Therapy of advanced lymphocytic lymphoma a preliminary report of a ...

Br. J. Cancer (1975) 31, Suppl. II, 474

THERAPY OF ADVANCED LYMPHOCYTIC LYMPHOMA A PRELIMINARY REPORT OF A RANDOMIZED TRIAL BETWEEN COMBINATION CHEMOTHERAPY (CVP) AND INTENSIVE RADIOTHERAPY G. P. CANELLOS, V. T. DEVITA, R. C. YOUNG, B. A. CHABNER, P. S. SCHEIN AND R. E. JOHNSON From the Medicine and Radiation Branches, National Cancer In8titute, Bethe8da, Maryland, U.S.A.

Summary.-The initial results of a randomized clinical trial comparing intensive cyclical combination chemotherapy (CVP) and total body radiation therapy in the treatment of advanced (Stage III and IV) lymphocytic lymphoma is presented. Sixty-five patients have been entered and randomized according to stage. Of the chemotherapy treated patients, (22/27 (81%) achieved a response with 55% complete responders. The radiation group or those treated with radiation 27/32 (84%) responded with 56% in complete response. There is no significant difference in overall survival between the two groups. Nodular lymphoma (44 patients) responds more often and has a significantly longer survival than diffuse lymphoma (21 patients). Approximately 50% of the complete remitters have relapsed but reinduction of disease control was possible in almost all cases.

LYMPHOCYTIC LYMPHOMA frequently presents with disseminated disease which is often detectable only by bone marrow or liver biopsy studies. The relatively high relapse rate for clinically localized disease treated with high dose radiotherapy to involved areas suggests that early spread of disease occurs despite local control (Jones et al., 1973a). Thus, for more effective control of this disease some form of systemic therapy is required. The utility of a variety of chemotherapeutic agents for this disease has long been recognized and in recent years combination chemotherapy programmes have been initiated. The complete remission rate exceeded that previously reported for single agents and the survival at one year varied between 70 and 80%, and in one study more than half the patients were alive at 2 years of follow up. These provocative findings were countered by the demonstration at the National Cancer Institute (NCI) that total body radiation therapy (TBI) could induce complete remissions in 25/27 patients with Stage III and IV (marrow) lymphocytic lymphoma and,

further, the median duration of unmaintained response was 26 months. In the face of evidence that these systemic therapies can induce complete remissions for long periods of time, we embarked on a trial whereby patients would be allocated randomly to either cyclical combination chemotherapy (CVP) or intensive radiation therapy in which total body irradiation would be included. The randomization would include stratification by stage to maintain comparable groups for eaclh modality. This report is a preliminary analysis of the data as of 8/1/73. PATIENTS AND METHODS

Patients with the diagnosis of lymphocytic lymphoma Stage III and IV were entered into the trial which began in January 1969. Patients with mixed lymphocytic or histiocytic lymphoma were not included. At the present time 65 patients have been entered. The details of the staging procedures are reported in an accompanying paper (Chabner et al., 1975). The histological features were reviewed by Dr Costan Berard, NCI, and all patients were reviewed at a joint staging conference before randomization.

