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CEP (CCNU, etoposide, and prednimustine) was tested as third-line chemotherapy in 40 patients resistant to both MOPP and ABVD. The observed response rate (complete remission, 35%, and partial remission, 25%) is encouraging. Treatment was generally well tolerated and all acute side effects were reversible.
Antitumour agents in which various steroids were used as carriers for different cytostatic groups have been synthesized at the Research Laboratories of AB Leo, Helsingborg, Sweden. The chemical and pharmacological properties of two of these agents, estramustine phosphate and prednimustine, are reported. These agents have been shown to have good effects in the treatment of advanced hormone-resistant cancer.
We evaluated 1179 consecutive patients with low-grade B-NHL diagnosed according to criteria of the Kiel classification and presenting with initial bone marrow involvement. Therapeutic approaches were not changed during the observation period 1975-1995. CLL (n=895) and IC (n=169) were treated palliatively with chlorambucil/prednisone or prednimustine. In CBCC (n=65) and CC (n=50) remission was induced with COP or CHOP. The overall response rate was 67%, but only 35% of CBCC and 23% of CC patients achieved complete remission. Median survival was 64 months in CBCC and 28 months in CC. As the median age of our patient population was 68 years (range: 23-93) it seems doubtful whether overall prognosis can be improved by aggressive therapeutic measures. One exception might be CBCC patients who were younger (median age 56 years) and who were usually in good general condition so that they might qualify for high dosage chemotherapy and stem cell support. Whether the prognosis of IC and CLL (median survival 74 months and 107 months, respectively) can be improved by treatment with drugs such as purine analogs will depend on the long-term outcome of clinical studies.
Between 1989 and 1993, 409 evaluable patients with breast cancer have been treated with tegafur and uracil (UFT) in an adjuvant setting in two different trials. Data from both trials were reviewed in December 1995 after a mean follow-up of 5.09 +/- 1.1 years (range, 2.9 to 7.1 years). The aim of the first trial was to demonstrate the activity of UFT 400 mg/day for 6 months plus prednimustine 60 mg/m2 for 7 consecutive days, every 28 days in 6 cycles given orally (arm B). This scheme was compared with 6 cycles of cyclophosphamide 600 mg/m2, plus methotrexate 40 mg/m2, plus fluorouracil 600 mg/m2, every 4 weeks (arm A). In this study, 187 premenopausal women were evaluable, 96 in arm A and 91 in arm B, all of whom had positive axillary nodes. Although there were more younger patients in arm A than in arm B, prognostic factors were similar in both groups. Disease-free survival and overall survival were similar in both arms. However, some concern is raised by the low disease-free survival rate. The toxicity was mild (mainly nausea and vomiting and alopecia) and slightly worse in arm A. We believe that oral administration could be a useful alternative to the parenteral route. In the second trial, 222 evaluable patients received 20 mg/day of tamoxifen (Nolvadex) for 1 year (arm A), or the same dose of tamoxifen plus UFT 400 mg/day for 6 months. All patients were postmenopausal, and the characteristics of the tumors were the same as those in patients in the first trial. In arm A there were 109 patients and in arm B, 113. The groups were well balanced. The overall survival and the disease-free survival rates were equal in both arms, but were longer in arm B in the subset of patients with five or more axillary-involved nodes. The toxicity was negligible in both arms. We conclude that UFT/tamoxifen might be useful in postmenopausal patients with five or more involved nodes who are unable to follow a more aggressive schedule because of their age or low performance status.
Forty-five patients with low grade non-Hodgkin's lymphomas were studied with respect to the fraction of S-phase cells in fresh tumour material by flow cytometric analysis. Patients with stage I lymphomas were treated with radiotherapy, patients with stage II-IV lymphomas with Prednimustine (Sterecyt). Patients with lymphocytic lymphomas of CLL type were only treated if they had symptoms. Median S-phase fraction in the samples was 2.0 per cent. A significantly shorter survival was found for patients with lymphocytic lymphomas with S-phase fractions > 2.0 per cent compared with cases showing lower S-phase fractions. No significant difference in survival was found in the subgroups of immunocytic or follicular and follicular/diffuse centroblastic/centrocytic lymphomas. In a Cox multivariate analysis, in which also age, constitutional symptoms, stage and morphology were included, the fraction of S-phase cells was found to be a statistically significant, prognostic parameter for low grade lymphomas, mainly due to the result in the subgroup of lymphocytic lymphomas.
