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Prognostic factors for advanced diffuse histiocytic lymphoma following treatment with combination chemotherapy
CLINICAL STUDIES
Prognostic Factors for Advanced Diffuse Histiocytic Lymphoma Following Treatment with Combination Chemotherapy
RICHARD I. FISHER, M.D. VINCENT T. DeVITA,
Jr., M.D
BONNY L. JOHNSON, B.S.N. RICHARD SIMON, Ph.D. ROBERT C. YOUNG, M.D. Bethesda, Maryland
Combination chemotherapy can dramatically improve the survival of those patients with advanced diffuse histiocytic lymphoma who enter complete remission. The age, sex, stage, constitutional symptoms, sites of disease and tumor mass of 56 consecutive patients with advanced diffuse histiocytic lymphoma were analyzed as prognostic factors. Twenty-four patients received cytoxan, vincristine, procarbazine’and prednisone (C-MOPP) and 32 patients received bleomycin, adriamycin, cytoxan, vincristine and prednisone (BACOP). In 26 of 56 (46 per cent) a complete remission was achieved, in 21 of 56 (36 per cent) a partial remission and in nine of 56 (16 per cent) no response. Median survival with a complete remission was not reached at three years with 82 per cent still alive, but was significantly greater than with a partial remission (7.6 months median) or no response (3.2 months median). Survival of those with a partial remission and no response did not differ statistically. Stage IV disease, bone marrow involvement, gastrointestinal involvement and a tumor mass greater than 10 cm in diameter in a single location were all poor prognostic factors. No other analyzed factor significantly affected survival in this study. Complete response rates and survival curves for patients treated with C-MOPP were similar to those treated with BACOP. Prior to the late 1960’s, the non-Hodgkin’s lymphomas were classified as lymphosarcoma, reticulum cell sarcoma or giant follicular lymphoma. Rappaport [l] suggested that these lymphomas be divided into nodular and diffuse forms with the cellular infiltrates being termed lymphocytic, histiocytic or mixed. Recent clinicopathologic studies have verified the usefulness of these histologic subtypes in defining the natural history and prognosis of patients with non-Hodgkin’s
From the Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Richard I. Fisher, Medicine Branch, Bldg. lO/Rm. 12N226, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted August 24, 1976.
lymphomas [2,3]. Diffuse histiocytic lymphoma has been considered one of the most rapidly progressive and invariably fatal types of non-Hodgkin’s lymphoma. Less than 20 per cent of all patients with diffuse histiocytic lymphoma treated during the 1960’s were alive at five years [2]. Radiation therapy has led to a significant percentage of long-term survivors only in patients with stage I diffuse histiocytic lymphoma [4]. In only 5 per cent of patients with advanced disease has complete remission been achieved with single agent chemotherapy [ 51. However, recent studies of combination chemotherapy have demonstrated
August 1977
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PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
TABLE
I
Clinical Characteristics of Patient with Diffuse Histiocytic Lymphoma
Characteristics
NO.
Total patients Males Females
%
56 36 20
Age (yr) Median Range Stage IIE III IV Constitutional symptoms* A B Prior therapy Radiation Single agent chemotherapy Treatment regimen C-MOPP BACOP
$4 36
50 20-74 2 12 42
21 75
4
26 30
46 54
15 3
27 6
24 32
43 57
NOTE: C-MOPP = cytoxan, vincristine, procarbazine and prednisone. BACOP = bleomycin, adriamycin, cytoxan, vincristine and prednisone. *Fever, night sweats or loss of 10 per cent of total body weight.
that long-term survival can be achieved in from 37 to 48 per cent of patients with advanced stages of diffuse histiocytic lymphoma [6,7] We have analyzed 56 consecutive cases of diffuse histiocytic lymphoma in order to determine the clinical factors that influenced the response to combination chemotherapy and ultimately the survival of these patients. The insights gained from this analysis may lead to a more rational selection of existing combination chemotherapy for certain groups of these patients and may define certain patient populations for whom new modalities of treatment need to be developed. PATIENTS AND METHODS Fifty-six consecutive patients with advanced stages of diffuse histiocytic lymphoma were treated by the Medicine Branch of the National Cancer Institute between 1966 and 1975. Several clinical features of these cases are outlined in Table
TABLE
II
Extranodal Diffuse
178
Sites of Involvement
Histiocytic
by
Lymphoma
Site
No.
