non-Hodgkin's lymphoma treated with combination chemotherapy has demonstrated differences between histological subgroups. Patients with diffuse histiocytic ...
Br. J. Cancer (1975) 31, Suppl. II, 465
RESULTS OF COMBINATION CHEMOTHERAPY OF NON-HODGKIN'S LYMPHOMA P. S. SCHEIN, B. A. CHABNER, G. P. CANELLOS, R. C. YOUNG, C. BERARD AND V. T. DEVITA Fromn the Medicine Branch and Laboratory of Pathology, National Cancer Institute, Bethesda,
Maryland 20014
Summary. The analysis of the results of CVP and MOPP chemotherapy in 80 patients with advanced stages of non-Hodkgin's lymphoma shows that 36 achieved a complete remission. Twenty-five percent of all patients remain free of disease for periods ranging from 4 months to over 7 years, with a projected median duration of complete remissions of 31 years. Well differentiated and nodular histology were positive determinants for survival, confirming the overall clinical validity of the Rappaport classification system for the non-Hodgkin's lymphomata. However, it has been demonstrated that it is possible to achieve a complete remission using combination chemotherapy even in the most clinically aggressive histological subgroups, and that these responses can be correlated with an extended survival. An analysis of patterns of relapse from complete remission in patients with non-Hodgkin's lymphoma treated with combination chemotherapy has demonstrated differences between histological subgroups. Patients with diffuse histiocytic lymphoma who achieved a complete remission after 6 months of treatment without maintenance have remained disease-free, whereas those with nodular poorly differentiated lymphocytic and diffuse well differentiated lymphocytic lymphomata demonstrate a pattern of continuous late recurrence. The initial sites of relapse from complete remission in lymphocytic lymphoma were lymph nodes and bone marrow which were involved before treatment.
As EARLY as 1956, a detailed histological classification system with prognostic significance for the non-Hodgkin's lymphomata was proposed by Rappaport, Winter and Hicks (1956). Nevertheless, the majority of clinical therapeutic trials conducted since that time have been reported in the nonspecific, generic terminology of " lymphosarcoma " and " reticulum cell sarcoma ". Little emphasis has been given to the importance of nodularity, degree of cytological differentiation or mixed cellular nature of these tumours as basic correlates for response and survival. The clinical importance of these histological parameters has recently been re-emphasized in a large retrospective series of patients treated with single agent chemotherapy reported from Stanford University (Jones et al., 1972).
This report presents the results of combination chemotherapy programmes initiated in 1965 at the National Cancer Institute for treatment of patients with advanced non-Hodgkin's lymphoma, which are correlated with the Rappaport classification. PATIENTS AND METHODS
Eighty patients with non-Hodgkin's lymphomata have completed treatment with combination chemotherapy programmes between April 1965 and May 1972. The original biopsy specimens have been reviewed and reassigned to one of 8 histological classifications based on cell type, cellular differentiation and nodular or diffuse pattern of involvement (Table I). There was an equal overall representation of nodular and diffuse histologies. The predominant cell type in the
466
P. S. SCHEIN ET AL.
TABLE I.-Non-HodIgkin's Lymphoma: St'age Histology Lymphocytic Well differentiated Poorly differentiated Nodular Diffuse Mixed histiocyticlymphocytic Nodular Diffuse Histiocytic Diffuse
NO.
IIE
III
daily for 5 days), vincristine (14 mg/M2 on Day 1) and prednisone (100 mg/r2 daily orally for 5 days) repeated every 21 days (Bagley et al., 1972). If a complete remission status was achieved after a minimum of 4 cycles, 2 additional " consolidation" cycles were administered. In those patients who failed to attain a complete remission, repeated cycles of chemotherapy were given until there was either a complete disappearance of disease, at which time 2 additional cycles were administered, or until regrowth of
IV
44 30 9 7
4 26
5
3 1
25 9
4 3
tumour
19% 801
occurred.
