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.
Head and neck neoplasms; Radiotherapy; Docetaxel; Combination chemotherapy
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.
nasopharyngeal carcinoma; intensity-modulated radiation therapy; chemotherapy
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.
Annexin A1; Oral squamous cell carcinoma; Induction chemotherapy
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.
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.
penis cancer; chemotherapy; metastatic; locally advanced
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.
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.
Docetaxel; Cisplatin; 5-Fluorouracil; Chemotherapy; Head and neck; Carcinoma
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.
Clinical Trial Identifier: NCT01245985 (clinicaltrials.gov)
EudraCT number: 2009 - 016489- 10
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.
Squamous cell carcinoma of the temporal bone; chemoradiotherapy; TPF; survival rates
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.
chemoradiotherapy; chemotherapy; docetaxel; head and neck carcinoma; induction; locally advanced; taxane
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.
This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m−2, cisplatin 75 mg m−2 on day 1 and fluorouracil 750 mg m−2 day−1 on days 2–5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m−2 week−1 for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week−1). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2–66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1–12.4), and the 1- and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3–4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified.
chemoradiotherapy; docetaxel; oesophageal cancer; phase II study
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.
Concurrent chemoradiotherapy; Docetaxel-Cisplatin-5FU regimen; induction chemotherapy
Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression.
Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m−2, followed by cisplatin 30 mg m−2 infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m−2 per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment.
From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities.
Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.
docetaxel; cisplatin; tegafur/uracil; leucovorin; gastric cancer
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.
oesophageal cancer; chemoradiotherapy; docetaxel; cisplatin
To evaluate the maximum tolerated dose (MTD) of docetaxel (DCT) and cisplatin (DDP) concurrently with three dimensional (3D) conformal radiotherapy or IMRT for patients with locally advanced non-small cell lung cancer (stage IIIa and IIIb) after 2–4 cycles of induction chemotherapy.
Fourteen patients with histological/cytological proven stage III non–small-cell lung cancer were eligible. 3D or IMRT radiotherapy (60-70Gy in 30-35 fractions, 6-7weeks, 2 Gy/fraction) was delivered concurrently with cisplatin and docetaxel, 2 cycles during concurrent chemoradiotherapy (CCRT). The level I dosage was composed of 56 mg/m2 DCT, on day 1 and 28mg/m2 DDP, on day 1 and day 2. The level II was composed of 60 mg/m2 DCT, on day 1 and 30 mg/ m2 DDP, on day 1 and day 2. The level III was composed of 64 mg/m2 DCT, on day 1 and 32 mg/ m2 DDP, on day 1 and day 2.
Fourteen patients were allocated and finished concurrent chemoradiotherapy. The dose-limiting neutropenia was at the dose Level III (64 mg/m2) and occurred in 2 of 5 patients. No dose limiting non-hematologic or hematologic toxicity occurred in the other patients.
Patients with locally advanced non-small cell lung cancer may tolerate 60mg/m2 docetaxel and 60mg/m2 cisplatin for 2 cycles during concurrent radiotherapy after 2-3 cycles of induction chemotherapy.
Non–small-cell lung cancer; Concurrent chemoradiotherapy; Cisplatin docetaxel; Toxicity
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.
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.
chemotherapy; cisplatin; docetaxel; esophageal cancer; gastric cancer; irinotecan
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.
Nasopharyngeal carcinoma; Replanning IMRT; Comprehensive treatment
This trial aimed to assess the feasibility and tumour control of concurrent chemoradiotherapy or radiotherapy alone after docetaxel-based induction chemotherapy in locally advanced non-small-cell lung cancer (NSCLC). Patients with stage IIIA/IIIB NSCLC received two 21-day cycles of induction chemotherapy with docetaxel (85 mg m−2, day 1) plus cisplatin (40 mg m−2, days 1 and 2). Patients without disease progression on day 43 were randomised to radiotherapy (2 Gy for 5 days week−1; total 60 Gy) alone or with docetaxel 20 mg m−2 once weekly every 6 weeks. Of 108 patients who received induction chemotherapy, 104 were evaluable for response. After induction chemotherapy, the overall response rate (ORR) was 44%; 91 (88%) patients had no disease progression and 89 were subsequently randomised to local treatment. After randomised therapy, the ORR was 53% (chemoradiotherapy 58%; radiotherapy 48%). Median survival and time to progression were 14.9 and 7.8 months, respectively, for chemoradiotherapy and 14.0 and 7.5 months, respectively, for radiotherapy. The most common toxicities during induction chemotherapy and randomised therapy were grades 3–4 neutropenia and grade 3 lymphocytopenia, respectively. Docetaxel–cisplatin induction therapy followed by concurrent docetaxel and thoracic radiotherapy is a feasible treatment option, showing good clinical activity and tolerability, for locally advanced NSCLC.
