Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials.

BACKGROUND: Patients with advanced solid tumors may be included in phase I clinical trials. In such studies, the benefit expected is generally lower than the likelihood of toxicity and may even be non-existent if the patient's life expectancy is too short. This study was performed to identify prognostic variables for toxicity and survival in patients who participate in phase I clinical trials. PATIENTS AND METHODS: One hundred fifty-four patients treated on a phase I clinical trial in our institute were evaluated retrospectively. Univariable and multivariable analyses of patients' characteristics were undertaken to determine their effects on the probability of grade 3 and 4 toxicity and on survival. RESULTS: Grade 3 or 4 toxicity was experienced by 56 patients (36%): dosage level at entry (P < 0.001) and age over 65 years (P = 0.03) were independently associated with the risk of toxicity. Median overall survival was 5 months. The multivariable analysis identified performance status 2 or 3 (P < 0.001) and lactate dehydrogenase levels greater than 600 UI (P < 0.001) as independent adverse prognostic variables for overall survival. Using these two parameters, we determined a prognostic index which allowed us to discriminate three risk groups of patients with an observed median survival of 8.5, 4.5 and 1.5 months, respectively. CONCLUSIONS: Subgroups with different survival expectancy can be identified among patients who are eligible for phase I clinical trials. If confirmed, the proposed prognostic model may be useful for therapeutic decision making in palliative oncology.

KW-2149-induced pulmonary toxicity is not prevented by corticosteroids: a phase I and pharmacokinetic study.

KW-2149 is a new, semisynthetic, C-7-N-Substituted, mitomycin C analog showing antitumor activity both in vitro and in vivo, equal or superior to mitomycin C. In a phase I study, KW-2149 was administered as an i.v. bolus injection every 21 days and at a dose of 100 mg/m2 pulmonary toxicity was dose limiting. Animal studies have indicated since that KW-2149-induced pulmonary toxicity can be prevented by pretreatment with corticosteroids. This paper presents the results of a further phase I study of KW-2149 with corticosteroid pretreatment. Patients were treated with oral dexamethasone 8 mg every 12 h, starting 24 h before KW-2149 administration, for 5 days. KW-2149 was given as an i.v. bolus injection every 21 days. Seventeen patients were treated with a total of 48 courses. Six patients received 60 mg/m2 and 11 patients 75 mg/m2. Two courses were not evaluable for toxicity. Significant lung toxicity was observed in at least three patients treated with a dose of 75 mg/m2 KW-2149 and pulmonary toxicity was therefore considered the dose-limiting toxicity at 75 mg/m2. No other important side effects were noted. One partial response was observed in a patient with colorectal cancer. Pretreatment with dexamethasone failed to suppress KW-2149-induced lung toxicity.

Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. EORTC Head and Neck Cooperative Group.

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.

Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group.

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 clinical and pharmacokinetic study of S9788, a new multidrug-resistance reversal agent given alone and in combination with doxorubicin to patients with advanced solid tumors.

PURPOSE: The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs. METHODS: A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination. RESULTS: The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 +/- 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 x 10[-3] microM) before each drug administration. S9788 plasma levels of up to 3.7 microM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration. CONCLUSION: The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens.

