Europ. J. CancerVol. 13, pp. 411-414. Pergamon Press 1977. Printed in Great Britain
Combination Chemotherapy with Adriamycine, VM 26, Cyclophosphamide and Predmsone xn Lymphosarcoma and Reticulosarcoma Stage III and IV J. L. MISSET, P. POUILLART, D. BELPOM.ME, L. S C H W A R Z E N B E R G , M. D E L G A D O , M. GIL, C. JASMIN, M. H A Y A T and G. M A T H E Institut de Canc/rologie et d'Immunog/ngtique (INSERM)* and Service d'Hdmatologie de l'Institut Gustave Roussyt
Abstract~Th9 work presents the results obtained on 34 patients with disseminated lymphosarcoma and reticulosarcoma (Stage III and IV) with a eydic combination of chemotherapy which combines adriamydn, epipodophyllotoxine (VM 26), cyclophosphamide, and prednisone. The complete remission rate is 56 % of the patients who entered the trial, the response rate is 85 ~o. Tolerance of the regimen is good. The study also demonstrated the prognostic value of the new histocytological classification of lymphosarcomas proposed by W.H.O.
INTRODUCTION
THERAPEUTIC management of lymphosarcoma and rcticulosarcoma has been modified in recent years under the influence of (a) better knowledge of the disease which has shown that most cases arc already disseminated at the time of diagnosis [I-3] and arc therefore, to bc treated by chemotherapy, (b) discovery of new drugs which proved efficientin the treatment of these tumors, particularly V M 26 or dirncthyl cpipodophyllotoxin [I, 4] and adHamycin [5--7]. W c present a preliminary study of a new combination of adHamycin, V M 26, cyclophosphamidc and prcdnisonc in the treatment of disseminated lymphosarcoma and reticulosarcoma, stage III and IV. This combination is based on the activityof each drug used alone [I, 4-8] and on the synchronization and potentiation obtained by sequential administration of adriamycine, V M 26, cyclophosphanalde [9, 10]. It must bc emphasized that some patientsin the trial had already been treated by other "14-16 Avenue Paul Vaillant Couturier, 94800Villejuif,France. 1"16 bis Avenue Paul Vaillant Couturier, 94800Villejuif,France. 411
chemotherapeutic regimens and/or radiotherapy. These patients can only "make the results appear worse as compared to a population of patients in the first perceptible phase of the disease. PATIENTS AND METHODS
Thirty-four patients (22 males and 12 females) aged 5 to 67 who received AVmCP regimen, as described in Table 2. All had lymphosarcoma or reticulosarcoma stage III or IV. Twenty-one percent of the patients were in the first perceptible phase of the disease; 11 had relapsed once, and two were in the third perceptible phase. The patients were classified according to the new histological classification of lymphosarcomas and reticnlosarcomas proposed by W.H.O. [ll]. Seven patients had "immunoblastic lymphosarcoma" stage III and IV; 4 had "lymphoblastic lymphosarcoma", 6 had "prolymphoeyrie lymphosarcoma", among which were the two "nodular lymphosarcoma" of the series; 5 had reticulosarcoma, two of which were bone primary localisation with lymph-node or pulmonary matastases. 12 patients could not be classified because of the lack of cytologic examination of the lymph nodes.
412
07. L. Misset et al. Table I.
Treatmentof lymphosarcoma and reticulosarcoma stage 11land IV by A VMCP results C.R.
I.R.
50%
Failure
Total
Jmmunoblastic
2
3
3
7
Lymphoblastic
4
0
0
4
Prolymphoeytic
4
2
0
6
Reticulosarcoma
3
2
0
5
Unclassified
6
3
3
12
Tot~
lO \ '~9%
16x~6%
5~5%
34
Table 2. Protocolof treatment of lymphosarcoma and reticulosarcoma stages III and IV with adriamycine, VM 26, cyclophosphamide and prednisone Day Day Day Day
1 2 3-4 3--4-5-6-7
Table 3.
Adriamycine V M 26 (epipodophyllotoxin) Cyclophosphamide Prednisone
Toxicity
Leucopenia 1.500 WBC
. . . . . .
14
Thromboeytopenia 50.000] ]
. . . . . .
4
Regressive infection . . . . . Lethal infection . . . . . . . . Alopecla . . . . . . . . Nausea .. . . . . . . Heart failure . . . . . . Asthenia .. . . . . . . Severe diabetes .. . . . . Haemorrhagic cystitis Pseudo anaphylactic acute intolerance Renal failure . . . . . . . o ,
. . .