%
Bone marrow Skin Bone Gastrointestinal tract Pleura Lwer Lung Kidney Central nervous system Other
12 12 11 10 7 6 5 4 3 9
21 21 19 18 13 11 9 7 5 16
August 1977
The American Journal of Medicine
ET AL.
I. There were 36 men and 20 women. The median age of the patients was 50 years with a range of 20 to 74 years. The patients’ extent of disease was staged as outlined by the Ann Arbor Conference [ 81. Staging procedures before treatment included chest roentgenogram, lymphangiography, bone roentgenograms and scans, liver-spleen scans, bilateral iliac crest bone marrow aspirations and biopsy, and routine laboratory studies. Laparotomies were not routinely performed. Since 197 1, percutaneous liver biopsies were performed; if negative, the patient underwent peritoneoscopy with multiple liver biopsies. Lumbar punctures were performed in patients with a clinical presentation suggesting meningeal or central nervous system involvement. An x-ray series of the upper and lower gastrointestinal tract was carried out in the presence of abdominal pain, obstruction or extensive intra-abdominal lymph node involvement. Two patients were stage IIE, 12 patients were stage Ill, and 42 patients were stage IV. Fifty-four per cent had “B” symptomatology consisting of fever, sweats or loss of 10 per cent of total body weight. The extranodal sites of involvement prior to chemotherapy are shown in Table II. The bone marrow, skin, bone and gastrointestinal tract were each involved in approximately 20 per cent of the patients with diffuse histiocytic lymphoma. Less commonly involved sites were pleura, liver, spleen, lung, kidney and central nervous system. Between July 1966 and July 1972 patients with advanced stages of diffuse histiocytic lymphoma were routinely treated with a combination chemotherapy regimen referred to as C-MOPP [6]. This consisted of cyclophosphamide (650 mg/m2 given intravenously on days 1 and 8) vincristine (1.4 mg/m* given intravenously on days 1 and 8), procarbazine (100 mg/m* given orally for 14 days) and prednisone (40 mg/m* daily given orally for 14 days). After the two weeks of chemotherapy the patients received no therapy for 14 days and then the cycle was repeated. Eighteen patients were treated with C-MOPP. Six patients were treated with the MOPP regimen in which nitrogen mustard (6 mg/m* given intravenously on days 1 and 8) was substituted for cyclophosphamide. Since the complete response rates to MOPP and C-MOPP were identical [6], patients treated with either of these two regimens have been grouped together for the purpose of this study. Thus, 24 patients were treated with C-MOPP or MOPP; in this paper they are termed the C-MOPP treatment group. Between August 1972 and December 1975, 32 patients received a regimen termed BACOP [7]. Cyclophosphamide 650 mg/m*, adriamycin 25 mg/m* and vincristine 1.4 mg/m* were each given intravenously on days 1 and 8. Bleomycin 5 U/m* was given intravenously on days 15 and 22, and prednisone 60 mg/m* was given orally on days 15 through 29. The cycle was then repeated. All patients receiving either C-MOPP or BACOP were treated for a minimum of six cycles or two cycles following clinical remission. Therapy was then stopped, and one month later each patient was restaged for evidence of residual tumor. Restaging included repeat physical examination, laboratory studies, lymphangiogram and biopsy of all previously involved extranodal sites. Only those patients with no evidence of residual tumor at restaging have been called complete responders. No maintenance therapy was given. Those in whom there was a 50 per cent decrease in tumor
Volume 83
PROGNOSTIC FACTORS FOR ADVANCED
TOTAL 66
DEAD 32
l
DIFFUSE HISTIOCYTIC
LYMPHOMA-FISHER
ALL PATIENTS
TOTAL
0’
’ 6
1 12
16
24
30
36
42
ET AL.