BACKGROUND: A pilot study of a new chemotherapy, the CIVIC regimen, was performed in 58 patients with metastatic breast carcinoma previously treated with chemotherapy with or without hormonal therapy (n = 41). Cisplatin, 20 mg/m2/day, was given (Days 1-5) every 21 days during a 1-hour intravenous (i.v.) infusion, and vinorelbine (VNB) was delivered at a dose of 6 mg i.v. bolus followed by VNB, 6 mg/m2/day, in continuous i.v. infusion (Days 1-5) every 21 days. METHODS: Fifty-eight patients were included in this trial between June 1992 and March 1994 (median age, 46.5 years; range, 28-69 years). The number of previous chemotherapy in the adjuvant or metastatic phase were: 1 in 9 patients, 2 in 33 patients, and > or = 3 in 16 patients. Forty-four and 12 patients, respectively, were previously treated in metastatic phase with regimens containing anthracyclines and paclitaxel. Overall, 210 cycles were given (median, 3 cycles; range, 1-6 cycles). RESULTS: Among the 58 patients assessable for tumor response to the CIVIC regimen, 24 patients (41%) (95% confidence interval, 28-54) achieved an objective response (complete response or partial response) with 2 complete response (3%) and 22 partial response (38%). The median time to response was 11 weeks (range, 4-16 weeks). The median survival time from the initiation of the CIVIC regimen was 9.2 months (range, 0-45 months). The response rate was 43% (19 of 44 patients) in patients refractory to anthracyclines and 58% (7 of 12 patients) in patients with disease progression after treatment with anthracyclines and paclitaxel. Myelosuppression was the most frequent side effect. World Health Organization Grade 3 neutropenia occurred in 8 of 58 patients (14%) and in 41 of 210 cycles (20%), Grade 4 neutropenia occurred in 37 of 58 patients (64%) and in 63 of 210 cycles (30%), and Grade 3 and 4 thrombopenia occurred in 7 of 58 patients (12%) and in 9 of 210 cycles (4%). Grade 2 peripheral neuropathy was observed in 6 of 58 patients (10%) and in 12 of 210 cycles (6%), and Grade 3 peripheral neuropathy was observed in 3 of 58 patients (5%) and in 4 of 210 cycles (2%). The risk of Grade 2-3 neuropathy was significantly higher after the fourth chemotherapy cycle (14 of 23 patients vs. 3 of 35 patients: P = 0.00002). CONCLUSIONS: The CIVIC regimen is effective and has acceptable tolerance in patients with metastatic breast carcinoma refractory to previous anthracycline- and/or paclitaxel-containing chemotherapy. Four cycles were found to provide the best toxicity-efficacy ratio.

High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

PURPOSE: To assess, on a multicenter basis, the feasibility of treating advanced cancer patients with high-dose irinotecan. PATIENTS AND METHODS: Thirty-five patients who met the usual phase I criteria (26 men and nine women) were included. Primary tumor sites were colon, head and neck, unknown primary, kidney, liver, and others. All had been previously treated. Irinotecan was given at the maximum-tolerated dose (MTD) (600 mg/m2) or the level below (500 mg/m2) as a 30-minute infusion once every 3 weeks. RESULTS: Eighteen patients were entered in the four participating centers at the MTD of 600 mg/m2. This dose level was clearly shown not to be feasible: 14 patients (78%) had grade 3 to 4 neutropenia, with febrile episodes in 11 patients; grade 3 to 4 diarrhea was observed in nine patients; and one toxic death occurred. Subsequently, 17 not heavily pretreated patients were included at 500 mg/m2 and carefully monitored. The safety of this dose level was considered acceptable: 41% of patients had grade 3 to 4 neutropenia, 24% experienced grade 3 to 4 diarrhea, and no febrile granulocytopenia or toxic death occurred. Six partial responses were documented in metastatic colorectal cancer, all in patients who had previously received conventional chemotherapy, four in patients who had exhibited progressive disease under fluorouracil (5FU)-based chemotherapy. CONCLUSION: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.

Phase I studies of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide in patients with metastatic offast cancer: the French experience.

