Weekly cisplatin paclitaxel and continuous infusion fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma: a phase II study

Background Cisplatin, paclitaxel and 5-fluorouracil (5-FU) have demonstrated significant activity in patients with advanced squamous head and neck cancer (HNSCC) despite relevant toxicity. A weekly administration of cisplatin and paclitaxel with continuous infusion of 5-FU could offer a better toxicity profile without affecting dose intensity or treatment outcome. We evaluated the toxicity and the activity of weekly cisplatin/paclitaxel with continuous infusion 5-FU in patients with recurrent and/or metastatic HNSCC.Methods A total of 44 patients were studied. Treatment consisted of two 6-week cycles with weekly cisplatin 20 mg/m² and paclitaxel 60 mg/m² and daily continuous infusion 5-FU 200 mg/m² from day 1 to 42. Patients were evaluated for toxicity and response.Results 40 out of 44 patients were evaluable for response. After two cycles we observed seven complete responses (16%) and 12 partial responses (27%), with a 43% (95% CI 28–58%) overall response rate. Stable disease was seen in 13 patients (29%) and progressive disease in 12 patients (27%). Toxicity was mild in treated patients: we observed less than 10% of grade 3/4 hematological and gastroenteric toxicity.Conclusions A weekly schedule of cisplatin and paclitaxel associated with continuous infusion 5-FU showed low toxicity in the treatment of advanced HNSCC while significant activity was conserved.     

A phase II study of paclitaxel and cisplatin combination chemotherapy in recurrent or metastatic head and neck cancer

The taxanes are the most active new agents for squamous-cell carcinoma of the head and neck (SCCHN) since the discovery of cisplatin. Our aim was to define the therapeutic efficacy and toxicity of paclitaxel and cisplatin combination therapy in patients with recurrent SCCHN. Patients with locally recurrent or metastatic SCCHN were enrolled in the study. Patients were required to be chemotherapy-naive, and should have completed radiation therapy at least 6 weeks prior to enrollment. A World Health Organization (WHO) performance status of less than 3 was required. Paclitaxel (Taxol, Bristol Myers Squibb Company, Princeton, NJ) and cisplatin therapy (PC) consisted of prophylaxis with pheniramine 50 mg i.v., ranitidine 150 mg i.v. and dexamethasone 20 mg i.v. given prior to paclitaxel 175 mg/m2 as a 3-hour i.v. infusion, followed by cisplatin 75 mg/m2 as a 1-hour infusion with an additional 3000 cc of saline for hydration. This treatment was repeated every 3 weeks for a maximum of six cycles. Patients were evaluated for response after the third and sixth cycles, or at the time of clinical progression. Fifty patients were enrolled in the study. The overall response rate was 32% with a 10% complete response rate. Forty-eight patients were assessable for toxicity. A total of 221 cycles of chemotherapy was given and the most common toxicity was myelosuppression; 7.7% of cycles had grade III-IV neutropenia. Severe neuropathy, nephropathy, mucositis, and emesis were uncommon (<10 %). At a median follow-up period of 25 months, the median overall survival was 10 months and the 1-year progression-free and overall survival rates were 16.7% and 35.2%, respectively. We conclude that patients with recurrent SCCHN have a moderate response to combination chemotherapy with cisplatin and paclitaxel. Given this moderate response rate, it is unlikely that this combination (PC) might ultimately prove to be superior to standard treatment regimens in terms of significant survival advantage.     

High-dose cisplatin for locally advanced or metastatic head and neck cancer. A phase II pilot study

High-dose cisplatin (40 mg/m2 every day X5) was administered to 14 patients (11 men, three women) with locally advanced or metastatic head and neck cancer not curable by surgery or refractory to previous chemotherapy and/or radiation therapy. All 14 patients were evaluable for toxicity; one patient was inevaluable for response due to early death. A total of 24 courses of therapy were administered. The dose-limiting toxicity was myelosuppression with 73% of patients experiencing Grade III or IV neutropenia. Grade II or above thrombocytopenia occurred in 30% of the patients. Renal and neurologic toxicity was minimal. Two patients experienced laryngeal edema from vigorous hydration with one of them requiring a tracheostomy for respiratory compromise. Partial responses were seen in six patients (46%). Two of the six patients had received previous treatment with standard dose cisplatin. Two patients achieved long-term responses (54+, 44+ months, respectively). Both of these patients were previously untreated, inoperable (T4N3M0, T3N1M0), and subsequently received radiation therapy after two cycles of chemotherapy. Median duration of response in the remaining responders was 3 months (range, 3-10 months). High-dose cisplatin may benefit selected patients with inoperable, advanced head and neck tumors. However, further randomized trials need to be conducted before firm conclusions can be established.     

