we investigated the influence of ethanol over a limited period of time (96 hr) on cell cycle-regulating proteins involved in G1/S phase transition. METHODS: Synchronized cells of SCCHN cell lines JPPA (larynx) and SCC 9 and SCC 25 (tongue), as well as HaCaT (human immortalized keratinocytes)-used as a control-were cultured for 96 hr in the presence or absence of ethanol (10-3M). At several time intervals the expression of cyclin D1 and p21 and the phosphorylation status of the retinoblastoma protein (pRb) were determined by Western or Northern Blot analysis, or both. RESULTS: Ethanol had no influence on the protein expression of cyclin D1. In contrast, a distinct downregulation of p21 at the protein as well as the mRNA level could be detected. Furthermore, as a downstream event, the hyperphosphorylated form of the pRb increased. CONCLUSIONS: In the acute alcohol in vitro experiments, the marked downregulation of the important cell cycle inhibitor p21 and the corresponding increase of hyperphosphorylated pRb accelerate the progression of cells from the G1 to the S phase in the cell cycle. The importance of these data and their relevance to in vivo conditions remain speculative, but it could be a critical step in the multistep process of SCCHN carcinogenesis induced by ethanol.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Head and Neck Neoplasms/metabolism , Retinoblastoma Protein/drug effects , rho GTP-Binding Proteins/drug effects , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Phosphorylation , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Retinoblastoma Protein/metabolism , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , rho GTP-Binding Proteins/metabolism
9.
Anticancer Drugs ; 12(3): 205-8, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11290867

ABSTRACT

A phase II study was performed to assess the safety and efficacy of ifosfamide and mitoxantrone in recurrent and/or metastatic squamous cell carcinomas of the head and neck. Treatment consisted of ifosfamide 1500 mg/m2 in 1000 ml saline, infused over 60 min and mesna 20% of the total dose of ifosfamide in three doses for 3 days combined with mitoxantrone 12 mg/m2 given as a short infusion on day 1. Treatment courses were repeated every 4 weeks until a total of six cycles. Twenty-two patients entered this trial, 13 of whom had received chemo- and radiation therapy, and nine patients who underwent radiation therapy with or without prior surgery. We observed no objective response, with the exception of two patients who experienced minor response (reduction of tumor size of 25%). The dose-limiting toxicity was myelosuppression with grade 3/4 leukocytopenia in seven patients (32%) and grade 3/4 neutropenia in 15 (68%). Severe organ toxicity except alopecia (91%) was not observed. Ifosfamide combined with mitoxantrone does not improve the therapeutic armentarium in recurrent squamous cell carcinoma of the head and neck.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , DNA Topoisomerases, Type II , Head and Neck Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Antigens, Neoplasm , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , DNA-Binding Proteins , Diarrhea/chemically induced , Female , Follow-Up Studies , Humans , Ifosfamide/administration & dosage , Ifosfamide/adverse effects , Isoenzymes/antagonists & inhibitors , Male , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effects , Nausea/chemically induced , Neoplasm Metastasis , Neoplasm Recurrence, Local , Neutropenia/chemically induced , Stomatitis/chemically induced , Topoisomerase II Inhibitors , Treatment Outcome , Vomiting/chemically induced
10.
Acta Otolaryngol ; 121(1): 103-9, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11270487

