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1.  Phase II study of induction chemotherapy with TPF followed by radioimmunotherapy with Cetuximab and intensity-modulated radiotherapy (IMRT) in combination with a carbon ion boost for locally advanced tumours of the oro-, hypopharynx and larynx - TPF-C-HIT 
BMC Cancer  2011;11:182.
Long-term locoregional control in locally advanced squamous cell carcinoma of the head and neck (SCCHN) remains challenging. While recent years have seen various approaches to improve outcome by intensification of treatment schedules through introduction of novel induction and combination chemotherapy regimen and altered fractionation regimen, patient tolerance to higher treatment intensities is limited by accompanying side-effects. Combined radioimmunotherapy with cetuximab as well as modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) and carbon ion therapy (C12) are able to limit toxicity while maintaining treatment effects. In order to achieve maximum efficacy with yet acceptable toxicity, this sequential phase II trial combines induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) followed by radioimmunotherapy with cetuximab as IMRT plus carbon ion boost. We expect this approach to result in increased cure rates with yet manageable accompanying toxicity.
The TPF-C-HIT trial is a prospective, mono-centric, open-label, non-randomized phase II trial evaluating efficacy and toxicity of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 50 patients with histologically proven locally advanced SCCHN following TPF induction chemotherapy. Patients receive 24 GyE carbon ions (8 fractions) and 50 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. Primary endpoint is locoregional control at 12 months, secondary endpoints are disease-free survival, progression-free survival, overall survival, acute and late radiation effects as well as any adverse events of the treatment as well as quality of life (QoL) analyses.
The primary objective of TPF-C-HIT is to evaluate efficacy and toxicity of cetuximab in combination with combined IMRT/carbon ion therapy following TPF induction in locally advanced SCCHN.
Trial Registration
Clinical Trial Identifier: NCT01245985 (
EudraCT number: 2009 - 016489- 10
PMCID: PMC3118195  PMID: 21595970
2.  Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001) 
British Journal of Cancer  2013;109(10):2554-2559.
Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease.
Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m−2 day 1, cisplatin 60 mg m−2 day 1, 5-flurouracil 750 mg m−2 per day days 1–5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival.
10/26 evaluable patients (38.5%, 95% CI: 20.2–59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event.
Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.
PMCID: PMC3833214  PMID: 24169355
penis cancer; chemotherapy; metastatic; locally advanced
3.  Low Annexin A1 expression predicts benefit from induction chemotherapy in oral cancer patients with moderate or poor pathologic differentiation grade 
BMC Cancer  2013;13:301.
The benefit of induction chemotherapy in locally advanced oral squamous cell carcinoma (OSCC) remains to be clearly defined. Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients and biomarker development might lead to identification of the patients whose tumors are to respond to a particular treatment. Annexin A1 may serve as a biomarker for responsiveness to induction chemotherapy. The aim of this study was to investigate Annexin A1 expression in pre-treatment biopsies from a cohort of OSCC patients treated with surgery and post-operative radiotherapy or docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery and post-operative radiotherapy. Furthermore we sought to assess the utility of Annexin A1 as a prognostic or predictive biomarker.
Immunohistochemical staining for Annexin A1 was performed in pre-treatment biopsies from 232 of 256 clinical stage III/IVA OSCC patients. Annexin A1 index was estimated as the proportion of tumor cells (low and high, <50% and ≥50% of stained cells, respectively) to Annexin A1 cellular membrane and cytoplasm staining.
There was a significant correlation between Annexin A1 expression and pathologic differentiation grade (P=0.015) in OSCC patients. The proportion of patients with low Annexin A1 expression was significantly higher amongst those with moderate/poorly differentiated tumor (78/167) compared to those with well differentiated tumor (18/65). Multivariate Cox model analysis showed clinical stage (P=0.001) and Annexin A1 expression (P=0.038) as independent prognostic risk factors. Furthermore, a low Annexin A1 expression level was predictive of longer disease-free survival (P=0.036, HR=0.620) and locoregional recurrence-free survival (P=0.031, HR=0.607) compared to high Annexin A1 expression. Patients with moderate/poorly differentiated tumor and low Annexin A1 expression benefited from TPF induction chemotherapy as measured by distant metastasis-free survival (P=0.048, HR=0.373) as well as overall survival (P=0.078, HR=0.410).
Annexin A1 can be used as a prognostic biomarker for OSCC. Patients with moderate/poorly differentiated OSCC and low Annexin A1 expression can benefit from the addition of TPF induction chemotherapy to surgery and post-operative radiotherapy. Annexin A1 expression can potentially be used as a predictive biomarker to select OSCC patients with moderate/poorly differentiated tumor who may benefit from TPF induction chemotherapy.
PMCID: PMC3702430  PMID: 23786757
Annexin A1; Oral squamous cell carcinoma; Induction chemotherapy
4.  Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323) 
British Journal of Cancer  2010;103(8):1173-1181.
