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Seventy-six North African patients (most from Algeria) affected with nasopharyngeal carcinoma (NPC) have been studied for their HLA-A, -B, and -DR phenotypes and compared with a control North African population. Antigens HLA-A3, HLA-B5 and HLA-Bw15 were found more frequently in the NPC group than in the control group (30.3% vs 17.6%, 38.2% vs 24.4% and 9.2% vs 0.8%, respectively). HLA-Aw33, HLA-B14 and HLA-DR4 were less frequent in the patients than in the controls (3.9% vs 16.8%, 1.3% vs 16% and 13.2% vs 29.1%, respectively). After correction for the number of specificities tested, these differences were not statistically significant. They were, however, more striking when compared to normal Kabyles (Algerian Berbers), a major ethnical population in Algeria, with lower incidences of the HLA-B5 antigen and of the HLA-Aw33-B14 haplotype. This could suggest, in North Africa, either the existence of MHC-linked genes of resistance or susceptibility to NPC, in Berbers especially, or a preferential occurrence of NPC in non-Berbers. Antibody titers against the Epstein-Barr virus (EBV) associated early antigen (EA) and viral capsid antigen (VCA) have been measured. No correlation was observed between HLA phenotypes and the anti-EBV serological response of the patients.

We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity.Advanced cancer patients with normal liver function, performance status (PS)3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy.Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02).Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.

Background Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. Patients and methods From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. Results Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P = 0.03). Venlafaxine side-effects included grade 1–2 nausea (43.1%) and asthenia (39.2%) without grade 3–4 events. Conclusions Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity.

4'-O-Tetrahydropyranyl adriamycin (THP adriamycin) is a new anthracycline active as a single drug in advanced breast cancer. We have undertaken a phase II study as first-line treatment for metastatic disease with THP adriamycin day 1 = 40 mg/m2 i.v. bolus and 5-fluorouracil day 1 to day 5 = 750 mg/m2 as a continuous i.v. infusion. The dose of THP adriamycin was further escalated up to the maximal tolerated dose defined as grade 3 granulopenia for each patient. Thirty-nine patients were included, 37 being so far evaluable for toxicity and for efficacy. The mean number of cycles given was 5 (range: 2-12). The overall response rate (CR + PR) was 54% (95% CI: 37.9-70.1) and the CR rate 8%. Sites of response were as follows: lung 6/9, liver 11/18, breast 4/8, nodes 7/14, skin 3/8, bone 2/8. Neutropenia with grade 3 + 4 nadir values was observed in 70.2% of the patients according to the objective of the study. No severe thrombopenia or anemia occurred. Stomatitis grade 3 was seen in 27% and grade 4 in 3% of the patients. Alopecia grade 2 was seen in 18% and grade 3 in 9%. No other toxicity was observed. We conclude that this association is effective in metastatic breast cancer, giving few alopecia. A high response rate in liver metastases warrants further evaluation.

Background: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. Patients and methods: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC) × 6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 × 4, then T 100 mg/m2 × 4 (EC→T) or the reverse sequence (T→EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. Results: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC→T and T→EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3–4 nail disorders, hand–foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC→T and T→EC, respectively. Conclusions: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T→EC regimen, the incidence of grade 3–4 events makes it difficult to recommend either dose-dense regimen for further investigation.

Purpose: To determine maximum tolerated dose, safety and efficacy of weekly 24 h infusional 5-fluorouracil (5-FU) combined alternately with oxaliplatin and irinotecan. Patients and methods: Advanced colorectal carcinoma patients in first- or second-line chemotherapy received increasing doses of 5-FU (weekly 24 h continuous intravenous infusion without leucovorin) on days 1, 8, 15 and 22, irinotecan days 1 and 15; and oxaliplatin days 8 and 22, every 35 days. Results: Thirty-four patients received 175 cycles. The median age was 64 years (range 47 – 78). Eighteen per cent of patients had the primary tumor in the rectum, with a median of one disease site (range one to three), and liver involvement in 88% and lung in 38%. Six (18%) patients had chemotherapy for prior advanced disease. The most frequent grade 3 – 4 toxicity was neutropenia (41% of patients), but the regimen was well tolerated clinically, with febrile neutropenia in two patients and grade 4 neutropenia lasting >7 days in one; grade 3 – 4 diarrhea, nausea and vomiting in 6% of patients; grade 3 – 4 peripheral neuropathy in 9% of patients. Seventeen patients had a partial response (50%; 95% confidence interval 33% – 67%), 13 had stable disease and one had progressive disease. Five patients underwent metastatic surgical resection after tumor shrinkage. Median response duration was 14 months (range 4.7– 29.2+) and median time to progression was 11.3 months (range 1.1+ – 30.7+). Conclusions: This combination three-drug regimen is feasible and well tolerated without toxicity overlap. Preliminary antitumor activity compares well with standard double combinations, with an unusually long median time to progression. The recommended dose is 5-FU 3000 mg/m 2 , weekly for 4 weeks, irinotecan 100 mg/m 2 days 1 and 15, oxaliplatin 80 mg/m 2 days 8 and 22. Further assess

