Induction chemotherapy in head and neck cancer.
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Antineoplastic Agents↗
Biomedical subjects
R Hitt
Publications and source records attributed to R Hitt.
beta-Catenin, Nf-kappaB and FAS protein expression are independent events in head and neck cancer: study of their association with clinical parameters.
In spite of much effort, no good markers have yet been found for predicting prognosis or response to therapy in advanced head and neck squamous cell carcinoma (HNSCCs) patients. beta-catenin, a protein involved in the cytoskeleton, cell-cell adhesion and gene transcription, is a factor associated with tumour progression. Recently, an interaction has been reported between beta-catenin, and NF-kappaB coupled with an inverse association of beta-catenin, and FAS (CD95/APO-1) protein expression in breast and colorectal tumours. To confirm these observations and to test their clinical impact in HNSCCs we have evaluated the expression of beta-catenin, NF-kappaB and FAS proteins. We used tissue microarrays to simultaneously analyse the levels of these proteins immunohistochemically in 118 HNSCCs. Among the 113 tumours evaluable for beta-catenin, increased and decreased levels were detected in 41 (36%) and 62 (55%) of the tumours, respectively. beta-catenin, protein staining was mainly membranous but 10 tumours (9%) showed the clear presence of protein in the cytoplasm, and none in the nucleus. Moreover, 81% of the tumours had decreased FAS protein expression, indicating that loss of FAS protein is a common feature of HNSCCs. Abnormal or nuclear NF-kappaB staining was observed in 24% of the tumours. No association was detected between the expression levels of the proteins evaluated. Regarding clinical associations, tumours from the hypopharynx had significantly lower levels of beta-catenin expression than those from other locations (P<0.05). Moreover, our data revealed that patients whose tumours had low levels of beta-catenin protein expression had decreased survival probability (24.8 months vs. NR, P=0.03) and reduced response to therapy (15.4 vs. 43 months; P=0.01) compared with patients whose tumours had high levels of beta-catenin. Taken together, our observations indicate that beta-catenin, NF-kappaB and FAS expression are independent events during HNSCC development and that levels of beta-catenin protein may identify subsets of advanced HNSCCs patients with different prognosis and response to therapy capabilities.
Biomarkers, Tumor↗
A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy.
AIMS: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) develops in around 72,000 people in Europe every year. Treatment options are limited, mainly consisting of platinum-based palliative chemotherapy, with median overall survival times of only 6-8 months. No standard second-line treatment after progression on platinum-based chemotherapy is available. Few data have reported the efficacy of these treatments and the outcome of the patients. In an effort to generate such data, this retrospective study analysed clinical records from 151 patients with SCCHN refractory to platinum-based chemotherapy treated between 1990 and 2000 at seven different centres around Europe. MATERIALS AND METHODS: Most patients (45%) received only best supportive care (BSC), and had a median survival of 56 days. A total of 28.5% of the patients received second-line chemotherapies: 16.6% radiotherapy and 9.9% chemoradiotherapy. RESULTS: No objective response was observed with the various second-line chemotherapies. The overall median survival was 103 days (95% confidence interval [CI]: 77-126 days) for the whole cohort. The overall objective response rate (ORR) to second-line treatment in this population was calculated to be 2.6%. CONCLUSION: These results highlight the need for additional treatment options for this disease. Similar, if not superior, response rates have already been observed in initial clinical studies of novel, targeted anti-cancer agents.
Adult↗
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.
Adult↗
Biweekly vinorelbine and gemcitabine: a phase I dose-finding study in patients with advanced solid tumors.