The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients' health-related quality of life (HRQOL) and symptoms was investigated.
HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol.
Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent.
Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.
PMCID: PMC2967049  PMID: 20842129
HRQOL; symptoms; head and neck cancer
5.  Combination of Taxanes, Cisplatin and Fluorouracil as Induction Chemotherapy for Locally Advanced Head and Neck Cancer: A Meta-Analysis 
PLoS ONE  2012;7(12):e51526.
Some investigations have suggested that induction chemotherapy with a combination of taxanes, cisplatin and fluorouracil (TPF) is effective in locally advanced head and neck cancer. However, other trials have indicated that TPF does not improve outcomes. The objective of this study was to compare the efficacy and safety of TPF with a cisplatin and fluorouracil (PF) regimen through a meta-analysis.
Four randomized clinical trials were identified, which included 1,552 patients with locally advanced head and neck cancer who underwent induction chemotherapy with either a TPF or PF protocol. The outcomes included the 3-year survival rate, overall response rate and different types of adverse events. Risk ratios (RRs) and their 95% confidence intervals (CIs) were pooled using RevMan 5.1 software.
The 3-year survival rate (51.0% vs. 42.4%; p = 0.002), 3-year progression-free survival rate (35.9% vs. 27.2%; p = 0.007) and overall response to chemotherapy (72.9% vs. 62.1%; p<0.00001) of the patients in the TPF group was statistically superior to those in the PF group. In terms of toxicities, the incidence of febrile neutropenia (7.0% vs. 3.2%; p = 0.001) and alopecia (10.8% vs. 1.1%; p<0.00001) was higher in the TPF group.
The TPF induction chemotherapy regimen leads to a significant survival advantage with acceptable toxicity rates for patients with locally advanced head and neck cancer compared with the PF regimen.
PMCID: PMC3517538  PMID: 23236511
6.  A Phase II Study of Docetaxel, Cisplatin and 5- Fluorouracil (TPF) In Patients with Locally Advanced Head and Neck Carcinomas 
The combination of cisplatin and 5-fluorouracil (PF) is currently considered a standard and effective regimen for the treatment of advanced head and neck carcinomas. The aim of this study was to evaluate the efficacy and safety of docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with unresectable head and neck carcinomas.
Forty-six patients with previously untreated non-metastatic stage IV head and neck carcinomas were enrolled. All patients received three cycles of induction chemotherapy with docetaxel (75 mg/m(2)), cisplatin (40 mg/m(2)) (days 1-2), and 5-FU (500 mg/m(2), days 1-3), repeated every 21 days. Following induction chemotherapy, all patients underwent concurrent chemoradiotherapy using weekly cisplatin (30 mg/m(2)) and a median total dose of 70 Gy was delivered. Clinical response rate and toxicity were the primary and secondary end-points of the study.
There were 31 men and 15 women. All patients had non-metastatic stage IV (T2-3N2-3 or T4N0-3) of disease. Overall and complete response rates were 74% and 24% respectively. Advanced T4 classification was associated with poorer response rate (p value=0.042). The major (grade 3-4) treatment-related toxicities were myelosuppression (78%), anorexia (13%), diarrhea (7%), emesis (11%) and stomatitis/pharyngitis (24%).
In comparison with the data of historical published trials of the PF regimen, the TPF regimen was more effective. However, the TPF regimen appears to be associated with a higher incidence of major toxicities. Therefore, our limited findings support the TPF regimen as an alternative chemotherapeutic regimen for advanced head and neck carcinomas.
PMCID: PMC3371950  PMID: 22737461
Docetaxel; Cisplatin; 5-Fluorouracil; Chemotherapy; Head and neck; Carcinoma
7.  Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival 
To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued.
Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m2/day (protracted IV) and docetaxel (DCT) 20 mg/m2/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/m2, plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients.
Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%).
Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen.
Trial Registration NCT00112697
PMCID: PMC3191360  PMID: 21943032
8.  The Efficacy of an Induction Chemotherapy Combination with Docetaxel, Cisplatin, and 5-FU Followed by Concurrent Chemoradiotherapy in Advanced Head and Neck Cancer 
This study was performed to determine the feasibility and safety of the use of induction chemotherapy combined with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiation therapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Materials and Methods
The patients, that were initially not treated for locally advanced SCCHN, underwent three cycles of induction chemotherapy every 3 weeks at a dose of 70 mg/m2 docetaxel D1, 75 mg/m2 cisplatin D1, 1000 mg/m2 5-FU D1-4, and subsequently received concurrent chemoradiation therapy.