. . . .
. . . .
, ,
to V M 26 . . .
2 0 29 2 1
0 1 1 1
2
Chemotherapeutic regimen is described in Table 2. Each cycle combines, on day I i.v. injection of adriamycine 40 mg/m 2, on day 2 V M 26 60 mg/m 2 by intraveinous infusions, on day 3 and 4, cyclophosphamide 300 mg]m 2 i.m. or i.v., on days 3-7, prednisone given orally at the dose of 40 mg/m 2. The interval between two cycles, necessary to hematologic and immunologic restoration is 15-21 days. Eight such cycles are given in about six months.
(1) Toxicity Toxicity is described in Table 3. It is mild or moderate. Leukopenia under 1500 white blood cells was observed in 14 cases with only
40"mg/m 2 60"rng/m a 300~mg/m 2 40~mg/m ~
I.V. I.V. I.M. P.O.
two cases of regressive infection. Thrombocytopenia under 50,000 platelets occurred in 4 cases. No hemorrhagic complication was observed. Alopecia was prae~ically constant. Nausea was mild. Other complications were rare. (2) Anti-tumor effect The overall response rate is very high. 85%, with a complete remission rate of 56%. Although the number of patients is still too small to draw definite conclusions, it seems that the various histocytological types have different sensitivity to the regimen. Two patients with immunoblastic lymphosarcoma failed to respond to the regimen, while the four patients with lymphoblastic lymphosarcoma and the four patients with prolymphocytic lymphosarcoma in the first perceptible phase underwent complete remission. Moreover when complete remission was achieved it never lasted more than six months in immunoblastic lymphosarcoma while the duration of remission was over one year in all patients but one with lymphoblastic or prolymhocytic lymphosarcoma. The remissions were obtained very rapidly, or often after the first cycle and all patients who underwent complete remission had achieved t after three cycles. Figures 1 and 2 are tentative survival curves of all patients in the first perceptible phase
Combination Chemotherapy in Lymphosarcoma and Reticulosarcoma
(Fig. 1) and of patients who underwent complete remission (Fig. 2). They seem to us very encouraging although they cannot yet be considered as significant.
DISCUSSION We present a therapeutic regimen which shows a very high degree of efficacy in lymphosarcoma and reticulosarcoma. The drugs were
chosen because of their maximal efficacy for m;n;ma], toxicity. Drugs with the high degree of toxicity like nitrosoureas were excluded from the regimen and tolerance of the regimen was remarkably good, at least on patients who had not been previously irradiated. Although further study has to be done with a greater number of patients and longer time of observation, it seems that the classification proposed by W.H.O. for lymphosarcoma is of significant prognostic value.
100%
ioo~.
50*/.
50%
•
I~on~h$ J
Fig. 1. Survival curve of 21 patients with lymphosareoma and reticulum cell sarcoma. Stage III and IV treated with A VmCP in first perceptible phase.
413
2
".
4
~
6
7
8
9
JO
II
2. 3. 4.
5.
6. 7. 8.
9.
13
Fig. 2. Survival curve of patients in C.R. with ~'mphosarcoma and retirulo-sarcoma. Stage III and I V treated with AD3f, VM 26, CP~I and PDN (N = 19 patients).
REFERENCES 1.
