The role of glutathione in the biological effects of cyclophosphamide (CP) was evaluated by investigating the following: effect of CP on hepatic glutathione levels; relationship between hepatic glutathione depletion (repletion) and the binding of [chloroethyl-3H]CP and [4-14C]CP to hepatic macromolecules; effects of interaction between CP (or acrolein) and diethyl maleate (a classical glutathione depletor), and/or between CP and cysteine on the binding of labeled CP to hepatic macromolecules, on the induction of hematuria, on the content of hepatic cytochrome P-450, on weight gain in rats, on survival in mice, and on the chemotherapeutic efficacy of CP against Walker 256 carcinoma in rats. CP and acrolein produced dose-dependent depletion of hepatic glutathione in mice, whereas phosphoramide mustard was at least one order of magnitude less effective. Acrolein caused death in mice; CP became covalently bound to hepatic macromolecules, prevented weight gain in rats, and produced hematuria and depression of hepatic cytochrome P-450 in vivo. These effects of CP (or acrolein) were enhanced by diethyl maleate but partially blocked by cysteine. On the other hand, reduction in the volume of Walker 256 carcinoma in rats by CP was not antagonized by cysteine. All these investigations point to the following conclusions: (a) acrolein produced during the metabolism of CP binds to proteins and, by doing so may denature these proteins; and (b) acrolein in vivo preferentially reacts with glutathione, and sulfhydryl-containing compounds may protect against acrolein toxicity and at the same time not interfere with the chemotherapeutic activity of CP.

https://cancerres.aacrjournals.org/content/canres/41/9_Part_1/3584.full.pdf

Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide.

Fifty-three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C-V-P). Complete remissions occurred in 68% with CVP and 48% with C-V-P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C-V-P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C-V-P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C-V-P in patients with nodular lymphoma. However, in patients with diffuse lymphocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197801%2941%3A1%3C23%3A%3AAID-CNCR2820410106%3E3.0.CO%3B2-Y

Combination versus successive single agent chemotherapy in lymphocytic lymphoma

A multiplicity of antineoplastic agents are active in the treatment of non-Hodgkin's lymphomas. In addition to a high order of responsiveness following single drug therapy, combination chemotherapy is usually even more efficacious in inducing complete remissions. The utility of the Rappaport classification for clinicians lies primarily in its ability to categorize patients with non-Hodgkin's lymphoma into favorable and unfavorable prognostic groups. Favorable histology lymphomas include the nodular poorly differentiated lymphocytic, mixed histiocytic lymphocytic and diffuse well-differentiated lymphoma. Since the natural history of these diseases is quite long, it is difficult to evaluate the impact of chemotherapy on survival. Thus, disease-free survival appears to be the more useful parameter in the evaluation of any new program. It is difficult to demonstrate an advantage for aggressive therapy in the treatment of favorable histology lymphomas. Prospective trials have not provided evidence to indicate that more intensive therapy will result in improved survival. In the unfavorable histology lymphomas such as diffuse histiocytic lymphoma and Burkitt's lymphoma, the results of combination chemotherapy are more dramatic and appear to have resulted in long-term disease-free survival. A significant fraction of these patients are probably cured as a result of this treatment. Effective regimens include the C-MOPP Program and BACOP both of which have resulted in approximately 50% complete remission rate with 30 to 40% disease-free long-term control. The demonstration that high dose methotrexate with citrovorum factor rescue is capable of achieving responses in unfavorable histology lymphoma that is refractory to previous therapy has resulted in its inclusion with BACOP in the primary management of these patients. In addition, high dose methotrexate is capable of entering the cerebrospinal fluid in concentrations that are cytotoxic to tumor cells, thus providing a potential prophylaxis against central nervous system involvement as well as nonmarow suppressive therapy for systemic disease. Using this regimen, the complete remission rate is approximately 75% in patients with unfavorable histology lymphoma and at the present time only one out of 30 patients has relapsed in the central nervous system.

Chemotherapy of the non-Hodgkin's lymphomas.

