Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.

BACKGROUND: No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. METHODS: In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. FINDINGS: Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. INTERPRETATION: In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. FUNDING: Schering-Plough/Merck and French Government.

Current chemotherapy for glioblastoma.

INTRODUCTION: Glioblastoma multiforme continues to be associated with a dismal prognosis, despite aggressive therapy. What limited therapeutic impact that has been made has come via multimodality treatment in which chemotherapy plays an important role. In this manuscript, we review current chemotherapy options for glioblastomas. METHODS: The current literature concerning glioblastoma multiforme chemotherapy was reviewed. In addition to a review of landmark references, a MEDLINE search of the literature published from January 2000 to November 2002 was performed using the key words "chemotherapy AND malignant glioma" and limiting responses to clinical trials. RESULTS: Several cytotoxic chemotherapeutic agents that are efficacious in treating glioblastoma are in common clinical use. These can be classified as first-line or second-line agents, depending on their efficacy. In addition, cytostatic chemotherapy agents are beginning to play a role in glioblastoma treatment. Finally, new methods to deliver high chemotherapy doses to brain tumors hold promise for future therapies. CONCLUSIONS: Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact. Strategies currently in clinical trials may improve this impact more in the future.

Neurofibromatosis type 1-associated unusual pleomorphic astrocytoma displaying continual malignant progression.

Patients with neurofibromatosis type 1 (NF1) often have gliomas as a complication, most of which are benign pilocytic astrocytomas which have arisen in optic pathways. In the present case, a 17-year-old girl (at death) with stigmata of NF1, initially had a bulky tumor mass in the left thalamus, developing into the lateral ventricle, at 13 years of age. Partially resected tissue samples showed pleomorphic astrocytoma with abundant xanthoma cells and degenerative structures such as Rosenthal fibers (RF) and eosinophilic granular bodies. Fine eosinophilic granules identical to RF, both immunophenotypically and ultrastructurally, were also seen. The residual tumor was subtotally resected 6 months later, and the tumor histology was essentially similar as before, accompanying the regenerative structures; this was believed to be a good prognostic indicator. However, several anaplastic features such as mitosis, necrosis and vascular proliferation appeared even in areas rich in the regenerative structures. After a 2-year, disease-free interval, multiple tumor relapse occurred in June 1997. Partially resected tumor tissues were composed of monotonous small anaplastic cells with prominent proliferative activity. Surprisingly, the tumor cells had retained eosinophilic granules within the cell bodies. Postoperative chemotherapy with procarbazine, MCNU and vincristine (PCV) suppressed the residual tumor dramatically, but the regrowing tumor finally became uncontrollable, leading to the patient's death. TP53 mutation was not detected, while p27 immunopositivity was constantly high during malignant progression, suggesting acquisition of proliferative activity to overcome p53 and p27 inhibitory functions. A review of previously published reports failed to reveal any cases of this type.

The impact of mild Leydig cell dysfunction following cytotoxic chemotherapy on bone mineral density (BMD) and body composition.

BACKGROUND: Overt testosterone deficiency is associated with a reduction in BMD and alteration in body composition. However, there are few data concerning the impact of mild hypogonadism on these parameters. PATIENTS AND METHOD: We have identified a cohort of 36 men aged < 55 years with mild Leydig cell impairment, defined by a raised LH level (LH >/= 8 IU/l) in the presence of a testosterone level in the lower half of the normal range or frankly subnormal (< 20 nmol/l), following treatment with procarbazine-containing chemotherapy regimens or high-dose chemotherapy for haematological malignancy. These men underwent measurements of BMD (measured by dual-energy X-ray absorptiometry (DXA), single energy X-ray absorptiometry (SXA) and quantitative CT (QCT)), body composition (DXA), markers of bone turnover, serum lipids and serum IGF-1. To allow for changes that may be directly attributable to the underlying disease or its treatment, results were compared with those obtained in 14 men who had received the same chemotherapy for the same diseases but had normal LH and testosterone levels (controls). RESULTS: When data from all 50 men were considered together there were significant reductions in BMD of the lumbar spine both by DXA (Z = - 0.34, P = 0.01) and QCT (Z = - 1.5, P < 0. 0001), at the femoral neck (Z = - 0.52, P < 0.0001) and distal forearm (Z = - 0.21, P = 0.05). Mean femoral neck BMD was significantly lower in patients compared with controls (Z = - 0.68 vs. Z = - 0.11, P = 0.05) and there was a nonsignificant trend towards lower lumbar spine BMD measured by QCT (Z = - 1.64 vs. Z = - 1.10; P = 0.09). In addition, serum testosterone level and testosterone:LH ratio significantly correlated with femoral neck BMD (r = 0.28, P = 0.05 and r = 0.37, P = 0.008, respectively). There were no significant differences in lean body mass, fat mass and percentage fat between the patients and controls. There was, however, a difference in the distribution of body fat with a propensity for the patients to accrue truncal fat, and the serum testosterone level significantly inversely correlated with percentage of truncal fat (r = - 0.29, P = 0.04). There were no significant differences in lipid levels, IGF-1 levels or markers of bone turnover between the patients and controls. CONCLUSIONS: These data suggest that mild Leydig cell impairment may have significant effects on bone mineral density and may result in subtle body composition changes, although in men who have received cytotoxic chemotherapy, other factors also contribute to the observed osteopenia. Testosterone replacement may be beneficial in some of these men and this requires further evaluation.