Triweekly reduced-dose docetaxel combined with cisplatin in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase II study

Purpose  

To test the efficacy and safety of a triweekly reduced-dose docetaxel (60 mg/m²) regimen combined with a standard dose of cisplatin in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).     

A phase II study of cisplatin and cytosine arabinoside for recurrent squamous cell carcinoma of the head and neck

Based on experimental data suggesting synergy between cisplatin and cytosine arabinoside, 17 patients with recurrent squamous cancer of the head and neck were treated with this combination. The response rate was 18% with no complete responses, and the partial responses were of brief duration. There were moderate hematologic and gastrointestinal toxicities and two therapy-related deaths. The study was stopped early because of low response. When compared to results reported for cisplatin alone, the combination of cisplatin and cytosine arabinoside offered no clear advantage.     

A phase II study of combination chemotherapy with capecitabine and cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck

BackgroundThe purpose of this study was to assess the efficacy and toxicity of capecitabine and cisplatin (XP) combination chemotherapy in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThe chemotherapy regimen consisted of capecitabine 1250 mg/m² orally twice a day on day 1 to day 14 and cisplatin 60 mg/m² i.v. on day 1. Each cycle was repeated every 3 weeks up to a maximum of six cycles.ResultsBy intent-to-treat analysis, the overall response rate was 50% [complete response, 0/36; partial response, 18/36; 95% confidence interval (CI) 32% to 67%]. The median progression-free survival was 3.7 months (95% CI 2.1–5.3 months), and the median response duration was 4.9 months. The median overall survival and 1-year survival rate were 10.3 months (95% CI 8.5–12.1 months) and 43.3%, respectively. The common grade 3 or 4 nonhematologic adverse events were anorexia (8.8%), fatigue (4.4%), diarrhea (4.4%), stomatitis (3.6%), and the hand–foot syndrome (1.5%). The most common grade 3 or 4 hematologic adverse event was neutropenia (14.6%), followed by anemia (1.5%). There was no treatment-related death.ConclusionThe XP combination regimen has antitumor activity and acceptable safety profile in patients with metastatic or recurrent SCCHN.     

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck.

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m(-2) by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1-9) per patient. The median cumulative dose was 449 mg m(-2). Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1-50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4-52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h(-1) m(-2) and an area under the curve of 6.00 microg ml(-1) h(-1) was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.     

A phase I-II trial of cisplatin and dichloromethotrexate in squamous cell cancer of the head and neck

Dichloromethotrexate, a dihalogenated analog of methotrexate, is excreted and metabolized by the liver; therefore, blood levels are not dependent on renal function. The possibility that dichloromethotrexate could be given at its maximally tolerated dose in combination with high-dose cisplatin has been evaluated in 30 patients with advanced squamous cell cancer of the head and neck. Overall, this regimen was well tolerated, and 13 of 24 evaluable patients had an objective response to therapy (25% complete response and 29% partial response). The maximum dose of dichloromethotrexate that could be delivered was related to the serum albumin. Patients with an albumin less than 3.8 g/100 mL rarely tolerated doses of 500 mg/m2 or greater. Cisplatin plus dichloromethotrexate is an active drug combination in squamous cell cancer of the head and neck, and deserves further evaluation in randomized studies and in an adjuvant setting.     

Phase II study of cisplatin continuous infusion plus vindesine in the treatment of non-small-cell lung cancer.