Forty-nine patients were enrolled in this study and forty-three of the patients completed the treatment. The median duration of follow-up was 18 months (range, 6~39 months). All of the patients had stage III (26.5%) or IV (73.5%) squamous cell carcinoma. After sequential therapy, a complete response and partial response was seen in 28 (65.2%) and 13 (30.2%) patients, respectively. The overall response rate was 95.4%. Overall survival and progression-free survival (PFS) at 2 years were 88.7% and 69.7%, respectively. Grade 3~4 neutropenia occurred in 42.2% of the patients and grade 4 thrombocytopenia in 1 cycle (0.7%). Two patients (4.1%) died during the induction chemotherapy due to pneumonia and a subdural hemorrhage, respectively. The group of patients over 65 years of age showed a significant lower dose intensity than that of patients under 65 years of age, but PFS was not significantly different between two groups (p=0.105).
TPF induction chemotherapy followed by concurrent chemoradiotherapy showed a high level of CR and moderate treatment-induced toxicity. Adequate dose modification in elderly patients should be considered to maintain efficacy and avoid treatment-related toxicity.
PMCID: PMC2739327  PMID: 19746222
Head and neck neoplasms; Radiotherapy; Docetaxel; Combination chemotherapy
9.  Concurrent chemoradiotherapy with tomotherapy in locally advanced non-small cell lung cancer: a phase i, docetaxel dose-escalation study, with hypofractionated radiation regimen 
BMC Cancer  2013;13:513.
Concurrent chemo-radiotherapy is demonstrately superior to sequential chemo-radiotherapy in the treatment of advanced Non-Small-Cell Lung Cancer not suitable for surgery. Docetaxel is considered to enhance the cytotoxic effect of radiotherapy on the tumour cells. Tomotherapy (HT) is a novel radiotherapeutic technique, which allows the delivery of Image Guided-IMRT (IG-IMRT), with a highly conformal radiation dose distribution.
The goal of the study was to estimate tolerability of Docetaxel concurrent with IMRT and to find the maximum tolerated dose of weekly Docetaxel concurrent with IMRT delivered with HT Tomotherapy after induction chemotherapy with Cisplatin and Docetaxel in patients affected with stage III Non-Small Cell Lung Cancer.
We designed a phase I, dose-finding study to determine the dose of weekly Docetaxel concurrent with Tomotherapy after induction chemotherapy, in patients affected by Non-Small Cell Lung Cancer with Stage III disease, not suitable for surgery.
Concurrent weekly Docetaxel and Tomotherapy are feasible; we did not reach a maximum tolerated dose, because no life-threatening toxicity was observed, stopping the accrual at a level of weekly docetaxel 38 mg/m2, a greater dose than in previous assessments, from both phase-I studies with weekly docetaxel alone and with Docetaxel concomitant with standard radiotherapy.
Concurrent weekly Docetaxel and Tomotherapy are feasible, and even with Docetaxel at 38 mg/m2/week we did not observe any limiting toxicity. For those patients who completed the combined chemo-radio treatment, median progression-free survival (PFS) was 20 months and median overall survival (OS) was 24 months.
PMCID: PMC4228391  PMID: 24176164
10.  Disease control and functional outcome in three modern combined organ preserving regimens for locally advanced squamous cell carcinoma of the head and neck (SCCHN) 
To report our experience on disease control and functional outcome using three modern combined-modality approaches for definitive radiochemotherapy of locally advanced SCCHN with modern radiotherapy techniques: radiochemotherapy (RChT), radioimmunotherapy (RIT) with cetuximab, or induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) combined with either RChT or RIT.
Toxicity and outcome was retrospectively analysed in patients receiving definitive RChT, RIT, or induction chemotherapy followed by RChT or RIT between 2006 and 2009. Outcome was estimated using Kaplan-Meier analyses, toxicity was analysed according to CTCAE v 3.0.
Thirty-eight patients were treated with RChT, 38 patients with RIT, 16 patients received TPF followed by either RChT or RIT. Radiotherapy was mostly applied as IMRT (68%). Long-term toxicity was low, only one case of grad III dysphagia requiring oesophageal dilatation, no case of either xerostomia ≥ grade II or cervical plexopathy were observed. Median overall survival (OS) was 25.7 months (RChT) and 27.7 months (RIT), median locoregional progression-free survival (PFS) was not reached yet. Subgroup analysis showed no significant differences between TPF, RChT, and RIT despite higher age and co-morbidities in the RIT group. Results suggested improved OS, distant and overall PFS for the TPF regimen.
Late radiation effects in our cohort are rare. No significant differences in outcome between RChT and RIT were observed. Adding TPF suggests improved progression-free and overall survival, impact of TPF on locoregional PFS was marginal, therefore radiotherapeutic options for intensification of local treatment should be explored.
PMCID: PMC3195102  PMID: 21942981
11.  Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer 
British Journal of Cancer  2010;104(2):265-271.
Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy.
Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15–30 mg m−2 per week and cisplatin 15–30 mg m−2 per week in six planned dose levels (DLs) in 3–6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy.
A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m−2, cisplatin 15 mg m−2) and grade 3 nausea in DL2 (20 mg m−2, 15 mg m−2). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial).