This report describes the physicochemical and pharmacokinetic parameters of seven chlorambucil esters, which were compared with those of chlorambucil. These esters were designed as chlorambucil prodrugs to increase the brain penetration and concentration vs time profile of chlorambucil within the CNS for potential treatment of brain tumors. They include four aliphatic esters from one to eight carbon chains in length (chlorambucil-methyl, -propyl, -hexyl, and -octyl esters) and three aromatic esters, including the phenylmethyl, phenylethyl and prednisolone ester of chlorambucil, prednimustine. The esters were lipophilic and possessed log octanol:water partition coefficients (log P values) that ranged from 4.05 to greater than 8.0. All retained alkylating activity, which was reduced compared with that of chlorambucil. In addition, all were metabolized in vivo in the rat to yield chlorambucil alone. Measurement of the in vitro rate of ester hydrolysis of the compounds to yield chlorambucil in rat plasma demonstrated that short-chain aliphatic and aromatic chlorambucil esters were rapidly broken down to their parent compound. The plasma half-lives of the compounds increased with the increasing length and complexity of their ester chain. This may have been related to an increase in the binding of the long-chain esters to plasma proteins, protecting the ester from nonspecific plasma esterases, and to a reduced affinity of plasma esterases to these esters. Pharmacokinetic analysis of chlorambucil-hexyl, -octyl, and -prednisolone esters by HPLC demonstrated that following their intravenous administration in the rat (in doses equivalent to equimolar chlorambucil, 10 mg/kg), they yielded only low concentrations of active compounds in plasma and brain. The brain:plasma ratio of these was low and similar to that of chlorambucil, and no ester demonstrated anticancer activity superior to that obtained after the administration of equimolar chlorambucil (5 mg/kg i.v., days 1-5) against brain-sequestered Walker 256 carcinosarcoma in the rat.
Secondary acute myeloid leukemia (s-AML) and secondary myelodysplastic syndrome (s-MDS) probably represent the worst possible long-term complications of cancer therapy in patients originally cured of their primary malignancy. The frequency and type of s-AML and s-MDS are reviewed for patients treated with standard and/or high-dose chemotherapy for Hodgkin's disease, non-Hodgkin's lymphoma (NHL), and breast or testicular cancer. Patients treated for Hodgkin's disease, have a 20- to 40-fold increased risk of developing s-AML, this risk increasing with the number of mechlorethamine-containing cycles given as well as following splenectomy and in patients more than 40-50 years of age. Generally, patients with NHL, breast or testicular cancer experience a lower, 2- to 15-fold, risk of developing s-AML. Epipodophyllotoxins appear to be the most important factor for s-AML in patients treated for testicular cancer. Doses of 2g/m2 or more are associated with an increased risk of s-AML and, with these high doses, a cumulative incidence of 2% 3% at 5 years is observed. Adjuvant cyclophosphomide, methobrexate, 5-Fu therapy in breast cancer patients does not appear to increase risk significantly as compared to the general population. The extent of the leukemogenic potential of anthracyclines remains to be defined. NHL patients receiving mechlorethamine, prednimustine or long-term maintenance therapy are also at an increased risk of s-AML. A considerably increased risk of developing AML, with a cumulative incidence of approximately 9% at 5 years, has been observed following allogenic bone marrow transplantation (ABMT) or peripheral stem cell transplantation (PBSCT) in patients with NHL. It is likely that the increased risk of s-AML/s-MDS following high-dose chemotherapy with ABMT or PBSCT is related to prior treatment rather than to high-dose chemotherapy itself. However, this issue remains to be conclusively addressed. s-AML or s-MDS rarely develops after allogenic bone marrow transplantation. s-AML and s-MDS increasingly represent a problem in modern cancer therapy because of better treatment strategies, which result in improved cure rates. Patients who receive chemotherapy must be informed about the potential risk of developing s-AML or s-MDS. Future studies should include a follow-up long enough to record the occurrence of all s-AML/s-MDS and all potential influencing factors reliably. These data would enable risk factors to be defined and risk/benefit analyses to be carried out, allowing the correct assessment of current and future therapy strategies.
