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P Carde

Publications and source records attributed to P Carde.

At least 55 records · Page 3Linked to original sources

[Hodgkin disease: should high-risk patients be selected and chemotherapy be intensified?].

Death still occurs in Hodgkin's disease (HD) patients with advanced stages, but also in early stages. Therefore, the identification of the population of HD patients who would best benefit from an intensification of treatment is a prerequisite in all stages. The best known prognostic factors are bulky mediastinum, B symptoms, and visceral involvement in advanced HD and, in early HD, the number of nodal areas. No satisfactory combination of these factors can clearly identify a group of patients requiring high dose- and potentially risky therapy. Therefore only a very small subgroup of patients with advanced disease (less than 5% of them) calls for intensified regimens, which makes randomized trials very difficult. A large data base, accrued through a cooperative effort and the addition of early stages to advanced stages, would help to clarify the prognostic analysis. In addition, the patient population needs to be selected on the basis of the best therapeutic approach to-date. The analysis parameter should take into account only the failures due to the tumor progression as opposed to those due to a combination of tumor progression and early plus late toxicities. Three successive steps are required to achieve the goal of high-risk patient's treatment optimization. The first is to define, on a well-defined tumor-risk scale, the kind of results that are to be considered as "unacceptable" when up-to-date conventional strategies are applied. The second is to infer the size of the "high-risk" population, in inverse ratio to the severity of the risk accepted for "normal-risk" patients. The third is to tailor the iatrogenic risk, ie the intensity of the high-dose treatment, to the size of the target population and to the anti-tumor benefit that is anticipated. Obviously, the definition of these parameters belongs to the medical decision-makers. Nevertheless, the availability of a quantified tumor-risk scale would allow to elaborate a reliable strategy in patients at risk for failure, lethal toxicity and unbearable health expenses. A collection of adequate recent trial is proposed through the Third International Symposium on Hodgkin's lymphoma in Köln (21-23 September 1995). This effort will be pursued through the International Data Base for Hodgkin's Disease (IDHD). Newer and more efficient strategies may then be designed.

Antineoplastic Combined Chemotherapy Protocols↗

[Randomized placebo trial of myeloprotection with goralatide in patients with squamous cell carcinoma of the upper respiratory and digestive tracts or esophagus, treated with a carboplatin-fluorouracil combination].

Eighty-four patients with locally advanced, non metastatic squamous cell carcinoma of head and neck or esophagus, were included in a multicentric double-blind randomized trial, comparing goralatide (12.5 or 62.5 micrograms/kg/day, d1-d4) to placebo, associated with carboplatin (400 mg/m2, d1) and 5-fluorouracile (1 g/m2/d continuous IV over 96 hours). Haematological toxicity was analysed on 221 cycles of chemotherapy. All but one patient were evaluable because of early death without haematological toxicity. No significant difference was observed for mean nadir of leukocytes, granulocytes, platelets counts and hemoglobin level. Duration of haematological toxicity was no significantly different for the two groups of patients. Anemia and lymphopenia were more frequent in the goralatide treated patients. Clinical and biological tolerability of goralatide was excellent.

Adolescent↗

Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease. EORTC Lymphoma Cooperative Group. Groupe Pierre-et-Marie-Curie.

In this phase III trial, 770 patients with clinical stage I-II Hodgkin's disease (HD) have been enrolled since November 1988. Preliminary results are given for the 605 (79%) patients who have completed their initial therapy. Patients were grouped according to 6 pretreatment prognostic characteristics. In the very favourable (VF) group, treatment consisted of mantle field alone. In the favourable (F) group, patients were randomized to either subtotal nodal irradiation (STNI), or 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone) followed by involved-field irradiation (IF-RT). Unfavourable (U) patients were randomized to either 6 cycles of EBVP plus IF-RT, or to 6 cycles of MOPP/ABV hybrid plus IF-RT. Of the 35 VF patients, none have progressed during radiotherapy. Four patients relapsed and were salvaged. Three-year failure-free survival (FFS) was 82%; overall survival (OS) was 100%. Of the 254 F patients, 130 were treated with STNI and 124 with EBVP plus IF-RT. At 3 years, FFS rates were 81% (1 progression, 14 relapses) and 79% (5 progressions, 8 relapses), respectively. Corresponding OS rates were 99% and 100%. Of the 316 U patients, 160 received EBVP and 156 MOPP/ABV. At 3 years, FFS rates were 72% (18 progressions, 20 relapses) and 88% (7 progressions, 6 relapses), respectively (p < 0.001). Although OS rates were identical (92%), the entry in the U-EBVP arm was stopped in November 1992. We conclude that a treatment strategy based on prognostic factors allows the use of less aggressive treatment in favourable patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

EORTC study of non-Hodgkin's lymphoma: phase III study comparing CHVmP-VB and ProMACE-MOPP in patients with stage II, III, and IV intermediate- and high-grade lymphoma.