Cisplatin and docetaxel each 30 mg m−2 per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.
PMCID: PMC3031899  PMID: 21157450
oesophageal cancer; chemoradiotherapy; docetaxel; cisplatin
12.  Induction chemotherapy with cetuximab, carboplatin and paclitaxel for the treatment of locally advanced squamous cell carcinoma of the head and neck 
Although controversy exists in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), clinicians often use induction chemotherapy for treatment of the most advanced cases. One promising regimen combines weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2) with carboplatin (AUC of 2) and paclitaxel (90 mg/m2). We retrospectively evaluated patients treated with this regimen prior to definitive chemoradiation or surgery between May 2008 and December 2011. The primary endpoint used for this retrospective analysis was feasibility. Thirty consecutive, unselected patients were included. Median follow-up was 13.7 months (range, 5.0–38.7 months). All but one patient had stage IV SCCHN. Dose intensity was high for carboplatin (92%), paclitaxel (93%) and cetuximab (85%). Grade 3–4 toxicities occurred in <7% of the study population and were limited to rash, neutropenia and infusion reactions. Response rate (RR) to induction chemotherapy was 97% (30% complete response, 67% partial response). All patients completed subsequent chemoradiotherapy or surgery. Nineteen patients (63%) demonstrated a complete response and 11 patients (37%) demonstrated a partial response. Median overall survival and progression-free survival data are not yet mature. The RR to therapy in our off-protocol experience is at least comparable to that observed in the two phase II studies of this regimen and appears superior to that observed with docetaxel, cisplatin and fluorouracil (TPF).
PMCID: PMC3628719  PMID: 23599744
locally advanced squamous cell carcinoma of the head and neck; head and neck cancer; induction chemotherapy; chemoradiotherapy
13.  Long-term results of concurrent chemoradiotherapy for T3/T4 locally advanced nasopharyngeal carcinoma 
Molecular and Clinical Oncology  2013;1(3):507-510.
Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed head and neck malignancies. This study investigated the outcome of locally advanced NPC patients on concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF). A total of 226 patients with locally advanced NPC received IMRT, with a total dose of 65–70 Gy and concurrent chemotherapy, with 2 cycles of TPF administered during radiotherapy, between March, 2005 and March, 2007. An additional 2 to 4 cycles of chemotherapy were administered every 21 days following radiotherapy. With a median follow-up time of 35 months (range, 7–60), the 5-year overall survival (OS) rate was 81.4%, with 93.6 and 75.0% for T3 and T4 lesions, respectively, (P=0.001). The 5-year progression-free survival (PFS) was 50.4%, with 66.7 and 46.9% for T3 and T4 lesions, respectively (P<0.001). T-classification was a significant prognostic factor for PFS and OS. The subgroup analysis revealed that pterygopalatine fossa invasion was associated with a significantly lower 5-year PFS (P=0.001) and OS (P=0.002), foramen rotundum invasion was associated with a significantly lower 5-year PFS (P<0.001) and OS (P=0.004), foramen ovale invasion was associated with a significantly lower 5-year PFS (P=0.013) and OS (P=0.024) and foramen lacerum and cavernous sinus invasion were associated with a significantly lower 5-year PFS (P<0.001 and P<0.001, respectively). Concurrent chemoradiotherapy is an advocated regimen for patients with locally advanced NPC, since it exhibits satisfactory 5-year PFS and OS rates. Our results suggest that the estimation of invasive range may identify a subgroup of patients with a higher risk of locoregional failure who may be better candidates for this treatment strategy.
PMCID: PMC3916170  PMID: 24649201
nasopharyngeal carcinoma; intensity-modulated radiation therapy; chemotherapy
14.  Concomitant Chemoradiotherapy as a Standard Treatment for Squamous Cell Carcinoma of the Temporal Bone 
Skull Base  2011;21(3):153-158.
We sought to characterize the effectiveness of concomitant chemoradiotherapy (CCRT) for patients with squamous cell carcinoma of the temporal bone. We performed a retrospective chart review of 14 patients with cancer of the temporal bone who were provided initial treatment in our hospital from December 2001 to November 2008. Four patients with stage I tumors were treated by radiation therapy alone or with oral administration of S1. One patient with a stage II tumor was treated by radiation therapy concomitant with low dose docetaxel. Nine patients with stage IV tumors were treated by CCRT using the TPF regimen (docetaxel, cisplatin, and 5-fluorouracil). As an initial treatment, all patients but one were treated by radiation therapy with or without chemotherapy. Grade 4 adverse events of patients who received CCRT using the TPF regimen involved the leukopenia in one patient and the neutropenia in two patients. Local recurrences were observed in three patients including two patients with T4 tumors. Five-year disease-specific survival rates for all patients and for patients with T4 tumors were 78% and 67%, respectively. CCRT using the TPF regimen is safe and effective as the first treatment for patients with cancer of the temporal bone.