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THERAPY OF ADVANCED LYMPHOCYTIC LYMPHOMA

Cihemotherapy (32 patients) The CVP combination programme has been described previously (Bagley et al., 1972). In brief, prednisone 100 mg/M2 and cyclophosphamide 400 mg/M2 body surface area are given orally for 5 days. In addition, on Day 1 vincristine 1-4 mg/M2 is given intravenously in a single dose. This cycle of treatment is repeated every 21 days for 6 cycles. If at that point the patient is in complete clinical remission, as defined by disappearance of all disease in previous sites of involvement, 2 further consolidation cycles are administered. Staging procedures are then repeated to evaluate the disappearance of disease more objectively. Patients achieving a partial response are continued on intermittent combination therapy until complete remission or evidence of refractoriness occurs. Partial response refers to a greater than 50% decrease of enlarged nodes for at least one month. Often partial responders will have disappearance of peripheral nodes and abnormal lymphangiogram with persistent disease in the marrow or on repeat liver biopsy. Similarly, patients in whom adenopathy quickly returned 3-5 weeks off treatment were considered partial responders. A dose reduction schedule was used for patients with persistent blood count suppression (Bagley et al., 1972). Vincristine and prednisone dosage could be modified in cases of non-haematological toxicity. Patients in complete remission are followed at regular intervals when not receiving treatment. Relapse of disease is retreated with combination therapy as described above. Radiation therapy (33 patients) Intensive radiation therapy in the form of total body irradiation alone was administered to 21 patients. Midline daily doses of 10 rad for 3-5 days per week were given to a total dose of 100-500 rad. Technical details have been described previously (Johnson et al, 1970, 1972). Six patients received total nodal irradiation to a dose of 2000-3000 rad in 2-4 weeks. Two patients received total nodal, preceded by total body irradiation to 150 rad. Four patients received additional localized radiation but including either hemibody or total nodal irradiation. A schematic representation of the patient randomization and therapy i-s shown in Table I.

TABLE I.-Lymphocytic Lymphoma Staging IV

IV Other

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RESULTS

Randomization.-Sixty-five patients have been randomized as of 8/1173-32 to chemotherapy and 33 to intensive radiation. Twenty patients were in Stage III; the remainder had various subtypes of Stage IV disease and were randomized according to one of 5 categories shown in Table II. There was an approximately TABLE II.-Lymphocytic Lymphoma Clinical Pathological Stages No. of patients A

Stage III IV Marrow IV Leukaemia IV Liver IV Liver, marrow IV Others Totals

Splenectomy Diffuse histology

Chemotherapy Radiotherapy 9

1 4 9 6 3 32 10 9

11 3

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33 11

12

equal distribution of patients who had prior splenectomy as part of a staging laparotomy. Randomization did not entail separation according to histological features. Of the total of 21 patients with diffuse histology 12 patients were in the radiation group and 9 given chemotherapy. Eleven patients out of 33 in the radiation group hadwell differentiated histology compared with 6/32 in the chemotherapy group. Figure 1 shows the age distribution of the patients in this study. The median age

476

G. P. CANELLOS ET AL. AGE DISTRIBUTION

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for both treatment groups was 50 years of age, with 34 males and 31 females.

TABLE

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Disease Response According to Treatment Chemotherapy

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Remnission of induction Total evaluable 27 32 15 (55%) 18 (56%) Complete Radiotherapy. As of 8/1/73, 33 pa- Relapse 7 9 tients have been treated, with 32 evalu- Median duration 22-31 (months) 12+ able for completeness of response since one Partial 9 (33%) 8 (25%) patient has not yet completed therapy. None 3 6 5 3 Eighteen patients (56%) achieved a com- Dead plete clinical remission and 8 patients (25%) had a partial remission (Table III). relapsed with a median duration of reOf the complete remitters, half (9) have sponse, determined from the end of LYMPHOCYTIC LYMPHOMA SURVIVAL / THERAPY

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Survival according to therapy (Life Table analysis).

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treatment, of no less than 22 nor greater than 31 months. Only 3 patients have died. Four patients subsequently received chemotherapy for relapse or primary refractoriness to radiation. At 42 months of follow up from onset of treatment, life table analysis reveals an 85% survival (Fig. 2).

good control of disease in partial responders. Five patients have died, 4, 4, 8, 11, 12 months respectively from the onset of therapy, with 80% surviving at 18 through 36 months of follow up (Fig. 2).