79 patients with advanced breast cancer were given Pirarubicin 20-25 mg/m2 during 3 consecutive days every 3 or 4 weeks. 78 were evaluable for response (41 without previous chemotherapy and 37 with only one previous regimen). The overall response rate was 35% (95% CI 24-45) and the complete response rate was 8%. In previously untreated patients, the response rate reached 41.5%. The limiting toxicity was a non-cumulative granulocystopenia, sometimes severe at these high doses, with a prompt recovery. The non-haematological toxicities were mild, and included 13% with grade 3 alopecia.

PURPOSE A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.

Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.

Eighty patients with measurable metastatic colon or renal cancer, melanoma, or sarcoma entered these Phase II studies. A dose of 25 mg/m2/day of Pirarubicin (THP) for 3 consecutive days every 4 weeks for the first patients, and then 20 mg/m2/day for 3 days every 3 weeks was given by i.v. push. These patients received 225 cycles for a median cumulative dose of 165 mg/m2 (range: 55-630). The mean number of cycles given was 2.8 (range: 1-8). Only 3 partial responses and 18 stable disease (22%) were observed. Hematologic toxicity was the main problem; it was responsible for one death and a 19% and 44% incidence of grade 3 and 4 WHO neutropenia, respectively. Alopecia was rare (4%). Chemotherapy was discontinued in three cases because of suspicion of cardiac toxicity, but only one patient had a significant drop in left ventricular ejection fraction at a cumulative THP dosage of 120 mg/m2. A lack of efficacy in renal and colon cancer and melanoma was presupposed and confirmed by these trials. Due to pretreatment with anthracycline in most patients, definite evaluation of THP in soft tissue sarcoma could not be given.

8582 Background: Interpatient variability in sorafenib (SOR) bioavailability and too-early treatment discontinuation might account for poor efficacy results of SOR in melanoma. A cohort of poor pro...

Doxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m2/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m2/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occurred in a heavily pretreated patient receiving a dose of 25 mg/m2/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.

Thirty elderly (over 70 years) women with measurable advanced breast cancer entered into this Phase II study. An initial dose of 30 mg/m2 of pirarubicin (THP) every 3 weeks was given intravenously. THP was escalated by levels of 10 mg/m2 according to the blood cell count done at day 14 and day 21 until a maximum dose per cycle of 70 mg/m2 was reached. The mean total cumulative dose of THP received was 204 mg/m2 (range 30-710 mg/m2). The mean number of cycles given was 5.5 (range 1-24). Of 28 evaluable patients, 1 achieved a complete response (CR), 6 had a partial response (PR) (CR + PR = 25%; 95% confidence interval 9-41%), 13 showed no change, and 5 had a progressive disease. The median time to progression was 3 months (range 0.5-18+ months). Of 28 patients evaluable for toxicity, the hematologic toxicity at day 15 was neutropenia grade 3 and 4 in 61% of the patients and thrombopenia grade 3 and 4, 0% of cycles. No cumulative hematologic toxicity was detected. Nonhematologic toxicities consisted of nausea and vomiting in 50% of patients (WHO grade 3 = 5%) and alopecia in 64% (WHO grade 2-3 = 36%). No stomatitis occurred. No cardiac toxicity was observed. The results of this study show that THP is an active drug in elderly patients with advanced breast cancer. Because of its safety, THP deserves further investigation in this application.

THP-adriamycin (pirarubicin) is a new anthracycline-analogue. In France, the drug is achieving the phase II studies and the step of phase III studies is going on. As this point of its development, it is already possible to conclude that the drug probably shares the same efficacy as adriamycine, especially in breast cancer, but exhibits a better tolerance in term of alopecia and cardiac toxicity, as predicted by preclinical studies. Its pharmacological properties make the drug an original compound, exciting for investigations in the field of loco-regional therapy.

We have analyzed lymphocytes infiltrating nasopharyngeal carcinomas, using a combination of immunoperoxidase staining of frozen and paraffin-embedded sections, and immunofluorescence on lymphocyte suspensions recovered from teased tumours. A panel of monoclonal antibodies was used to define lymphocytic subsets on frozen sections of 14 different tumours. The vast majority of peri- and intra-tumoral lymphocytes were stained by OKT3 antibody. In 8 sections, T4 positive cells were largely predominant, while T8 positive cells were the majority in three sections. Twenty-nine paraffin-embedded sections from other NPC patients stained with HNK-1 antibody showed a variable percentage of positive cells reaching 6 to 15% in nine patients. Most HNK-1 positive cells had the morphology of large granular lymphocytes typical of natural killer cells. Double staining experiments on lymphocytes isolated from 7 tumours revealed a constant presence of T3 positive, HLA-DR positive lymphocytes (from 6 to 29% of mononuclear cells), and of lymphocytes coexpressing the T3 and the Tac (IL-2 receptor) antigens (from 5 to 12% of mononuclear cells). Lymphocytes with a phenotype of activated T-cells are thus constantly found in NPC tumours. Images Figure 1 Figure 2 Figure 3 Figure 4