PMCID: PMC3312106  PMID: 22451818
Squamous cell carcinoma of the temporal bone; chemoradiotherapy; TPF; survival rates
15.  Sequential therapy (triple drug-based induction chemotherapy followed by concurrent chemoradiotherapy) in locally advanced inoperable head and neck cancer patients – Single institute experience 
India has a high incidence of head and neck squamous cell carcinoma (HNSCC) mostly presenting in advanced stage. In the majority of inoperable patients a combination of chemotherapy and radiotherapy (CRT) is considered as the treatment of choice. Adding induction chemotherapy (ICT) before CRT has shown to decrease systemic relapse. Incorporation of taxanes to the cisplatin and 5-FU-based ICT has shown increase in response rates.
To evaluate the efficacy and toxicity of triple drug-based ICT followed by CCRT in locally advanced, inoperable HNSCC in the Indian context.
Settings and Design:
Prospective, non-controlled, observational study, a single-institute experience.
Materials and Methods:
Consecutive, locally advanced inoperable HNSCC patients were put on sequential therapy consisting of docetaxel, 5-FU and cisplatin for three cycles followed by concurrent weekly cisplatin and radiotherapy for responding or stable disease patients.
Forty-four patients were enrolled with male,female ratio of 33/44(75%) and 11/44(25%). Hypopharynx 16/44(36.36%) was the most common site followed by oral cavity 12/44(27.27%) and oropharynx 12/44(27.27%); 38/44(86.36%) patients could complete the planned treatment. Seven patients required dose reduction in ICT. As per the RECIST criteria, 16 patients had Complete Response (CR) and 15 had partial response (PR), 10 had stable disease (SD) and three had progressive disease (PD) after ICT. Thirty-eight patients received concomitant chemo radiotherapy (CCRT); 28/44 (66.63%) patients achieved CR, 10/44 (22.72 %) had PR. The main toxicity was mucositis 18/44 (40.90%) secondary to ICT. Grade III and IV hematological toxicity was seen in 16/44(36.36%), of which 6/44 (13.63%) had febrile neutropenia.
Triple drug-based sequential therapy is tolerable in our context. In this trial from a single institute the results are very encouraging.
PMCID: PMC3237186  PMID: 22174496
Concurrent chemoradiotherapy; Docetaxel-Cisplatin-5FU regimen; induction chemotherapy
16.  Docetaxel in the treatment of squamous cell carcinoma of the head and neck 
Squamous cell carcinoma of the head and neck (SCCHN) presents at a locally advanced (LA) stage in many patients. Chemotherapy has been successfully integrated into first-line treatment programs, either during or prior to radiotherapy (RT) – the cornerstone modality for local disease control of inoperable disease or when organ preservation is desired. Concomitant chemoradiotherapy (CCRT) provides an absolute survival benefit when compared with other types of locoregional therapy that exclude chemotherapy. Nonetheless, distant metastases still represent the most common cause of treatment failure. Consequently, adding induction chemotherapy (ICT) to definitive non-surgical local therapies with a curative intent has been vigorously explored in LA SCCHN. Recently, it has been shown that ICT using the combination of the taxane docetaxel with cisplatin–5-fluorouracil provides significant survival benefit over cisplatin–5-FU, when used before either definitive RT (TAX323 trial) or carboplatin-based CCRT (TAX324 trial). Docetaxel is also being investigated in metastatic or recurrent (M/R) disease, with promising initial results. It is very likely that the future management strategies of SCCHN will incorporate biologic agents as an add-on to docetaxel-containing schemas, administered either as ICT prior to CCRT in the LA setting or for the management of M/R disease.
PMCID: PMC2621396  PMID: 19209269
chemoradiotherapy; chemotherapy; docetaxel; head and neck carcinoma; induction; locally advanced; taxane
This dose escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma.
Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography (EUS) and CT. Two cycles of docetaxel (80 mg/m2) and carboplatin (target area under the concentration curve 6 mg*min/mL) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m2), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500 mg to 3500 mg) given prior to each fraction of radiotherapy. Following re-staging, responding patients continued to esophagectomy within 4–8 weeks of completing chemoradiotherapy.
Forty-four patients (pts) were enrolled and 40 were evaluable for the dose-ranging component of concurrent chemoradiotherapy. EUS stages at enrollment were T3N1 (29 pts), T3N0 (4 pts), T2N1 (6 pts), and T4N0 (1 pts). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection and 17% had complete pathological response. Median overall survival was 23.5 months, with 34% and 27% alive at three and five years.
The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well-tolerated and remarkably active. This regimen holds promise for treatment of esophageal carcinoma and warrants further investigation.