Tailored therapy for aggressive non-Hodgkin's lymphoma: results of a phase II study with a long-term follow-up.

Aim of the study was to improve cure rate and survival of aggressive non-Hodgkin's lymphoma (NHL) with a tailored program of therapy based on histologic type, prognostic characteristics of patients and response to therapy, and with the use of differentiating or cytostatic agents such as Ara-C at low doses and alphaIFN. Fifty-four consecutive patients with aggressive NHL were treated in the induction phase with 4 sequential courses of a third generation regimen (modified CODBLAM IV), followed in responsive patients by 1 cycle of doxorubicin and cyclophosphamide and 1 cycle of high dose methotrexate with folinic acid rescue (AC-MTX). Patients who achieved partial response (PR) were treated with the combination of CCNU + vinblastine if affected by high grade NHL, or with low dose Ara-C plus alphaIFN if affected by intermediate grade NHL. Patients who obtained complete response (CR) with basal adverse prognostic factors were treated with alphaIFN as maintenance therapy for two years. Radiotherapy and surgery were effected in selected cases. Thirty-four patients (62.9%) achieved CR and 12 patients (22.2%) showed PR after induction therapy. Among the 12 patients who achieved PR, 6 prolonged CRs were obtained in 7 patients treated with Ara-C at low doses plus alphaIFN and 4 CRs were obtained in 5 patients treated with CCNU + vinblastine. After completion of treatment, 44 patients (81.5%) obtained CR, 2 patients (3.7%) showed PR and 8 patients (14.8%) presented progression of disease (PD). Fifteen patients received alphaIFN as maintenance therapy. The overall survival and failure-free survival rates are 53.7% and 50% respectively, with a median follow-up of 82 months: 27 patients remain alive, disease-free without relapses, and can be considered cured. This tailored program of therapy resulted effective and moderately toxic and may improve the outcome in aggressive NHL.

Advances in chemotherapy for large cell lymphoma.

Three generations of chemotherapy regimens for the treatment of aggressive lymphomas have evolved in the past decade. The first-generation combination regimen, CVP, also known as COP (cyclophosphamide, vincristine, prednisone), produced maximum long-term survivals in considerably less than 20% of patients. With the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen, 40% of patients achieved complete remission (CR). This signal study was paralleled by other first-generation studies including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), HOP (doxorubicin, vincristine, prednisone), CHOP-Bleo/BACOP (CHOP plus bleomycin), and COMLA (cyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine). None of the regimens was shown to be particularly superior to the others. Survival plateaus were seen in approximately 20% to 40% of patients. Second-generation therapies, COP-BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine), ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone), M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), and m-BACOD (same as M-BACOD, but with a moderate dose of methotrexate and modified leucovorin given on days 8 and 15 instead of just day 10) were characterized by an increasing number of drugs, more frequent administration of myelosuppressive agents, and flexible dose schedules. This new treatment intensity resulted in CRs in excess of 70%. The third generation regimens have been characterized by innovative concepts of chemotherapy, including alternative modes of drug administration, greater use of marrow-sparing, cycle-active, and/or putatively non-cross-resistant agents, and more frequent and/or intense dose administration. These regimens, COP-BLAM III, MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin), ProMACE-CytaBOM (ProMACE plus cytarabine, bleomycin, vincristine, methotrexate), and high-dose doxorubicin with cytarabine, have produced over 80% CRs and survival plateaus in excess of 60%. In the COP-BLAM III regimen, 84% of patients achieved a pathologic CR. Overall, 65% of patients are alive, well, and free of disease, and potentially in the survival plateau. COD-BLAM IV (same as COP-BLAM, except dexamethasone is substituted for prednisone) is a new program that further intensifies treatment by using sequential, rather than alternate-cycle, infusions of bleomycin and vincristine. Results are still preliminary, with a short median follow-up of 19 months.(ABSTRACT TRUNCATED AT 400 WORDS)

The usefulness of human tumor cell lines in the study of chemosensitivity. A study of malignant melanomas.