Twenty-two patients with advanced colorectal cancer (CRC) (12 without prior chemotherapy) and fourteen with pretreated breast cancer (BC) were given mitozolomide (MTZ), IV infusion, every six weeks. The starting dose was 90 mg/m2. When it was well-tolerated, dose escalation was done up to 100-115 mg/m2. Toxicity was mild, limited to thrombocytopenia with a median nadir of 1.27 x 10(5) (0.20-4.86). No response was observed in these patients. MTZ, according to these schedule and dosage, does not show activity in human CRC and pretreated BC.

Nineteen patients with advanced head and neck cancer were given mitozolomide (MTZ), i.v. infusion, every 6 weeks. The starting dose was 100 mg m-2. When it was well tolerated, dose escalation was performed up to 110-115 mg m-2. The limiting toxicity was thrombocytopenia, often mild, but occasionally severe, with hemorrhage and the need for platelet transfusions in two patients. The platelet nadir was 85 x 10(9) l-1 (11-225). No response was observed in 14 evaluable patients. MTZ, according to this schedule and dosage does not show significant activity in human squamous cell head and neck cancer.

We investigated the clonal relationship of malignant cells in a patient affected with both chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL cells and malignant plasma cells synthesized IgG1 kappa and IgA kappa molecules, respectively; these monoclonal Ig shared idiotypic determinants, providing evidence that a single clonal disease occurred in this patient. Furthermore, when leukemic CLL cells were driven to differentiate in vitro to immunoblasts and plasma cells, a switch from IgG to IgA occurred in a significant percentage of cells that were double producers. These data suggest that, in some circumstances, CLL leukemic B cells may reach a more mature state, leading to the occurrence of clinical MM.

Thirty patients with advanced colorectal adenocarcinoma were treated by chemotherapy with an alternating regimen consisting of 5-fluorouracil (5-FU)-mitomycin C and 5-FU-dacarbazine at 3-week intervals. Two patients had a partial response (6%) and 14 a stable disease (47%). The toxicity of this regimen was essentially digestive with 30% of grade 3 or 4 nausea and vomiting. In spite of the reported active and synergistic action of drug association in colorectal carcinoma, this treatment schedule is not better than 5-FU alone. Moreover, gastrointestinal toxicity is increased.

Clinical and histological findings of six patients with low grade non-Hodgkin lymphoma (NHL) which transformed to high grade tumours are reported: 5 out of the 6 cases showed transformation from the centroblastic-centrocytic type to the centroblastic-polymorphic type (Kiel classification). Clinical aggressivity, large tumour mass, high frequency of extranodal sites of disease, systemic symptoms and resistance to treatment were observed. This type of transformation is not rare, estimated to be about 20 p. 100 of cases in the literature, and is more common than Richter's syndrome in chronic lymphocytic leukaemia.

A case of high grade malignant lymphoma in a young woman with congenital disseminated lymphangiectasis, exudative enteropathy and immunodeficiency is reported. Lymphoid malignancies occur with a high frequency in the course of this rare disease, possibly as a consequence of immunodeficiency. In this case, a selective defect of the OKT4+ peripheral blood lymphocyte subset has been shown. The relationships between congenital lymphangiectasis, immunodeficiency and malignant lymphoma are discussed.

We report a new case of histiocytic proliferation, which histologically resembles histiocytosis X, in a lymph node affected by non-Hodgkin's malignant lymphoma. This brings the total number of such reported cases to 12. Histiocytosis X cells, with folded nuclei, expressed S100 protein and an antigen recognized by anti-CD1 monoclonal antibodies. Ultrastructural study did not show any Birbeck granules and demonstrated a morphology similar to that of interdigitating cells. In the absence of Birbeck granules, the term 'Langerhans' cell granulomatosis' is not correct and should be replaced by either 'interdigitating cell granuloma' according to immunohistochemistry and ultrastructure or 'histiocytosis X-like granuloma' according to optical morphology. The fact that some cells with folded nuclei were positive for lysozyme argues in favor of the existence of transitional cells between histiocytes hnd interdigitating cells. The 11 other reported cases were reviewed. In 6 cases, this type of granuloma was associated with B cell lymphoma. In 3 cases the lymphoma was also probably of B cell type. In 2 cases, no information could be found. We could speculate that these histiocytosis X-like lesions are reactive, resulting from immune disturbances due to the lymphoma and/or the treatment.