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Biomedical subjects

P Carde

Publications and source records attributed to P Carde.

106 records · Page 6Linked to original sources

Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia.

Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days. Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m2/d X 5 I.V. The highest dose given was 8 mg/m2/d X 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m2/d X 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m2/d.

Acute Disease↗

Combined radiotherapy-chemotherapy for early stages non-Hodgkin's lymphoma: the 1975-1980 EORTC controlled lymphoma trial.

Patients with stage I and II non-Hodgkin's lymphoma (NHL) are considered to have a relatively good prognosis. For this reason, they are seldom referred to specialized centers and the accrual of such patients in controlled studies is limited. Therefore, significant studies of homogeneously treated patients are difficult to collect and the management of these patients remains controversial. Some patients do very well after treatments with minimal toxicity while others require a much more aggressive approach. The Radiotherapy-Chemotherapy Group of the EORTC carried out its second controlled trial on patients with stage I and II NHL from 1975 to 1980. Its first aim was to assess the prognostic value of histologic classifications independently of treatment. The second aim was to compare two therapeutic options within each stage. In stage I, 124 patients were randomized to receive extended field radiotherapy (RT) either with or without adjuvant cyclophosphamide, vincristine prednisone (CVP) chemotherapy (CT). Relapse-free survival (RFS) was higher in patients who received adjuvant CVP but the total survival rates were not different. The RFS was lower in patients with diffuse than in those with follicular architectural histologies; in the former, RFS was not influenced by adjuvant CVP. Those patients who underwent a staging laparotomy had a higher 5-year total survival (TS) independent of the histologic type. Fifty-six stage II patients were included and extended field was randomized versus total nodal irradiation. Subsequently, adjuvant CVP was given to all patients. Results are good in follicular histologies but the advantage for total nodal irradiation is not significant. In diffuse histologies, results were unsatisfactory in both arms; a new therapeutic strategy was designed in which RT and CT are alternated and has been successfully tested in a pilot study.

Adolescent↗

[Primary chemotherapy in soft tissue sarcomas considered inoperable].

Fourteen adult patients with inoperable soft tissue sarcoma (with metastases in 4 cases) received chemotherapy as primary treatment. Nine cases were treated by CYVADIC (cyclophosphamide, vincristin, doxorubicin, DTIC) and five cases by DECAV (DTIC, cyclophosphamide, cis-platinum, doxorubicin, vindesine). An objective response was obtained in 7 cases (1 complete remission and 6 regressions greater than 50%) and stabilization in 4 cases. Seven patients became operable after 2 to 6 courses of chemotherapy and a complete resection could be performed in 6 cases. The duration of the response was 2 to 39 months. Toxicity with both combinations was acceptable. We conclude that chemotherapy can provide initial tumor reduction and permit subsequently less radical surgery.

Adolescent↗

A dose and time response analysis of the treatment of Hodgkin's disease with MOPP chemotherapy.

A dose-response analysis of the results of MOPP chemotherapy in 132 patients with Hodgkin's disease was carried out. Complex statistical methods were utilized including 40 different dose-time variables and multivariate logistic analyses of 21 clinical variables, both simply and in stepwise regression. These covariates were not independent, and in stepwise regression analysis only B-symptoms and the mean three-cycle rate of drug delivery significantly influenced complete remission attainment. Two parameters, bone marrow involvement (negative) and lung involvement (positive), significantly influenced the duration of complete remission. Survival was influenced adversely by pleural involvement (effusion), advanced age, and B-symptoms. Analyses indicate that the dose of all three drugs (mustard, vincristine, and procarbazine), and the rate of drug delivery during the first three cycles are important in achieving maximal complete response rates, especially for patients with B-symptoms.

Adult↗

[Interactions between X-rays and antimitotic drugs: cellular effects (author's transl)].

The interactions between three drugs and X-rays were examined in rat hepatoma cells in vitro. Incubation with Daunomycine or 9-hydroxy ellipticine decreases the survival of both exponential and plateau phase cells, whereas cis-Pt (II) decreases the survival of plateau cells, especially irradiated in anoxia. The decrease in the Do was greater when the cells were incubated with the drugs prior to X-irradiation, and was greater in the case of plateau cells than in the case of exponential cells. The repair of potentially lethal damages was inhibited by these three compounds. However, the repair of sublethal damages was inhibited by cis-Pt II, but was modified neither by Daunomycine nor 9-hydroxy ellipticine.