In the EORTC lymphoma cooperative group, a randomized phase III study was done for patients with stage II, III, IV intermediate- and high-grade lymphoma. Eight courses of CHVmP-VB were compared to eight courses of ProMACE-MOPP. Response was evaluated after 8 courses. Of 430 patients entered, 346 were eligible for this first analysis. Additional radiotherapy was given at initial large masses or residual disease after three courses. Response rate was higher in the CHVmP-VB arm in comparison to the ProMACE-MOPP arm, 82% vs. 65% (p < 0.0005). In the ProMACE-MOPP arm, treatment had to be interrupted because of patient refusal in 7% of the patients. So far there has been no significant difference in freedom from progression at 5 years (49% vs. 47%), relapse-free survival (59% vs. 59%), or overall survival (55% vs. 49%). Patients with early response at 4 courses showed no better RFS in comparison with late responders between 4 and 8 courses. The International Index, based on age, stage, SLDH, performance status, and number of extranodal localizations showed a good prognostic significance in this series of patients.

Adult↗

A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.

PURPOSE: We report a prospective randomized study comparing the relative efficacy of alternating chemotherapy mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) with the standard MOPP chemotherapy in patients with stage IIIB and IV Hodgkin's disease (HD). The purpose is to study the influence of time of remission on clinical outcome. PATIENTS AND METHODS: After two courses of MOPP, patients were randomized to receive six further courses of MOPP, or two courses of ABVD followed by two courses of MOPP and two courses of ABVD. Radiotherapy was given to areas presenting with masses > or = 5 cm and to residual masses after course no. 4. Evaluation of response (complete remission [CR]) took place after two courses (CR2), after four courses (CR4), at the end of chemotherapy (CR8), and after additional radiotherapy (CR(CT + RT)). Logistic regression analysis was used to study prognostic factors for response at the end of chemotherapy. Cox analysis was used to study prognostic factors for survival. Two hundred seven patients were registered, 192 (93%) of whom were randomized. RESULTS: The CR rate at the end of chemotherapy (CR8) was similar in both arms (57% v 59%). However, there were more progressions in the MOPP arm compared with the MOPP/ABVD arm (23% v 8%, P = .014). A significantly higher failure-free survival (FFS) rate was found in the MOPP/ABVD arm (60% v 43% at 6 years, P = .025). There was no difference in the relapse-free survival (RFS) or survival rate. Of patients not in CR4, only 28% still reached a CR8. RFS at 6 years of patients with CR4 (69%) was not different from that of patients with CR8 (68%); patients with a CR(CT + RT)) had a lower RFS rate (48%). CR4 (P < .001) predicted strongly for final remission at the end of chemotherapy. Cox analysis showed that age more than 50 years, six or more involved lymph node areas, no CR by the fourth cycle, chemotherapy with MOPP alone, and no radiotherapy were unfavorable factors for survival. CONCLUSION: MOPP/ABVD chemotherapy significantly improved response and FFS rates, but had no influence on RFS and survival rates. Early CR (CR4) is an important factor for final remission and might be used to select a group of patients with a good prognosis.

Adolescent↗

[Inhibitors of hematopoiesis: from physiology to therapy].

A balance of both stimulatory and inhibitory factors interfere with gross and precise hematopoiesis regulation. A number of inhibitory molecules may endeavour a physiological role (cytokines like TGF beta, TNF alpha, platelet factor 4 PF4, Interferons, MIP1 alpha or peptides like p-EEDCK, Ac-SDKP. Hemopoietic primitive stem cells are relatively spared from chemo- or radiotherapy toxicity when they stay in a quiescent G0 state. They suffer from repeated toxic treatments when they undergo cycling. Molecules like the AcSDKP (seraspenide) inhibit in a reversible way stem cell and progenitors cycling, affording them a significant degree of protection from chemotherapy (cytarabine, cyclophosphamide, 5FU, AZT) and ionizing radiation toxicity. A clinical phase Ib study suggests protective effects from cytarabine toxicity.

Amino Acid Sequence↗

[Treatment of early stage Hodgkin disease].

In early stage Hodgkin's disease the optimal choice of treatment is still an unresolved issue. Twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out world-wide. The preliminary results of a global meta-analysis of these trials indicate that we still do not definitively know whether or not the early addition of prophylactic chemotherapy improves survival. Arguments in favour of early chemotherapy are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against early chemotherapy is: that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone, results are, however, conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for general clinical use.