Response according to histology Patients with nodular lymphoma (44 patients) had 94% overall complete and Combination chemotherapy.- Of the 32 partial response rate as opposed to 67% patients randomized, 4 are too early in in the diffuse histology group (Table IV). their treatment for evaluation and one patient refused therapy after 2 cycles. TABLE IV.-Tumour Response by Histology Fifteen patients (550%) out of 27 evaluable Radiotherapy Chemother apy went into complete remission, as assessed Nodular Diffuse Nodular Diffuse by repeat marrow and liver biopsies where 12 20 9 indicated. Nine patients (33 ,/%) had a Total evaluable 18 12(67%) 3(33%) 15(75%) 3(25%) Complete partial response. Seven of the 15 com- Partial 5 4 3 5 plete remitters have relapsed with a None 4 2 2 1 2 1 1 4 median duration of remission which will Dead exceed 12 months. Thirteen patients are currently receiving intermittent combina- The survival of the nodular patients is tion therapy because of either relapse significantly better than those with diffuse from complete remission (6 patients) or lymphoma (Fig. 3). Of the 17 patients LYMPHOCYTIC LYMPHOMA SURVIVAL / HISTOLOGY (35) (44) (25)

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G. P. CANELLOS ET AL.

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with well differentiated disease, 82% had a complete or partial response as opposed to 75% of patients with poorly differentiated histology. There appears to be no significant difference between either therapy at 3 years of follow up in the survival of nodular lymphoma patients (Fig. 4). With smaller numbers, patients with diffuse lymphoma treated with radiation have an appreciably greater survival up to 18 months of follow up. However, the curves begin to converge at 24 months (Fig. 5).

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Toxicity The haematological toxicity of the CVP regimen has been described in detail elsewhere (Bagley et al., 1972). The predominant finding is reversible granulocytopenia following each cycle. Thrombocytopenia < 100,000 mm3 is rare in the first 6 cycles, as previously reported. Neurotoxicity of some degree is seen in most cases but did not require withdrawal of the drug. The toxicity of the total body irradiation programme have been described previously (Johnson, 1970, 1972). The degree of myelosuppression is variable but may be prolonged following this form of treatment.

48

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6 30 18 24 12 MONTHS FROM ONSET OF TREATMENT FIG. 5.-Survival of diffuse lymphoma according to

therapy. DISCUSSION

Lymphocytic lymphoma is a fatal disease in most instances. The single drug experiences of Stanford indicates that 50% of patients with diffuse lymphoma have a probability of dying in 4-8 months from the onset of treatment (Jones et al., 1972). The results in


nodular lymphocytic lymphoma suggest that this form generally has a better prognosis although, even in this group, half the patients are dead by 3 years. Early single drug studies from 2 co-operative groups, and a more recent sequential drug trial from the Southwest Group, demonstrated a median survival of about one year (Carbone and Spurr, 1968; Luce et al., 1971). It is to improve on these grim statistics that more intensive combination chemotherapy regimens were designed utilizing drugs with a high order of effectiveness as single agents (Hoogstraten et al., 1969, Luce et at., 1971; Bagley et al., 1972). The results of the initial clinical experience with various modifications of combined therapy containing an alkylating agent, usually cyclophosphamide, vincristine and prednisone, indicate a high response rate (ca. 90%) and better than 80% of the complete responders surviving at 2 and 3 years (Bagley et al., 1972). Recently, the prognostic importance of the presence of nodularity in non-Hodgkin's lymphoma has been emphasized (Jones et al., 1973b). Most of the earlier studies of combination therapy are not described in terms of nodular Vs diffuse, degree of differentiation or extent of mixed lymphocytic-histiocytic infiltration of the tumour. Since only 6 of our original 35 patients on CVP had diffuse lymphoma, an appreciation of the efficacy of CVP in this form was not possible. In concert with attempts to improve survival with intensive combination chemotherapy, a pilot study of primary therapy for advanced lymphoma with total body irradiation, with or without total nodal irradiation, resulted in 93% complete remission rate in 27 patients with Stage III and IV (marrow) lymphocytic lymphoma (Johnson, 1972). The median duration of unmaintained remission was 26 months. The preliminary results of the present randomized trial suggest that there is no overall difference in survival between the 2 modes of treatment at 3 years of follow up. There is some sur-