In an attempt to develop new, active, and convenient outpatient combination-chemotherapy regimens for patients with metastatic breast cancer, we performed two phase I studies combining paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus anthracycline for the first-line treatment of metastatic disease, without the use of hematopoietic growth factors. Study I was designed to test the tolerability and antitumor activity of a 3-hour infusion of paclitaxel in combination with an epirubicin intravenous bolus. Study 2 explored a three-drug chemotherapy regimen: a 3-hour paclitaxel infusion with epirubicin and cyclophosphamide. Courses were repeated every 3 weeks. If any dose-limiting events occurred in two or more of six patients in the first course of a given dose level, that dose level was defined as the maximum tolerated dose. Dose-limiting criteria included the following: neutrophils less than 0.25 x 10(9)/L lasting for > or = 5 days, any febrile neutropenia, World Health Organization grade 4 thrombocytopenia, World Health Organization grade > or = 3 nonhematologic toxicity or grade > or = 3 mucositis for more than 5 days, and absence of hematologic recovery at day 35. In both studies, paclitaxel doses were escalated in subsequent groups of three to six patients. For study I, the initial dose level consisted of paclitaxel (110 mg/m2)/epirubicin (50 mg/m2). To date 40 patients have entered the study at eight dose levels. Of the 181 cycles evaluated, grade 3 or 4 neutropenic episodes were observed in 63% of courses, with only five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity was observed in 43% of patients. Two patients experienced clinical heart failure. The dose-limiting toxicity has not been reached so far. At dose level 7 (paclitaxel [250 mg/m2]/epirubicin [50 mg/m2]), only one patient of six experienced febrile neutropenia. We are currently testing paclitaxel (200 mg/m2)/epirubicin (75 mg/m2). Preliminary evaluation of response documents two complete and 16 partial responses in 37 evaluable patients (48% overall response rate). In study 2, the initial dose level consisted of paclitaxel (150 mg/m2)/epirubicin (50 mg/m2)/cyclophosphamide (500 mg/m2). To date, three dose levels have been investigated in 16 evaluable patients (82 cycles). Grade 3 or 4 neutropenic episodes were observed in 80% of courses, and five episodes were associated with neutropenic fever. Grade 2 neurotoxicity was observed in 28% of patients. The dose-limiting toxicity has not been reached, and we are currently investigating dose level 4 (paclitaxel 225 mg/m2). These trials confirm the tolerability of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide. The antitumor activity is encouraging.

A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.

A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors.

Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination of doxorubicin with the cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received PSC at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses given every 12 h. Doxorubicin was given by i.v. push on day 3 of PSC administration, 4 h after the morning dose of PSC. Pharmacokinetic analyses of PSC and doxorubicin were performed. A total of 38 patients received a combination of PSC and doxorubicin, and 27 received doxorubicin alone in the first course. The major toxicity of the combination was hematological and was significantly more severe than that with doxorubicin alone; severe myelosuppression was already observed at the first PSC dose level, which required doxorubicin dose reduction from 50 to 35 mg/m2. At all dose levels of PSC, up to 17.5 mg/kg/day, there were at least two patients with grade 3 or 4 hematological toxicity, which was manageable in less heavily pretreated patients. A further PSC dose escalation was performed to 25 mg/kg/day, together with doxorubicin, at a further reduced dose of 20 mg/m2. At this dose, central nervous system toxicity became the most relevant side effect. The increase of toxicity in the combined treatment was supported by a significant increase of the area under the plasma concentration-time curve to infinity of doxorubicin (54%) and a 10-fold increase of the area under the plasma concentration-time curve to infinity of doxorubicinol. The pharmacological interaction was not dependent on the plasma concentration of PSC. The total body clearance of doxorubicin decreased by 30%. PSC plasma concentrations of >1 microM at the time of doxorubicin administration were, in general, found at a dose of 7.5 mg/kg/day or higher. One patient had a partial response. In conclusion, PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin. However, a marked pharmacological interaction was found between doxorubicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxorubicin dose. Further study of PSC may be warranted, in association with the investigation of P-glycoprotein expression and concentration of drugs in the tumor tissues.

Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies.

BACKGROUND: CPT-11 (irinotecan), a camptothecin-derived anticancer agent with DNA topoisomerase 1 inhibitory activity, has demonstrated a broad spectrum of in vitro and in vivo activity in solid tumour models including multidrug-resistant tumours. This review details the rationale for the dosage schedule of CPT-11 selected for phase II studies, based on the results of 3 European phase I dose-escalating trials in patients with solid tumours. PATIENTS AND METHODS: CPT-11 was administered as a 30-minute intravenous infusion once every 3 weeks (schedule 1), once daily for 3 consecutive days every 3 weeks (schedule 2) or once weekly every 3 out of 4 weeks (schedule 3). RESULTS: Neutropenia and diarrhoea were the major dose-limiting toxicities in all of the studies. The maximum tolerated dose of CPT-11 was 115 and 145 mg/m2/day for schedules 2 and 3, respectively. With schedule 1, diarrhoea became dose-limiting at 350 mg/m2 but was manageable with high-dose loperamide therapy. CONCLUSIONS: CPT-11 350 mg/m2 administered as an intravenous infusion once every 3 weeks was chosen for further evaluation in early phase II studies, since this dosage regimen allowed the highest dose intensity with the least toxicity and was convenient for outpatient use. The place of higher doses (with intensive antidiarrhoeal support) and other administration schedules (e.g., protracted infusion) warrant further investigation.

Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

PURPOSE AND METHODS: The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. RESULTS: Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION: The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer: a preliminary report on safety.

Attempting to develop a new active, convenient regimen, we initiated a phase I study of paclitaxel (Taxol; Bristol-Myers squibb Company, Princeton, NJ) combined with epirubicin (Farmitalia Carlo Erba, Milan, Italy) in patients with metastatic breast cancer. In addition to standard eligibility criteria, patients with chemotherapy-naive metastasis and at least one measurable lesion had to have left ventricular ejection fractions of at least 50%; the metastatic relapse had to have occurred more than 6 months after adjuvant treatment. Anthracycline-pretreated patients could not have received cumulative doses of more than 300 mg/m2 doxorubicin, 450 mg/m2 epirubicin, or 70 mg/m2 mitoxantrone. An intravenous bolus dose of epirubicin was followed by a 3-hour paclitaxel infusion, with courses repeated every 3 weeks. To date, seven dose levels have been investigated and 31 patients have been treated, 19 of whom had already received anthracyclines. Grades 3 and 4 neutropenia occurred in 37% and 19% of 123 courses, respectively, with five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity has been observed in 42% of patients and cardiac toxicity in four patients (13%), all of whom had already received anthracyclines. One patient experienced transient myocardial ischemia, one had an asymptomatic decrease in ejection fraction, and two patients had clinical heart failure that required treatment. Dose-limiting toxicity was reached at dose level 5 (paclitaxel 200 mg/m2 plus epirubicin 60 mg/m2), with two of three patients experiencing febrile neutropenia. Reducing the epirubicin dose to 50 mg/m2, however, allowed the paclitaxel dose to be escalated to 250 mg/m2. At this dose level, only one of six patients experienced febrile neutropenia. At a preliminary response evaluation (dose levels 1 to 6), 11 patients (44%) had partial responses, 12 patients (48%) had stable disease, and disease progressed in two patients. We conclude that the combination paclitaxel/epirubicin is safe for patients with metastatic breast cancer and, at this early evaluation, shows promising antitumor activity. Additional patients will be treated at dose level 5 to confirm whether dose-limiting toxicity occurs at this step. Indeed, we took into consideration that dose-limiting toxicity observed at this particular dose level in two of three patients might be due to hazard, since paclitaxel dose escalation up to 250 mg/m2 was further possible in association with 50 mg/m2 epirubicin.

Phase II study of rhizoxin in squamous cell head and neck cancer. The EORTC Early Clinical Trials Group.

To test the anti-tumour activity of rhizoxin in recurrent and/or metastatic squamous cell head and neck cancer, we performed a phase II study. Eligibility required histologically proven squamous cell head and neck cancer. Patients could only have received one prior chemotherapy. Patients were entered if WHO PS was < or = 2 and organ functions were normal. Treatment consisted of rhizoxin 1.5-2.0 mg m-2 i.v. bolus injection once every 3 weeks. Thirty-two patients entered the study. All were eligible, 31 were evaluable for toxicity and 25 for response. Toxicity mainly consisted of pain at the tumour site and leucocytopenia. Mild asthenia and stomatitis were also observed. Two objective partial responses, lasting 7.5 and 3.5 months, were seen. Rhizoxin at this dose and schedule has minor activity in recurrent and/or metastatic squamous cell head and neck cancer.

Phase II clinical trials with rhizoxin in breast cancer and melanoma. The EORTC Early Clinical Trials Group.