chemoradiotherapy; taxane; docetaxel; cisplatin; non-small-cell lung cancer; concurrent therapy; radiation therapy
The purpose of this study was to evaluate the maximum tolerated dose, dose-limiting toxicities and preliminary efficacy of chemotherapy with cisplatin, docetaxel and S-1 (TPS) to treat advanced head and neck squamous cell cancer. S-1 was administered orally twice daily on days 1–14 and docetaxel and cisplatin were injected intravenously on day 8, with one course lasting 4 weeks. The recommended dose obtained from a phase I study was set at docetaxel 60 mg/m2, cisplatin 60 mg/m2 and S-1 80 mg/m2/day. The phase II study revealed that the overall response rate was 81%, comprising 95% in untreated patients with localized advanced cancer and no distant metastases, 50% in untreated patients with distant metastases and 33% in previously treated patients with recurrence. The overall survival rate of untreated patients with localized advanced cancer and no distant metastases was 95% at 1 year and 64.33% at 2 years. In terms of grade 3 or higher hematotoxicity, neutropenia occurred in 100%, thrombocytotopenia in 4% and anemia in 4%. Febrile neutropenia occurred in 46%, with the rate rising to 57% in elderly patients ≥66 years. Grade 3 or higher non-hematotoxicity consisted of loss of appetite in 8%, diarrhea in 8%, hyponatremia in 13% and hypokalemia in 13%. This TPS therapy may be recommended for use as induction chemotherapy. For patients ≤65 years, the appropriate dose was docetaxel 60 mg/m2, cisplatin 60 mg/m2 and S-1 80 mg/m2, whereas for those ≥66 years, it was docetaxel 60 mg/m2, cisplatin 60 mg/m2 and S-1 60 mg/m2.
head and neck squamous cell carcinoma; chemotherapy; cisplatin; docetaxel; S-1
Gastric cancer remains a significant problem in terms of global health, and is the most common cancer in Korea. Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. Randomized trials have demonstrated that chemotherapy for advanced gastric cancer improves the quality of life and extends survival, by 4~6 months, compared with best supportive care alone. Single agents with a proven activity in a first-line setting include 5-fluorouracil (5-FU), doxorubicin, mitomycin C, cisplatin, taxanes (docetaxel and paclitaxel) and oral fluoropyrimidines (capecitabine and TS-1). Based on the results from several large scale randomized trials, FP (5-FU/cisplatin) and ECF (epirubicin/cisplatin/5-FU) combinations are the most widely used regimen against advanced gastric cancer. Phase II studies of the FP and ECF combination reported a 40~51% response rate in previously untreated patients, and this regimen also produced a significantly higherresponse rate than the FAM (5-FU/doxorubicin/ mitomycin) and FAMTX (5-FU/doxorubicin/methotrexate) regimens, respectively. However, significant treatment related-toxicities and discomfort were reported from ECF, which prevents this combination from becoming the standard treatment regimen. While no one combination chemotherapy regimen is accepted as the standard for advanced gastric cancer, FP is currently considered a suitable reference regimen worldwide. New agents, such as taxane, irinotecan and oxaliplatin, combined with old agents, such as cisplatin and 5-FU, are currently under evaluation to further improve treatment outcomes. Also, oral 5-FU prodrugs are replacing the cumbersome 5-FU long-term infusion due to its convenience and superior toxicity profile. However, the low complete response rate and short response duration are still the main obstacles in the chemotherapy for gastric cancer. Only large scale comparative clinical trials will give clues to improve the results of gastric cancer treatments.
Chemotherapy; Stomach neoplasm; Palliative treatment; Review
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.
HRQOL; symptoms; head and neck cancer
Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil.
A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone.
Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively.
Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.
The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2–3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy. © 2000 Cancer Research Campaign http://www.bjcancer.com
oropharyngeal cancer; chemotherapy; randomized trial; cisplatin; fluorouracil