BACKGROUND: The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose of a combination of vinorelbine plus gemcitabine administered on a biweekly schedule in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with advanced or refractory solid tumors included in this phase I study were treated with vinorelbine followed by gemcitabine. Vinorelbine was given intravenously over 10 min, and gemcitabine was given intravenously at an fixed-dose infusion rate of 10 mg/m(2)/min. Six dose levels of vinorelbine/gemcitabine were explored: 20/2000, 25/2500, 25/3000, 30/3000, 30/3500 and 30/2500 mg/m(2). RESULTS: Nineteen patients were included in the study. Fourteen patients were pretreated with chemotherapy and/or radiotherapy. A total of 123 cycles of chemotherapy were administered. DLTs were neutropenic fever and grade 3 asthenia at dose level 5 (30/3500 mg/m(2)); at dose level 4 (30/3000 mg/m(2)) they were grade 3 asthenia, and a radiation-recall reaction and pneumonitis. Sixteen patients were evaluable for efficacy. Five patients had an objective response (one complete response and four partial responses), for an overall response rate of 31%. CONCLUSIONS: The recommended dose for phase II study is vinorelbine 30 mg/m(2) and gemcitabine 2500 mg/m(2) administered once every 2 weeks. This regimen is feasible and well-tolerated at this dose, and shows a good clinical activity in all levels explored.
Aged↗
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.
Adult↗
Side effects of chemotherapy. Case 2. Radiation recall reaction induced by gemcitabine.
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Antimetabolites, Antineoplastic↗
Centenarians: the older you get, the healthier you have been.
A retrospective analysis of the health and functional status of centenarians shows they are healthy and independent for most of their lives and experience a relatively rapid terminal decline.
Activities of Daily Living↗
p53 expression in locally advanced pharyngeal squamous cell carcinoma.
BACKGROUND: Prognosis for advanced head and neck squamous cell carcinoma remains poor despite advances in treatment, although a small number of patients may benefit from induction therapy leading to increased local control. Mutations of the p53 gene, which are present in a considerable percentage of head and neck squamous cell carcinomas, have been associated with poor response to chemotherapy. The role of p53 protein overexpression (which is associated with p53 gene mutations) in predicting the response to chemotherapeutic agents and survival rates is not clear. OBJECTIVE: To determine the association of p53 expression with chemotherapy response rates and disease-free survival rates in 62 patients with locally advanced pharyngeal cancer treated with induction cisplatin-5-fluorouracil chemotherapy between 1983 and 1995. DESIGN: Historical cohort. Archival tissue from biopsies done before chemotherapy was immunohistochemically stained for the p53 tumor suppressor gene (clone D0-7; DAKO Corp, Glostrup, Denmark). RESULTS: Positive staining for p53 occurred in 45 (73%) of 62 cases, with the percentage of reactive cells ranging from 35% to 98%. Chemotherapy response rates were higher in the p53-negative group (15/17 [88%]) compared with the p53-positive group (27/45 [60%]) (P =.07). The risk of recurrence was lower in the p53-negative group compared with the p53-positive group at 2, 3, and 5 years after treatment (P = .03, P = .01, and P = .007, respectively). The median relapse-free survival rates of patients in the p53-negative group was 16 months, whereas those with p53 protein expression demonstrated a median relapse-free survival time of 9 months (P = .07). In multivariate analyses, the only independent factor of relapse-free survival rates was age older than 70 years. CONCLUSION: The present study shows a trend favoring p53 overexpression as a predictive and prognostic factor in locally advanced pharyngeal cancer treated with induction chemotherapy.
Adult↗
Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS: Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.
Adult↗
Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation.
The endoplasmic reticulum contains a quality control system that subjects misfolded or unassembled secretory proteins to rapid degradation via the cytosolic ubiquitin proteasome system. This requires retrograde protein transport from the endoplasmic reticulum back to the cytosol. The Sec61 pore, the central component of the protein import channel into the endoplasmic reticulum, was identified as the core subunit of the retro-translocon as well. As import of mutated proteins into the endoplasmic reticulum lumen is successfully terminated, a new targeting mechanism must exist that mediates re-entering of misfolded proteins into the Sec61 pore from the lumenal side de novo. The previously identified proteins Der3p/Hrd1p and, as we show here, Hrd3p of the yeast Saccharomyces cerevisiae, are localised in the endoplasmic reticulum membrane and are essential for the degradation of several substrates of the endoplasmic reticulum degradation machinery. Based on genetic studies we demonstrate that they functionally interact with each other and with Sec61p, probably establishing the central part of the retro-translocon. In the absence of Hrd3p, the otherwise stable protein Der3p/Hrd1p becomes rapidly degraded. This depends on a functional ubiquitin proteasome system and the presence of substrate molecules of the endoplasmic reticulum degradation system. When overexpressed, Der3p/Hrd1p accelerates CPY* degradation in Delta(hrd3) cells. Our data suggest a recycling process of Der3p/Hrd1p through Hrd3p. The retro-translocon seems to be build up at least by the Sec61 pore, Der3p/Hrd1p and Hrd3p and mediates both retrograde transport and ubiquitination of substrate molecules.