479

vival advantage to radiotherapy in diffuLse lymphomata but the differences disappear at 2 years. The apparent differences in remission duration between the 2 groups may reflect the frequency of repeat marrow and/or liver biopsies in the chemotherapy group since these studies are required before termination of chemotherapy and are repeated periodically to evaluate remission. Relapse from complete remission has occurred in almost half the patients but only 2 complete remitters have died. Disease control can be sustained by re-treatment with either form of therapy, especially in patients with nodular histology. There appears to be no advantage of one therapy over the other in achieving remission in either diffuse or nodular disease. Similarly, there does not appear to be an advantage of one therapy over the other in the various subgroups of Stage IV disease. The acute haematological toxicity and neurotoxicity of chemotherapy are balanced by the rather prolonged myelosuppression which can result from radiation. The ultimate value of these intensive therapies will be determined with longer follow up, and whether a fraction of patients can survive free of disease without therapy for prolonged periods. The utility of both therapies suggests a role for their combined administration, particularly in those patients with diffuse histological patterns. REFERENCES BAGLEY, C. M., DEVITA, V. T. JR, BERARD, C. W. & CANELLTOS, G. P. (1972) Advanced Lymphosarcoma: Intensive Cyclical Combination Chemotherapy and Cyclophosphamide, Vincristine, and Prednisone. Ann. intern. Med., 76, 227. CARBONE, P. P. & SPURR, C. (1968) Management of Patients with Malignant Lymphoma: A Comparative Study with Cyclophosphamide and Vinca Alkaloids. Cancer Res., 28, 811. CHABNER, B. A., JOHNSON, R. E., CHRETIEN, P. B., SCHEIN, P. S., YOUNG, R. C., CANELLOS, G. P., HUBBARD, S. H. & DEVITA, V. T. JR (1975) Percutaneous Liver Biopsy, Peritoneoscopy and Laparotomy: An Assessement of Relative Merits in the Lymphomas. Br. J. Cancer, 31, Suppl. II. 242.

HoOGSTRATEN, B., OwENs, A. H., BENHARD, R. E., GLIDEWELL, 0. J., LEONE, L. A., OLSON, K. B., HARLEY, J. B., TOWNSEND, S. R., MILLER, S. P.

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& SPURR, C. C. (1969) Combination Chemotherapy in Lymphosarcoma and Reticulum Cell Sarcoma. Blood, 33, 370. JOHNSON, R. E. (1972) Remission Induction and Remission Duration with Primary Radiotherapy in Advanced Lymphosarcoma. Cancer, N. Y., 29, 1473. JOHNSON, R. E., O'CONOR, G. T. & LEVIN, D. (1970) Primary Management of Advanced Lymphosarcoma with Radiotherapy. Cancer, N.Y., 25, 787. JONES, S. E., ROSENBERG, S. A., KAPLAN, H. S., KADIN, M. E. & DORFMAN, 'R. F. (1972) NonHodgkin's Lymphomas II. Single Agent Chemotherapy. Cancer, N. Y., 30, 31.

JONES, S. E., FUKS, Z., BULL, M., KADIN, M. E., DORFMAN, R. F., KAPLAN, H. S., ROSENBERG, S. A. & KIM, H. (1973a) Non-Hodgkin's Lymphomas IV. Clinicopathologic Correlation in 405 Cases. Cancer. N. Y., 31, 806. JONES, S. E., FUKS, Z., KAPLAN, H. S. & ROSENBERG, S. A. (1973b) Non-Hodgkin's Lymphomas V. Results of Radiotherapy. Cancer, N.Y., 32, 682. LUCE, J. K., GAMBLE, J. F., WILSON, H. E., iVLONTrO, R. W., IsAAcs, B. L., PALMER, R. L., COLTMAN, C. A., HEWLETT, J. S., GEHAN, E. A. & FREI, E. (1971) Combined Cyclophosphamide, Vincristine, and Prednisone Therapy of Malignant Lymphoma. Cancer, N.Y., 28, 306.