IZ
EORTC CLINmAL SCREE~,nNOGROUP, Clinical screening of 4 de-methylepipodophyllotoxin fl-D. Thenilidene glucoside (VM 26) in malignant lymphomas and solid tumors. Brit. reed. J. 2, 744 (1972). R.E. JOHXSON,Patterns of involvement in non-Hodgkin's lymphomas and the implications for treatment decision making. Brit. J. Cancer. In press (1976). G. MATH~, Les h6matosarcomes non hodgkiniens. Introduction, classification et inventaire topographique pr6th6rapeutique. Rev. Prat. (Paris). 26, 1367 (1976). O.M.*TH~, L. SCa'~'aa~ZE~,n3ERO,P. POUInnART, R. WEL'~R, R. OnDH.~i, C. JASMIN, C. ROSENFELD, M. HAYAT, M. SCHNEIDER, J. L. AMIEL, B. CEOA~¢,, M. ]VIUSSET-STE~SCOand F. DE VASSAL,Essai de traitement de divers h6matosarcomes par le 4--d6methyl-epipodophyllotoxine D. th6nyhd~ne glucoside (VM 26 ou EPT). Nouv. Presse mgd. 3, 447 (1974). G. BONADO~,~A, S. MONFARmm, M. DE LENA, F. FOSSATI-BELLANI and G. BERETTA, Phase I and preliminary phase II. Evolution of adriamycin. Cancer Res. 30, 2572 (1970). J . A . GOTTLIEB,J. u. Gurr~a~t~, K. B. McG~Dv-zj, V. RODRIOUEZand E. FFa~I III, Chemotherapy of malignant lymphoma with adriamycin. Cancer Res. 33, 3024 (1973). S. JONES, D. A. ROSE.'~rRO, H. S. K.~LAN, M. K.~ZN and R. D o t a r d , Non-Hodgkin's lymphoma, single agent chemotherapy. Cancer (Philad.) 30, 31 (1972). G. MATH~, O. SCmVEISGUTH,G. BRUL#, ~[. SCHNEIDER,J. L. AMIEL, L. SCnWARZE.WBEROand A. CATT,~, Essai de traitement par la cyclophosphamide de la leucfimie aign~ lymphoide et du lymphosarcome. Presse rMd. 71,402 (1963). P. POUILLA~T, L. SCn~'AmZENBERO, J. L. AMIEL, G. MATHI~., P. HUGUENIN, P. MO~N, A. BARON,C. LAPARl~Sand R. PARROT.Potentiation of drugs using sequential chemotherapy against disseminated breast, bronchia| and central nervous system solid tumors. In Chemotherapy (Edited by K. Hellman and T. A. Conners) Vol. 8, p. 387. Plenum, New York (1967).
414
07. L. Misset et al. 10.
11.
P. POUILLAltT, L. SCHWASZEm3ERG,G. bIATH~., M. Scm~xDE~., C. JASMm, M. HAYAT, 1~. WEINER, F. DE VASSAL,J. L. ,~ur~L, H. P. BEvxR and S. FAJBXSowxc,z, Essai clinique de combinaisons chimiothSmpiques bas~'es sur la notion de tentative de synchronisation ceilulalre. Administration premiere d'un antimitotique suivie de l'application de produit(s) cycle ou phase d,pendant(s). Nouv. Pressendd. 1, 1757 (1972). G. MATHg and H. R~PAPORT. Histocytological Typing of the Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues. Vol. 1. World Health Organization, Geneva (1976).
Combination Chemotherapy with Adriamycine, VM 26, Cyclophosphamide and Predmsone xn Lymphosarcoma and Reticulosarcoma Stage III and IV J. L. MISSET, P. POUILLART, D. BELPOM.ME, L. S C H W A R Z E N B E R G , M. D E L G A D O , M. GIL, C. JASMIN, M. H A Y A T and G. M A T H E Institut de Canc/rologie et d'Immunog/ngtique (INSERM)* and Service d'Hdmatologie de l'Institut Gustave Roussyt
Abstract~Th9 work presents the results obtained on 34 patients with disseminated lymphosarcoma and reticulosarcoma (Stage III and IV) with a eydic combination of chemotherapy which combines adriamydn, epipodophyllotoxine (VM 26), cyclophosphamide, and prednisone. The complete remission rate is 56 % of the patients who entered the trial, the response rate is 85 ~o. Tolerance of the regimen is good. The study also demonstrated the prognostic value of the new histocytological classification of lymphosarcomas proposed by W.H.O.
INTRODUCTION
THERAPEUTIC management of lymphosarcoma and rcticulosarcoma has been modified in recent years under the influence of (a) better knowledge of the disease which has shown that most cases arc already disseminated at the time of diagnosis [I-3] and arc therefore, to bc treated by chemotherapy, (b) discovery of new drugs which proved efficientin the treatment of these tumors, particularly V M 26 or dirncthyl cpipodophyllotoxin [I, 4] and adHamycin [5--7]. W c present a preliminary study of a new combination of adHamycin, V M 26, cyclophosphamidc and prcdnisonc in the treatment of disseminated lymphosarcoma and reticulosarcoma, stage III and IV. This combination is based on the activityof each drug used alone [I, 4-8] and on the synchronization and potentiation obtained by sequential administration of adriamycine, V M 26, cyclophosphanalde [9, 10]. It must bc emphasized that some patientsin the trial had already been treated by other "14-16 Avenue Paul Vaillant Couturier, 94800Villejuif,France. 1"16 bis Avenue Paul Vaillant Couturier, 94800Villejuif,France. 411
chemotherapeutic regimens and/or radiotherapy. These patients can only "make the results appear worse as compared to a population of patients in the first perceptible phase of the disease. PATIENTS AND METHODS
Thirty-four patients (22 males and 12 females) aged 5 to 67 who received AVmCP regimen, as described in Table 2. All had lymphosarcoma or reticulosarcoma stage III or IV. Twenty-one percent of the patients were in the first perceptible phase of the disease; 11 had relapsed once, and two were in the third perceptible phase. The patients were classified according to the new histological classification of lymphosarcomas and reticnlosarcomas proposed by W.H.O. [ll]. Seven patients had "immunoblastic lymphosarcoma" stage III and IV; 4 had "lymphoblastic lymphosarcoma", 6 had "prolymphoeyrie lymphosarcoma", among which were the two "nodular lymphosarcoma" of the series; 5 had reticulosarcoma, two of which were bone primary localisation with lymph-node or pulmonary matastases. 12 patients could not be classified because of the lack of cytologic examination of the lymph nodes.
