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.     

Phase II study of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck

We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m(-2) on day 1 and oral capecitabine 825 mg m(-2) twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8-2.0 Gy 1 fraction day(-1) to a total dose of 70-70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN.     

Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial.

BACKGROUND: The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: Seventy patients with previously untreated stage III-IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m(2) as a 3-h infusion on day 1, cisplatin 100 mg/m(2) on day 2, and 5-fluorouracil (5-FU) 500-750 mg/m(2)/day as a 24-h continuous infusion on days 2-6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m(2)/day to 500 mg/m(2)/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery. RESULTS: Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2-3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40-63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively. CONCLUSIONS: The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.     

Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer

BACKGROUND:

Both concomitant chemotherapy and altered fractionation radiotherapy (RT) have been shown to improve outcomes for patients with locoregionally advanced head and neck squamous cell carcinomas. However, both strategies also increase acute toxicity, and it is questionable whether the 2 can be safely combined. Traditional concomitant chemotherapy regimens include high‐dose cisplatin given at 100 mg/m² every 3 weeks. The authors' purpose was to report efficacy and toxicity after weekly cisplatin (30 mg/m²/wk) concurrent with altered fractionation RT.

METHODS:

One hundred twenty‐one patients with American Joint Committee on Cancer stages II (3%), III (13%), or IV (84%) squamous cell carcinomas of the oropharynx (70%), hypopharynx (20%), or larynx (10%) were treated between 2000 and 2006 at the University of Florida with hyperfractionated RT (55 patients) or concomitant boost RT (66 patients) and concomitant cisplatin (30 mg/m²/wk).

RESULTS:

Median follow‐up was 2.9 years; median follow‐up on survivors was 3.6 years. Seventy‐nine percent of patients completed ≥6 cycles of chemotherapy; 94% received ≥7200 centigrays. Seven (6%) patients changed from cisplatin to carboplatin because of bone marrow toxicity. Gastrostomy tube feeding was required in 54% of patients either before (16%) or during RT (38%). Two (1.6%) patients died from therapy‐related complications. The 5‐year outcomes were: local control, 83%; locoregional control, 79%; distant metastasis‐free survival, 88%; cause‐specific survival, 76%; and overall survival, 59%. Seven (6%) patients had severe late complications. Three (3%) patients required a permanent gastrostomy tube.

CONCLUSIONS:

Concomitant weekly cisplatin with altered fractionation RT is a safe and effective treatment regimen. Cancer 2010. © 2010 American Cancer Society.     

Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck

Background: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck.Patients and methods: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks.Results: Twenty-four patients with a median age of 59 years (range 42–74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%–42%). The main toxicity was hematological: neutropenia grade 3–4 in 28% of the cycles and thrombocytopenia grade 3–4 in 16%. The most significant non-hematological toxicity was asthenia grade 2–3 in 24% of the cycles.Conclusions: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.     

A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck

BACKGROUND:

Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisp latin and 5‐f luorouracil [5‐FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction na b‐paclitaxel and c etuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.

METHODS:

Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab‐paclitaxel 100 mg/m²/week; cetuximab 250 mg/m²/week; cisplatin 75 mg/m² on day 1; 5‐FU 750 mg/m²/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m² on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.

RESULTS:

Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty‐nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2‐year overall and progression‐free survival rates were 84% and 65%, respectively.

CONCLUSIONS:

Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted. Cancer 2013. © 2012 American Cancer Society.     

Docetaxel and cisplatin: An active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck

Background: Docetaxel and cisplatin are among the most active antitumor agents in head and neck cancer, and phase I studies found the combination of the two drugs to be feasible. The EORTC ECSG performed a multicenter phase II study in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck to evaluate the antitumor efficacy and toxicity of this combination.Patients and methods: Eligibility criteria included written informed consent, a WHO performance status <2, life expectancy of >12 weeks, and adequate bone marrow, liver and renal function. Neoadjuvant pretreatment with cisplatin-based chemotherapy or prior radiotherapy were allowed. Patients were ineligible if pretreated with taxoids, had CNS involvement, concurrent malignancy, peripheral neuropathy, or no measurable disease. Treatment consisted of docetaxel 100 mg/m2 (one-hour i.v. infusion), followed by cisplatin 75 mg/m2 (three-hour i.v. infusion), repeated every three weeks. Supportive care included hydration, 5HT3- antagonists, and corticosteroids.Results: Forty-four patients (median age 55 years, range 35–76) entered the trial; 41 patients were eligible, 164 cycles of treatment were evaluable for toxicity, and 31 patients for response. Fourteen patients had undergone prior surgery, 15 had received radiotherapy, and five had had chemotherapy. A median number of four treatment cycles (range 1–6) was given. Hematologic and non-hematologic toxicities were common, but hypersensitivity reactions and fluid retention were very infrequent due to corticosteroid prophylaxis. Four patients were taken off the study due to toxicity, and one toxic death occurred due to pneumonia. Among 41 eligible patients, objective responses as confirmed by independent review included six complete remissions and 16 partial remissions, resulting in an overall response rate of 53.7% (95% confidence interval: 37.4%–69.3%). Responses occurred in locally advanced, recurrent and metastatic disease, both in pre- and non-pretreated patients. Of 22 evaluable, non-pretreated patients with locally advanced or metastatic disease, five achieved complete responses, and 14 partial responses. Observed among nine evaluable pretreated patients with locally advanced or metastatic head and neck cancer were one complete response and two partial responses.Conclusion: The combination of docetaxel and cisplatin is feasible and active in locally advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck.     

Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer

Background: Cisplatin is one of the most active cytotoxic agents available for the treatment of patients with head and neck cancer. In a previous phase II study with weekly administration of cisplatin, a response rate of 51% was achieved. However, only in a minority of the patients the planned high dose intensity of 80 mg/m²/week could be reached because of toxicity, mainly thrombocytopenia and ototoxicity. Amifostine is a cytoprotective drug that can diminish the toxicity of alkylating agents and platinum compounds. Therefore the effect of amifostine on toxicity and activity of weekly cisplatin was investigated in a randomized study.Patients and methods: Patients with locally advanced, recurrent or metastatic head and neck cancer were eligible. Patients were randomized to weekly cisplatin 70 mg/m² for six cycles preceded by amifostine 740 mg/m², or cisplatin only. Cisplatin was administered in hypertonic saline (3% NaCl) as a one-hour infusion; amifostine was administered as a 15-minute infusion directly before the administration of cisplatin.Results: Seventy-four patients were entered in the study. The median number of cisplatin administrations was 6 (range 2–6), equal in both arms. In both treatment arms the median dose intensity of cisplatin achieved was the planned 70 mg/m²/week. In the cisplatin only arm 6 out of 206 cycles were complicated by thrombocytopenia grade 3 or 4 versus 1 of 184 cycles in the amifostine arm (P = 0.035). Hypomagnesaemia grade 2 + 3 was significantly less observed in the amifostine arm (P = 0.04). Neurotoxicity analyzed by serial vibration perception thresholds (VPT) showed a diminished incidence of subclinical neurotoxicity in the amifostine arm (P = 0.03). No protective effect on renal and ototoxicity could be shown. Hypotension was the main side effect of amifostine but only of relevance in one patient. The antitumor activity of cisplatin was preserved as 63% of the evaluable patients in the amifostine arm responded compared to 50% of the evaluable patients in the cisplatin alone arm.Conclusion: Our study indicated that in combination with weekly administered cisplatin amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of amifostine did not compromise the antitumor effect of cisplatin.     

Efficacy and tolerability of weekly low-dose cisplatin concurrent with radiotherapy in head and neck cancer patients

Aims: In this retrospective analysis, we describe the efficacy and tolerability of weekly cisplatin 40 mg/m² used in concurrent chemoradiation of head and neck cancer at the Townsville Cancer Centre. Methods: Review of medical records of patients who received radical chemoradiotherapy for head and neck cancer at Townsville Cancer Centre from 2003 to 2009. Results: In all 102 patients were analysed, 62 of whom had definitive chemoradiation and the remainder adjuvant chemoradiotherapy. Median follow up was 20.1 months (range 5–86 months). Overall 68.6% of patients received 5 weeks or more of planned chemotherapy. Radiotherapy interruptions occurred in four (6.4%) patients. The rate of grade 3–4 adverse events was 51% including neutropenia (18.6%), mucositis (21.8%) and dysphagia (12.9%) and 30.7% of patients needed hospital admission to manage toxicities. For definitive and adjuvant groups, estimated 3‐year survival was 64.5 and 71.5%, respectively, and estimated 3‐year disease‐specific survival rates were 70.3 and 81.6%, respectively. The 3‐year overall survival for patients who received five or more cycles of chemotherapy was 75.2%, compared to 52.6% for those receiving fewer than five cycles (P = 0.018). Conclusion: Despite this is being a small retrospective study, survival figures and toxicity profiles of low dose weekly cisplatin are comparable to historical controls using high‐dose regimens, hence justifying our approach. In addition, radiotherapy interruptions are minimized and cisplatin is easy to administer in outpatient settings. Future three‐arm studies could include this regimen as the basis of treatment combined with targeted therapies.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

