Treatment of Low-grade Non-Hodgkin’s Lymphomas at Advanced Stage
Cyclophosphamide plus Somatostatin, Bromocriptin, Retinoids, Melatonin and ACTH in the Treatment of Low-grade Non-Hodgkin’s Lymphomas at Advanced Stage: Results of a Phase II Trial (full pdf)
Purpose
Somatostatin, prolactin, retinoids, melatonin and ACTH have been shown to influence the lymphatic growth, and the action of the Cyclophosphamide in lymphoproliferative disorders is well known. This provided the rationale to conduct, in patients with low-grade non-Hodgkin‘s lymphomas (NHL), a Phase II Trial of a combined association of Cyclophosphamide, Somatostatin, Bromocriptin, Retinoids, Melatonin and ACTH.
Patients and methods
Twenty patients with a diagnosis of low-grade NHL, stage III or IV, were included in this study. Patients received for one month the following treatment: Cyclophosphamide, Somatostatin, Bromocriptin, Retinoids, Melatonin, and ACTH. The therapy was continued for two additional months in patients with stable or responding disease. Afler three months, the responding patients continued the therapy for three months and more.
Results
Twenty patients where assessable for toxicity and response; 70% (14 of 20 patients; 95% confidence interval [CI], 50% to 90%) had a partial response; 20% (4 of 20) had stable disease, and 10% (2 of 20) progressed on therapy. Going on with the treatment, none of the 14 patients with partial response had a disease progression (average follow-up time of 21 months, range, 7 to 25), and 50% of these patients had a complete response; among 4 patients with stable disease, 25% (1 of 4) had a partial response and 75% (3 of 4) progressed on therapy (mean time to progression [TTP] 14.3 months, range, 7 to 21). The toxicity was very mild, the most common side effects being drowsiness, diarrhea and hyperglycemia.
Conclusions
The association of Cyclophosphamide, Somatostatin, Bromocriptin, Retinoids, Melatonin, and ACTH is well tolerated and effective in treatment of low-grade NHL at advanced stage.
INTRODUCTION
Recently, several new agents bave been shown to inhibit the lymphatic growth. Among these, especially the ones without bone marrow toxicity, as Somatostatin, aroused great interest for the possibility to be used with myelosuppressive chemotherapy regimens without determining a further myelosuppression.
An association like this was first reported in 1979 by Di Bella et al. [1], who reported to have used the cyclophosphamide together with somatostatin, bromocriptin, retinoids, melatonin and ACTH in several cancers, including non Hodgkin’s lymphomas (NHL).
On the basis of this pharmacological association and, in particular, of the use of somatostatin and bromocriptin, there is the assumption, formulated by Di Bella, that growth hormone (GH) and prolactin are involved in neoplastic growth. Such an assumption, in acute lymphoblastic leukernia, was formulated by other authors also, in the same period, even if just for GH [2]. Subsequently, Payan et al demonstrated that somatostatin inhibits the growth of cultured primary human liymphocytes and Molt-4 cells [3]; Nakamura et al identified somatostatin receptors on the membrane of several lymphoid cell lines [4] and Hiruma et al found somatostatin receptors on primary leukemia human cells [5] Furthermore, most of lymphomatous lesions were shown to be identifiable with radiolabelled somatostatin analogs. [6 - 7 - 8 - 9 - 10]
In agreement with the above mentioned results, Witzig et al in 1995 [11] reported that octreotide, a somatostatin analog, shows activity in patients with low-grade NHL. The influence on lymphatic growth has been also demonstrated for prolactin, retinoids, melatonin and ACTH. The prolactin has been shown to stimulate the growth of experimental lymphomas both in vivo and in vitro, [12] and prolactin receptors are present on the surface of normal and neoplastic lymphoid cells.[13 - 14 - 15 - 16] Matera et al demonstrated that prolactin is an autocrine growth factor for a human leukemic cell line, [17] and Hooghe et al returned on the hypothesis, already mantained by Di Bella, that prolactin and GH have an important role in lymphoma and leukemia [18]. In hematology, the antitumor effect of retinoids is based on several evidences reporting the effect of trans-retinoic acid in promyelocytic leukemia, [19 - 20] T-cell lymphoma localized to the skin [21- 22 - 23 - 24 - 25 - 26] and also in B- cell lymphomas. [27 - 28 - 29]
Melatonin inhibits thymidine incorporation in normal lymphocytes and in lymphoblastoid cell lines [30] and inhibits the proliferative response to mitogens. [31 - 32] In addition, melatonin carries on an antimyelodysplastic action [33] and decreases the bone marrow toxicity of chemotherapeutic agents. [34] T and B lymphocytes have been shown to express the ACTH receptor on their cell surface [35]; moreover, ACTH depresses the lymphocyte blastogenesis in response to phytoemagglutinin and concanavallin A [36] and has a role in the modulation of NK celi activity. [37]
These studies, together with the well known action of cyclophosphamide, provided the rationale to design a phase II study to determine if a combined therapy based on cyclophosphamide, somatostatin. brinocriptin, retinoids, melatonin and ACTH has activity in patients with low-grade NHL at advanced stage.