Glucocorticoid receptors (GR) have been suggested to have prognostic significance in patients with CLL treated with chemotherapy containing glucocorticoid. In this study, the GR levels in 65 patients with advanced CLL and immunocytoma (clinical stages III and IV according to Rai) were determined by means of a whole cell assay. The median GR-level was 1,920 bs/c with a range from 0 to 9591. The patients were subsequently treated according to a prospective, randomized trial with either a combination of chlorambucil and prednisolone, or with prednimustine. No significant difference in receptor levels was found between responders (median = 1940 bs/c; n = 47) and nonresponders (median = 1950 bs/c; n = 14). To assess the influence of receptor content on prognosis we have analyzed the relationship between GR content and survival time and duration of response. There was no significant difference in duration of response and in survival between those patients with high (greater than 1920 bs/c) and those with low GR levels (less than 1920 bs/c) (log-rank test). Our data suggest that determination of GR provides no reliable indicator for clinical response to regimens with glucocorticoid as a component in patients with CLL and immunocytoma.
Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of disorders which can either be classified according to their biology, represented by corresponding counterparts of normal lymphocyte development as in the Kiel classification, or according to their clinical course, used in the Working Formulation. The recently proposed Revised European-American Lymphoma (R.E.A.L.) classification may unify both aspects and facilitate the comparability of international studies. Besides histology, the extent of disease still comprises the major determinant of therapy. In high-grade lymphomas combination chemotherapy with cyclophosphamide, hydroxydaunorubin, vincristine and prednisone (CHOP) represents the treatment of first choice, and may be restricted to 3-4 cycles in patients with limited stages of the disease when followed by involved field radiotherapy. In more extended, bulky stage II to IV disease, treatment must be extended to six courses of CHOP and, potentially, additional irradiation. Even in advanced states of the disease, long-term remission and potential cure are achieved in 30-50% of cases. In low-grade lymphomas, most patients present with advanced stages III and IV for which chemotherapy can be applied with palliative intention only. Hence, a watch-and-wait approach still seems appropriate outside clinical investigations until the disease requires a therapeutic intervention. This consists preferentially of chemotherapy of moderate intensity such as cyclophosphamide, vincristine and prednisone (COP) or prednimustine and mitoxantrone (PmM). In responding patients, maintenance therapy with interferon-alpha is currently being explored and may result in prolongation of disease-free and, possibly also, overall survival. In both high- and low-grade lymphomas, intensification of therapy by myeloablative chemotherapy or combined chemoradiotherapy followed by autologous bone marrow transplantation (ABMT) or peripheral stem cell transplantation provides a promising and potentially curative prospective. In addition, new cytostatic agents such as the purine analogues--fludarabine, chlorodeoxyadenosine and deoxycoformycin--enlarge the therapeutic spectrum. More experimental approaches consist of the application of immunotoxins or radioisotypes, coupled to monoclonal antibodies directed against lymphoma-specific antigens. Overall, the substantial advances that have been achieved in the understanding of the biology and pathogenesis of malignant lymphomas, as well as the current achievements of therapy and the new promising perspectives, justify the hope that curative therapy can soon be offered to an increasing proportion of patients with NHL.
We have evaluated the clinico-pathological and therepeutical outcome of patients aged 70 and older with malignant lymphomas treated at a single institute over a 20-year period of time. Among the several studies evaluated, the most important is a prospective randomized study comparing a new regimen, VMP (VP 16, Mitoxantrone and Prednimustine) vs the goal standard CHOP in unfavorable non-Hodgkin's lymphoma (NHL), showing that CHOP is significantly better than VMP in terms of objective response rate, progression free and overall survival. Therefore CHOP remains the standard regimen also for patients of over 70 years of age and stage II--IV intermediate and high grade NHL.
