Extended versus involved fields irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin's disease.

From 1976 to 1981, 335 patients with untreated Hodgkin's disease, clinical stages I, II, and IIIA, have been treated by MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy, three to six cycles according to the prognostic factors, combined with radiotherapy. Irradiation was always performed after the first three cycles of chemotherapy, and was randomized between extensive radiotherapy, ie, mantle and paraaortic areas for supradiaphragmatic presentations, and radiotherapy restricted to the involved areas. No significant difference was observed between the two randomized branches for the disease-free survival (86% after six years in the involved field branch v 90% in the extended field branch), and none for the overall survival. Most of the relapses occurred in nonirradiated areas in the first group, and in irradiated areas in the second. Relapses were especially frequent in the IIE stages with pulmonary extension; extranodal relapses occurred with osseous and cutaneous localizations. Two cases of secondary leukemia were observed after three- or six-cycle MOPP plus radiotherapy limited to the involved areas.

Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer.

PURPOSE: The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit. RESULTS: The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p=0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p=0.18). Median survival was significantly longer (p=0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively. CONCLUSION: VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative.

Oral vinorelbine given as monotherapy to advanced, elderly NSCLC patients: a multicentre phase II trial.

Vinorelbine intravenously (i.v.) demonstrated its efficacy and tolerability in advanced non-small cell lung cancer (NSCLC) patients, including elderly subjects. Since vinorelbine is now available as an oral formulation this phase II open study was designed to evaluate its activity and tolerability in advanced, elderly NSCLC patients. A total of 56 chemonaive patients were recruited from April 2001 through to March 2002. The dosage schedule, already tested in younger NSCLC patients, was 60 mg/m(2)once a week for three weeks (first cycle), followed by 80 mg/m(2) once a week until disease progression or development of unacceptable toxicity. A limited sampling scheme was used for performing pharmacokinetic analysis on 52 of 56 patients enrolled in the study. Treatment was well tolerated with grade 3/4 neutropenia in 11/17 patients (20/30%) and febrile neutropenia in 1 (2%). Six partial responses (11%) and 25 stable disease responses were recorded, with a disease control rate of 55%. Median overall survival was 8.2 months (95% Confidence Interval (CI) [6.2-11.3]). The clinical benefit response rate was 31% on 32 evaluable patients. Pharmacokinetic profiles appeared quite similar to the historical profiles recorded following i.v. administration. Oral vinorelbine appears to be a reasonable alternative to i.v. vinorelbine, both in terms of activity and tolerability, in advanced, elderly NSCLC patients.

[Results of a cooperative prospective study of treatment of primary digestive localizations of non-Hodgkin's lymphoma]. / Résultats d'une étude prospective et coopérative pour le traitement des localisations digestives initiales des lymphomes non Hodgkiniens.

We report the results of chemotherapy treatment in 82 patients presenting with primary digestive lymphoma and included in a study conducted between October 1977 and October 1985. There were 31 gastric lymphoma, 18 small intestinal lymphomas, and 19 with multiple involvement: 63 patients had had a surgical staging with total tumor resection in 15 cases. Nineteen patients with limited disease (ID and IID) were randomly assigned to either a 3-week chemotherapy regimen associated with whole abdominal radiotherapy or chemotherapy for 3 years. Twenty-seven stage IIID and thirty-six stage IV were treated with chemotherapy alone for 3 years. Low grade lymphomas (16 patients) received a cyclophosphamide, vincristine, prednisone association. Intermediate (56 patients) and high grade (10 patients) lymphomas received cyclophosphamide, vincristine, adriamycin, prednisone. The overall complete remission obtained was 63 p. 100 (51 patients) with 17 patients in relapse within 6 to 40 months. Overall survival was 46 p. 100 at 5 years. Survival was dependent on abdominal extension, histologic grade according to the new working formulation used for lymph-node lymphomas, initial localization (gastric lymphomas have the best survival) and achievement of complete remission. Chemotherapy is an effective treatment for primary digestive lymphomas. The role of surgery in the management of lymphomas has to be defined by further studies.

[Non-Hodgkin's malignant lymphoma. Therapeutic value of autologous bone marrow transplantation]. / Lymphomes malins non hodgkiniens. Intérêt thérapeutique de l'autogreffe de moelle osseuse.