Female↗

Ways of minimising hematopoietic damage induced by radiation and cytostatic drugs--the possible role of inhibitors.

Acute and chronic bone marrow toxicities are the major limiting factors in the treatment of cancer. They are related to two factors. (i) The first is a decrease in the number of hematopoietic stem cells and progenitors caused by both a lethal effect of cytotoxic agents on these cells and by differentiation of stem cells provoked by a feed-back mechanism, itself induced by the depletion of more mature marrow compartments. (ii) The second factor is a reduction in self-renewal capacity of stem cells, which is also related to both direct (mutation) and indirect (ageing of stem cell population) effects. Stimulators and inhibitors of bone marrow kinetics play a prominent role in the induction of damage and recovery patterns. Acute effects can be circumvented by an increase in the number of cell divisions in the more mature compartments. This amplification is enlarged by the administration of hemopoietic growth factors which enhance regeneration and shorten the duration of blood aplasia. However, these stimulators may contribute to the exhaustion of the stem cell pool and they may increase the severity of late effects. Protection against chronic effects is difficult; however, the ability to 'switch on' and 'switch off' proliferation opens new avenues which are currently being explored. In particular, inhibitors may protect stem cells against early and late damage by maintaining them in a quiescent state during a course of radiotherapy or chemotherapy. Several inhibitors of hematopoietic stem cell proliferation have been identified during the past 5 years. AcSDKP (Seraspenide) was the first to be isolated and its protective effects against cytotoxic agents were described over a decade ago in mice. Its physiological role is now well established in mouse and man. Preliminary results of a Phase I-Phase II clinical trial strongly suggest that it may have a useful clinical role. Further research is necessary to assess the long-term protective effects of this new family of regulators.

Animals↗

Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients.

Brequinar (DUP 785, NSC 368390) is a 4-quinoline carboxylic acid derivative with broad spectrum antitumour activity in experimental models that acts as an antimetabolite by specific inhibition of de novo pyrimidine synthesis. We performed a phase I study of brequinar administered as a 10 min intravenous (i.v.) infusion for 5 consecutive days, every 4 weeks. 67 evaluable patients were entered in this study and a total of 130 courses were administered at doses ranging from 2 to 350 mg/m2. The dose-limiting toxicity was myelosuppression with predominant thrombocytopenia. Myelosuppression was dose-related and non-cumulative, with considerable interpatient variability depending on haematological risk factors. The maximum tolerated dose of brequinar was 210 mg/m2/day in poor risk patients whereas patients with good risk haematological profile tolerated higher doses (up to 350 mg/m2/day). Other non-limiting toxicities included nausea and vomiting, mucositis and skin reactions. Brequinar plasma pharmacokinetic profiles were biphasic with alpha half-life ranging from 0.1 to 0.7 h, and beta half-life ranging from 1.5 to 8.2 h. Increase in brequinar area under the plasma concentration versus time curves (AUC) was nonlinear. Day 5 brequinar pharmacokinetics obtained in 21 patients indicated a significant increase in AUC (47%) and half-life beta (133%) compared to day 1 pharmacokinetics in the same patient. Brequinar plasma AUC and the per cent change in platelet count at nadir were correlated (P < 0.001). Although no objective response was observed in this study, one minor response was noted in cervical lymph nodes of a Hodgkin's disease patient.

Adult↗

Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group.

PURPOSE: To compare (1) clinical staging and irradiation alone versus staging laparotomy and treatment adaptation in patients with a favorable prognosis (H6F); (2) two combined modalities in patients with an unfavorable prognosis (H6U). PATIENTS AND METHODS: The H6F trial (n = 262) consisted of randomization to clinical staging plus subtotal nodal irradiation (STNI) or to staging laparotomy plus treatment adaptation (adjuvant chemotherapy [CT] only in the 33% with negative laparotomy). The H6U trial (n = 316) consisted of no laparotomy, randomization to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), and mantle irradiation. RESULTS: In the H6F trial, 6-year freedom from progression (FFP) rates (78% v 83%; P = .27) were similar in clinical and laparotomy stagings, respectively. Survival rates were 93% and 89%, due to laparotomy-related deaths. In the H6U trial, the ABVD arm had superior results (6-year FFP rate, 88% v 76%; P = .01), but they were not significant for survival (91% v 85%; P = .22). CT discontinuation due to hematologic intolerance occurred more often with MOPP (14.5% v 7.3%). Decrease of the pulmonary vital capacity ([VC] < 70% of the theoretic value) was observed more frequently after ABVD than after MOPP (12% v 2%; P = .08), with two lethal pulmonary insufficiencies occurring in the ABVD arm. No modification of the isotopic left ventricular ejection fraction (LVEF) occurred. Gonadal toxicity was less in the ABVD arm. CONCLUSION: Early-stage patients benefit from treatment adaptation to initial characteristics in terms of tumor control and late toxicities. Staging laparotomy before STNI may be deleted even in favorable patients at no cost to survival or FFP. In unfavorable patients, ABVD achieved better results than MOPP, at lower hematologic and gonadal cost. Therefore, despite its pulmonary toxicity, ABVD is the best choice to design improved CT regimens associated with mantle irradiation.