Amino Acid Sequence↗
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.
Adult↗
Lack of ability of ciprofloxacin-rifampin prophylaxis to decrease infection-related morbidity in neutropenic patients given cytotoxic therapy and peripheral blood stem cell transplants.
We compared ciprofloxacin alone with ciprofloxacin plus rifampin (C + R) as a prophylactic antibacterial regimen for 40 patients with solid tumors treated with high-dose chemotherapy and autologous stem cell transplantation support. No differences were found between groups in the time elapsed to the onset of fever, incidence of febrile episodes, amphotericin B use, and length of hospital stay. However, C + R combination prophylaxis significantly reduced the incidence of gram-positive bacteremia (five versus zero episodes) but was associated with a higher incidence of drug-related side effects.
Adult↗
Patient selection in high-dose chemotherapy trials: relevance in high-risk breast cancer.
PURPOSE: To evaluate the impact of the selection criteria that are used in current high-dose consolidation chemotherapy (HDCT) trials on the outcome of high-risk breast cancer patients treated with conventional adjuvant chemotherapy. PATIENTS AND METHODS: From 1975 to 1995, 265 breast cancer patients at our institution showed involvement of ten or more positive axillary lymph nodes. Of these, 171 received standard adjuvant combination chemotherapy, but not HDCT consolidation, and were the subjects of our study. One hundred twenty-eight patients met the standard selection criteria for HDCT with hematological support (< 60 years, no significant concomitant disease, and no progression during adjuvant treatment), whereas 43 did not. Clinical outcome was analyzed by using disease-free survival (DFS) and overall survival (OS) as endpoints. To provide an assessment of the short-term efficacy of HDCT, we also evaluated the outcome in a cohort of 39 patients from the last 4 years who met the criteria for, and were actually treated with, HDCT after adjuvant chemotherapy. RESULTS: With a median follow-up of 4.4 years (range, 0.7 to 17.2 years), 112 of the 171 patients have had a relapse, and 87 have died. The estimated 5-year DFS was 32.3%, and OS was 49.4%. DFS was significantly higher for patients who met the HDCT criteria (36.6% at 5 years) than for those who did not (15.8% at 5 years; P < .05). OS was also significantly more favorable in patients meeting HDCT criteria (55.4% at 5 years) than in patients not meeting HDCT criteria (22.7% at 5 years; P < .01). We performed a multivariate analysis to adjust for other potential prognostic factors and found that meeting the HDCT criteria and having undergone locoregional radiotherapy were the only significant independent predictors for DFS and OS. Finally, we compared the outcome of the 128 patients who met the HDCT criteria and were treated with conventional adjuvant chemotherapy only with that of the 39 patients who met the criteria and who actually underwent HDCT, and we did not observe significant differences in the DFS or OS between these groups. CONCLUSIONS: Meeting HDCT inclusion criteria is an independent indicator of favorable prognosis in high-risk breast cancer patients. The selection of patients by these criteria may explain, at least in part, the promising short-term results of nonrandomized adjuvant HDCT trials in high-risk breast cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Study of escalating doses of paclitaxel plus cisplatin in patients with inoperable head and neck cancer.