Twelve patients with non-Hodgkin malignant lymphoma of poor prognosis were treated with heavy chemotherapy of the TACC type (cyclophosphamide 45 mg/kg/day i.v. X 4; cytosine arabinoside 200 mg/m2/12 hours i.v. X 7; 6-thioguanidine 100 mg/m2/12-hourly p.o X 7 and CCNU 200 or 250 mg/m2 p.o. single dose) followed by autologus bone marrow transplantation (853 to 20.000 CFUc/kg). The patients were divided into 2 groups depending on whether they received an induction treatment for large visible tumoral mass (group I: 3 initial presentations, 3 relapses) or a consolidation treatment for small residual tumour (group II: 6 complete and 1 partial remissions). The results show that autologous bone marrow transplantation shortens the duration of the therapeutic aplasia. White cell (greater than 10(9)/l) and platelet (greater than 50.10(9)/l) recovery was observed on days 12 (range 9-19) and 14 (range 8-27) respectively. In group I, 1 patient died of myocardial TACC toxity and acute renal failure on tumoral kidney; there were 2 failures and 3 complete remissions (8, 21, 45 + months). Remissions occurred in patients treated initially; the overall survival since diagnosis was 48+, 48+ and 60+ months. In group II patients there were 1 failure and 5 complete remissions persisting after a 2+ months to 30+ months follow-up; the overall survival was 23+, 24+, 27+, 42+ and 70+ months. The 3 failures in the series occurred in circumstances suggesting contamination of the cryopreserved bone marrow by tumoral cells. The toxicity, largely due to infection, of the TACC-bone marrow transplantation combination was tolerable. It was clearly lower in group II (6 patients, no septicaemia) than in group I (5/6 patients with septicaemia). These preliminary results confirm that there is room for autologous bone marrow transplantation in highly malignant non-Hodgkin lymphomas, particularly during complete remissions to facilitate the use of an aggressive consolidation chemotherapy.

[Protective effect of isaxonine against vincristine-induced neuropathy (author's transl)]. / Activité protectrice de l'isaxonine dans la neuropathie à la vincristine.

A double-blind survey versus a placebo was carried out with C.P.V. protocole on 25 patients treated for lymphosarcoma or reticulosarcoma; its aim was to appraise the preventive action of isaxonine on the appearance of neuropathy induced by vincristine. The frequency of such neuropathy was clearly lower in the isaxonine group (3/10) than in the placebo group (8/10) in a statistically significant manner. The protective effect of isaxonine was particularly striking on tendon reflexes and on the number of motor units recorded at musculus extensor digitirum pedis brevis; on the contrary, the patients treated with the placebo showed real denervation.

[The early phase of vincristine-induced neuropathy. Electrophysiological evidence of a "dying-back" phenomenon (author's transl)]. / Phase précoce de la neuropathie à la vincristine. Arguments électrophysiologiques en faveur d'une axonopathie distale rétrograde.

Electrophysiological exploration was carried out in 12 patients before and during administration of vincristine sulphate 1,4 mg/m2 body surface area. The patients had stage III or IV lymphoreticulosarcoma and received one injection of vincristine weekly for 6 weeks. Compared with pretreatment findings, (1) motor and sensory conduction velocity, as well as delay in triceps surae H reflex remained unchanged; (2) sensory nerve amplitude and density of distal muscle electromyographic recordings rapidly decreased; (3) the amplitude of distal tendinous reflexes rapidly diminished, whereas that of the H reflex remained stable. These results being similar to those observed in experimental acrylamide toxicity, where a "dying back" hemopathy has been demonstrated, it is suggested that the neuropathy induced by vincristine in man is of the same type.

Pipobroman therapy of polycythemia vera.

