Intoplicine (RP 60475F; NSC 645008) Is a novel 7H-benzo[ e]pyrldo[4,3-b]lndole derivative which Interacts with both topolsomerases I and II. Because of Its high activity In procllnlcal cancer models, original mechanism of action and acceptable toxlclty profile, Intoplicine was further evaluated in a phase I and pharmacology study. Thirty-three (33) patients (24 men and nine women) meet- Ing 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 courses 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 toxlclty was reversible In two of three patients, but was 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 triphaslc with the following pharmacoklnetlc values (mean ± SEM): half-life α, 0.04 ± 0.004 h; half-life β, 0.61 ± 0.13 h; terminal half-life, 19.4 ± 4.0 h; mean residence time (MRT), 11.3 ±2.4 h; total plasma clearance (CL), 74 ± 5 l/h; volume of distribution β (Vβ), 1982 ± 477 I; volume of distribution at steady state (Vss): 802 ± 188 I. 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; slope=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 pharmacoklnetlc 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 Vf (r=0.809, p< 0.001), and the V.. (r=0.804, p<0.001). This was probably due to a longer detectablllty 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 triphaslc with the following pharmacoklnetic parameter values (mean ± SEM): halflife a, 0.04 ± 0.01 h; half-life /», 0.94 ± 0.22 h; terminal half-life, 57.1 ± 6.6 h; MRT, 82.2 ± 9.9 h; CL, 18 ± 3 l/h; Vf, 1188 ± 147 I; V., 1163 ± 138 I. Blood pharmacokinetics was linear, since AUC and Cmax Increased linearly with dose (AUC: r=0.879; slope=0.06884; p< 0.001; Cmax: r=0.835, slope=0.01223; p< 0.001). Blood AUC values could also be determined by the blood Cm« (r=0.768; slope=5.0206; p<0.001). Other blood pharmacokinetlc parameter values presented a dose dependence, e.g. the terminal half-life (r=0.626, p s 0.005), the Vf (r=0.682, p=0.002) and the V,. (r=0.555, p s 0.017). The plasma or blood intoplicine concentrations achieved in vivo In humans are potentially cytotoxlc levels based on precllnlcal 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 cytotoxlc concentrations were reached at clinically achievable doses

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.

A multicentre randomised, double-blind parallel group study has been carried out in order to confirm the antiemetic efficacy of orally administered ondansetron. A total of 259 chemotherapy-naive breast cancer patients treated with a 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) or 5-fluorouracil, epirubicin, cyclophosphamide (FEC) regimen were randomly assigned to ondansetron (OND) 8 mg tablet or alizapride (ALI) 150 mg intravenous (i.v.) injection, prior to chemotherapy. These treatments were then followed by OND 8 mg tablet or ALI 50 mg tablet, respectively, 8 to 12 h later. Oral treatment was then continued twice a day over 3-5 days. The number of emetic episodes (EE = vomits + retches) and the grade of nausea were recorded; quality of life was assessed using a specific questionnaire. Of the 254 patients analysed for efficacy, complete or major control (success: 0-2 EE) over the 24 h following start of chemotherapy was obtained in 81% of the OND group compared with 47% of the ALI group (P < 0.001). A significant difference in favour of OND was also observed for nausea (P < 0.0001). For on days 2 to 4 emesis, the arm containing OND was superior to that with ALI (worst day analysis): 77% success versus 63% (P < 0.002). The overall control of emesis (from day 1 to day 4) was better with OND (64% patients success in the OND group versus 41% in the ALI group; P < 0.0001). At the end of the study the number of patients wishing to receive the same anti-emetic treatment for their next course was 83% for OND compared with 54% for ALI (P < 0.0001). In terms of quality of life in relation to emesis phenomena, OND was significantly superior to ALI (P = 0.04). Both treatments were well tolerated. In the prevention of the prolonged emesis induced by FAC/FEC-type emetogenic chemotherapy, orally administered OND was superior to ALI, given as an i.v. injection and followed by tablets.