Adolescent↗

Catabolism of the tetrapeptide N-Ac-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of hematopoietic stem cell (CFU-S) proliferation, following in vitro incubation with hematopoietic tissues from normal and leukemic mice.

The comparative degradation of N-Ac-Ser-Asp-Lys-Pro (AcSDKP), a negative regulator controlling the proliferation of the hematopoietic pluripotent stem cell, was investigated following incubation with plasma, bone marrow and spleen cells from normal mice and mice bearing a transplantable myeloid leukemia. Using the tetrapeptide, specifically radiolabelled in the lysyl residue, degradation of [3H]AcSDKP was followed by measurement of [3H]Lys formation resulting from its catabolism. It was shown that already after 1 h the degradation of AcSDKP in plasma from leukemic mice was higher compared to that following incubation in plasma from normal mice, whereas incubation with bone marrow cells exhibits a small difference only after 4 hours incubation. However, no increase of AcSDKP catabolic activity was observed following incubation with spleen cells from leukemic animals when compared with incubation of normal spleen cells.

Animals↗

Phase II study of cytarabine in Hodgkin's disease. The EORTC Lymphoma Cooperative Group.

Cytarabine was administered to 24 patients with previously treated Hodgkin's disease in the EORTC Lymphoma Cooperative Group. The drug was administered at the dose of 80 mg/m2 subcutaneously twice a day on 5 consecutive days every 3 weeks. The overall response rate was 17.6% (3 responses among 17 evaluable patients) with a short duration (2-6 months). The main toxicity was myelosuppression. Our experience in the EORTC Lymphoma Cooperative Group could not demonstrate a significant activity at this dose and schedule in Hodgkin's disease.

Adult↗

Immunoscintigraphy in Hodgkin's disease and anaplastic large cell lymphomas: results in 18 patients using the iodine radiolabeled monoclonal antibody HRS-3.

Immunoscintigraphy (IS) using the HRS-3 Hodgkin associated monoclonal antibody (MoAb) was performed in 18 patients with Hodgkin's Disease (HD) at staging or restaging. Either F(ab')2 fragments (14 patients) or whole HRS-3 (4 patients) labeled with 77-260 Mbq 131-I were used. Whole body images, including anterior and posterior views, were taken from a digital gamma camera, within 4 to 8 hours after injection and then daily for 5 days. In one patient IS was discontinued due to iodine intolerance. Seventeen patients were evaluable: 14 showed a true positive result including 2 cases which were reviewed as anaplastic large cell lymphoma (ALCL). Nodal, splenic, bone marrow and muscle involvements were imaged, many of these sites were previously unsuspected. In 7 patients with true positive findings the Pressman Specificity Index, as measured from biopsied material, ranged from 1.5-3 in 4 patients and from 5 to greater than 100 in 3 patients. Imaging was equivocal or failed in 1 patient (lymph nodes). In 2 patients, IS imaging was truly negative due to the absence of active HD, and a false negative result occurred once (inguinal node). In none of the patients a false positive image was observed. In order to rule out non-specific iodine uptake a control, anti-ACE MoAb, labeled with 125-Iodine was injected simultaneously in 10 patients. The evaluation of the study gave a sensitivity of 87% and a good specificity. IS using radioiodine labeled MoAbs is feasible and represents a reliable non-invasive diagnostic method for the staging and follow-up of HD and ALCL.

Animals↗

Radiotherapy versus combined modality in early stages.

In early stage Hodgkin's disease the optimal choice of treatment for the individual patient is still an unresolved issue. So far, twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out worldwide. The preliminary results of a global metaanalysis of these trials indicate that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front improves survival. Arguments in favour of the addition of chemotherapy up front are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against the use of chemotherapy up front is: that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone. The results of these trials are however conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for general clinical use.

Combined Modality Therapy↗