No
maintenance
drug
therapy was given to documented complete remitters, with the exception of 8 patients with lymphocytic lymphoma who achieved a complete remission in 1970. This group of patients was given maintenance cycles of CVP chemotherapy every 6-12 weeks. The other 2 basic treatment programmes were MOPP, consisting of nitrogen mustard (6 mg/ m2 intravenously on Days 1 and 8), vincristine (14 mg/M2 intravenously on Days 1 and 8), procarbazine (100 mg/M2 daily orally for 14 days) and prednisone (40 mg/M2 daily orally for 14 days) (DeVita, Serpick and Carbone, 1970), or a modification, CMOPP, which substitutes cyclophosphamide 650mg/M2 on Days 1 and 8 for nitrogen mustard. These latter 2 regimens were used in the treatment of patients with histiocytic or mixed histiocytic-lymphocytic lymnphoma. One month after completion of chemotherapy, all patients who were considered to be in complete remission were re-evaluated for evidence of residual tumour, with repetition of staging studies that were previously abnormal, including bone marrow and hepatic biopsies and repeat lymphangiography if
nodular category was t-he poorly differentiated lymphocytic lymphonna, which constituted 38% of the series. I'here were no cases of nodular well differenltiated lymphocytic or nodular histiocytic 1l ymphoma. The most frequent cell type enc ountered in the diffuse histological forms was the diffuse histiocytic lymphoma (33%). Sttaging procedures routinely employed includled lymphangiography, unless intravenous pyE-lography was positive, bone marrow and perc-utaneous liver biopsies in addition to biopsy 4of other apparent sites of extranodal involve,ment. The extent of disease is designated iia terms of pathological stage as outlined by t he Ann Arbor Conference (Carbone et al., 1971) and reported in detail elsewhere (Schiein et al., 1974) and outlined in Tables I arid II. Eighty per cent of patients presented iwith Stage IV involvement. The only histiiological subtype with substantial representa,tion of less advanced disease was the nodullar mixed histiocyticlymphocytic lymphomla, where 3 of 7 cases were Stage III at the tiime of treatment. Three basic treatmient programmes were necessary. used: CVP, a cyclical combination protocol No patient was excluded because of consisting of cyclopho)sphamide (400mg/M2 toxicity, incomplete therapy or insufficient
TABLE II.-Non-Hodgkin's Lymphoma: Predominant Sites of Extranodal Involvement (Stage I V) Percentage of cases with involvement Histology
Lymphocytic Well differentiated Poorly differentiated Nodular Diffuse Mixed histiocytic-lymphocytic Nodular Diffuse Histiocytic Diffuse
No.
Bone marrow
Bone
4
100%
25 9
63%
4 3
25% 67%
25%
19
16%
58%
76%
8%
Liver
G.I.
25% 28% 63% 25% 67%
4% 25%
11%
16%
COMBINATION CHEMOTHERAPY OF NON-HODGKIN'S LYMPHOMA
data. Partial remission for the purpose of this study was defined as a 75% reduction but not complete disappearance of all evidence of disease. Complete remission indicates disappearance of all evidence of disease and return to a normal performance status. Duration of remission was calculated from the last day of treatment to the first objective evidence of relapse. Survival was determined from the start of therapy to death. The data were presented by the life table method of Hill (1961) and life table curves were compared using the generalized Wilcoxon test (Gehen, 1965). Statistical evaluation of small numbers in various subgroups was performed with 2 x 2 contingency tables (Finney et al., 1963) and computed according to the method of Yates (1934). RESULTS
Response rate by histology (Table III) Lymphocytic lymphomata.-Two of 4 patients with well differentiated lymphocytic lymphoma achieved a complete remission. Both have relapsed, at 20 and 24 months post-treatment respectively. Sixty per cent of patients with nodular poorly differentiated lymphocytic lymphoma obtained a complete remission. The median duration of complete response is 17 + months with a range of 1-40 months. The overall response, complete and partial, for this histological group is 93 %. In contrast, only 2 of 9 patients, 22%, with diffuse poorly differentiated lymphocytic lymphoma achieved a complete remission, with an overall response
of 62%. This lower remission rate is significantly different from that recorded for the nodular form of the same histology (P < 0-05). However, the 2 complete responders remain in remission at 9 and 31 months post-treatment respectively. Mixed histiocytic-lymphocytic lymphomata.-Five of 7 patients with nodular mixed histiocytic-lymphocytic lymphoma (71 %) obtained a complete remission, with an overall complete and partial response rate of 100%. The median duration of complete response is 46 + months. Only one patient who achieved a complete remission has relapsed. Two patients are continuously free of disease for over 5j years after completion of therapv. In contrast, none of the 4 patients with diffuse mixed histiocytic-lymphocytic lymphoma obtained a complete remission. Two patients demonstrated a partial response. The difference in response of the nodular versus diffuse forms of this histology is significant. Histiocytic lymphoma.-Nine of 26 patients (35%) with diffuse histiocytic lymphoma obtained a complete response and none had relapsed at time of last follow up. The median duration of complete remissions is in excess of 2 years, and 3 patients remain in an unmaintained disease-free status for 4 to 61 years. Sixty-one per cent of patients demonstrated a pattern of apparent complete or near complete disappearance of disease with early courses of treatment and rapid
TABLE III.-Non-Hodgkin's Lymphoma: Response to Combination Chemotherapy Complete remission
Overall response
Histology Lymphocytic Well differentiated Poorly differentiated Nodular Diffuse Mixed histiocytic-lymphocytic Nodular Diffuse Histiocytic Diffuse
467
No.