The chemosensitivity of human melanoma cells has been studied before and after continuous in vitro culture. Altogether, nine cell lines were studied, two derived from patients' biopsies, and seven from xenografts in athymic mice. The sensitivity to the agents DTIC (Dacarbazine), CCNU (Lomustine), procarbazine, vinblastine, abrin and ricin was assayed. Furthermore, in five cases the chemosensitivity of the cell lines was compared to that of tumors obtained by injecting the cell lines into athymic mice. In all cases the sensitivity was measured in an in vitro soft agar assay. Upon cultivation in vitro, two of the cell lines, one derived from a patient's metastasis and one from a xenograft in athymic mice, showed marked increases in sensitivity to some of the drugs, whereas sensitivity to other drugs showed little or no change. For the other cell lines small, but definite increases or decreases in chemosensitivity were observed. Permanent cultures showed the same chemosensitivity as early subcultures. The tumors formed by injecting the cell lines into athymic mice showed moderate changes in chemosensitivity, as compared to the cell lines in vitro. The data indicate that considerable changes in chemosensitivity may occur when cells are brought from in vitro to in vitro conditions and vice versa and that such changes may be highly specific. Therefore, although cell lines may be useful in some respects, they should be used with caution in attempts to evaluate quantitatively the sensitivity of human tumors to cancerostatic drugs.

Hypophosphatemia in a patient with lymphoma in leukemic phase.

A patient with histiocytic lymphoma had abdominal masses, hypophosphatemia, normocalcemia, and a normal serum parathyroid hormone value. After chemotherapy, transient hyperphosphatemia ensued, the abdominal masses resolved, and other manifestations of the disease were suppressed. One week after discontinuation of the chemotherapy, the abdominal masses and other signs indicative of reactivation of the malignant disease reappeared. During the relapse, the serum phosphorus level fell to 0.7 mg/dL, and urinary excretion of phosphorus became negligible. After resumption of chemotherapy, serum concentration and urinary excretion of phosphorus increased. These observation suggest that severe hypophosphatemia may be a complication of hematologic neoplasia. It is proposed that this abnormally may be caused by a shift of excessive amounts of extracellular phosphorus into the rapidly replicating malignant cells.

The effect of procarbazine on the chromosomes of normal and malignant mouse cells.

The effects of the cancer drug methylhydrazine derivative procarbazine (PC) on the chromosomes of normal and malignant cells in the mouse strains Swiss Albino, CF1, and BDF1 have been analyzed. PC broke chromosome in the hypotetraploid Ehrlich and the diploid P388 ascites tumors. Practically all breaks seemed to be of the G2 type and, as far as could be determined, took place in the quinacrine-dark or the corresponding Giemsa-light regions. The vast majority of the broken ends had rejoined to form chromatid translocations. No increase in chromosome breaks were seen in any of the normal tissues treated in vivo: spleen, bone marrow, spermatocytes, or spermatogonia (in this tissue the cells were not counted). The chromosomes of the Ehrlich ascites tumor have been studied by means of both Q-banding and G-banding. Very few, if any, chromosomes seem to have an exact homologue or to correspond to any of the normal mouse chromosomes.

Pituitary function in patients receiving intermittent cytotoxic and corticosteroid therapy for malignant lymphoma.

Diurnal variation in plasma-cortisol was studied immediately before and after intermittent steroid therapy in seven patients receiving monthly courses of quadruple chemotherapy for Hodgkin's or non-Hodgkins lymphoma over a period of 6 months. The serum-thyroid-stimulating-hormone (T.S.H.) response to intravenous T.S.H.-releasing factor was also measured before and during the first course and before the second and fourth courses. The morning plasma-cortisol concentration fell significantly over 6 months when measured immediately before the start of each course. The mean evening cortisol concentration also fell over this period. In most patients the T.S.H. response showed a downward trend during treatment, although in two patients the response returned to normal whilst they were still undergoing therapy.

[Possibilities and limits of pre-therapeutic neoplasm sensitivity cytostatics tests under short-term conditions]. / Möglichkeiten und Grenzen der prätherapeutischen Sensibilitätstestung von Tumoren gegen Zytostatika im Kurzzeittest

The following cytostatic agents were tested for activity in vivo and in vitro inWalker carcinosarcoma 256 of the rat: cyclophosphamide, triaziquon, 5-fluorouracil, methotrexate, adriamycin, dactinomycin, daunorubicin, hydroxyurea, procarbazin and vincritine. With the exception of vincristine, the results of therapy in vivo could be predicted by using a rapid in vitro test system. This involved, for cyclosphosphamide, triaziquon, adriamycin, and daunorubicin, the measurement of 3H-uridine or 3H-thymidine incorporation. The activities of methotrexate and 5-fluorouracil could be determined from 3H-deoxyuridine incorporation and that of dactinomycin from 3H-uridine incorporation. The results of short-term tests (uring adriamycin, daunorubicin, and dactinomycin) in roughly 100 human tumors were compared with data in the literature on therapy with the same cytostatic agents. Good agreement was found between the results of in vitro tests and the literature data on clinical therapy.