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.     

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.     

Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer

Background: Amifostine has reduced toxicities associated with radiationtherapy and platinum-based chemotherapy. In a phase II randomized trial, weinvestigated the ability of amifostine to reduce the toxicity of carboplatinplus radiotherapy (RCT) in patients with head and neck cancer.Patients and methods: Thirty-nine patients with stage III or IV squamouscell carcinomas of the head and neck received RCT (following surgery or asprimary treatment). Radiotherapy was given five days per week with dailyfractions of 2 Gy, up to a total dose of 60 Gy in conjunction withcarboplatin 70 mg/m² on days 1 through 5 and days 21 through26. Eligible patients were randomised to receive RCT alone or preceded by arapid infusion of amifostine (500 mg) on the days when carboplatin wasadministered.Results: Patients receiving amifostine + RCT (n = 25) had significantlyreduced mucositis (P = 0.0001) and xerostomia (P = 0.0001) in comparisonwith patients receiving RCT alone (n = 14). Additionally, patients receivingamifostine + RCT had significantly less thrombocytopenia (P = 0.001) andleukopenia (P = 0.001). At 12 months following therapy, 79% ofpatients receiving amifostine + RCT had no evidence of disease compared with64% of those receiving RCT alone.Conclusions: Amifostine reduces the RCT-induced toxicities in patients withhead and neck cancer and has no negative impact on antitumour efficacy.     

The role of amifostine in the treatment of head and neck cancer with cisplatin-radiotherapy

Although head and neck cancer is not one of the most common cancers, it is a debilitating disease with poor prognosis and considerable post-treatment normal tissue toxicity. The unremitting search to increase the therapeutic ratio between tumour control and late normal tissue injury led to the adoption of altered fractionation schedules. While the increase in acute toxicity can be managed with appropriate medical support, damage produced to late responding tissues is usually irreversible, therefore clinically unacceptable. By altering the conventionally fractionated radiotherapy both loco-regional control and overall survival are increased. Moreover, phase III randomized trials indicated that the combined administration of cisplatin and radiotherapy further improves treatment outcome. Although the uptake of cisplatin in normal cells is not amplified by the combined modality treatment, cisplatin, by itself is a highly cytotoxic agent. Therefore, the need for normal tissue protection has arisen. Amifostine is a selective, radio-protective drug used in both radiotherapy and chemotherapy to reduce normal tissue toxicity. This paper provides an overview of clinical trials employing cisplatin-radiotherapy treatment for advanced head and neck cancer with specific focus on normal tissue toxicity. The emerging role of radioprotectors and furthermore, the effectiveness of amifostine in combined cisplatin-radiotherapy trials are presented.     

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma

Background: Cisplatin is an active drug in head and neck cancer. Paclitaxel seems a promising drug. This article reports a phase II assessment of the combination of the two.Patients and methods: Twenty-three patients were treated with paclitaxel 90 mg/m² over three hours plus cisplatin 60 mg/m² every other week. Sixteen patients had locoregional disease and seven had metastatic disease. None of the patients had previously been treated with chemotherapy. Nine patients had had radiotherapy to the target lesions.Results: One patient was not evaluable for response. Partial responses were observed in 32% of evaluable patients. Toxicity included asthenia (56%), neutropenia, peripheral neuropathy, anemia and vomiting.Conclusions: The overall response rate observed in this study does not seem to justify the use of this chemotherapy regimen in the palliative setting.     

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 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.     

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.     

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: Final results of a randomized, double-blind, placebo-controlled, phase 3 study

BACKGROUND:

Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum‐based chemotherapy is often a first‐line treatment. Pemetrexed has shown single‐agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed‐cisplatin for SCCHN.

METHODS:

In a double‐blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²; n = 398) or placebo plus cisplatin (75 mg/m²; n = 397) to assess overall survival (OS) and secondary endpoints.

RESULTS:

Median OS was 7.3 months in the pemetrexed‐cisplatin arm and 6.3 months in the placebo‐cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75‐1.02; P = .082). Median progression‐free survival (PFS, months) was similar in both treatment arms (pemetrexed‐cisplatin, 3.6; placebo‐cisplatin, 2.8; HR, 0.88; 95% CI, 0.76‐1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed‐cisplatin (n = 347) led to longer OS and PFS than placebo‐cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed‐cisplatin (n = 86) resulted in longer OS and PFS than placebo‐cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed‐cisplatin toxicity was consistent with studies in other tumors.

CONCLUSIONS:

Pemetrexed‐cisplatin compared with placebo‐cisplatin did not significantly improve survival for the intent‐to‐treat population. However, in a prespecified subgroup analysis, pemetrexed‐cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. © 2012 American Cancer Society.     

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。     

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.     

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.     

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.     

Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer

Adaptation to cellular stress is not a vital function of normal cells but is required of cancer cells, and as such might be a sensible target in cancer therapy. Piperlongumine is a naturally occurring small molecule selectively toxic to cancer cells. This study assesses the cytotoxicity of piperlongumine and its combination with cisplatin in head-and-neck cancer (HNC) cells in vitro and in vivo. The effect of piperlongumine, alone and in combination with cisplatin, was assessed in human HNC cells and normal cells by measuring growth, death, cell cycle progression, reactive oxygen species (ROS) production, and protein expression, and in tumor xenograft mouse models.Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells. It increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Piperlongumine induced selective cell death in HNC cells by targeting the stress response to ROS, leading to the induction of death pathways involving JNK and PARP. Piperlongumine increased cisplatin-induced cytotoxicity in HNC cells in a synergistic manner in vitro and in vivo. Piperlongumine might be a promising small molecule with which to selectively kill HNC cells and increase cisplatin antitumor activity by targeting the oxidative stress response.     

Local control in advanced head and neck cancer by combined modalities of treatment

From July 1979 to January 1983, 20 patients with locally advanced head and neck cancer were treated with a combination of chemotherapy and irradiation with or without surgery. A majority of the patients were in the age range of 45 to 54 years. Eighty-five percent of the patients were male. Seventy-five percent of the patients had oral cavity lesions, the tongue being the most common site. Eighty percent of the patients had T₄ lesion and 35% had N₃ disease in the neck. A majority of the patients had combination chemotherapy, including bleomycin, methotrexate, and cis-platinum (BMP). All patients received irradiation with megavoltage equipment and 55% of patients received a dose of 5,000 to 6,000 rads in 5–6 weeks time. The tumor was converted to be resectable in ten patients. Nine patients (45%) had the neck and primary tumor completely controlled, while six patients (30%) had partial control. Six of the ten patients who had resection had the tumor controlled at the primary site and neck. The median duration of follow-up is 12 months (range, 4–32 months). The median survival of the whole group of patients is 12.5 months. A brief review of the current literature is also done in this paper.     

Phase II trial of chemoradiotherapy with S‐1 plus cisplatin for unresectable locally advanced head and neck cancer (JCOG0706)

We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S‐1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S‐1 twice daily on days 1–14 at 60 mg/m²/day and cisplatin at 20 mg/m²/day on days 8–11, repeated twice at a 5‐week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow‐up of 3.52 years, 3‐year local progression‐free survival was 62.2%, with 3‐year progression‐free survival of 60.0%, 3‐year overall survival of 64.4%, and 3‐year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment‐related deaths were observed. This combination showed promising efficacy with acceptable 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.     

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.