BACKGROUND Irinotecan (CPT-11) is a novel water-soluble camptothecin derivative selected for clinical testing based on its good in vitro and in vivo activity in various experimental systems, including pleiotropic drug-resistant tumors. Its mechanism of action appears mediated through topoisomerase I inhibition. The purpose of this study was to describe CPT-11 and active metabolite SN-38 population pharmacokinetics, examine patient characteristics that may influence pharmacokinetics, and to investigate pharmacokinetic-pharmacodynamic relationships that may prove useful in the future clinical management of this drug. PATIENTS AND METHODS As part of 3 Phase I studies including 235 patients, pharmacokinetics of CPT-11 and metabolite SN-38 were determined in 107 patients. CPT-11 was administered as a 30-min i.v. infusion according to 3 different schedules: daily for 3 consecutive days every 3 weeks, weekly for 3 weeks, and once every 3 weeks. Patients characteristics were the following: median age 53 years; 62 men, 45 women; 105 caucasians, 2 blacks; performance status was 0-1 in 96 patients; tumor sites were predominantly colon, rectum, head and neck, lung, ovary and breast; with the exception of 6 patients, all had been previously treated with surgery, chemotherapy and/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneously determined by HPLC using fluorescence detection. Pharmacokinetic parameters were determined using model-independent and model-dependent analyses. RESULTS 168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)

BACKGROUND:We conducted a phase I and pharmacokinetic study to determine the maximum tolerable dose (MTD), toxicities, pharmacokinetic profile, and antitumor activity of Irinotecan (CPT-11) in patients with refractory solid malignancies.PATIENTS AND METHODS:Forty-six patients were entered in this phase I study. CPT-11 was administered intravenously over 30 minutes for 3 consecutive days every 3 weeks. Dose levels ranged from 33 mg/m2/day to 115 mg/m2/day on days 1 through 3. The pharmacokinetics of total CPT-11 and its active metabolite SN-38 were assayed by HPLC.RESULTS:The combination of leukopenia and diarrhea was dose-limiting toxicity at 115 mg/m2/day dose level, since 50% of the patients (5/10) experienced either grade 3-4 leukopenia, or diarrhea, or both. Leukopenia appeared to be a cumulative toxicity, with a global increase in its incidence and severity upon repeated administration of CPT-11. Other toxicities included nausea, vomiting, fatigue and alopecia. CPT-11 and active metabolite SN-38 pharmacokinetics were determined in 21 patients (29 courses). Both CPT-11 and SN-38 pharmacokinetics presented a high interpatient variability. CPT-11 mean maximum plasma concentrations reached 2034 ng/ml at the MTD (115 mg/m2). The terminal-phase half-life was 8.3 h and the mean residence time 10.2 h. The mean volume of distribution at steady state was 141 l/m2/h. CPT-11 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Total body clearance did not vary with increased dosage (mean = 14.3 l/h/m2), indicating linear pharmacokinetics within the dose range administered in this trial. The total area under the plasma concentration versus time curve (AUC) increased proportionally to the CPT-11 dose. Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD. A significant correlation was observed between CPT-11 area under the curve (AUC) and its corresponding metabolite SN-38 AUC (r = 0.52, p < 0.05). SN-38 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Mean 24-h urinary excretion of CPT-11 accounted for 10% of the administered dose by the third day, whereas SN-38 urinary excretion accounted for 0.18% of the CPT-11 dose. In this phase I trial, the hematological toxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrhea grade correlated significantly with CPT-11 AUC. Two partial (breast adenocarcinoma and carcinoma of unknown primary) and 2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responses were observed.CONCLUSION:The MTD for CPT-11 administered in a 3 consecutive-days-every-3 weeks schedule in this patient population is 115 mg/m2/day. The recommended dose for phase II studies is 100 mg/m2/day.

PURPOSE:To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival.PATIENTS AND METHODS:Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity.RESULTS:Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups.CONCLUSIONS:Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1–2 h) at various dose levels (70–115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl wasCl=BSA(θ1+θ2×AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh−1 m−2) and 37.2 l/h with interpatient coefficients of variation (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.2 l for NPML versus 124 l for NONMEM) and in terminal half-lives, notably the meant1/2γ, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss andt1/2γ, respectively. However, the NPML-estimated probability density function (pdf) oft1/2γ, was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.