Animals↗

Cell-mediated immune responsiveness of patients with acute lymphocytic leukemia in remission.

Children with acute lymphocytic leukemia (ALL) in remission and undergoing either chemotherapy or immunotherapy were tested for general cell-mediated immunocompetence and cell-mediated reactivity to tumor-associated antigens (TAA) using the following parameters: skin tests with recall antigens and extracts of lymphoblastoid cell lines; primary sensitization to dinitrofluorobenzene and picryl chloride; in vitro tranformation by mitogens and PPD; and lymphocyte-mediated cytotoxicity against a lymphoblastoid cell line and a panel of cryopreserved leukemic blasts. Reactivity in all assays of children on continuous chemotherapy was significantly depressed compared to similar patients later in the study. Patients on intermittent chemotherapy demonstrated much less immunodepression. The groups tested early during immunotherapy with BCG and allogeneic leukemic blasts were hyper-responsive (compared to published data) to primary sensitization with picryl chloride. Skin test reactivity to recall antigens and to tumor-derived lymphoblastoid cell lines was suppressed (as analyzed serial comparison) in this hyperimmunized group, possibly due to antigenic competition, and reactivity in all other assays was normal. The patients tested after 2-8 years of immunotherapy showed significantly higher positive skin-test responses to extracts of tumor-derived lymphoblastoid cell lines as compared to the other groups. The results of this multiphasic screen support the known effects of chemotherapy on immunocompetence. Moreover, they document the prompt return of immunocompetence with intermittent chemotherapy and during immuno-therapy. These results do not, however, indicate a striking augmentation of the immune response during immunotherapy as measured by these parameters.

Antigens, Bacterial↗

The prognostic significance of large mediastinal masses in the treatment of Hodgkin's disease. The experience of the Institut Gustave-Roussy.

At the Institut Gustave-Roussy we undertook a study of 154 patients with clinical stages I and II Hodgkin's disease treated by irradiation to evaluate the prognostic significance of the mediastinal mass size. The population under study included those patients treated at our institute and entered into the H2 and H5 E.O.R.T.C. trials between 1972 and 1981. Patients were divided into three groups for purposes of analysis; large mediastinal masses (MT ratio greater than or equal to 0.35) were noted in 20 cases (13 per cent), moderate mediastinal invasion (MT ratio less than 0.35) was observed in 60 cases (39 per cent), and 74 patients (48 per cent) had no mediastinal involvement on presentation. Intrathoracic relapses were more frequent in those patients with mediastinal involvement at presentation (p less than 0.001) but there was no statistically significant difference between those patients with 'large' masses and patients with 'small' masses. Additionally multivariate analyses showed that neither the presence nor the size of mediastinal disease adversely affected relapse free survival or overall survival. These results can perhaps be linked to the technique of radiotherapy where a 'split course' technique was habitually used for large masses and the radiation fields were routinely modified during treatment according to the tumour response. Consequently we do not advocate the routine use of extensive primary treatment such as combined modality therapy utilizing MOPP chemotherapy for all patients presenting with bulky mediastinal masses. Rather chemotherapy should be reserved for those tumours which are particularly voluminous (MT ratio greater than 0.50) where primary radiotherapy may potentially result in unsatisfactory late pulmonary complications. We also advise the use of combined modality therapy for those patients who may additionally have certain unfavourable prognostic factors which we have previously identified.

Adolescent↗

[the role of radiotherapy for limited stage Hodgkin's disease in 1999: limitations and perspectives].