Rhizoxin is a new anti-tumour agent isolated from the pathogenic fungus Rhizopus chinensis. It has shown broad activity against murine tumour models and is also active against vinca alkaloid-resistant cells. The purpose of our studies was to determine the clinical activity of this compound in patients with advanced breast cancer and melanoma. Based on the results of a phase I study, 2.0 mg m-2 was administered as intravenous infusion over 5 min every 21 days. Nineteen patients were entered into the breast cancer phase II trial and received a total of 50 courses (median 2, range 1-6). Of these, dose reductions were performed in three courses because of leucopenia or stomatitis (1.5 mg m-2, one course; 1.45 mg m-2, two courses). Twenty-six patients were entered into the melanoma trial and received a total of 70 courses (median 2, range 1-12). No dose reductions were required. All patients were eligible for toxicity. Haematological toxicity included neutropenia CTC grade 3 (29/120 courses, 24.2%) and grade 4 (11/20 courses, 9.2%). Only drug-related CTC grade 1 thrombocytopenia was observed. Non-haematological toxicity included alopecia in all patients after two courses of treatment as well as CTC grade 3/4 stomatitis and asthenia. In the breast cancer study, one patient achieved a more than 50% tumour reduction after six cycles but was progressing after 6 weeks. Another patient showed a partial remission after the first course but was taken off the study because of CTC grade 3 skin toxicity. One patient was not evaluable for response (early death). No objective remissions were observed in 15 evaluable patients. In melanoma, no objective remissions were observed. We conclude that rhizoxin can be safely administered at 2.0 mg m-2 every 3 weeks. However, it has little activity in patients with advanced breast cancer and melanoma.

Phase I and pharmacology study of intoplicine (RP 60475; NSC 645008), novel topoisomerase I and II inhibitor, in cancer patients.

Intoplicine (RP 60475F; NSC 645008) is a novel 7H-benzo[e]pyrido[4,3-b]indole derivative which interacts with both topoisomerases I and II. Because of its high activity in preclinical cancer models, original mechanism of action and acceptable toxicity profile, intoplicine was further evaluated in a phase I and pharmacology study. Thirty-three (33) patients (24 men and nine women) meeting standard phase I eligibility criteria were included: median age was 56 years, performance status 0-1 in 28 patients and 2 in five patients. Tumor primary sites were head and neck (9), colon (6), lung (3) and various other sites (15). Thirty-one patients had received prior radiotherapy and/or chemotherapy. Sixty-nine coursed of intoplicine were administered as a 1 h i.v. infusion at dose levels ranging from 12 to 360 mg/m2. Dose-dependent and reproducible hepatotoxicity was dose limiting in three out of four patients at 360 mg/m2: this toxicity was reversible in two of three patients, but fatal in one. Two sudden deaths occurred in this study at 12 and 48 mg/m2, and the drug implication could not be excluded. No myelosuppression was noted. Hepatotoxicity is therefore dose limiting at 360 mg/m2, and the phase II recommended dose is 270 mg/m2 every 3 weeks with close monitoring of hepatic and cardiac functions. Intoplicine pharmacokinetics was determined in plasma (23 patients) and whole blood (18 patients) at doses ranging from 12 to 360 mg/m2. Intoplicine plasma concentration decay was either bi- or triphasic with the following pharmacokinetic values (mean +/- SEM): half-life alpha, 0.04 +/- 0.004 h; half-life beta, 0.61 +/- 0.13 h; terminal half-life, 19.4 +/- 4.0 h; mean residence-time (MRT), 11.3 +/- 2.4; total plasma clearance (CL), 74 +/- 5 l/h; volume of distribution beta (V beta), 1982 +/- 477 l: volume of distribution at steady state (Vss): 802 +/- 188 l. both the area under the plasma concentration versus time curves (AUC) and the maximum plasma concentrations (Cmax) increased linearly with the intoplicine dose, indicating linear pharmacokinetics (AUC: r = 0.937; slope = 0.01305; p < 0.001; Cmax: r = 0.847; slop = 0.01115; p < 0.001). Plasma AUC was also predicted very accurately by the Cmax values (r = 0.909; slope = 1.0701; p < 0.001). Other plasma pharmacokinetic parameter values increased significantly with dose, e.g. the terminal half-life (r = 0.748, p < 0.001) the MRT (r = 0.728, p < 0.001), the V beta (r = 0.809, p < 0.001), and the Vss (r = 0.804, p < 0.001). This was probably due to a longer detectability of the drug in plasma at higher doses. Blood pharmacokinetics was also evaluated in 18 patients since it was found that red blood cells represented a significant drug reservoir for intoplicine. Blood intoplicine disposition curves were either bi- or triphasic with the following pharmacokinetic parameter values (mean +/- SEM): half-life alpha, 0.04 +/- 0.01 h; half-life beta, 0.94 +/- 0.22 h; terminal half-life, 57.1 +/- 6.6 h; MRT, 82.2 +/- 9.9 h; CL, 18 +/- 3 l/h; V beta, 1188 +/- 147 I; Vss 1163 +/- 138 I. Blood pharmacokinetics was linear, since AUC and Cmax increased linearly with dose (AUC: r = 0.879; slop = 0.06884; p < 0.001; Cmax: r = 0.835, slop = 0.01223; p < 0.001). Blood AUC values could also be determined by the blood Cmax (r = 0.768; slop = 5.0206; p < 0.001). Other blood pharmacokinetic parameter values presented a dose dependence, e.g. the terminal half-life (r = 0.626, p = 0.005), the V beta (r = 0.682, p = 0.002) and the Vss (r = 0.555, p = 0.017). The plasma or blood intoplicine concentrations achieved in vivo in humans are potentially cytotoxic levels based on preclinical in vivo and in vitro data. In conclusion, the phase II recommended dose of intoplicine is 270 mg/m2 administered as a 1 h i.v. infusion every 3 weeks. Plasma and blood pharmacokinetics were linear within the dose range studied. Potentially cytotoxic concentrations were reached at clinically achievable doses.