We administered chemotherapy consisting of a combination of 5-day continuous intravenous infusion of cisplatin (25 mg/m2/day) plus vindesine (3 mg/m2, as a bolus, on days 1 and 8) to 30 patients with advanced non-small-cell lung cancer (NSCLC) and examined the effectiveness and safety of the treatment. Fifteen patients achieved a partial response, and the overall response rate was 50%, with a median response duration of 30.1 weeks (range 5-108.6 weeks) and a median survival of 39 weeks. Observed side effects were leukopenia (less than 3000/mm3) in 90% of patients (including less than 1000/mm3 in 23%), thrombocytopenia (less than 75000/mm3) in 30%, anemia (hemoglobin less than 9.5 g/dl) in 50%, vomiting in 43%, and alopecia in 77%. Elevated serum creatinine was not seen, and there were no treatment-related deaths. Toxicity was quite acceptable, but hematological toxicity was increased, and treatment was delayed for six patients because of leukopenia. We conclude that this regimen is generally well tolerated in patients with advanced NSCLC. Further studies in which the optimum therapeutic schedule can be made sufficiently safe to reduce leukopenia are needed.     

Four-day continuous infusion of cisplatin and 5-fluorouracil in head and neck cancer

A combination of cisplatin and 5-fluorouracil, both administered 4 days continuously as infusion, was assessed in advanced head and neck cancer. Of the 37 patients studied, there were 15 complete and 17 partial responses (40.5% and 45.9%, respectively). Survival is 79.1% at 22 months. None of the patients in complete response has relapsed. In general toxic effects were moderate. Given as initial treatment, the regimen is effective and of considerable use in this type of patient.     

Clinical phase II evaluation of paclitaxel in combination with cisplatin in metastatic or recurrent squamous cell carcinoma of the head and neck

Background: Paclitaxel as single agent has shown marked activity in several malignancies. The aim of the present phase II trial was to determine the activity of paclitaxel/cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.Patients and methods: 200 mg/m² paclitaxel was administered over three hours followed by cisplatin (100 mg/m²), repeated every 22 days. Twenty-eight patients were entered and received a total of 99 cycles (median 2, range 1–6). All patients were evaluable for toxicity, and 25 for response.Results: Hematologic toxicities included leukopenia CTC grade 3 in 13 patients, and grade 4 in five patients, neutropenia grade 3 in nine patients, and grade 4 in eigth patients, grade 3 anemia and grade 2 thrombocytopenia in one patient each. Non-hematologic toxicities included hypotension grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients). A decline in renal function was observed in 15 courses and 10 patients, leading to a median delay of 2.5 days. Neurosensory and neuromotor toxicity grade 1 were observed in 13 patients (grade 2: 12 patients; grade 3: one patient), myalgia grade 3 in one patient, asthenia grade 3 in two and grade 4 in one patient. Partial responses were observed in 12 patients for an overall response rate of 48% (95% CI: 28%–68%) with a median response duration of 6.5 months (range 1-10 months). Stable disease was observed in seven patients, of who two also had clinical benefit.Conclusions: Paclitaxel 200 mg/m² administered over three hours combined with cisplatin 100 mg/m² is an active regimen warranting further evaluation.     

Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: A phase II study

Purpose:Chemotherapy regimens for patients with advanced breastcancer or large primary tumours (including locally advanced disease) usuallycontain anthracyclines, taxanes or both. We investigated a multi-agent regimenfor patients for whom anthracyclines and/or taxanes may not be suitable. Weassessed efficacy in terms of response rate and time to progression of acombination with continuous infusion 5-fluorouracil (5-FU), vinorelbine andcisplatin (ViFuP regimen), as a first or subsequent line treatment formetastatic breast cancer patients. Patients and methods:One hundred consecutive patients withadvanced breast cancer were treated with 5-FU 200 mg/m²administered continuously through a permanent central venous line; vinorelbinewas given on days 1 and 3 at a dose of 20 mg and cisplatin was administeredat 60 mg/m² on day one. Therapy was given every three weeks. Themedian age was 50 years (range 23–72). Fifty-two patients had receivedprior chemotherapy for metastatic breast cancer, and sixty-one percent hadpreviously received anthracyclines, thirty-five percent taxanes andtwenty-nine percent 5-FU as a bolus injection. All patients were assessablefor toxicity, four patients were not assessable for response. Results:There were four complete responses (4%).Forty-nine patients had a partial response (overall response rate, 55%;95% confidence interval (CI): 45%–65%). After amedian follow-up of 10.2 months, median duration of response is 5.2 months(range 1.5–20.7+ months), time to progression (TTP) is 6.8 months (range0.3–24.7 months). Acute toxicity, including myelosuppression, was mild:only 18% of patients had grade 4 granulocytopenia and one patientexperienced grade 4 diarrhea. Only 15% of patients had anynon-hematological grade 3 toxicity including nausea (4%), stomatitis(4%), diarrhea (2%), fatigue (1%), fever (1%),photosensitivity (1%), hand–foot syndrome (1%). Grade 2alopecia was observed only in six patients (6%). Eleven patientsdeveloped a right diaphragmatic supra elevation, while deep vein thrombosis,central venous catheter associated, occurred in eight patients. Conclusions:We identified a combination chemotherapy withnoteworthy efficacy and well tolerated subjectively as either a first- orsecond-line treatment for metastatic breast cancer patients. The regimenwarrants further development focusing on the comparison with either continuousadministration of oral fluoropyrimidine derivatives.     