46
54
0
60
6
12
DEAD
OCR
26
41
API? l NR
21 9
19; 9,P’
18
30
24
P6 001
36
16
48
42
54
60
MONTHS
MONTHS
fgure 1. Survival of a// patients with diffuse histiocytic lymphoma treated with combination chemotherapy.
igwe 2. Survival of patients with diffuse histiocytic phoma accozdjns to response to chemotherapy.
lym-
size and those attaining a complete clinical remission with microscopic disease present at restaging were considered partial responders. All other patients are classified as nonresponders. Survival was calculated from the start of therapy and plotted by the life table method. Survival curves were analyzed by the generalized Wilcoxon test [9]. Response rates were compared statistically by the Fisher exact test [ lo]. No patients were excluded because of toxicity, incomplete therapy or insufficient data.
The median survival of the 12 patients whose disease was in stage Ill, as shown in Figure 3, is not reached at three years with 66 per cent alive, but it is significantly greater than that of the 42 patients whose disease is in stage IV, with a median of 9.5 months (P = 0.02). Bone marrow involvement carries the worst prognosis of all the sites of disease in this series (Figure 4). All but one of the 12 patients with a positive bone
RESULTS The survival curve for all 56 patients with diffuse histiocytic lymphoma treated with combination chemotherapy is shown in Figure 1. The median survival is 11.4 months with 38 per cent of all patients alive at five years. The achievement of a histologically confirmed complete remission is the single most important determinant of survival as shown in Figure 2. Twenty-six patients or 46 per cent of the total group had complete remissions. Only four patients have had a relapse. Thus, the median survival of complete responders is not reached at three years with 82 per cent still alive but receiving no maintenance therapy. Twenty-one patients (38 per cent) had partial remissions with a median survival of 7.6 months. Nine patients had no response to chemotherapy and survived 3.2 months median. Survival of patients with a complete response is significantly better than those with either a partial response or no response at P
August
5
L--i_ 10
15
20
25
30
I 35
I~_~_.
40
45
5i-
5k
-6Od5
MONTHS I
Figure 3. Survival of patients with diffuse hisphoma according to stage.
1977
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Volume 63
179
PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
ET AL
Total Dead
i/,i,, 0
5
10
15
20
25
30
,
,
,
,
/,
35
40
45
50
55
, 60
10 0
65
0
" 5
10
" 15
20
' 25
' 30
" 35
40
" 45
50
" 55
60
' 65
MONTHS
MONTHS
,
igure 4. Survival of patients with diffuse histiocytic lymphoma according to presence or absence of marrow involvement.
igure 5. Survival of patients with diffuse histiocytic Iymphoma without marrow involvement according to presence or absence of gastrointestinal disease.