ABSTRACT

The biologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], inhibits proliferation and induces differentiation for various malignant cells, including squamous cell carcinoma cell lines of the head and neck (SCCHN). These effects are due to an arrest of cells in the G0/G1 phase of the cell cycle and are predominantly mediated by the vitamin D receptor. To further explore the molecular mechanisms of the antiproliferative activity in SCCHN we studied the influence of 1,25(OH)2D3 on the expression of the G1 phase-regulating proteins cyclin D1, p21 and p27. Furthermore, as a direct target of G1 protein complexes, we investigated the phosphorylation status of the retinoblastoma protein (pRb). Synchronized cells of 2 SCCHN cell lines [JPPA (laryngeal carcinoma) and SCC 9 (tongue carcinoma)] and human immortalized keratinocytes (HaCaT) were cultured for 96 h in the presence or absence (ethanol as control) of 1,25(OH)2D3 (10(-7) M). At various time intervals the cell cycle status was detected by fluorescence-activated cell sorting (FACS) analysis and in parallel the expression of cell cycle-regulating proteins was determined at the protein and mRNA levels. In all cell lines tested 1,25(OH)2D3 caused an arrest of cells in the G0/G1 phase of the cell cycle and markedly induced the expression of the inhibitors p21 and p27. No influence was detectable on the expression of cyclin D1. Induction of p21 and p27 mRNA revealed transcriptional regulation by the vitamin D receptor. Simultaneously, hyperphosphorylated pRb was transformed to the hypophosphorylated form. Our results demonstrate that the biologically active form of vitamin D3 directly regulates the expression of p21 and p27, inducing a G0/G1 phase arrest: one mechanism by which 1,25(OH)2D3 controls cell proliferation inSCCHN.


Subject(s)
Calcitriol/pharmacology , Carcinoma, Squamous Cell/genetics , Cell Cycle Proteins , Cell Cycle/drug effects , Cyclins/metabolism , Head and Neck Neoplasms/genetics , Microtubule-Associated Proteins/metabolism , Tumor Suppressor Proteins , Cell Line , Cyclin-Dependent Kinase Inhibitor p21 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclins/genetics , Flow Cytometry , Humans , Immunoblotting , Microtubule-Associated Proteins/genetics , Polymerase Chain Reaction , RNA/analysis , Retinoblastoma Protein/analysis , Tumor Cells, Cultured
11.
Laryngoscope ; 111(10): 1834-41, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11801954

ABSTRACT

OBJECTIVES: Vascular endothelial growth factor receptor 2 (VEGFR2; Flk-1 [fetal liver kinase]/KDR [kinase insert domain containing receptor]) has been identified as a high affinity receptor for vascular endothelial growth factor (VEGF) on vascular endothelium. Head and neck squamous cell carcinomas (HNSCC) have already been shown to produce substantial amounts of VEGF. VEGFR2 is supposed to play a major role in tumor-neoangiogenesis. METHODS: We investigated 24 tumor specimens and 4 HNSCC cultured tumor cell lines for the incidence and distribution of VEGFR2 by immunohistochemistry using monoclonal antibodies (mAbs) and RT-PCR. RESULTS: Analysis of frozen sections by immunohistochemistry showed that in 90% of tumor specimens VEGFR2-positive cells were found which were associated with vascular endothelium. VEGFR2 was also expressed on tumor cells and vessels, which was confirmed by double immunolabeling of tumor cells with an a-cytokeratin mAb. Furthermore, 2 (JPPA, SCC9) of 4 HNSCC cultured tumor cell lines revealed positive VEGFR2 immunoreactivity. Synthesis of VEGFR2 mRNA on all 4 HNSCC cultured tumor cell lines (JPPA, SCC9, SCC25, and LFFR) and in 6 tumor specimens was confirmed by RT-PCR. In conclusion, our results showed that VEGFR2 is expressed in HNSCCs on tumor cells. VEGFR2 expression is associated with the beginning of vasculogenesis represented by accumulation of VEGFR2-positive cells budding into new vessels ("hot spots"). The focal expression pattern of VEGFR2 on tumor cells suggests an autocrine loop for VEGF in tumor cell growth.


Subject(s)
Carcinoma, Squamous Cell/genetics , Otorhinolaryngologic Neoplasms/genetics , RNA, Messenger/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Growth Factor/genetics , Adult , Aged , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/pathology , Cell Division/physiology , Endothelial Growth Factors/metabolism , Female , Gene Expression Regulation, Neoplastic/physiology , Humans , Lymphokines/metabolism , Male , Middle Aged , Neoplasm Staging , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Otorhinolaryngologic Neoplasms/blood supply , Otorhinolaryngologic Neoplasms/pathology , Receptors, Vascular Endothelial Growth Factor , Reverse Transcriptase Polymerase Chain Reaction , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
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