Between 1971 and 1981, 74 patients with polycythemia vera were treated with pipobroman using a high-dose induction, low-dose maintenance regimen. Complete remission was achieved in 51 of 54 previously untreated patients (94.4%) and in 17 of 20 patients (85%) previously treated wih radioactive phosphorus (32 p) and busulfan. The earliest modifications were noted on day 16, and on the average, blood counts were normal by day 45. Thirty percent of the patients relapsed, the mean duration of the remission being 17.5 mo. Following recurrence pipobroman was consistently effective in the same doses but the mean duration of the next remissions was 10 mo. Transient leukopenia and thrombocytopenia occurred in 8% and 7% of patients, respectively, during initial phase, and anemia was noted in 3 patients. Macrocytosis was noted in 20% of patients during maintenance phase. Three cases of acute leukemia and 3 cases of osteomyelosclerosis were recorded, all occurring in patients who had previously received 32 p and/or busulfan. No hematologic malignancies were seen among patients treated with pipobroman alone; follow-up exceeded 6 yr for 20 patients and the median follow-up period was 3.6 yr. Pipobroman appears safer than other alkylating agents; it is as effective as 32 p and works more quickly. Longer follow-up will be required to evaluate the drug's oncogenic potential, which is still not known.

Combination chemotherapy with cyclophosphamide, vincristine, prednisone and the contribution of adriamycin in the treatment of adult non-Hodgkin's lymphomas a report of 131 cases.

Between January 1973 and January 1979, 131 patients with malignant non-Hodgkin's lymphomas (107 lymphocytic lymphomas, 24 histiocytic lymphomas) were treated with cyclophosphamide-vincristin-prednisone (CVP) either alone or combined with Adriamycin (CVP-A). Stage I and II lymphocytic lymphomas were all treated by CVP combined with radiotherapy. The survival curve for this group of patients plateaued at 89% from the 12th to the 60th month, which was the endpoint of the study. For Stage III and IV nodular lymphocytic lymphomas, actuarial survival was 69% at five years in the CVP-treated group as compared to 54% at three years in the group treated with CVP-A. For Stage III and IV diffuse lymphocytic lymphomas, the complete response rate and median survival were respectively 25% and 24 months in patients treated with CVP, as compared to 67% (P less than 0.01) and 26 months in the group treated with CVP-A. For histiocytic lymphomas, the complete response rate was 50% in the CVP-treated group as compared to 83% in the group treated with CVP-A. Most remarkable was the fact that while in the CVP treated group median survival was only 17 months, the small group of patients treated with CVP-A exhibited considerably improved survival with a horizontal survival curve at 90% after 36 months (12 patients). These results show that the CVP protocol remains an excellent treatment for nodular lymphocytic lymphomas. The addition of Adriamycin (CVP-A) as well as its inclusion in other drugs combination, has raised hopes for remissions of long duration and even for cures in patients with histiocytic lymphomas. Finally, in diffuse lymphocytic lymphomas, efforts will have to be pursued to improve the prognosis which remains poor despite the increased complete response rate achieved by the addition of Adriamycin.

[Adriamycin for the treatment of non HOdgkin's lymphomas (author's transl)]. / Intérêt de l'adriamycine dans le traitement des lymphomes non Hodgkiniens.

One hundred and thirty one patients with non-Hodgkin's lymphomas (107 lymphomas and 24 histiocytic lymphomas) have been treated between January 1973 and January 1976, by an association of cyclophosphamide, vincristine and prednisone alone (CVP) or combined with adriamycin (CVP-A). All lymphomas stage I and II received CVP + radiotherapy: the actuarial analysis shows a stationary survival from 1 to 5 years at 89%. In the group of lymphoid lymphomas stage III and IV with nodular pattern, the survival is longer for patients who received CVP (69% at five years) than for patients treated with CVP-A (54% at three years). In the group of lymphoid lymphomas stage III and IV with diffuse pattern, the complete remission rate is 25% for the CVP and 67% for the CVP-A (p less than 0.01). However, the median duration of life is not different for the two groups (24 and 26 months respectively). In the group of histiocytic lymphomas, the complete remission rate in 50% for the CVP combination and 83% for the CPV-A. However, the median time of life which is 17 months for the CVP, is not reached for the CVP-A (Stationary survival at 90% from the 12th to the 36th months). These results show that the CVP combination is a good treatment for the lymphoïd lymphoma with nodular pattern. The addition of adriamycin gives hope of long remissions and perhaps cure for histiocytic lymphomas, until now of bad prognosis. For the lymphoid lymphoma with diffuse pattern, the prognosis is still bad although we obtained with adriamycin a better rate of complete remission. The high dose chemotherapy rescued by autologous bone marrow transplantation may be a new possibility for this last type of non Hodgkin lymphomas.