%
Median duration (months)
4
50%
22 (20-24)
30 9
60%
17+(1-40)
7 4
71% 0%
46+ (2-68+)
100% 50%
26
35%
25+(4+-79+)
96%
22%
9+, 31+
75% 93%
62%
468
P. S. SCHEIN ET AL.
regrowth between cycles. This latter lymphoma is in excess of 30 months, with group was scored as having a partial 10 of the 30 patients at risk alive over 3 years. In contrast, patients with a response. diffuse pattern of lymph node histology of the same cell type have a median Survival survival of 14 months, which is signiOverall survival by histology (Fig. 1).- ficantly different from the nodular group The survival of the 4 patients with well (P < 0.05). differentistted lymphocytic lymphoma is The median survival of the 7 patients significantly better than all other histo- with nodular mixed histiocytic-lymphological categories. cytic lymphoma is in excess of 34 months. The median survival for patients with One patient is alive 4- years and 2 patients nodular poorly differentiated lymphocytic have survived 6 years after the initiation NON-HODGKIN'S LYMPHOMA: SURVIVAL
(I)
80
(I 1)
(8)
60
(4)
z (
(I) --
v Well Differentiated Lymphocytic, Diffuse (4) Poorly Differentiated Lymphocytic Nodular (30) Diffuse (9) Mixed Histiocytic-Lymphocytic A
A
o * o
Nodular (7) Diffuse (4) Histiocytic, Diffuse (26) I
I
I
4 MO
NTHS
1u
FIG. 1.-Survival following combination chemotherapy for each of the histological subgroups non-Hodgkin's lymphoma; actuarial analysis with numbers in parentheses indicating patients risk.
of at
COMBINATION CHEMOTHERAPY OF NON-HODGKIN'S LYMPHOMA
469
NON - HODGKIN'S LYMPHOMA: SURVIVAL OF COMPLETE RESPONDERS .
10X
_
5)
1' 1~~~~~~~~6 (16)
90
(3) (6)
4)
80
-
(3)
70
0
60
-
z
5;
0>
50
Poorly differentiated lymphocytic A Nodular (18) A Diffuse ( 2) Mixed histiocytic - lymphocytic o Nodular ( 5) o Diffuse histiocytic ( 9)
cn
40 ,30 20
-
10
-
OI
1
1 15
1
1
1
30
35
40 MONTHS FIG. 2.-Survival of patients in each histological subgroup of non-Hodgkin's lymphoma obtaining a complete remission with combination chemotherapy; actuarial analysis with numbers in parentheses indicating patients at risk. 5
10
20
of treatment. In contrast, none of the 4 patients with diffuse mixed histiocyticlymphocytic lymphoma lived longer than 4 months after the start of chemotherapy. The survival pattern of patients with diffuse histiocytic lymphoma demonstrates 2 distinct phases. The overall median survival of 6 months is contributed by patients who had either a partial or no response to treatment. The flattening of the curve describes the subgroup of patients (35%) who achieved a complete remission and who are alive up to 7 years after the initiation of chemotherapy. There are no statistical differences in survival between the nodular poorly differentiated lymphocytic and nodular mixed histiocytic-lymphocytic groups, or between the diffuse poorly different-
25
iated lymphocytic and diffuse histiocytic groups.