This phase I/II study sought to determine the response rate and toxicity profile of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered with fixed doses of cisplatin with granulocyte colony-stimulating factor support in 28 patients with head or neck cancer. The study was designed as a modified dose-finding trial and contained five dose-escalation levels of paclitaxel. Dose level 1 contained seven patients, and doses ranged from 175 to 220 mg/m2; dose level 2, 230 to 250 mg/m2 (five patients); dose level 3, 250 mg/m2 only (four patients); dose level 4, 260 to 280 mg/m2 (six patients); and dose level 5, 280 to 300 mg/m2 (six patients). Dose levels greater than 200 mg/m2 were supported with concomitant granulocyte colony-stimulating support. Paclitaxel was given on day 1 by 3-hour infusion; cisplatin 75 mg/m2 was given on day 2. Courses were given every 3 weeks. All patients were evaluable for toxicity and 27 were evaluable for response. The overall response rate was 77% (10 complete responses, 11 partial responses, four no change, and two disease progression). Over a median follow-up of 15 months (range, 7 to 22 months), 16 patients showed no evidence of disease and three are alive with disease. A dose-effect relationship was found between paclitaxel and peripheral neuropathy. Twenty-seven of 28 patients experienced alopecia, peripheral neuropathy, myalgias, and arthralgias. Most toxicities were grade 1 or 2; the mean duration of symptoms was 7 days. No dose-limiting hematologic toxicity was observed, nor was any significant neutropenia seen in those patients receiving filgrastim. The paclitaxel/cisplatin combination was found to be an effective first-line regimen for patients with head or neck cancer. Although the number of patients in this study was small, no relationship was noted between patient response and disease site.
Adult↗
Phase I/II study of paclitaxel/cisplatin as first-line therapy for locally advanced head and neck cancer.
A phase I/II study was conducted to determine the response rate and the toxicity of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus cisplatin with granulocyte colony-stimulating factor support in patients with untreated advanced head and neck carcinoma. Twenty-eight patients with locally advanced inoperable squamous cell head and neck carcinoma were included. Median age was 51 years. Karnofsky performance status was > or =90% in all patients. Primary tumor sites were oropharynx, hypopharynx, larynx, oral cavity, parotid gland, nasal cavity, and unknown primary. We observed 13 complete responses, eight partial responses, four patients with stable disease, and two patients with progressive disease for an overall response rate of 78%. Toxicity was paresthesia grade 1/2 in 27 patients, and myalgias were grade 1/2 in 23 patients and grade 3 in four patients. One patient died 5 days after the first cycle due to acute renal failure, respiratory distress, and pancytopenia. No dose-limiting hematologic toxicity has been observed, and intrapatient escalations were performed in all patients when planned. Calculated dose intensity for the two drugs was 100% in all evaluable patients. The combination of escalating doses of paclitaxel 175 to 300 mg/m2 and cisplatin 75 mg/m2 was active in untreated head and neck carcinoma, with an overall response rate of 78%. No dose-limiting toxicity has been encountered at paclitaxel doses up to 300 mg/m2 given with granulocyte colony-stimulating factor.
Adolescent↗
Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors.