The role of radiotherapy in limited stage Hodgkin's disease (HD) has been gradually changing in the past few decades, resulting in the almost complete disappearance of exclusive irradiation treatment. In reality, exclusive radiotherapy yielded satisfactory results in terms of long-term survival, but in 1999 it was becoming impossible not to take into account the late mortality rates observed in all large cohorts of HD patients. This increased mortality rate has been shown to be related to 1) cardiac toxicity of irradiation, and 2) secondary radiation-induced solid tumors. Thus, the search for efficient but less toxic new strategies can no longer be avoided. For clinically staged, limited HD, precisely defined according to specific prognostic factors, the association of chemotherapy and radiotherapy appears more and more as a standard, and with this therapeutic burden comes parallel efforts for its alleviation. The Previous Radiotherapy experience has shown that, after a chemotherapy-induced complete remission, irradiation of only the initially involved areas was enough. Ongoing trials are now exploring the possibility of a dose de-escalation, from the conventional 36 Gy to 20 Gy (as for children HD), and to maybe 0 Gy (no radiotherapy at all). In parallel, deescalation in the number of chemotherapy cycles is also being investigated. For unfavorable cases, the problem is slightly different, as a higher percentage of cases still appears to be refractory to treatment in this subgroup. Thus, while chemo-radiotherapy has clearly became the standard strategy, efforts are essentially being devoted to identify new--and hopefully more efficient--chemotherapy schemes. In Europe, most of these pending questions will be addressed in the recently initiated trials of the EORTC/GELA and of the GHSG (German Hodgkin Study Group), with the aim of offering to patients treatment which could be at least as efficient as the present schedules, and less toxic in the long term.

Cardiovascular System↗

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC.

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.

Adult↗

[Treatment of hepatic metastases with unknown primary cancer].

A series of 15 cases of hepatic metastases of unknown etiology is reported. All patients had a needle biopsy of the liver. The search for primary tumor was restricted to only those tumors requiring specific therapeutic protocols. Patients received intravenous chemotherapy in accordance with histopathological classification. This chemotherapy induced objective improvement in 46 percent of cases. The average survival of responding patients is about 16 months. Three patients had complete remissions and underwent a second laparotomy with excision of necrotic lesions in one case and installation of a catheter for endarterial hepatic chemotherapy in another. The investigators propose a diagnostic and therapeutic protocol for such patients.

Adult↗

Current trend in the treatment of Hodgkin's disease.

The analysis of three subsequent randomized trials carried out within the frame of the European Organization for Research on Cancer (E.O.R.T.C.) enables to define a strategy for the staging and the treatment of early stages of Hodgkin's disease. Several prognostic factors were identified by multivariate analyses: 1) erythrocyte sedimentation rate, which has a greater impact on relapse-free survival than systemic symptoms but which can be combined with them; the combination of the two is a more powerful prognostic indicator than ESR alone; 2) the number of involved lymphatic areas: patients with one or two lymphatic areas involved (CS I and II2) have a better outcome than stage II patients with 3 or more areas involved (CS II3). Patients with favorable prognostic indicators are submitted to staging laparotomy because for them spleen involvement has a pejorative impact. For patients with unfavorable indicators, the spleen involvement has little prognostic significance and therefore those patients who need, anyway, an aggressive treatment do not undergo staging laparotomy. Patients with favorable prognostic indicators and negative staging laparotomy can be treated by radiotherapy alone, patients with positive laparotomy or patients with unfavorable prognostic indicators are treated by combination of multiple chemotherapy and radiotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

Pharmcokinetics in healthy volunteers and patients of NAc-SDKP (seraspenide), a negative regulator of hematopoiesis.

NAc-SDKP is a peptide being tested as a bone marrow hematopoiesis protector in chemotherapy trials in cancer patients. We studied the pharmacokinetics of NAc-SDKP in six healthy human volunteers and in five patients undergoing chemotherapy. Plasma concentrations of NAc-SDKP were monitored using a specific enzyme immunoassay. Because NAc-SDKP is an endogenous compound, a preliminary study was undertaken to determine intra- and interday baseline variations in healthy subjects. The baseline value (range 1.7-3.2 nM) differed between subjects, but was constant over time. The influence of the route of administration was studied in six healthy volunteers with 128 nmol/kg given as a 12-hr intravenous infusion or as a single subcutaneous or intramuscular injection. After cessation of intravenous infusion in healthy volunteers, NAc-SDKP was characterized by a quick elimination phase, with a mean half-life of 4.5 min. The volume distribution was 117 ml/kg and the area under the curve was 117 nM hr. After subcutaneous and intramuscular administrations, peak plasma drug concentrations occurred at 0.26 and 0.28 hr, with Cmax values of 156 and 110 nM, respectively. The bioavailabilities determined after subcutaneous and intramuscular administrations were 100 and 81%, respectively. NAc-SDKP pharmacokinetics was studied in patients after intravenous infusion over 48 hr of a dose of between 51.3 and 513 nmol/kg. Area under the curve values increased proportionately with the dose. Mean clearance was lower in patients than in healthy volunteers: 524 vs. 1120 ml/hr/kg, respectively.

Adult↗