PMCID: PMC3600150  PMID: 23370365
18.  Concurrent Docetaxel-Based Chemoradiotherapy in Squamous Cell Esophageal Cancer 
The incidence of esophageal cancer has risen worldwide in recent decades. In Romania, the incidence is 5.3/100,000 population in males and 0.7/100,000 in females, with mortality rates of 4.8/100,000 and 0.5/100,000 in males and females, respectively. Esophageal cancer is a treatable but rarely curable cancer, as many patients have advanced-stage disease at diagnosis. We evaluated a multimodality approach of preoperative radiochemotherapy for patients with squamous cell esophageal carcinoma in terms of safety, tumor response, and resectability rate.
From January 2004 to May 2007, 87 patients were included in the study. Inclusion criteria were histologically confirmed squamous esophageal cancer not amenable to curative surgery, no distant metastases, ECOG performance status ≤ 2, and no previous anticancer therapy. The preoperative treatment schedule was conformal radiotherapy (40 Gy) with concomitant weekly docetaxel (25 mg/m2) and carboplatin (AUC=2). Patients were evaluated at baseline, after having received 40 Gy radiotherapy, and 3 months after treatment ended. Endoscopy, barium swallow X-ray, and CT scan of the chest and upper abdomen were used to evaluate patients. Patients whose tumors were resectable underwent surgery; those with unresectable tumors continued radiotherapy to a total dose of 60 Gy and received four cycles of docetaxel (75 mg/m2) and carboplatin (AUC=6) (q3wk regimen). The resected patients received adjuvant chemotherapy with four cycles of the same docetaxel/carboplatin q3wk regimen.
The median patient age was 53.6 years (range, 32–70 years); 78 of the patients were males and 9 were females. Median follow-up time was 35 months. Survival rate at 1 year was 57.5% and at 2 years, 44.8%. After patients had received 40 Gy radiotherapy, 39 were determined to have resectable disease and 30 underwent surgery (6 patients refused surgery and 3 had contraindications for surgery); 48 patients had tumor regression with clinical benefit but were not operable. No patient progressed. Six of the 30 patients undergoing surgery had complete remissions. The treatment schedule was well tolerated, with no treatment-related deaths or additional hospitalizations. All except 5 of the patients were able to receive the intended chemoradiotherapy regimen. These 5 patients stopped chemoradiotherapy because of hematologic toxicity; radiotherapy was continued (after an approximate 1-week delay) following hematologic recovery. The operated patients had no additional perioperative complications. Radiation therapy was delivered as intended with no toxicity-related interruptions, except in the 5 patients mentioned above. Chemotherapy was delayed in 15 additional cases due to grade 3–4 hematologic effects; a 25% dose reduction was necessary in 9 cases.
Multimodality treatment of locally advanced esophageal cancer (concurrent radiochemotherapy ± surgery) can be considered superior to each method as single-agent therapy. Radiotherapy and chemotherapy may convert some tumors considered initially unresectable to resectable status. The weekly docetaxel/carboplatin regimen was well tolerated when administered concurrently with radiation therapy. This regimen resulted in a 44.8% resectability rate in patients considered initially unresectable, and 15.4% of patients undergoing surgery had complete remissions. Further investigation of this regimen is warranted.
PMCID: PMC3056309
19.  Concurrent conventionally factionated radiotherapy and weekly docetaxel in the treatment of stage IIIb non-small-cell lung carcinoma 
British Journal of Cancer  1999;80(11):1792-1796.
Docetaxel has shown remarkable radiosensitizing in vitro properties. In a previous phase I/II dose escalation study in non- small-cell lung cancer (NSCLC) we observed a high response rate after concomitant boost radiotherapy and weekly docetaxel. The maximum tolerated dose was 30 mg m−2 week−1. In the present phase II study we evaluated whether weekly docetaxel and conventionally fractionated radiotherapy could be better tolerated and equally effective in the treatment of locally advanced NSCLC. Thirty-five patients with T3, T4/N2, T3/M0-staged disease were recruited. Docetaxel (30 mg m−2) was given as a 30 min infusion once a week. Asthenia and radiation-induced oesophagitis were the main side-effects of the regimen enforcing 2-week treatment delay in 6/35 (17%) patients and minor delay (3–7 days) in another 11/35 (31%) patients. Neutrophil, platelet and haemoglobin toxicity was minimal, but pronounced lymphocytopenia was observed. Complete response (CR) of the chest disease was observed in 12/35 (34%) patients and partial response in 16/35 (46%). Although not statistically significant (P = 0.19), a higher CR rate (8/18; 44%) was observed in patients who accomplished their therapy within the scheduled treatment time (44–47 days) as compared to patients that interrupted their treatment for several days due to treatment-related toxicity (CR 4/17; 23%). The overall survival and the local progression-free survival at 1 year was 48% and 60% respectively. We conclude that docetaxel combination with radiotherapy is a promising approach for the management of locally advanced NSCLC that results in high CR rate. Further trials with docetaxel-based radiochemotherapy should integrate accelerated radiotherapy together with cytoprotection. © 1999 Cancer Research Campaign