Phase II study of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck

Background:Results with docetaxel as single drug in squamous-cellhead and neck cancer have been encouraging. The purpose of the present phaseII study is to evaluate the antitumour efficacy and toxicity of thecombination of docetaxel and cisplatin in patients with recurrent ordisseminated squamous-cell carcinoma of the head and neck (SCCHN) for whom nocurative therapy is available. Patients and methods:Eligibility criteria included: writteninformed consent; WHO performance status 2; age 18–70 years;adequate bone marrow, liver, and renal function; measurable or evaluabledisease; no previous systemic chemotherapy (prior radiotherapy and/or surgerywere allowed); no other previous or concurrent malignancy; no peripheralneuropathy. Treatment consisted of docetaxel 75 mg/m² in a one-hourinfusion after pre-treatment with prednisolone, followed by cisplatin 75mg/m² in a half-hour infusion preceded and followed by hydration.Treatment was repeated every three weeks for a maximum of eight cycles. Results:Twenty-five patients (median age 52 years, range33–66) entered the trial, all were evaluable for survival, twenty-fourfor response and toxicity. Twenty-four patients had undergone priorradiotherapy and seventeen had also had surgery. Nineteen had local-regionalrecurrence only, three had local-regional disease and distant metastases, andthree had distant metastases only. Patients received a median of 5 treatmentcycles (range 2–8). Overall response rate was 33% (8 of 24) ofpatients; complete response rate was 8% (2 of 24) of patients, lasting2.2 and 17.1 months, respectively; partial response rate was 25% (6 of24) of patients, lasting for a median of 4.9 months (range 1.7–11.6months). Median survival was 11 months. Toxicity was relatively welltolerated. However, one patient died of probable toxicity (neutropenia andinfection) and three patients discontinued treatment because of toxicity(massive oedema, myocardial infarction, persistent thrombocytopenia). The mostfrequent moderate-to-severe toxicity (75% of patients) was grade3–4 neutropenia, transient in all but one patient. Grade 3 neuropathyoccurred in one patient, none had grade 4. Grade 3 oral mucositis occurred inthree patients, none had grade 4. Grade 2–3 hypomagnesaemia occurred in10 patients requiring magnesium infusion. Conclusions:Docetaxel and cisplatin is an active combination inpatients with recurrent or disseminated SCCHN. Remissions are however fairlyshort. Toxicity is significant, but generally manageable.     

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck

Background: Paclitaxel has been demonstrated to have significant activityin recurrent or metastatic head and neck cancer (HNC). In addition, thecombination of paclitaxel and cisplatin is active in untreated patients withinoperable HNC. Substitution of carboplatin for cisplatin allows the treatmentto be delivered on an outpatient basis.Purpose of the study: To evaluate the activity and toxicity of thecombination of paclitaxel by three-hour infusion and carboplatin as first-linechemotherapy in patients with recurrent or metastatic HNC.Patients and methods: From March 1994 until August 1996, 49 patients withrecurrent or metastatic HNC were treated with paclitaxel (200mg/m², by three-hour infusion) followed by carboplatin at anAUC of 7 mg·min/ml, every four weeks. G-CSF was administeredprophylactically on days 2 to 12 of each cycle. There were 41 men and 8 womenwith a median age of 57 years (range 23–73). The majority of thepatients were symptomatic and they had recurrent disease locoregionally.Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cellcancers of other areas of the head and neck region (non-NPC).Results: At the completion of treatment, two patients with NPC demonstratedcomplete and six partial responses for an overall response rate of 57%(95% CI 29%–82%). Among patients with non-NPC, theresponse rate was 23% (95% CI 9%–37%). Aftera median follow up period of 15 months, the median time to progression was 4.3months in the non-NPC group and 16.5 months in the NPC group. At the time ofthe analysis, median survival had not been reached in NPC while it was 7.3months in non-NPC patients. Grade 3–4 toxicities included anemia(2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting anddiarrhea (4% each).Conclusions: The combination of paclitaxel and carboplatin appears to bewell tolerated but only moderately active in patients with advanced non-NPCof the head and neck region. However, its activity appears promising in NPCand deserves further investigation.     