Cultured cells with a high content of the extremely cysteine-rich protein metallothionein (MT) have previously been shown to exhibit resistance when exposed to otherwise lethal doses of cis-dichlorodiammineplatinum (cis-DDP), chlorambucil or prednimustine, and to have a significant proportion of intracellular drug associated with MT after such treatment. In order to study this protective mechanism in vivo, cells from a MT-rich variant of a murine fibroblast line resistant to cis-DDP and its parent sensitive line with only trace amounts of MT, were injected subcutaneously into nude mice (24 animals in each group), and tumour growth was compared during cis-DDP treatment. Animals in the treatment groups received 3 intravenous doses of either 4 mg/kg or 8 mg/kg of cis-DDP on day 12, 26 and 33 after inoculation of cells, whereas the control groups received saline. The 8 mg/kg dose produced an almost complete growth inhibition of the tumours derived from the parent cells, as well as from the MT-rich variant. However, following the injections with 4 mg/kg of cis-DDP, tumour volume was reduced by approximately 80% in tumours from the parent cells, whereas the tumours from MT-rich cells were almost completely resistant. This study provides for the first time evidence that metallothionein-conferred protection against cis-DDP toxicity also is mediated in tumours in vivo.
The activity of some alkylating agents widely used in clinical practice was studied by an in vitro antimetabolic assay, which evaluates the interference of drugs on the incorporation of 3H-thymidine and 3H-uridine in short-term cultures of human tumors. The effect of CCNU, chlorambucil, cisplatin, melphalan, prednimustine, procarbazine and the pro-active derivatives of cyclophosphamide and ifosfamide, 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, was tested on non-Hodgkin lymphomas, germ cell testicular tumors, breast and ovarian cancers. Similar effects were generally produced by the drugs on both DNA and RNA precursor incorporation, and the in vitro response rates were similar to those clinically obtained for the same tumor types by using the same drugs in monochemotherapy. The effects of different alkylating agents on the individual tumors were not significantly associated, except for the analogues 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, for which a significant agreement rate was observed. No evidence of acquired resistance to 4-hydroperoxycyclophosphamide and cisplatin after clinical treatment with the same drug was found in samples from ovarian cancer and non-Hodgkin lymphoma, but there was a definite trend in germ cell testicular tumors to lower sensitivity to cisplatin in previously treated patients.
One-hundred, twenty-eight patients with Hodgkin's disease in remission or who had failed a mechlorethamine, vincristine, procarbazine and prednisone (MOPP), a doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and/or lomustine, etoposide and prednimustine (CEP) regimens have been treated with a high-dose therapy (HDT) containing cyclophosphamide, etoposide, carmustine (CVB) and autologous bone marrow transplantation (ABMT). Forty patients were treated while they were in resistant or progressive disease states using alternating MOPP/ABVD protocol; 15 patients received ABMT in first relapse; 51 patients had a complete remission (CR) with first-line therapy but later relapsed and then received conventional salvage therapy; 16 achieved no response or progression ("resistant relapse" patients) and 35 responded partially or completely ("sensitive-relapse" patients). The other 22 patients received ABMT in remission. Following HDT, 56 patients (52.8%) achieved CR and 23 patients (21.6%) achieved a partial remission for an overall response rate of 74.4%. Sixteen patients failed to respond and died in progressive disease 1 to 10 months (median 6 months) after ABMT. High-dose therapy produced severe toxicity including vomiting (100%), mucositis (75%) and liver enzymes and alkaline phosphatase elevations (51%). There were 10 treatment-related deaths. A multivariate analysis identified poor performance status and resistant-relapse patients as very important adverse risk factors for survival immediately after ABMT. These results, while validating this procedure for inducing remissions in advanced highly-treated patients, at the same time confirm the need of employing this approach in first relapse or in second complete remission after standard therapy and before ABMT or, in first complete remission in very high risk Hodgkin's disease patients. Our experience in 15 very poor prognosis Hodgkin's disease patients transplanted in first CR demonstrated to be much significant.