412
07. L. Misset et al. Table I.
Treatmentof lymphosarcoma and reticulosarcoma stage 11land IV by A VMCP results C.R.
I.R.
50%
Failure
Total
Jmmunoblastic
2
3
3
7
Lymphoblastic
4
0
0
4
Prolymphoeytic
4
2
0
6
Reticulosarcoma
3
2
0
5
Unclassified
6
3
3
12
Tot~
lO \ '~9%
16x~6%
5~5%
34
Table 2. Protocolof treatment of lymphosarcoma and reticulosarcoma stages III and IV with adriamycine, VM 26, cyclophosphamide and prednisone Day Day Day Day
1 2 3-4 3--4-5-6-7
Table 3.
Adriamycine V M 26 (epipodophyllotoxin) Cyclophosphamide Prednisone
Toxicity
Leucopenia 1.500 WBC
. . . . . .
14
Thromboeytopenia 50.000] ]
. . . . . .
4
Regressive infection . . . . . Lethal infection . . . . . . . . Alopecla . . . . . . . . Nausea .. . . . . . . Heart failure . . . . . . Asthenia .. . . . . . . Severe diabetes .. . . . . Haemorrhagic cystitis Pseudo anaphylactic acute intolerance Renal failure . . . . . . . o ,
. . .
. . . .
. . . .
, ,
to V M 26 . . .
2 0 29 2 1
0 1 1 1
2
Chemotherapeutic regimen is described in Table 2. Each cycle combines, on day I i.v. injection of adriamycine 40 mg/m 2, on day 2 V M 26 60 mg/m 2 by intraveinous infusions, on day 3 and 4, cyclophosphamide 300 mg]m 2 i.m. or i.v., on days 3-7, prednisone given orally at the dose of 40 mg/m 2. The interval between two cycles, necessary to hematologic and immunologic restoration is 15-21 days. Eight such cycles are given in about six months.
(1) Toxicity Toxicity is described in Table 3. It is mild or moderate. Leukopenia under 1500 white blood cells was observed in 14 cases with only
40"mg/m 2 60"rng/m a 300~mg/m 2 40~mg/m ~
I.V. I.V. I.M. P.O.
two cases of regressive infection. Thrombocytopenia under 50,000 platelets occurred in 4 cases. No hemorrhagic complication was observed. Alopecia was prae~ically constant. Nausea was mild. Other complications were rare. (2) Anti-tumor effect The overall response rate is very high. 85%, with a complete remission rate of 56%. Although the number of patients is still too small to draw definite conclusions, it seems that the various histocytological types have different sensitivity to the regimen. Two patients with immunoblastic lymphosarcoma failed to respond to the regimen, while the four patients with lymphoblastic lymphosarcoma and the four patients with prolymphocytic lymphosarcoma in the first perceptible phase underwent complete remission. Moreover when complete remission was achieved it never lasted more than six months in immunoblastic lymphosarcoma while the duration of remission was over one year in all patients but one with lymphoblastic or prolymhocytic lymphosarcoma. The remissions were obtained very rapidly, or often after the first cycle and all patients who underwent complete remission had achieved t after three cycles. Figures 1 and 2 are tentative survival curves of all patients in the first perceptible phase
Combination Chemotherapy in Lymphosarcoma and Reticulosarcoma
(Fig. 1) and of patients who underwent complete remission (Fig. 2). They seem to us very encouraging although they cannot yet be considered as significant.