Head and neck cancer: guidelines for chemotherapy.

Head and neck cancer is estimated to be one of the most prevalent cancers in the world. This tumour type accounts for 5% of all new cancer cases in the US and Europe each year. Patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck have a poor prognosis, with a median duration of survival between 4 and 6 months. During the past few years, screening for potentially active new compounds, new associations and new modalities of chemotherapy administration have had some degree of success. Clinical investigations have also focused on the addition of chemotherapy to locoregional treatment for patients with locally advanced disease. Induction chemotherapy or concomitant chemo- and radiation therapy can result in high response rates, and reduced incidence of distant metastases. However, there is no clear demonstration of any benefit from the addition of chemotherapy to locoregional therapy on overall survival in patients with resectable disease. In patients with resectable laryngeal or hypopharyngeal cancer, chemotherapy combined with radiotherapy can be considered as a standard treatment option for larynx preservation, keeping total laryngectomy reserved for salvage therapy. In patients with unresectable head and neck cancer, simultaneous chemoradiotherapy has been shown to improve locoregional control and survival, at the cost of greater toxicity. Outside clinical trials, this approach can also be considered as a standard therapy for unresectable disease.

[Synthetic progestational hormones in the treatment of neoplastic cachexia]. / Utilité des progestatifs de synthèse dans le traitement de la cachexie néoplasique.

Cachexia frequently occurs in cancer patients. Indeed, this syndrome affects about 50% of hospitalized patients. This clinical entity may be described by different characteristics: appetite and weight loss, several metabolic abnormalities, possible influence of cytokines, poor prognosis. During the last decade, several papers have shown the beneficial activity of medroxyprogesterone acetate (MPA) and megestrol acetate (MA) in cancer cachexia. Seven randomized trials emphasized their activity on patients weight and appetite. Megestrol acetate doses in those trials are different: from 160 mg/24 h to 1600 mg/24 h; this drug is similar to MPA in terms of clinical and pharmacological properties. Iatrogenic toxicity due to MA and MPA is mild, but numerous questions still subsist: optimal date of introduction during the course of the disease, posology, treatment duration and its impact on quality of life of cancer patients.

[Future trends in chemotherapy and impact on the management of emesis]. / Perspectives en chimiothérapie et répercussions sur la prise en chargede l'émésis.

The treatment of cancer patients has improved over the few past years. The improvement includes new chemotherapy modalities and the new treatments for side effects. The introduction over the last 5 years of 5-HT3 receptor antagonists, a recent class of antiemetic agents, and hematopoietic growth factors, has allowed oncologists to improve success rates and survival of cancer patients, by developing new cytotoxic agents and increasing drug doses and/or modifying the design and administration of conventional chemotherapy treatment schedules. At present, dose-intensifications of several cytotoxic agents are available. Pharmacomodulation with 5 FU and folinic acid is more emetogenic than 5 FU alone. In contrast, chronomodulation seems to be less emetogenic. For new cytotoxic agents and oral chemotherapy, the emetogenic potential differs according to the drug and the antiemetic treatment must be therefore adapted to each situation.