Long-term effects of interferon-alpha in five HIV-positive patients with chronic hepatitis B.

Chronic hepatitis B viral infection is common in human immunodeficiency virus (HIV) carriers, but the effectiveness of interferon therapy is still unknown. We report the results of a long-term pilot study of five patients, who were infected with HIV and chronic hepatitis B, treated by interferon. Five males co-infected with HIV and hepatitis B virus (HBV) (mean age 27 years) were given a 6-month course of interferon (IFN)-alpha 2b 5 million units (MU) three times weekly. On initiating the treatment, their CD4 lymphocyte count was 340-553 mm-3, their CDC stage was IIa-III; all had histologically proven chronic hepatitis, with Knodell's score ranging from 6-10, and active HBV replication (HBV DNA and hepatitis B e antigen (HBeAg) were detectable). There was no associated hepatitis delta virus (H delta V) or hepatitis C virus (HCV) infection. Follow-up was for 53 months on average (24-74 months). After the treatment, hepatitis B e antibody (HBeAb) and hepatitis B s antibody (HBsAb) seroconversion was observed in one patient, HBeAb seroconversion alone in two patients, HBV DNA was absent from serum in three patients, and HBV DNA significantly decreased in one patient. The serum alanine aminotransferase (ALT) activity was normal in four patients. Histological improvement was obtained in four patients. The HIV stage remained unchanged in all patients during the whole follow-up. These preliminary results suggest that interferon can be successfully used in immunocompetent HIV carriers with chronic hepatitis B as well as in HIV-negative patients.

Delayed kinetics of recovery of haemopoiesis following autologous bone marrow transplantation. The role of excessively rapid marrow freezing rates after the release of fusion heat.

Thirty-five patients were treated by intensive chemotherapy and/or whole-body irradiation followed by reinjection of cryopreserved autologous bone marrow. In 8 patients the kinetics of recovery of haemopoiesis was delayed (recovery to 10(9) leucocytes/litre beyond day 27 and recovery to 50 X 10(9) platelets/litre beyond day 25). This delay was directly responsible for the death of 3 patients and contributed to a fatal outcome in 2 others (mortality rate 9-14%). Retrospective analysis of these 8 cases revealed that failure of autologous transplantation was associated with poor recovery of CFUc, which was in turn related to an excessively rapid freezing rate after the release of fusion heat. Recovery of CFUc to 50% or more was achieved in 100% of cases when the freezing rate was less than 5 degrees C/min, 45% for freezing rates between 5 and 10 degrees C/min and 22% when the freezing rate exceeded 10 degrees C/min (n = 71, P less than 0.001). There was an inverse linear or logarithmic relationship between CFUc recovery and freezing rate after the transition phase (r = -0.46, r = -0.43, P less than 0.001). The quantity of nitrogen introduced into the freezing chamber to annul the fusion heat must therefore be calibrated with accuracy so that the desired shortening of the transition phase will not be accompanied by an overly marked increase in the freezing rate, which would result in the destruction of stem cells. To ensure an adequate freezing rate, it is crucial to monitor the temperature continuously in each sample of bone marrow during the freezing process. This study also suggested that other factors may have interfered with the kinetics of recovery after autologous bone-marrow transplantation. These factors include myelofibrosis, the presence of an Australia antigen and administration of compounds that are toxic for the bone marrow after reinjection of cryopreserved marrow. However, the responsibility of these factors cannot be stated with certainty.

[Management of polycythaemia with pipobroman]. / Traitement des polyglobulies par le pipobroman.