Primary osteosarcoma of the pelvic bones represents less than 10% of all osteosarcoma. Despite mutilating surgical procedures or high-dose radiotherapy and neoadjuvant chemotherapy, local failures and distant metastases remain common. The 2-year actuarial survival rate is less than 50% and the disease-free survival is under 20% at 2 years. We report 4 cases of pelvic osteosarcoma treated by a combination of chemotherapy, photon beam and neutron beam radiotherapy. After a median follow-up of 24 months, all 4 patients are alive and disease free.

BACKGROUND:Docetaxel, a semisynthetic analog of paclitaxel, made for the needles of the European yew, Taxus baccata, is a potentially important chemotherapeutic agent for the treatment of cancer.PATIENTS AND METHODS:In a phase II study patients with advanced and/or metastatic breast cancer and bidimensionally measurable disease, were treated with docetaxel 100 mg/m2 every 3 weeks as a 1 hour infusion without any premedication. Treatment was evaluated after 2 courses and every 2 subsequent courses.RESULTS:Thirty-nine patients were entered, 32 were eligible. The eligible patients had a median age of 51 years (range 30-73) and a performance status WHO 1 median, (range 0-2). Twenty-eight patients had been treated with surgery, 24 with radiation. Hormonal treatment was previously given in 23, chemotherapy in 32. Of 24 patients treated as second line strategy, 13 achieved a partial remission, 1 a complete remission (overall response rate 58% (95% CI 37%-78%)). Eight patients treated as first line: 2 PR's, 1 CR. The median overall response duration was 38 weeks. The main toxicity consisted of transient grade 4 neutropenia in 149 of 167 evaluable courses (89%). However, the related infection rate was low. Re-treatment at 3 weeks, as scheduled, was nearly always possible. Other toxicities consisted of skin reactions (81%) and nail changes (41%), neurosensory toxicity (59%) and occasionally hypersensitivity reactions (16%). Fluid retention was a toxicity of major concern, observed in 59% of patients.CONCLUSION:Docetaxel is a very active drug against breast cancer. Further studies are required to alleviate the non-hematological toxicities.

Paclitaxel and docetaxel are the two presently clinically available representatives of the new class of taxane drugs. They share major parts of their structures and mechanisms of action, but differ in several other aspects. For instance, there is a difference in their tubulin polymer generation, and docetaxel appears twice as active in depolymerization inhibition. In vitro docetaxel also tends to be more potent in different cell lines and investigational models. While in vitro and in vivo studies suggest that prolonged exposure to paclitaxel is better than a brief exposure, no such tendency is seen for docetaxel, indicating it to be a schedule-independent drug. Clinical studies have not confirmed an advantage for prolonged exposure to paclitaxel; but do show differences in the toxicity profiles of the two drugs. These topics will be addressed in detail.

BACKGROUND:Current regimens for treatment of distant metastases of soft tissues sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigational groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult.PATIENTS AND METHODS:In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 mg/m2 in a 1-hour i.v. infusion q 3 weeks.RESULTS:Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 = 17%, C.I. 6%-36%) have been observed. Grade > or = 3 leucopenia occurred in 76% of patients and grade > or = 3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 x 10(9)/l. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts.CONCLUSION:Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

BACKGROUND:The cross-over resistance between different anthracyclines in breast carcinoma has not been largely evaluated in clinical trials.PATIENTS AND METHODS:Nineteen patients with metastatic breast cancer who had failed prior first line FEC chemotherapy (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 cyclophosphamide 500 mg/m2, every 4 weeks) were treated with a combination of fluorouracil 500 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 4 weeks (FAC).RESULTS:Five patients achieved partial responses, ranging in duration from 5 to 8 months. The main toxicity was cardiac, with congestive heart failure documented in five patients.CONCLUSION:The findings indicate an absence of cross resistance of doxorubicin in some epirubicin-resistant patients.

Background: Docetaxel (Taxotere(R)) is a new cytotoxic agent acting as a promotor of tubulin polymerisation with broad spectrum antitumor activity in preclinical testing. Phase I clinical trials have shown promising activity of docetaxel in patients with breast, ovarian and lung carcinomas. The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer.Patients and methods: Patients with proven advanced and/or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial. Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks. Dose reductions were performed according to hematological and non-hematological toxicities. No pre-medication was given to prevent hypersensitivity reactions.Results: Fourty-three patients entered this trial: 39 patients were evaluable for toxicity and 37 patients were evaluable for response. Sixty-five percent of the patients had loco-regional disease, 28% had metastatic disease, and 7% had both. Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy. A total of 166 docetaxel courses were administered. The most frequent side-effects associated with docetaxel were alopecia (90% of the patients), asthenia (69% of the patients) and short lasting neutropenia (grade 3-4 neutropenia in 61% of the courses). Fifty-four percent of the patients experienced skin toxicity, 23% experienced hypersensitivity reaction, and 31% developed peripheral edema. Ten partial and 2 complete responses were observed, yielding a response rate of 32% (95% confidence interval 17%-47%).Conclusion: Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck.