PATIENTS AND METHODS
Patient Selection
Patients were selected on the basis of a clinical diagnosis of low-grade NHL, stage III or IV. Additional criteria of selection weree: a performance status (PS) between 0 and 3, according to the Eastern Cooperative Oncology Group, and the presence of bidimensionally measurable lesion, as demonstrated by physical examination, chest radiograph, ecotomography, or computed tomographic or magnetic resonance scans. Patients who had received other treatment were included in this study only upon evidence that the previous treatment was not effective.
Patients receiving chemotherapy were asked to suspend any drug admnistration for at least 15 days prior to the beginning of the combined therapy.
Toxicity was evaluated using criteria developed by the World Health Organization.
Treatment
Patients received a combination of cyclophosphamide, somatostatin, bromocriptin, retinoids, melatonin and ACTH. Cyclophosphamide was given orally at a dose of 75 mg/day (50 mg at 2 pm and 25 mg at 9 pm). Somatostatin was administreted subcutaneously (SQ) at a dose or 1.5 mg/day within 8 hours using a syringe pump. The administration started at least three hours after dinner and those patients who were psychologically unable to accept this type of administration received single SQ injection of octreotide (0,5 mg/day) three hours after dinner. Bromocriptin was given orally at a dose of 2.5 mg/day (1.25 mg at 2 pm and at 9 pm). Retinods: all-trans retinoic acid, vitamin A palmitate and beta-carotene were administered orally, at 8 am, in 5 ml of vitamin E, respectively at doses of 5 mg, 5000 UI and 20 mg/day. Melatonin was given orally at a dose of 20 mg/day (10 mg at 2 pm and at 9 pm). ACTH was administered intermuscularly at a dose of 1 mg/week.
All the patients were treated for at least one month. At the end of this period, those who had stable disease or partial response received additional two months of treatment, and the ones who responded after three months were treated for three months and more.
Criteria for Response
Complete response or remission was defined as the complete regression of all the measurable lymphomatous lesions. Partial response was defined as a ≥ 50% reduction in the sum of the products of the two diameters (the longest diameter and the one perpendicular to it) of one or more lesions lasting at least 4 weeks.
Progression was defined by the increase in size of the pre-existing lesions of at least 25%, the onset of new lesions or the increase of spleen or liver of at least 2 centimeters due to lymphoma.
Those patients who could not be clearly placed in any of the described categories were defined in stable condition. The assessment of the response was made after 1 month from the beginning of the treatment. Such an assessment was carried on after another 2 months and, later, every 3 months in patients going on with the treatment.
RESULTS
All the 20 patients were evaluable for the toxicity. The must common side effects were gastrointestinal signs. Twenty-five percent of the cases had diarrhea first grade (2 patients) or second grade (3 patients); 20% (4 patients) had nausea or grade 1 vomit, and 5 patients had loss of appetite and anorexia. These side effects did not require suspension of the therapy but only all adjustment of the dose of somatostatin. Drowsiness was observed in 20% (4 of 20) of patients, and required an adjustment of the daily schedule of administration of melatonin (20 mg/day were subdivided into three doses, instead of two, one of which at bedtime).
[ Di Bella Method - Di Bella Giuseppe: Reply to the statements (toxicity and so on) of Prof. Serravezza ]{jumi [jumi/Player.html]}
Twenty five percent of patients (5 of 20) had grade I hyperglycemia (≤ 160/dL) and 20% (4 of 20) showed ankle and/or face edema; in both these cases the dose of ACTH was reduced to 0.5 mg/week.
DISCUSSION
The low-grade NHL at advanced stage are stili incurable disease, whose treatment, just in consequence of these therapeutic limits, is very disputed, coexisting single agent chemotherapy, combination chemotherapy, combined radiotherapy-chemotherapy, high-dose intensive chemotherapy with autologous bone marrow transplanation or autologous blood progenitor cell transplantation.