From 1971 to 1980, 86 patients with polycythaemia (vera 69, undetermined 15 and respiratory 2) were treated with pipobroman (N,N' bis bromopropionyl piperazine). The initial treatment in doses of 75 mg/day resulted, within 45 days, in complete remission in 46/49 new patients (93.9%), and in 17/20 previously treated patients with polycythaemia vera (85%) and in 14/15 patients with apparently primary polycythaemia. The main duration of the first remission was 17.5 months. Relapses occurred in 30% of the cases but responded to pipobroman at the initial high dosage level. Low-dose maintenance treatment appears to be necessary. Adverse effects on the blood were rare; they included leucopenia (8%) and moderate thrombocytopenia (7%); macrocytosis was noted in 20% of the patients. Acute leukaemia (3 cases) and osteomyelofibrosis (3 cases) were only observed in patients previously treated with 32 P or busulfan. Pipobroman therefore appears to be much less toxic than other alkylating agents. Its is as effective as 32 P but acts more rapidly. It seems to have little oncogenic power, but a more prolonged study is required to ascertain this point.

Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte.

BACKGROUND: Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma. METHODS: The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone. RESULTS: As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P < 0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent). CONCLUSIONS: The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.

Autologous bone marrow transplantation in the treatment of poor prognosis non-Hodgkin's lymphomas.

Twelve patients with non-Hodgkin's lymphomas of poor prognosis were treated by TACC high-dose chemotherapy (cyclophosphamide 45 mg/kg/day X 4, cytosine arabinoside 200 mg/m2 i.v. q 12 hr X 7,6-thioguanin 100 mg/m2 p.o. X 7 and CCNU 200 or 250 mg/m2 p.o., single dose) followed by autologous bone marrow transplantation (ABMI) (infused dose: 853-20,000 CFU-c/kg). Patients were divided into 2 groups: those in primary therapy with high tumor load (group 1; 3 initial diagnoses, 3 relapses) and those in consolidation therapy for a low tumor load (group 2; 5 complete and 1 partial remissions). Results show that: (1) the aplasia following autologous bone marrow transplantation was short. Leukocyte (greater than 10(9)/1) and platelet (greater than 50 X 10(9)/1) recoveries were observed on day 12 (range, 9-19) and day 14 (range, 8-27). (2) In group 1 there were 3 complete remissions (8,21, 45+ months) and 3 failures, including 1 death to toxicity of TACC. The 3 remissions occurred in patients in primary therapy and overall survival of these patients from the time of initial diagnosis was 48+, 48+ and 60+ months. In group 2 there were 5 persisting complete remissions (12+ to 40+ months) and 1 failure. Overall survival of these patients was 23+, 24+, 27+, 42+ and 70+ months. In both groups failures were associated with contamination of the frozen marrow by tumor. The toxicity of the association TACC + ABMT was acceptable and dominated by the risk of pericardial effusion and infection. The latter was absent in group 2 and occurred in 5/6 cases in group 1. These preliminary results indicate that autologous bone marrow transplantation has a possible role in the aggressive treatment of non-Hodgkin's lymphomas of high-grade malignancy and that its use should preferentially be in the consolidation mode.

[Studies of immunological status, following autologous bone marrow transplantation in man (author's transl)]. / Situation immunitaire des patients soumis à une autogreffe de moelle osseuse. Relation avec la dose de moelle administrée.

Following transplant, circulating immunoglobulin levels fell moderately and remained depressed less than 2 months for IgG, and for variable and longer periods of time for IgM and IgA. Repeated quantitative determinations of antibodies against multiple antigens did not show any decrease in the pretransplant levels. Indeed some patients developed herpes and cytomegalovirus infections to which they responded by a sharp increase in antibody titers. In 2 cases, a primary immunization was demonstrated (against CMV and BK virus) with increasing levels of IgM and IgG antibodies. Lymphocyte counts in peripheral blood returned to 500 mm# between day 10 and 29 (median day 18) and to pretransplant values within 6 weeks. Non specific stimulation of lymphocytes by mitogens in the immediate post-transplant period showed a decreased response to PHA and Con A, whereas the responses to pokeweek mitogens and alloantigens were only slightly diminished. The degree of the responses was related to the dose of cryopreserved marrow infused. We conclude that:--although the minimum dose for autologous bone marrow transplantation in man is around 0,5 10(8) nucleated bone marrow cells/Kg, much higher doses should be used to ensure faster and better restoration of immune reactivity.--The similarity of the immunological dysfunction following autologous and allogeneous bone marrow transplantation suggest that, in the immediate post-transplant period, the role of GVHD in cellular immunity depression may be minimal.