Response and survival were analyzed in 97 patients with NLPD (Nodular Lymphocytic Poorly Differentiated Lymphoma) and 77 with DLPD (Diffuse Lymphocytic Poorly Differentiated) treated by intensive versus moderate chemotherapy regimens. The complete and overall response rate in NLPD of 47% and 81% was significantly superior to 25% and 59% obtained in DLPD. The estimated two year survival of 83% in NLPD was also significantly superior to 47% two year survivorship of DLPD (p less than .001). The chemotherapy responsiveness had a significantly favorable effect on DLPD survivorship with two year survivals of 84% for CR, 58% for PR and 17% for PD. In NLPD the effect of chemotherapy responsiveness on survival was less striking (CR 91%, PR 85%, and PD 72% surviving two years). The data, in our opinion, confirm the rationale for the use of aggressive multiple agent chemotherapy regimens in DLPD where achievement of compelte response appears to be the single most important factor in improving survivorship. On the other hand NLPD, with excellent survival rates which appear to be only partially dependent on chemotherapy responsiveness might serve as an ideal model for moderate intensity or single agent chemotherapy trials.

Survival of nodular versus diffuse pattern lymphocytic poorly differentiated lymphoma.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for indolent non-Hodgkin's lymphoma (NHL), predominantly follicular lymphoma, is based on 108 scientific reports including 31 randomised studies, 38 prospective studies and 18 retrospective studies. These studies involve 8,699 patients. The conclusions reached can be summarized into the following points: In initially localized disease-- The addition of chemotherapy to radiotherapy as primary treatment has not convincingly prolonged remission duration or survival. In initially advanced disease-- Alkylating agents are useful palliative treatment options which can result in improved well-being for most patients, often for long periods. Combinations of chemotherapy have not convincingly resulted in more or longer remissions. There is no proof that initial combination chemotherapy will prolong survival in comparison with single drugs. The addition of interferon to initial combination chemotherapy may increase the response rate, significantly prolong remission duration, but prolonged survival has not been unequivocally proven. In the absence of disease-related symptoms, treatment can safely be deferred. For patients with relapsed lymphoma-- Patients may repeatedly respond to alkylating agents or combinations containing an alkylating agent, although the proportion responding decreases with each relapse. Patients relapsing after or who are refractory to treatment with alkylating agents often respond to treatment with combinations containing an anthracycline. Responses are also often seen in patients treated with purine analogues alone or in combination with other drugs. High dose chemotherapy followed by autologous or allogeneic reestablishment of bone marrow function can induce long-term remissions but it is not proven whether they are more frequent or of longer duration than with conventionally dosed therapy. The impact of the novel treatment strategies including high-dose therapy on overall survival is still uncertain. A monoclonal antibody, rituximab, is a new active substance for patients with relapsed lymphoma. It can induce remissions also in chemoresistant patients.

https://www.tandfonline.com/doi/pdf/10.1080/02841860118520

A systematic overview of chemotherapy effects in indolent non-Hodgkin's lymphoma.

The Eastern Cooperative Oncology Group has studied 113 patients with generalized progressive malignant lymphomas in a randomized clinical trial. Pathologic diagnosis was subclassified by cell type and nodal pattern by The Pathology Panel for Lymphome Clinical Trials. Patients were randomly assigned treatment with either cyclophosphamide (C), vincristine (O), and prednisone (P) (COP) or CO without prednisone. Initial treatment was given for 8 weeks and further randomization of responders to observation or additional chemotherapy was carried out. A significant difference in complete remission rate between treatments was shown: with COP, 43%, and with CO, 17%, indicating an important role for prednisone in inducing CR. COP was also associated with longer remission durations and improved survival. Complete remission following initial chemotherapy is also associated with longer duration of disease-free time and survival. The initial pathologic cell types and nodal pattern also strongly influence survival. Extended "maintainence" CO treatment improved disease-free remission duration, but not survival.

Ross L. Prentice

Papers

Combination chemotherapy of the malignant lymphomas: a controlled clinical trial.