In this study we evaluated toxicity and efficacy of a regimen, known as Di Bella’s multitherapy (DBM), resulting by the association of a chemotherapeutic agent, the cyclophosphamide, with other non-myelosuppressive substances (somatostatin, bromocriptin, retinoids, melatonin and ACTH).
The results we obtained - seventy percent of partial responses after 1 month, fifty percent of which became complete responses going on with the treatment - have been really better than the ones described with single agent chemiotherapy with alkylants, with wiich Kimby et al. [38] described 36% of global response with complete response in 5% of 132 previously untreated patients, or than the ones described by Witzig et al with somatostatin as single agent (36% of partial) response in 28 previously treated and untreated patients). This demonstrates the therapeutic superiority of such a pharmacological association versus its single costituents.
Moreover, the activity of the regimen depended on the kind of previous therapy and on the TFT. We documented 100% of global response among the previously untreated patients, the patients in first relapse with TFT ≥ 6 months and the patients with TFT ≤ 1.5 months non-responding or progressed during interferon therapy.
This result, better than others obtained with widely used chemotherapy regimens [Kimby et al described 60% of global response with CHOP in 127 previously untreated patients with lowgrade NHL stage III and IV] [38], and the very good tolerance of DBM (all the patients carried on the treatment at home, going on with their normal activities) suggest further clinical trials using this regimen in NHL.
With regard to this, the recent availability of depot formulations of somatostatin may allow a better feasibility of this regimen, where the main discomfort was in the daily SQ injection of somatostatin, especially if done with syringe pump.
[1] Di Bella L, Rossi MT, Scalera O. - Perspectives in pineal functions. Prog Brain Res 1979;52:475-8;
[2] Rogers PC, Komp D, Rogol A, Sabio H. - Possible effects of growth hormone on development of acute lymphoblastic leukaemia. Lancet 1977;2:434-5;
[3] Payan DG, Hess CA, Goetzl EJ. - lnhibition by somatostatin of the proliferation of T-lymphocytes and Molt-4 lymphoblasts. Cell Immunol 1984;84:433-8;
[4] Nakarnura H, Koike T, Hiruma K, Sato T, Tomioka H, Yoshida S. - Identification of lymphoid cell lines bearing receptors for somatostatin. Immunology 1987;62:655-8;
[5] Hiruma K, Koike T, Nakamura H, Sumida T, Maeda T, Tomioka H, Yoshida S, Fujita T. - Somatostatin receptors on human lymphocytes and leukaemia cells. Immunology 1990;71:480-5;
[6] Krenning EP, Kwekkeboom DJ, Reubi JC, Van Hagen PM, van Eijck CH, Oei HY, Lamberts SW. - 111In-octreotide scintigrapby in oncology. Metabolism 1992;41 (9 Suppl 2):83-6;
[7] Reubi JC, Waser B, van Hagen M, Lamberts SW, Krenning EP, Gebbers JO, Laissue JA. - In vitro and in vivo detection of somatostatin receptors in human malignant lymphornas - Int J Canc 1992;50:895-900;
[8] Reubi JC, Waser 8, Horisberger U, Krenning E, Lamberts SW, Gebbers JO, Gersbach P, Laissue JA - In vitro autoradiographic and in vivo scintigraphic localisation of somatostatin receptors in human lymphatic tissue. Blood 1993; 82:2143-51;
[9] Bares R, Galonska P, Dempke W, Handt S, Bull U, Osieka R.- Somatostatin receptor scintigraphy in malignant lymphoma: first results and comparison with glucose rnetabolism measured by positron emission tomography. Horm Metab Res 1993;27:56-8;
[10] Rettenbacher L, Galvan O. - Differentiation between residual cancer and thymic hyperplasia in malignant non Hodgkin’s lymphoma with somatostatin receptor scintigraphy. Clin Nucl Med 1994;19:64-5;