DISCUSSION We present a therapeutic regimen which shows a very high degree of efficacy in lymphosarcoma and reticulosarcoma. The drugs were
chosen because of their maximal efficacy for m;n;ma], toxicity. Drugs with the high degree of toxicity like nitrosoureas were excluded from the regimen and tolerance of the regimen was remarkably good, at least on patients who had not been previously irradiated. Although further study has to be done with a greater number of patients and longer time of observation, it seems that the classification proposed by W.H.O. for lymphosarcoma is of significant prognostic value.
100%
ioo~.
50*/.
50%
•
I~on~h$ J
Fig. 1. Survival curve of 21 patients with lymphosareoma and reticulum cell sarcoma. Stage III and IV treated with A VmCP in first perceptible phase.
413
2
".
4
~
6
7
8
9
JO
II
2. 3. 4.
5.
6. 7. 8.
9.
13
Fig. 2. Survival curve of patients in C.R. with ~'mphosarcoma and retirulo-sarcoma. Stage III and I V treated with AD3f, VM 26, CP~I and PDN (N = 19 patients).
REFERENCES 1.
IZ
EORTC CLINmAL SCREE~,nNOGROUP, Clinical screening of 4 de-methylepipodophyllotoxin fl-D. Thenilidene glucoside (VM 26) in malignant lymphomas and solid tumors. Brit. reed. J. 2, 744 (1972). R.E. JOHXSON,Patterns of involvement in non-Hodgkin's lymphomas and the implications for treatment decision making. Brit. J. Cancer. In press (1976). G. MATH~, Les h6matosarcomes non hodgkiniens. Introduction, classification et inventaire topographique pr6th6rapeutique. Rev. Prat. (Paris). 26, 1367 (1976). O.M.*TH~, L. SCa'~'aa~ZE~,n3ERO,P. POUInnART, R. WEL'~R, R. OnDH.~i, C. JASMIN, C. ROSENFELD, M. HAYAT, M. SCHNEIDER, J. L. AMIEL, B. CEOA~¢,, M. ]VIUSSET-STE~SCOand F. DE VASSAL,Essai de traitement de divers h6matosarcomes par le 4--d6methyl-epipodophyllotoxine D. th6nyhd~ne glucoside (VM 26 ou EPT). Nouv. Presse mgd. 3, 447 (1974). G. BONADO~,~A, S. MONFARmm, M. DE LENA, F. FOSSATI-BELLANI and G. BERETTA, Phase I and preliminary phase II. Evolution of adriamycin. Cancer Res. 30, 2572 (1970). J . A . GOTTLIEB,J. u. Gurr~a~t~, K. B. McG~Dv-zj, V. RODRIOUEZand E. FFa~I III, Chemotherapy of malignant lymphoma with adriamycin. Cancer Res. 33, 3024 (1973). S. JONES, D. A. ROSE.'~rRO, H. S. K.~LAN, M. K.~ZN and R. D o t a r d , Non-Hodgkin's lymphoma, single agent chemotherapy. Cancer (Philad.) 30, 31 (1972). G. MATH~, O. SCmVEISGUTH,G. BRUL#, ~[. SCHNEIDER,J. L. AMIEL, L. SCnWARZE.WBEROand A. CATT,~, Essai de traitement par la cyclophosphamide de la leucfimie aign~ lymphoide et du lymphosarcome. Presse rMd. 71,402 (1963). P. POUILLA~T, L. SCn~'AmZENBERO, J. L. AMIEL, G. MATHI~., P. HUGUENIN, P. MO~N, A. BARON,C. LAPARl~Sand R. PARROT.Potentiation of drugs using sequential chemotherapy against disseminated breast, bronchia| and central nervous system solid tumors. In Chemotherapy (Edited by K. Hellman and T. A. Conners) Vol. 8, p. 387. Plenum, New York (1967).
414
07. L. Misset et al. 10.
11.
P. POUILLAltT, L. SCHWASZEm3ERG,G. bIATH~., M. Scm~xDE~., C. JASMm, M. HAYAT, 1~. WEINER, F. DE VASSAL,J. L. ,~ur~L, H. P. BEvxR and S. FAJBXSowxc,z, Essai clinique de combinaisons chimiothSmpiques bas~'es sur la notion de tentative de synchronisation ceilulalre. Administration premiere d'un antimitotique suivie de l'application de produit(s) cycle ou phase d,pendant(s). Nouv. Pressendd. 1, 1757 (1972). G. MATHg and H. R~PAPORT. Histocytological Typing of the Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues. Vol. 1. World Health Organization, Geneva (1976).