BACKGROUND: Several randomized trials have tested the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in relieving chemotherapy-induced bone marrow suppression. However, the use of CSFs in the treatment of neutropenic fever remains virtually unexplored. PURPOSE: This study evaluated the benefits of adding CSF therapy to the standard antibiotic treatments given to cancer patients for chemotherapy-induced neutropenic fever. The usefulness of CSFs was quantified in terms of reducing the following: (a) the duration of neutropenia, (b) the length of hospitalization, and (c) the overall cost of the treatment. METHODS: A randomized trial was conducted to test whether the administration of either G-CSF or GM-CSF improved the outcome of standard antibiotic therapy (ceftazidime plus amikacin) in nonleukemic cancer patients with fever (> 38 degrees C) and grade IV neutropenia (absolute neutrophil count [ANC] < 500/mm3) induced by standard-dose chemotherapy. Of 121 patients who entered the trial, 39 received G-CSF (5 micrograms/kg body weight per day), 39 received GM-CSF (5 micrograms/kg body weight per day), and 43 received a placebo beginning just after the first dose of antibiotics. Treatments were continued for at least 5 days (7 days with clinically or microbiologically documented infections) or until 2 days after fever subsided and ANCs rose above 1000/mm3. RESULTS: The median duration of grade IV neutropenia (ANC of < 500/mm3) was 2 days in both CSF arms and 3 days in the placebo arm (P < .001). The median duration of neutropenia with an ANC of less than 1000/mm3 was also significantly shorter in patients receiving G-CSF or GM-CSF (P < .001). The median duration of fever was similar in the three arms. The median hospital stay was 5 days (range, 5-14 days) in the G-CSF arm, 5 days (range, 5-10 days) in the GM-CSF arm, and 7 days (range, 5-34 days) in the placebo arm (P < .001). The median time on CSF was 4 days in both treatment arms. The mean cost of overall treatment was reduced by $1300-$1400 in the CSF arms compared with the placebo arm (P = .11 for G-CSF versus placebo; P = .06 for GM-CSF versus placebo; P = .7 for G-CSF versus GM-CSF). CONCLUSIONS: Adding G-CSF or GM-CSF therapy to antibiotic treatment shortens the duration of neutropenia and the duration of hospitalization in patients with neutropenic fever. A statistically nonsignificant trend toward lower cost was observed in the CSF arms as compared with the placebo arm. IMPLICATIONS: The benefits of CSFs to cancer patients with chemotherapy-induced neutropenic fever merit further evaluation in large randomized trials.
Antineoplastic Combined Chemotherapy Protocols↗
A phase I/II study of paclitaxel plus cisplatin as first-line therapy for head and neck cancers: preliminary results.
Improved outcomes among patients with head and neck carcinomas require investigations of new drugs for induction therapy. Preliminary results of an Eastern Cooperative Oncology Group study of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) reported a 37% response rate in patients with head and neck cancer, and the paclitaxel/cisplatin combination has been used successfully and has significantly improved median response duration in ovarian cancer patients. We initiated a phase I/II trial to determine the response and toxicity of escalating paclitaxel doses combined with fixed-dose cisplatin with granulocyte colony-stimulating factor support in patients with untreated locally advanced inoperable head and neck carcinoma. To date, 23 men with a median age of 50 years and good performance status have entered the trial. Primary tumor sites were oropharynx, 10 patients; hypopharynx, four; larynx, two; oral cavity, three; unknown primary, two; and nasal cavity and parotid gland, one each. Of 20 patients evaluable for toxicity, four had stage III and 16 had stage IV disease. Treatment, given every 21 days for a maximum of three cycles, consisted of paclitaxel by 3-hour infusion followed the next day by a fixed dose of cisplatin (75 mg/m2). The dose levels incorporate escalating paclitaxel doses, and intrapatient escalations within a given dose level are permitted if toxicity permits. At the time of this writing, dose level 4 (260, 270, and 280 mg/m2) is being evaluated; three patients from this level are evaluable. With paclitaxel doses of 200 mg/m2 and higher, granulocyte colony-stimulating factor 5 micrograms/kg/d is given (days 4 through 12). Of 18 patients evaluable for response, seven (39%) achieved a complete response and six (33%) achieved a partial response. Three patients had no change and disease progressed in two. The overall response rate is 72%. Eleven responding patients had subsequent surgery/radiotherapy or radical radiotherapy. Two pathologic complete responses were observed in patients who had achieved clinical complete responses. Alopecia, paresthesias, and arthralgias/myalgias have occurred frequently, but with one exception (a grade 3 myalgia) they have been grade 1 or 2. No dose-limiting hematologic toxicity has been seen. Paclitaxel/cisplatin is an effective first-line regimen for locoregionally advanced head and neck cancer and continued study is warranted. Results thus far suggest no dose-response effect for paclitaxel doses above 200 mg/m2.
Adult↗