BACKGROUND Gemcitabine is a new pyrimidine antimetabolite with novel metabolic properties and mechanism of action. Phase I clinical trials have demonstrated acceptable toxicity and promising antitumor activity. The objectives of this open multicenter phase II trial were to determine the efficacy and toxicity of this agent in patients with advanced head and neck cancer. PATIENTS AND METHODS Sixty-one patients with advanced and/or recurrent squamous cell carcinoma of the head and neck were treated with Gemcitabine as a weekly 30 minutes i.v. administration for 3 consecutive weeks followed by one week rest. The Gemcitabine starting dose was 800 mg/m2/week in 47 patients (a majority being pre-treated with chemotherapy) and was later increased to 1250 mg/m2 in 14 chemotherapy-naive patients. Dose adjustments were based on hematologic and non-hematologic toxicities. RESULTS Seven partial responses were observed among 54 evaluable patients, yielding a response rate of 13% (95% confidence interval: 4%-22%). The incidence of hematologic toxicity was low, with grade 3-4 neutropenia in less than 10% of the courses. Fifty-three percent of the patients experienced an increased in liver enzymes, mainly grade 1 or 2. Fatigue was reported by 39% of the patients, frequently associated with flu-like symptoms. CONCLUSION Gemcitabine is a drug with documented anti-tumor activity in patients with advanced squamous cell carcinoma of the head and neck.

A double-institution phase II study was performed in patients with metastatic renal cell carcinoma treated subcutaneously (s.c.) with interleukin 2 (IL-2) and alpha-interferon (INF-alpha). Thirty-eight patients were treated over a course of 7 weeks. Initially (day 1 + 2) patients received s.c. IL-2 at 18 x 10(6) IU m-2. During the following 6 weeks, patients received s.c. IL-2 at 3.6 x 10(6) IU m-2 for 5 days per week and s.c. INF-alpha at 5 x 10(6) for 3 days per week. Thirty-eight patients were evaluated for response. An objective response was seen in seven patients (18.4 +/- 12.3%), with one complete response and six partial responses. Median duration of response was 6.7 months. Toxicity could be evaluated in 38 patients and was limited. Mild to moderate toxicity included fever (97%), fatigue or malaise (76%), nausea or vomiting (50%), anorexia (32%), hypotension (26%), neurological disturbances (26%) and hypercreatininaemia (39%). In addition, four grade IV haematological toxicities were noted. No cardiac side-effects were seen. IL-2 and INF-alpha given by this schedule can be safely administered in an outpatient setting. The objective response rate was similar to our previous treatments with high-dose IL-2 given as a continuous infusion.

Background. The EORTC Head and Neck Cancer Cooperative Group conducted a randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in chemotherapy naive patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The primary objectives of this study were to investigate whether the CF regimen was in anyway superior to the CABO regimen and to detect any superiority of these two combinations over cisplatin alone.Patients and methods: Three hundred eighty-two patients were randomized to one of three treatments: (1) methotrexate (40 mg/M2) days 1 and 15, bleomycin (10 mg) and vincristine (2 mg) days 1, 8 and 15, cisplatin (50 mg/M2) day 4, repeated every 21 days, (2) cisplatin (100 mg/M2) and 5-FU (1 g/m2 x 4), repeated every 21 days, and (3) cisplatin (50 Mg/M2) days 1 and 8, repeated every 28 days. After 3 cycles, all responding and stable disease patients in the three arms of the study continued with cisplatin alone.Results: The overall response rates to CABO (34%) and CF (31%) were superior to C (15%) (p < 0.001, p = 0.003, respectively). In addition, complete response rate to CABO (9.5%) was superior to that of C (2.5%) (p = 0.02), and also superior to that of CF (1.7%) (p = 0.01). Response was associated with performance status and prior treatment, but by multivariate analysis treatment type was the important determinant of response (p = 0.0006). Although CABO and CF were superior to C with respect to time to progression within the first 6 to 8 months after randomization, there was no overall difference in progression-free survival or survival between the three arms of the study. Both hematologic and non-hematologic toxicity were worse in the combination chemotherapy arms.Conclusion: We conclude that the CF regimen has no advantage over the CABO regimen, which in fact showed a higher complete response rate. Both combinations showed improved response rates but also more toxicity and no improvement in overall survival in comparison with cisplatin alone.