Phase II study of carboplatin and continuous infusion bleomycin followed by cisplatin and 5-fluorouracil in recurrent head and neck cancer

BACKGROUND: Recurrent squamous cell carcinoma of the head and neck is poorlyresponsive to most chemotherapy regimens. Carboplatin and bleomycinare effective single agents with non-overlapping toxicity; therefore,we sought to explore the efficacy of this regimen in a phaseII study. In the second stage of the study, patients who didnot respond to carboplatin and bleomycin were given treatmentwith cisplatin and 5-fluorouracil (5-FU). PATIENTS AND METHODS: Patients with recurrent squamous cell carcinoma of the headand neck were treated with carboplatin 400 mg/m² followed bybleomycin 15 units intravenously as a continuous infusion for4 days. Patients with no tumor response after 3 cycles of carboplatinand bleomycin were crossed-over to receive cisplatin 100 mg/m²and 5-FU 1000 mg/m²/day continuous infusion for 5 days. RESULTS: Among the 20 carboplatin-bleomycin patients evaluable for toxicity,no cases of grade 4 granulocytopenia were reported and grade3 or 4 thrombocytopenia developed in only three patients. Threepartial responses occurred among the 19 patients (16%) [95%Cl. 0% to 32% evaluable for response to carboplatin-bleomycin.None of the 11 patients crossed-over to cisplatin and 5-FU hada major response. CONCLUSION: The combination of carboplatin and bleomycin is well toleratedin patients with recurrent head and neck cancer, but the activitydoes not appear to be superior to the activity of either agentalone. Patients who did not respond to carboplatin and bleomycinwere also resistant to the cisplatin and 5-FU regimen. head and neck cancer, chemotherapy     

Randomized phase II study of cisplatin and 5-FU continuous infusion (PF) versus cisplatin, UFT and vinorelbine (UFTVP) as induction chemotherapy in locally advanced squamous cell head and neck cancer (LA-SCHNC)

OBJECTIVES: We conducted a multicentric randomized phase II trial comparing 5-FU continuous infusion (PF) and cisplatin, UFT and vinorelbine (UFTVP) as induction chemotherapy (IC) in locally advanced squamous cell head and neck cancer (LA-SCHNC). Primary objective was complete response (CR) to IC and overall survival (OS) was a secondary objective. MATERIALS AND METHODS: PF: cisplatin 100 mg/m(2) i.v. Day 1 (D1) and 5-FU 1,000 mg/m(2) per day i.v. continous infusion D1-D5, every 21 days. UFTVP: cisplatin 100 mg/m(2) i.v. D1; UFT 200 mg/m(2) per day p.o. D1-D21 and vinorelbine 25 mg/m(2) i.v. D1 and D8, every 21 days. Four IC courses were planned in both arms. RESULTS: A total of 206 patients (pts) were included (PF/UFTVP: 99/107): oral cavity: 8%/10%, oropharynx: 20%/25%, hypopharynx: 17%/14%, larynx: 54%/50%. Stage (TNM, 2002): III: 41%/35%, IVA: 23%/27%, IVB: 35%/38%. Complete response to IC: PF:36%/UFTVP:31% (P: no significative (NS)). G 3-4 toxicity (PF/UFTVP): neutropenia: 52%/72%; febrile neutropenia: 3%/20% (P < 0.001); anaemia:1%/14% (P < 0.001); trombocytopenia: 5%/0% (P = 0.02); mucositis: 15%/7% (P < 0.001). Deaths during IC: 2(2%)/3(3%). IC with UFTVP was associated with a favourable OS in the Cox analysis (actuarial 5 year OS: 49% vs. 34%; HR: 0.67, 95% CI: 0.47-0.95, P: 0.03). CONCLUSIONS: Although clinical response is equal in both arms, overall survival (Cox) is better in the UFTVP arm. Febrile neutropenia and anaemia were more frequent with UFTVP while mucositis and trombocytopenia were more severe with PF.     