Relationship of magnitude of response to survival (Fig. 2, 3) There is no significant difference between histological groups, in survival of patients in complete remission (Fig. 2). The median survival for complete responders in each of the histological subgroups is as follows: nodular poorly differentiated lymphocytic, in excess of 32 months (range of 11-50 + months); diffuse poorly differentiated lymphocytic, 18 + and 44 + months; nodular mixed histiocytic-lymphocytic, in excess of 55 months (range 22-74 + months); diffuse histiocytic, in excess of 31 months (range
P. S. SCHEIN ET AL.
470
NON-HODGKIN'S LYMPHOMA: SURVIVAL OF PARTIAL RESPONDERS Poorly Differentiated Lymphocytic A Nodular (10) * Diffuse (3) Mixed Histiocytic-Lymphocytic o Nodular (2) * Diffuse (2) o Histiocytic, Diffuse (15)
CD z
n
5
10
15
20 MONTHS
25
30
35
40
FIG. 3.-Survival of patients in each histological subgroup of non-Hodgkin's lymphoma obtaining a partial remission with combination chemotherapy; actuarial analysis with numbers in parentheses indicating patients at risk.
12 +-85 + months).
The projected sur- ents with nodular mixed histiocyticcomplete remitters at 40 lymphocytic lymphoma have had a commonths is 82%. parable course, only one of 5 patients In contrast, the median survival for achieving complete remission having repatients who achieved only a partial lapsed. In contrast, patients with nodremission is 8 months (Fig. 3). ular poorly differentiated lymphocytic and diffuse well differentiated lymphocytic Disease-free survival and sites of relapse lymphomata have demonstrated a pattern from complete remission (Fig. 4) of continuous relapse from complete For patients with diffuse histiocytic remission. and diffuse poorly differentiated lymphoAn analysis of sites of relapse from cytic lymphomata who achieved a com- complete remission in lymphocytic lymplete remission, the disease-free survival phomata demonstrates that 69% of recurand overall survival are the same. Pati- rences were in lymph nodes. In 28 sites
vival of
all
COMBINATION CHEMOTHERAPY OF NON-HODGKIN S LYMPHOMA
100l n
NON-HODGKIN'S LYMPHOMA: DURATION OF COMPLETE REMISSIONS (4) (6t o _ _a (2) (I)
80
471
(3)
(4)
(3)
0
--o
w u,
ct
w
Cl en LiL
0 Id w
60
_
cr
z I-
Id
I. 40 _ 4 z 0r
Diffei rentioted Lymphocytic, Diffuse (2) Poorly Differ entioted Lymphocytic A Nodular (IEB) A Diffuse (9) o Mixed Histiiocytic-Lymp,hocytic, Nodular (5: O Histiocytic, ,Diffuse (9) v Well
20
nIul
5
I
I
10
15
20 MONTHS
-1-1025
--iI,
30
35
40
FIG. 4.-Duration of complete remission in each histological subgroup of non-Hodgkin's lymphoma after completion of chemotherapy.
ficance of the detailed features of lymph node histology. The well differentiated lymphocytic lymphomata were found to have a significantly better survival than other histological groups, independent of remission status. Both in clinical course and lymph node histology this group appears comparable with chronic lymphocytic leukaemia, suggesting that the two disorders represent a different clinical expression of the same disease process. DISCUSSION The favourable influence of nodular This analysis of the results of com- histology on both remission rate with bination chemotherapy in non-Hodgkin's chemotherapy and overall survival is well lymphoma confirms the prognostic signi- illustrated by the comparison of the of lymph node relapse, 22 (80%) have been in nodes thought to be involved clinically before treatment, the most common sites of relapse being the inguinal, (8) and abdominal (7) lymph node regions. Three patients relapsed simultaneously in both bone marrow and lymph nodes which had been abnormal before therapy, and in bone marrow alone in one additional patient.