[11] Witzig TE, Letendre L, Gerstner I, Schroeder O, Mailliard JA, Colon-Otero G, MarschKe RF, Windschill HE. - Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group Trial. J Clin Oncol 1995;13:2012-5;
[12] Friesen HG, Shiu RP, Elsholtz H, Simpson S, Hughes J. - Prolactin and growth hormone receptors. Ciba Found Symp 1982;90:263-78;
[13] Shiu RP, Elsholtz HP, Tanaka T, Friesen HG, Gout PW, Beer CT, Noble RL. - Receptor-mediated mitogenic action of prolactin in a rat lymphoma cell line. Endocrinology 1983; 113:159-65;
[14] O’Neal KD, Schwarz LA, Yu-Lee LY. - Prolactin receptor gene expression in lymphoid cells. Moll Cell Endocrinol 1991 ;82: 127-35;
[15] Hooghe R, Delhase M, Vergani P. Malur A. Hooghe-Peters EL. - Growth hormone and prolactin are paracrine growth and differentiation factors in the haemopoietic system. Immunol Today 1993; 14:212-214;
[16] Leite De Moraes MC, Touraine P, Gagnerault MC, Savino W, Kelly PA, Dardenne M. - Prolactin receptors and the immune system. Ann Endocrinol (Paris) 1995 ;56:567-70;
[17] Matera L, Cutufia M, Geuna M, Conlarini M. Buttiglieri S, Galin S, Fazzari A, Cavaliere C. - Prolactin is an autocrine growth factor for the Jurkat human T-leukemic cell line. J
Neuroimmunol 1997;79: 12-21;
[18] Hooghe R, Merchav S, Gaidano G, Naessens F, Matera L. - A role for growth hormone and prolactin in leukaemia and lymphoma? Cell Mol Life Sci 1998;54: 1095-101;
[19] Sacchi S, Russo D, Avvisati G, Dastoli G, Lazzarino M, Pelicci PG, Bonora MR, Visani G, Grassi C, Iacona I, Luzzi L, Vanzanelli P. - All-trans retinoic acid in haematological malignancies, an update. GER (Gruppo Ematologico Retinoidi). Haematologica 1997; 82:106-21;
[20] Kessler JF, Meyskens FL Jr, Levine N, Lynch PJ, Jones SE. - Treatment of cutaneous T-cell lymphoma (mycosis fungoides) with 13-cis-retinoic acid. Lancet 1983;I: 1345-7;
[21] Neely SM, Mehlmauer M, Feinstein DI. - The effect of isotretinoin in six patients with cutaneous T-cell lymphoma. Arch lntern Med 1987;147:529-31;
[22] Mahrle G, Thiele B. - Retinoids in cutaneous T cell lymphomas. Dermatologica 1987; 175 (Suppl I): 145-50;
[23] Zachariae H, Thestrup-Pedersen K. - Interferon alpha and etretinate combination treatment of cutaneous T-cell lymphoma. J Invest Dermatol 1990:95(6 Suppl):206-8;
[24] Chow JM, Cheng AL, Su IJ, Wang CH. - 13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-1 lymphoma. Cancer 1991;67:2490-4;
[25] Su IJ, Cheng AL, Tsai TF, Lay JD. - Retinoic acid-induced apoptosis and regression of a refractory Epstein-Barr virus containing T cell lymphoma expressing multidrug-resistance phenotypes. Br J Haematol 1993; 85: 826-8;
[26] Chou WC, Su IJ, Tien HF, Liang DC, Wang CH, Chang YC, Cheng AL. - Clinicopathologic, cytogenetic, and molecular studies of 13 Chinese patients with Ki-1 anaplastic large cell lymphoma. Special emphasis in the tumor response to 13-cis retinoic acid. Cancer 1996;78: 1805-12;
[27] Turley JM, Funakoshi S, Ruscetti FW, Kasper J, Murphy WJ, Longo DL, Birchenall-Roberts MC. - Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor beta. Cell Growth Differ 1995; 6:655-63;
[29] Sundaresan A, Claypool K, Mehta K, Lopez-Berestein G, Cabanillas F, Ford RJ Jr. - Retinoid-mediated inhibition of cell growth with stimulation of apoptosis in aggressive B-cell lymphomas. Cell Growth Differ 1997;8: 107 1-82;
[30]
[31] Konakchieva R, Kyurkchiev S, Kehayov I, Taushanova P, Kanchev L. - Selective effect of methoxyindoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells. J Neuroimmunol. 1995 Dec 31;63(2):125-32;
[38] Kimby E, Björkholm M, Gahrton G, Glimelius B, Hagberg H, Johansson B, Johansson H, Juliusson G, Järnmark M, Löfvenberg E, et al. - Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin's lymphomas: a randomized trial from the Lymphoma Group of Central Sweden. Ann Oncol. 1994;5 Suppl 2:67-71.