A phase II study of primary reirradiation in squamous cell carcinoma of head and neck.

BACKGROUND AND PURPOSE: In this prospective study, the effect of a second course of primary radiotherapy on locoregional control, survival and toxicity was investigated, in patients who underwent a second course of high dose irradiation for second primary or locoregional recurrent squamous cell head and neck carcinoma (HNSCC) in a previously irradiated area. PATIENTS AND METHODS: A total of 34 patients with second primary (n=26) or locoregional recurrent (n=8) tumours were treated with a second course of high dose radiotherapy. Patients were selected for re-irradiation in case of inoperable and/or unresectable tumours. In most cases, the target volume for re-irradiation was confined to the gross tumour volume (GTV). No elective radiotherapy was applied in the former high-dose area. A total dose of 46 Gy was applied to elective areas with a boost up to 60 Gy with conventional fractionation. The median follow-up period was 32 months. RESULTS: The locoregional control rate after 2 years was 27%. The 3-year overall survival was 22%. The most frequently reported acute side-effect was acute mucositis resulting in swallowing complaints. Pharyngeal and oesophageal late morbidity was also the most important late side-effect. In general, acute and late radiation-induced morbidity remained within acceptable limits. CONCLUSIONS: In conclusion, primary re-irradiation appears to be feasible in terms of acute and late radiation-induced toxicity. To improve outcome in terms locoregional control and survival, future studies should be focussed on optimising radiation schedules and the addition of concomitant chemotherapy.     

A phase II study of piritrexim in patients with advanced squamous head and neck cancer.

Piritrexim (PTX) is a newly developed lipid-soluble folate antagonist that crosses the cell membrane by a simple, rapid, carrier-independent diffusion process. A Phase II study was conducted to evaluate the activity of PTX in 34 patients with previously chemotherapy-naive squamous cell cancer of the head and neck area (SCCHN). Among them, 30 patients had received previous radiation therapy and/or surgery. Of 33 patients who could be examined, 3 had a complete response (CR), 6 had a partial response (PR), 11 had no change, and 13 had disease progression. The overall response rate (CR + PR) was 27% (9 of 33; 95% confidence interval, 13% to 46%). The response duration ranged from 36 to 360 + days (median, 162) and was similar to the best studies reported with methotrexate. The three most severe side effects (Grades 3 and 4 by World Health Organization criteria) were leukopenia, thrombocytopenia, and mucositis. These occurred in 41%, 26%, and 15% of the 34 patients, respectively. This study established PTX as an agent with some activity in SCCHN. The use of PTX in combination chemotherapeutic regimens needs to be explored.     

A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer

Objective

The objective of this study was to evaluate the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy in patients with metastatic esophageal cancer.

Methods

Patients with untreated metastatic squamous cell esophageal cancer, which was histologically proven with at least one measurable lesion, were eligible for the study. Docetaxel 70 mg/m² and cisplatin 70 mg/m² were intravenously given on day 1 of 21 days schedule.

Results

From December 2004 to December 2007, total of 39 patients (M/F = 39/0) were enrolled. The median age was 65 years. Thirty-four patients were evaluable for response. There were 3 (7.7%) complete remission, 10 (25.6%) partial remission, 11 (28.2%) stable disease, and 10 (25.6%) progression disease. The objective tumor response rate was 33.3% in intention-to-treat (ITT). Median PFS was 5.0 months and median survival was 8.3 months. Median number of cycles administered was 3. The relative dose intensity of docetaxel and cisplatin was 92 and 91%, respectively. This treatment was comparatively tolerated with grade 3/4 neutropenia in 20.5%/10.3%, grade 3 infection in 2.6% of patients.

Conclusion

Docetaxel plus cisplatin combination chemotherapy showed promising antitumor activity with manageable toxicities in patients with metastatic squamous esophageal cancer.