PMCID: PMC2363119  PMID: 10468298
docetaxel; radiotherapy; lung cancer
20.  Current Management of Esophageal Squamous-Cell Carcinoma in Japan and Other Countries 
The incidence of adenocarcinoma of the distal esophagus or esophagogastric junction has increased considerably in Western countries during the past 3 decades, whereas the incidence of squamous-cell carcinoma has decreased slightly. In Japan, most esophageal cancers are squamous-cell carcinomas. Endoscopic examinations are more frequently performed in Japan for routine screening and diagnosis and treatment than in other countries, thereby increasing the detection rate of superficial esophageal carcinomas. In Europe and North America, many clinical trials have been conducted to assess the effectiveness of neoadjuvant chemoradiotherapy followed by surgery in patients with resectable, advanced esophageal cancer. In Japan, surgical resection had been the mainstay of treatment for esophageal cancer. Since the results of the Japan Clinical Oncology Group (JCOG) 9907 study were reported, neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil followed by surgery has emerged as a new standard treatment. As for definitive chemoradiotherapy, cisplatin, 5-fluorouracil, and concurrent radiotherapy dosed to 50.4 Gy are used as standard treatment in a randomized clinical trial performed in North America. In patients who have T4 tumors and/or M1 lymph-node metastasis, chemoradiotherapy with cisplatin and 5-fluorouracil is considered standard treatment, but docetaxel, cisplatin, and 5-fluorouracil plus concurrent radiotherapy is also being studied. Controlled studies have not shown that palliative chemotherapy is superior to best supportive care, but cisplatin plus 5-fluorouracil is still considered standard therapy. Clinical trials of targeted agents are in progress. It is hoped that targeted agents will be effective for esophageal cancer.
PMCID: PMC2739640  PMID: 19742141
21.  Curative treatment can be an option for patients with metastatic squamous cell cancer of the head and neck 
No specific study has focused on patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) at diagnosis. Due to high response rates of induction chemotherapy in chemo-naïve patients with localized disease, their prognosis should be better than patients with recurrent disease.
From January 1, 2008 to July 1, 2012, we retrospectively collected all patients’ records with SCCHN diagnosed as metastatic. Patients, disease, treatment and its results were analyzed. Survival was calculated using the Kaplan–Meier method.
Of the 749 new patients treated for SCCHN in our institution, 16 (2.1%) were metastatic at diagnosis, of whom five had cytological results to prove it. Six patients died before treatment or had palliative care and ten received initial chemotherapy and then surgery and/or radiotherapy according to the primary response. Four patients treated with first-line chemotherapy with docetaxel-5FU-cisplatin (TPF) showed a complete response of metastatic lesions allowing locoregional treatment. The overall survival at 1 year and 3 years was 50% and 24%, respectively. The median survival was 7 months (1–72 months). Seven patients (43.7%) had a higher survival at 12 months, including five (31.5%) who are still alive without recurrence with a mean follow-up of 30 months. There was a significant difference in overall survival (P<0.01) between patients who had chemotherapy with TPF versus other therapeutic protocols. The median survival of patients with lung metastases only was 15 months (1–72 months), significantly higher than that of patients with liver and/or bone localizations, which was 2 months (1–9 months).
Patients with metastatic SCCHN treated by TPF followed by multimodal treatment could achieve long survival.
PMCID: PMC4271786  PMID: 25548517
squamous cell carcinoma; head and neck; metastases; TPF; cetuximab
22.  Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a multicenter phase II trial in patients with metastatic esophagogastric cancer 
Annals of Oncology  2009;20(3):475-480.
Background: Recent studies have examined the addition of docetaxel to fluorouracil and cisplatin in advanced esophagogastric cancer.
Patients and methods: We carried out a phase I dose-escalation study of weekly docetaxel, cisplatin, and irinotecan (TPC), given on days 1 and 8 every 3 weeks, in patients with chemonaive solid tumors. Subsequently, we completed a multiinstitutional phase II study of TPC in patients with previously untreated, metastatic esophagogastric cancer.
Results: Thirty-nine patients were enrolled in the phase I trial; a weekly schedule of TPC was well tolerated. On that basis, docetaxel 30 mg/m2, cisplatin 25 mg/m2, and irinotecan 65 mg/m2 were selected for the phase II trial, where in the first 18 patients irinotecan 65 mg/m2 caused too much diarrhea and was reduced to 50 mg/m2. Among 56 eligible patients with previously untreated, metastatic esophagogastric cancer enrolled in the phase II trial, three complete and 27 partial responses were observed (overall response rate = 54%), and 15 patients (30%) had stable disease. Median progression-free survival was 7.1 months, and median survival was 11.9 months. At the final irinotecan dose of 50 mg/m2, grade 3 or higher toxicity included diarrhea (26%), neutropenia (21%), nausea (18%), fatigue (16%), anorexia (13%), and thrombosis/embolism (13%).