472
P. S. SCHEIN ET AL.
results obtained in the respective nodular and diffuse forms of poorly differentiated lymphoctyic and mixed histiocytic-lymphocytic lymphomata. In addition, there is no significant difference in survival between the diffuse poorly differentiated lymphocytic and the diffuse histiocytic groups. These results demonstrate the overall clinical relevance of the Rappaport classification for the non-Hodgkin's lymphomata; however, the system did not predict for the ability to achieve a longterm disease-free state in individual patients. This study emphasizes the importance of obtaining an initial complete remission for extended survival; in general, a partial response does not appear to be meaningful. This was particularly true for patients with diffuse histiocytic lymphoma, where the median survival for partial responders was only 6 months, in contrast to disease-free survivals ranging from 1 to an excess of 7 years for patients obtaining a complete remission. There is no significant difference between histological groups in survival of patients in complete remission. There were, however, differences in duration of unmaintained disease-free survival. For patients with diffuse histiocytic and diffuse poorly differentiated lymphocytic lymphoma who achieved a complete remission, the disease-free survival and overall survival are the same. Patients with nodular mixed histiocytic-lymphocytic lymphoma have had a comparable course with only one of 5 patients achieving complete remission having relapsed. In contrast, patients with lymph node histology considered to impart the better overall prognosis-diffuse well differentiated and nodular poorly differentiated lymphocytic lymphoma-have demonstrated a pattern of continuous relapse from complete remission. Nevertheless, despite the apparent inability to maintain a disease-free state, the overall survival of these latter two groups is favourable. Whether these relapses represent a primary failure to control all disease or a
subsequent reinduction or activation of new disease by a remaining aetiological factor remains speculative. Support for the former possibility comes from the demonstration that those patients in complete remission who relapsed did so exclusively in areas of previous known involvement and in 69% of the instances in lymph nodes alone. This raises the question as to whether the combined use of radiotherapy, to areas of predominant disease and chemotherapy, or the use of maintenance chemotherapy, might lead to significantly longer disease-free survival in nodular poorly differentiated lymphocytic lymphoma. In the past, chemotherapy for nonHodgkin's lymphoma has largely been regarded as, at best, palliative for patients with advanced disease since, with single agent therapy, few patients achieved complete remission and even fewer were kept free of disease despite continuous drug therapy. The results of the present study with combination chemotherapy suggest that a small but significant number of patients can be offered a prolonged disease-free survival without maintenance treatment. Further improvements in therapy might be expected with the application of our increasing understanding of the natural history of these diseases and newly identified active agents in the design of treatment programmes. Aggressive attempts at remission induction appear warranted in patients with diffuse histiocytic lymphoma because of the potential for extended disease-free survival. Patients with nodular, poorly differentiated lymphocytic lymphoma may benefit from the use of maintenance chemotherapy or radiotherapy to regions of previous known disease involvement after initiation of remission with chemotherapy. REFERENCES BAGLEY, C. M., DEVITA, V. T., BERARD, C. W. & CANELLOS, G. P. (1972) Advanced Lymphosarcoma: Intensive Cyclic Combination Chemotherapy with Cyclophosphamide, Vincristine and Prednisone. Ann. intern. Med., 76, 227.
COMBINATION CHEMOTHERAPY OF NON-HODGKIN S LYMPtIOMA CARBONE, P. P., KAPLAN, H. S., MUSSHOFF, K., SMITHERS, D. W. & TUBIANA, M. (1971) Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res., 31, 1860. DEVITA, V. T., SERPICK, A. A. & CARBONE, P. P. (1970) Combination Chemotherapy in the Treatment of Advanced Hodgkin's Disease. Ann. intern. Med., 73, 881. FINNEY, D. H., LATSCHA, R., BENNETT, B. M. & Hsu, H. (1963) Tables for Testing Significance in a 2 x 2 Contingency Table. Cambridge, Mass: Harvard University Press. GEiEN, E. A. (1965) A Generalized Wilcoxon Test for Comparing Arbitrarily Singly Censored Samples. Biometrika, 52, 203. HILL, A. B. (1961) Principles of Medical Statistics. New York, London: Oxford University Press.
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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. RAPPAPORT, H., WINTER, W. J. & HICKS, E. B. (1956) Follicular Lymphoma: A Pre-evaluation of its Position in the Scheme of Malignant Lymphomas, based on a Survey of 254 Cases. Cancer, N. Y., 9, 792. SCHEIN, P. S., CHABNER, B. A., CANELLOS, G. P., YOUNG, R. C., BERARD, C. & DEVITA, V. T. (1974) Potential for Prolonged Disease-free Survival Following Combination Chemotherapy of Non-Hodgkin's Lymphoma. Blood, 43, 181. YATES, F. (1934) Contingency Tables Involving Small Numbers and the Chi-Square Test. J. R. Statit. Soc., 1. Suppl., 217.