This article described strategies that can be used to reduce the carcinogenic risk of cytostatic chemotherapy and summarizes our recent experimental results. Reduction of neoplasms caused by the carcinogenic potency inherent in cytostatic agents can be obtained. (A) by chemical modifications such as: (1) exchanging a chlorine atom in N, N'-bis-(2-chloroethyl)-N-nitrosourea (BCNU) in the chloroethyl group at N'-position for a hydroxyl group to form the less carcinogenic analog N-(2-chloroethyl)-N'-(2-hydroxyethyl)-N-nitrosourea (HECNU); (2) linking chlorambucil to the steroid prednisolone to obtain a conjugate (prednimustine) with distinctly lower carcinogenic potential than chlorambucil; (3) progressive ring halogenation of phenyl-triazenes to generate agents with decreased long-term toxic risk; (B) by replacing cyclophosphamide within the carcinogenic drug combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) by vincristine to form the combination VMF which has no detectable carcinogenic potential; (C) by coadministration of cyclophosphamide and mesna to achieve a dose-related reduction of cyclophosphamide-induced urinary bladder carcinomas; (D) by administration of dinaline, a compound which reduces the spontaneous incidence of malignant tumors in rats. These examples demonstrate that the carcinogenic risk of single agents and drug combinations used for antineoplastic chemotherapy has successfully been reduced, as assessed in long-term bioassays. Such strategies should be considered in the treatment of patients with long life expectancy following cytotoxic chemotherapy.
The effects on T-lymphoma cells of the antineoplastic drugs Ara-C, cisplatin, vinblastine, chlorambucil and prednimustine were studied by microcalorimetry and a conventional viability assay. The heat production rate for cells was measured immediately after drug treatment and was compared with the change in cell concentration during the following generation time. The results of the microcalorimetric observations were correlated with cell death. Such correlations varied considerably for the different drugs, in particular between chlorambucil and the other drugs investigated.
The clinical course of two patients with prolymphocytic leukemia of the suppressor T-cell phenotype is presented. Diagnosis was established by specific monoclonal antibody tests, cytochemical, ultrastructural and cytogenetic studies. The bone marrow showed a diffuse infiltration with medium sized lymphocytes displaying a prominent nucleolus. Both patients presented with pronounced splenomegaly, diffuse lymphnode involvement, leukocytosis, thrombocytopenia and anemia. One of them was refractory to chemotherapy using CHOP, Asparaginase, IMVP16, and irradiation to the spleen. He benefited from prednimustin and repeated leukaphereses, without reaching complete remission (C.R.). The second patient achieved a C.R. of 4 months duration with CHOP-Bleomycin. Survival was 16 and 11 months respectively.
Mitoxantrone is similar to Adriblastin in its mechanism of action and antitumor activity. Objective remissions were obtained in 20-30% pretreated patients and in 23-44% of untreated patients by single-drug treatment of patients suffering from metastatic breast cancer. The objective response rates to Mitoxantrone in combination with CTX, 5-FU, MTX, VCR, MMC. Prednimustine or Vindesine were 16-46% in treatment and 38-89% in primary treatment. Randomized studies comparing Mitoxantrone with Adriblastin in single-drug and combination treatment did not show any significant differences in efficacy. However, Mitoxantrone was significantly less toxic. Remission rates of between 24 and 54% were achieved by single-drug treatment in pretreated patients suffering from non-Hodgkin lymphoma. Mitoxantrone appears to be active in ovarian cancer, lung cancer and hepatocellular carcinoma.
Results of the first randomized trial of the National Prostatic Cancer Project (NPCP) revealed an advantage for cytoxan and 5-FU over standard therapy in hormonally resistant stage D prostate carcinoma. A subsequent trial for patients previously irradiated, receiving the less myelosuppressive agents estracyt or streptozotocin also revealed an advantage over standard therapy. Other completed randomized trials have revealed activity for prednimustine and DTIC. Trials underway for newly diagnosed stage D disease or for stage D disease clinically stable to diethylstilbestrol (DES) show promising activity for cytoxan and DES combined. Current randomized trials in advanced disease are comparing methyl CCNU and hydroxyurea wih cytoxan, and estracyt or vincristine alone or in combination. Chemotherapy in earlier staged patients as adjuvants to definitive surgery or irradiation is underway in two trials, comparing the effects of cytoxan or estracyt as long-term therapies with no additional treatment.