Conclusions: Weekly TPC is an active and well-tolerated regimen for patients with esophagogastric cancer.
PMCID: PMC2733072  PMID: 19139178
chemotherapy; cisplatin; docetaxel; esophageal cancer; gastric cancer; irinotecan
23.  Using neoadjuvant chemotherapy and replanning intensity-modulated radiotherapy for nasopharyngeal carcinoma with intracranial invasion to protect critical normal tissue 
To investigate the feasibility of neoadjuvant chemotherapy and replanning intensity-modulated radiotherapy (IMRT) for intracranial invasion nasopharyngeal carcinoma (NPC).
Methods and materials
From June 2007 to January 2012, 32 patients with intracranial invasion NPC treated with TPF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, 5-FU 2500 mg/m2 every 3 weeks for 3 cycles) neoadjuvant chemotherapy, and replanning IMRT with concurrent chemotherapy were retrospectively studied. The first IMRT plan for each patient was generated based on the original planning CT scan acquired before the start of treatment. Because of tumor shrinkage during radiotherapy, modified gross tumor volume of primary tumor (GTV-P) and high risk clinical target volume (CTV-H), and a new plan was generated and used to complete the course of IMRT. The DVHs of IMRT plan with or without replanning were compared.
There weren’t statistically significant differences in the V95, D-mean, D-95, and D-99 to the modified PTVGTV-P and PTVCTV-H with and without replanning IMRT. Replanning reduced the doses to the brain stem, optic nerve, optic chiasm and temporal lobe. Objective responses were 100.0% 3 months after completion of radiotherapy. Acute toxicities were well tolerated, except for the relatively high incidence of neutropenia. The 2-year local control rates and distant-metastasis free survival were 88.2% (95% CI, 72.9% to 100.0%) and 89.6% (95% CI, 75.9% to 100.0%).
Neoadjuvant chemotherapy and replanning IMRT according to tumor shrinkage during the treatment is essential to ensure safe doses to normal tissues, and produces encouraging outcome for intracranial invasion NPC.
PMCID: PMC3874595  PMID: 24083351
Nasopharyngeal carcinoma; Replanning IMRT; Comprehensive treatment
24.  A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study 
British Journal of Cancer  2005;93(9):993-998.
The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150 mg m−2) were given on days 2 and 30, followed by low-dose LV (20 mg m−2) and 5FU (350 mg m−2), both given on days 1–5 and 29–33. Surgery was performed 6–10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31–79), 24 males and eight females. The MTD was reached at 150 mg m−2 when four out of six patients experienced DLT. Dose-limiting grade 3 or 4 diarrhoea was reported in two out of six patients at 85 mg m−2, 5 out of 20 at 130 mg m−2 and four out of 6 at 150 mg m−2. Grade 3 neuropathy was reported at 130 mg m−2 (1 out of 20) and at 150 mg m−2 (two out of six), and serious haematological toxicity was minimal; one grade 3 anaemia at 150 mg m−2. In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR+Tmic 5 out of 27 (19%), pT0–2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150 mg m−2 given days 2 and 30 when added to the described 5FU LV and 45 Gy radiation preoperatively. The acceptable toxicity and compliance at 130 mg m−2 recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group.
PMCID: PMC2361684  PMID: 16249791
5-fluorouracil; oxaliplatin; locally advanced rectal cancer; preoperative chemoradiation
25.  A phase I trial of docetaxel and 5-day continuous infusion of 5-fluorouracil in patients with advanced or recurrent breast cancer. 
British Journal of Cancer  1998;77(11):1937-1943.
To determine the maximum-tolerated doses (MTDs), the dose-limiting toxicities (DLTs) and the recommended doses for further trials of docetaxel in combination with a 5-day continuous infusion of 5-fluorouracil (5-FU) in advanced or recurrent breast cancer patients who had been treated previously with at least one chemotherapeutic regimen, patients were treated with docetaxel as a 1-h infusion on day 1 followed by 5-FU as a continuous infusion on days 1 through 5 every 3-4 weeks. Three or six patients were assessed at the following escalating dose levels of docetaxel/5-FU per day: 40/150, 40/300, 50/300, 50/500 and 60/500 mg m(-2). Nineteen patients entered this trial, of whom 18 could be assessed for adverse event and therapeutic efficacy. The DLTs were neutropenia and diarrhoea. The MTDs were 60 mg m(-2) of docetaxel on day 1 and 500 mg m(-2) per day of 5-day continuous infusion of 5-FU. One of 18 patients achieved a complete response and eight achieved partial response (over all response rate: 50%). The recommended doses of docetaxel and 5-day continuous infusion of 5-FU for a phase II trial are 50 mg m(-2) and 500 mg m(-2) per day every 3 or 4 weeks.
PMCID: PMC2150334  PMID: 9667671

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