PRIMARY CUTANEOUS 33 cell lymphomas (CBCL) are rare, and closely resemble those described in 195 1 by Crosti as reticulohistiocytoma [l]. Patients usually present with localised indolent nodular skin lesions with slow progression and low propensity for extracutaneous spread [2, 31. Because of this favourable prognosis, CBCL have been considered “skin-associated lymphoid tissue” (SALT)-derived lymphoma by a parallel with the lymphomas of “mucosa-associated lymphoid tissue” (MALT) [ 1, 31. Conventional therapy includes surgical excision, electron beam radiation therapy (EBRT) and systemic chemotherapy. All of these are effective, but remissions are mostly transient. To date, the optimum management for localised cutaneous lymphoma still remains controversial. A 53-year-old man presented in 1976 with nodular skin lesions on the left side of the thorax, progressing slowly for 6 years. Histological diagnosis was not certain (lymphocytoma cutis? malignant lymphoma?). One year later, he noticed a rapid increase in the size of the nodules. Histological examination revealed findings compatible with Crosti’s reticulohistiocytoma. He was treated with systemic combination chemotherapy (cyclophosphamide, doxorubicin, VM-26, prednisone) from May 1977 to December 1977, with complete response (CR). A first relapse occurred in May 1978, close to the site of onset. EBRT (32 Gy) led to prompt disappearance of lesions. Radiotherapy was followed by consolidation systemic chemotherapy (cyclophosphamide, vincristine, prednisone) from May 1978 to May 1980. Three years later, the patient developed nodules confined to a circumscribed area of the back. Histological features were compatible with Jessner and Kanof’s lymphocytic infiltration. EBRT (32 Gy) was performed, with clinical CR. He relapsed in the skin outside the initial site involved (but always on the trunk), and outside the previous radiotherapy fields, in 1985, 1986 and 1989. He was re-irradiated and showed good response. He was re-admitted to the hospital in October 1991 because of papulonodular lesions, ranging in diameter from 2 to 6 cm, on the left side of the thorax and abdomen (Fig. 1). Histological examination revealed a diffuse neoplastic dermal infiltrate without epidermotropism. Electron microscope examination confirmed lymphoid cells. Referring to the working formulation for clinical usage, the lymphoma was classified as diffuse small cleaved cells (centrocytic type), intermediategrade. Immunohistochemical data confirmed the B cell nature of the Fig. 1. Clinical presentation in October 1991, showing cutaneous nodules on the left side of the thorax and abdomen.

Background: Current regimens for treatment of distant metastases of soft tissue sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigational groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult.Patients and methods: In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 Mg/M2 in a 1-hour i.v. infusion q 3 weeks.Results: Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 = 17%, C.I. 6%-36%) have been observed. Grade greater-than-or-equal-to 3 leucopenia occurred in 76% of patients and grade greater-than-or-equal-to 3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 x 10(9)/l. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts.Conclusion: Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

Paclitaxel and docetaxel are the two presently clinically available representatives of the new class of taxane drugs. They share major parts of their structures and mechanisms of action, but differ in several other aspects. For instance, there is a difference in their tubulin polymer generation, and docetaxel appears twice as active in depolymerization inhibition. In vitro docetaxel also tends to be more potent in different cell lines and investigational models. While in vitro and in vivo studies suggest that prolonged exposure to paclitaxel is better than a brief exposure, no such tendency is seen for docetaxel, indicating it to be a schedule-independent drug. Clinical studies have not confirmed an advantage for prolonged exposure to paclitaxel; but do show differences in the toxicity profiles of the two drugs. These topics will be addressed in detail.