Michel Clavel

Breast cancer prognostic significance of some modified urinary nucleosides

The prognostic significance of six urinary modified nucleosides, 5-methylcytidine (5-MeCyd), 4-acetylcytidine (4-AcCyd), 1-methylinosine (1-MeIno), 1-methyladenosine (1-MeAdo), 7-methylguanosine (7-MeGua) and pseudouridine (psi-Urd) was evaluated in 68 breast cancer patients of the specialized cancer hospital of Lyon (France). Excretions of 1-MeIno and 1-MeAdo were significantly higher in patients hospitalized in the medical rather than surgical ward, reflecting more advanced disease, and also among patients who died within 5 years of follow-up as compared to those still alive. These results suggest an unfavourable prognostic significance of high urinary excretion of 1-MeIno and 1-MeAdo in breast cancer patients.

Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.

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.

Cis-platinum as second-line chemotherapy in advanced gastric adenocarcinoma. A phase II study of the EORTC gastrointestinal tract cancer cooperative group☆

Thirty-four patients with measurable metastatic gastric adenocarcinoma refractory to prior chemotherapy were treated with cis-platinum 100 mg/m2 in a 6-hr infusion at 3-week intervals. Thirty-one patients were evaluable for response. There were three complete and three partial responses. Median duration of response was 4 months. Toxicity consisted mainly of nausea and vomiting and was severe in 12 patients. One patient had a severe but reversible renal failure. These results confirm other data reported in the literature. Cis-platinum has activity in gastric adenocarcinoma and should now be further investigated in first-line chemotherapy.

Iproplatin and carboplatin induced toxicities: overview of phase II clinical trial conducted by the EORTC Early Clinical Trials Cooperative Group (ECTG).

Data of five phase II clinical trials on iproplatin and carboplatin, conducted by the ECTG, have been pooled in order to evaluate the extent of toxicities of these compounds. One hundred and seventy patients treated with iproplatin and 65 patients treated with carboplatin were evaluable. Most of them (81%) had been previously treated with chemotherapy. Doses ranged from 180 to 300 mg/m2 every 4 weeks for iproplatin, and from 350 to 450 mg/m2 every 5 weeks for carboplatin, according to the initial status of the patient. WHO criteria were used to grade toxic effects. Weekly blood counts were performed, and lowest observed counts were analysed by non-parametric methods. Censored data were analysed by actuarial methods. Thrombocytopenia was the dose-limiting toxicity and was dose related. Leucopenia was less severe. The risk of thrombocytopenia varied largely amongst patients, and could be predicted from the initial platelet count, the initial creatinine level and prior therapy with alkylating agents. The cumulative risk increased with the total dose, but with a decreasing hazard rate, and without additional delay to platelet recovery. Nausea, vomiting and diarrhoea were the most frequently observed non-haematological side-effects, and were more severe with iproplatin than with carboplatin. Peripheral neuropathy was observed in some cases, but could be due to prior treatments. Renal toxicity did not cause major problems. Our results confirm the findings of the phase I trials: thrombocytopenia is dose-limiting for both drugs, and renal side-effects are negligible. The risk model of thrombocytopenia, consistent with Egorins model for carboplatin, could serve as a basis for dose adjustment. The feasibility of the scheme could be insufficient for prolonged treatment.

Intensification of Adjuvant Chemotherapy: 5-Year Results of a Randomized Trial Comparing Conventional Doxorubicin and Cyclophosphamide With High-Dose Mitoxantrone and Cyclophosphamide With Filgrastim in Operable Breast Cancer With 10 or More Involved Axillary Nodes

PURPOSE To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

Complete remission of a primary cutaneous B cell lymphoma treated with intralesional recombinant interferon alpha-2a

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.

Combination chemotherapy with cisplatin, methotrexate, bleomycin, and vincristine (CABO) in advanced squamous cell carcinoma of the head and neck

A combination of cisplatin, methotrexate, bleomycin, and vincristine (CABO) was assessed in advanced epidermoid head and neck cancer. Among 72 patients with recurrent or metastatic disease and measurable lesions, there were 9 complete and 27 partial responses for an overall response rate of 50%. These results were adversely affected by prior surgery plus prior radiotherapy. The median response duration was 28 weeks (16‐l00+) in complete responders and 16 weeks (6‐84) in partial responders. CABO was also administered to 56 patients with measurable, previously untreated, locoregional disease. In these patients, complete and partial response rates were 18% and 46%, respectively. Toxic effects were generally mild to moderate. In spite of its encouraging therapeutic efficacy, CABO is unlikely to be clearly superior to single‐agent chemotherapy, at least in recurrent or disseminated disease. Increased effectiveness of CABO given as initial treatment suggests that chemotherapy might play an effective adjuvant role in carefully selected patients.

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 × 10–3μM ) before each drug administration. S9788 plasma levels of up to 3.7 μM 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.

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

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

Pharmacokinetically guided dosing for intravenous melphalan: a pilot study in patients with advanced ovarian adenocarcinoma

Pharmacokinetically guided administration of melphalan was investigated during a pilot study in patients with advanced ovarian adenocarcinoma. The schedule involved a fixed dose on day 1 (7.9 mg) followed by a second dose on day 2, calculated on the basis of pharmacokinetic data to achieve a target area under the concentration-time curve (AUC). 20 courses of intravenous melphalan were administered to 7 patients. AUC, standardised to 1 mg/m2, ranged between 4.3 and 8.9 (mg/l) min. In 12 fully evaluable courses, less than 15% deviation from the target AUC was found, showing that AUC monitoring was possible by means of the test dose. Pharmacodynamic effects showed a positive correlation with melphalan AUC. Myelosuppression appeared at 47 (mg/l) min and grade 3 or 4 haematological toxicities were observed in 4 cycles, associated with AUC values ranging between 86 and 112 (mg/l) min. Relative leucocyte decreases were well correlated with AUC values.