紫杉醇联合顺铂方案同步放疗治疗局部进展期宫颈癌的疗效分析

目的 分析紫杉醇联合顺铂方案同步放疗对局部进展期宫颈癌患者的疗效及不良反应.方法 选取局部进展期宫颈癌患者68例,FIGOⅢ~Ⅳa期,接受根治性放疗,累积剂量为80 Gy,同时每周给予顺铂30 mg/m2+紫杉醇50 mg/m2.观察记录患者的疗效及不良反应.结果 68例患者的不良反应包括胃肠道损害、贫血及脑梗死等,2年累积远期不良反应发生率为25%.中位随访时间27个月,2年PFS为83.8%(75.1%~92.6%),2年OS为92.7%(86.4%~98.9%),2年DM为13.2%(5.2%~21.3%).结论 紫杉醇联合顺铂同步放疗治疗局部进展期宫颈癌的疗效显著,且方案安全可行.     

持续静脉滴注氟尿嘧啶联合顺铂治疗晚期头颈部癌

背景与目的:顺铂与氟尿嘧啶是治疗晚期头颈部肿瘤疗效确切的药物,但有一定的毒性反应。本研究观察持续静脉滴注氟尿嘧啶联合顺铂治疗晚期头颈部癌的疗效及安全性。方法:22例晚期头颈部癌患者给予氟尿嘧啶750mg/(m2.d)持续静脉滴注5d(120h),顺铂25mg/(m2.d),d1～3。21d为一个周期,2个周期后评价疗效。结果:CR1例(4.5%),PR8例(36.4%),近期客观有效率为40.9%(9/22)。中位TTP7.4个月,1年生存率为72.7%。初治与复治有效率分别为75.0%(6/8),21.4%(3/14),统计学差异有显著性(χ2=6.04,P<0.05)。主要毒副反应为骨髓抑制、胃肠道反应和粘膜炎。结论:持续静脉滴注氟尿嘧啶联合顺铂治疗晚期头颈部癌具有较好的疗效,安全性好。     

Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I-II feasibility study.

PURPOSE: To determine the safety profile and activity of the combination of docetaxel, cisplatin and 5-fluorouracil (5-FU) in chemotherapy-naive patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with locally advanced unresectable SCCHN were treated with docetaxel and cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5-FU for 5 days. Cycles were planned every 3 weeks up to four cycles, whereafter the patients were treated with locoregional radiotherapy. Two dose levels were studied. Doses in level I were 75 mg/m(2) of docetaxel, 75 mg/m(2) of cisplatin and 750 mg/m(2)/day of 5-FU; in level II the cisplatin dose was escalated to 100 mg/m(2). Following chemotherapy, all patients were to receive curative radiotherapy according to the standards in the different institutions. RESULTS: Twenty-five patients were treated at dose level I with 86 cycles (median four; range one to four), and 23 at dose level II with 84 cycles (median four; range two to four). The median relative dose intensity was 0.99 (range 0.86-1.04) at level I and 0.94 (range 0.79-1.02) at level II. The response rate in the intention-to-treat population was 64% [95% confidence interval (CI) 42.5% to 82%] in level I and 78.3% (95% CI 56.3% to 92.5%) in level II; all were partial responses. The maximum tolerated dose was reached at level II with renal toxicity, nausea, stomatitis and thrombocytopenia as principal dose-limiting toxicities. The median survival of the 48 patients was 18.5 months. The survival at 12, 18, 24 and 30 months was 69, 54, 41 and 31%, respectively. CONCLUSIONS: The combination of docetaxel, cisplatin and 5-FU associated with prophylactic ciprofloxacin is feasible and active in patients with SCCHN. Dose level I is recommended for phase III testing.     

Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer.

Background:Concomitant chemoradiotherapy (CCRT) for squamous cancers of the head and neck (SCCHN) improves survival but increases toxicity. Pegylated liposomes localise to solid cancers and may deliver radiosensitizing agents preferentially to tumour tissue, potentially improving the therapeutic ratio of CCRT. Patients and methods:A phase I–II trial of pegylated liposome encapsulated cisplatin (SPI-077^TM) was conducted in 18 patients with treatment-naïve locally advanced, inoperable SCCHN. The first 10 patients received 2 cycles of 200 mg/m², and the next 8 received 260 mg/m², every 3 weeks before commencing radical radiotherapy (RT). Results:Only 2 of 18 (11%) patients had partial responses to SPI-077^TM, with 2 responses in 29 (6.9%) evaluable sites. SPI-077^TM was tolerated well with no haematological, renal, hepatic or neurological toxicities. Nausea and vomiting were minimal. There were no drug-related delays in the delivery of RT. RT-induced mucosal and cutaneous toxicity were not significantly increased. Conclusions:SPI-077^TM is essentially inactive against SCCHN and, in its present formulation, does not merit further evaluation as induction chemotherapy or as part of a CCRT approach.     

Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer

BACKGROUND:

A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m²) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks.

RESULTS:

Fifty‐eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow‐up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow‐up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow‐up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy–dependent at the time of last follow‐up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]‐1, and IL‐6) and lower levels of anti‐inflammatory cytokines (IL‐13) were noted. No changes in C‐reactive protein levels were noted.

CONCLUSIONS:

Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. Amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen. Cancer 2009. © 2009 American Cancer Society.     

Phase II trial of cisplatin and capecitabine in patients with squamous cell carcinoma of the head and neck, and correlative study of angiogenic factors

The combination of cisplatin and capecitabine was evaluated in patients with recurrent or unresectable squamous cell carcinoma of the head and neck (HNSCC), and outcome parameters were correlated with the expression of thymidine phosphorylase (TP), thymidilate syntetase (TS), vascular endothelial growth factor receptor (VEGFR) 1-3, and microvessel density (MVD). Patients with recurrent or unresectable HNSCC were eligible if they had received prior neoadjuvant chemotherapy, concurrent chemo-radiotherapy, or no prior systemic therapy. Patients received cisplatin (75 mg m(-2) day 1), and capecitabine (2000 mg m(-2) day 1-14) every 3 weeks. A total of 41 patients received 194 cycles. In all, 16 complete responses (39%) and 12 partial responses (29%) were documented, for an overall response rate of 68% (95% CI, 53-80%). Grade 3-4 uncomplicated neutropenia was documented in five subjects. Asthenia, anorexia, hand-foot syndrome, and constipation were the most frequent nonhaematologic events. Median progression-free and overall survival were 6.4 and 12.6 months. Cytoplasmic TP expression was more prevalent in patients with a laryngeal location vs other, and in patients with a recurrence vs primary disease. Microvessel density count was higher in patients with recurrent vs primary disease. The combination of cisplatin and capecitabine is effective in recurrent or unresectable HNSCC, and shows a manageable toxicity.     

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

Purpose

To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients and methods

Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m²/day: 4 patients; 15 mg/m²/day: 4, 20 mg/m²/day: 5 and 25 mg/m²/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level.

Results

The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m² level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m² level (grade 3 GI disorders), one at 10 mg/m² level (grade 4 mucositis). PK analysis showed no significant difference of C_max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum).

Conclusion

Due to 3 DLTs experienced at 25 mg/m²/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m²/day.     

Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer

In a phase I study we demonstrated the feasibility of a bi-weekly combination of paclitaxel 180 mg x m(-2) with cisplatin 60 mg x m(-2). In this study we further assessed toxicity and efficacy of this schedule in the treatment of advanced cancer of the oesophagus or the gastro-oesophageal junction. Patients received paclitaxel 180 mg x m(-2) administered over 3 h followed by a 3-h infusion of cisplatin 60 mg x m(-2). Patients were retreated every 2 weeks unless granulocytes were <0.75x10(9) or platelets <75x10(9). Patients were evaluated after three and six cycles and responding patients received a maximum of eight cycles. Fifty-one patients were enrolled into the study. The median age was 56 years (range 32-78). WHO performance status were: 0 (19 patients); 1 (29 patients); 2 (three patients). All patients received at least three cycles of chemotherapy and all were evaluable for toxicity and response. Haematological toxicity consisted of uncomplicated neutropenia grade 3 in 39% and grade 4 in 31% of patients. Five patients (10%) were hospitalised, three patients because of treatment related complications and two patients because of infections without neutropenia. Sensory neurotoxicity was the predominant non-haematological toxicity; grade 1 and 2 neurotoxicity was observed in 43 and 20% of patients, respectively. Response evaluation in 51 patients with measurable disease: complete response 4%, partial response 39%, stable disease 43% and progressive disease in 14% of the patients. The median duration of response was 8 months. The median survival for all patients was 9 (range 2-29+) months and the one-year survival rate was 43%. Four patients who received additional local treatment (two patients surgery and two patients radiotherapy) are still disease free after a follow-up of 20-29 months. This bi-weekly treatment of paclitaxel and cisplatin is well tolerated by patients with advanced oesophageal cancer. The toxicity profile of this regimen compares favourable to that of previously used cisplatin- and paclitaxel-based regimens. Trials are underway evaluating this bi-weekly regimen in a neo-adjuvant setting.