marrow are dead. Median survival with a positive bone marrow is 7.6 months versus 36 months for all other patients (P = 0.004). The only other site associated with a significantly shorter survival is the gastrointestinal tract (Figure 5). Excluding those patients with a positive bone marrow, the median survival of those with gastrointestinal disease is 9.5 months versus 50.8 months in those without it (P <0.05). There is no statistical correlation between age, sex or constitutional symptoms and response to chemotherapy. Likewise, no significant adverse effect on survival is detected from any other extranodal or nodal sites of disease. Survival of the patients previously treated with radiation therapy did not differ statistically from that in the previously untreated group. An attempt was made to determine the effect of tumor mass on the response to combination chemotherapy. There is no correlation between the total number of sites of nodal or extranodal tumor involvement and survival. However, there is a correlation between the size of a patient’s largest lesion and the prognosis. A huge mass was defined as a single site of tumor measuring greater than 10 cm in diameter. The complete response rate of the 20 patients whose largest lesion was greater than 10 cm in diameter is 25 per cent. This is significantly less than the 58 per cent complete response rate achieved in all other patients (P <0.025). The preceding data allow us to classify patients with
diffuse histiocytic lymphoma into three groups of approximately equal size as shown in Table III. Eighteen of the 56 patients presented with stage III disease or
160
August 1977
The American Journal of Medicine
stage IV disease by virtue of skin involvement only. The complete response rate for this group is 78 per cent. Twenty-one patients had stage IV disease involving the marrow or gastrointestinal tract. Their complete response rate is only 14 per cent. The remaining 17 patients had stage IV disease in other extranodal sites. Complete remissions are found in 53 per cent. All patients with advanced stages of diffuse histiocytic lymphoma were treated with C-MOPP between 1966 and 1972. From 1972 to the present time, BACOP has been utilized. In 46 per cent of the patients treated with C-MOPP and in 47 per cent of those treated with BACOP complete remission was achieved. Figure 6 demonstrates that the survival curves of the patients treated with the two regimens are identical. Therefore we have attempted to determine whether the prognostic factors are similar in each group. Table IV illustrates the number of patients in each TABLE
III
Complete Response Rate of Patients with Diffuse Histiocytic Lymphoma by Sites of Involvement Involvement
stage III + stage IVSki” Stage IVM arrow or gastrointestinal Stage 1VOther
Volume 63
tract
No.
%
14118 3121 9117
78 14 53
PROGNOSTIC FACTORS FOR ADVANCED
DIFFUSE HISTIOCYTIC
LYMPHOMA---FISHER
ET AL.
tients with stage II or III diffuse histiocytic lymphoma was only 25 per cent, and there were no survivals with Total
Dead
24
15
‘1 CMOPP
32
17
- BACOP
I
rp=8g
20
10
---2.
15
20
25
30
_L~_~
35
40
45
50
-l55
--.a
60
/
65
MONTHS
I
Figure 6. Survival of patients with diffuse histiocytic phoma treated with C-MOPP or BACOP.
Iym-
treatment group with a poor prognostic factor. Stage IV disease, bone marrow involvement and huge bulk disease are slightly more common in the patients treated with BACOP, although the differences are not statistically significant. Table V shows that there is no difference in the complete remission rate of patients classified as having stage Ill or stage IVskin, stage h/other they were or stage lVhnarrow or gastrointestinal tract whether treated
with C-MOPP or BACOP.
COMMENTS Diffuse histiocytic lymphoma has often been considered a rapidly progressive and invariably fatal disease. Before the Rappaport classification, these patients were included in the literature under reticulum cell sarcomas. Such studies are now difficult to interpret since diffuse histiocytic lymphoma only comprised about 55 per cent of the reticulum cell sarcomas [2]. Jones et al. ]4] obtained a five year survival of 65 per cent for patients with stage I diffuse histiocytic lymphoma treated by radiotherapy. However, their five year survival in paTABLE
IV
Poor Prognostic
Factors
Each Treatment
Group
stage IV disease. Patients with diffuse histiocytic lymphoma, who had failed prior radiotherapy or presented initially with stage IV disease, were treated with single agent chemotherapy at Stanford. The median survival was six months, and less than 20 per cent were alive at two years [ 51. In contrast, combination chemotherapy for patients with advanced stages of diffuse histiocytic lymphoma can lead to a significant percentage of complete remissions with long-term survival. DeVita et al. 161 reported a 4 1 per cent complete response rate in 27 patients with advanced diffuse histiocytic lymphoma treated with MOPP or C-MOPP. Thirty-seven per cent were alive and free of disease with no maintenance chemotherapy at five years. Schein et al. [ 71 obtained a 48 per cent complete response rate in 25 previously untreated patients with the BACOP regimen. None of the complete responders had a relapse with a median follow-up in excess of one year. Using cyclophosvincristine, phamide, methotrexate and cytosine arabinoside, Berd et al. [ 111 obtained six complete remissions in eight patients with diffuse histiocytic lymphoma. These patients were followed for up to five years with only one relapse among the complete responders. The median survival of the 56 patients in the study is 11.4 months. However, of more importance is the fact that a significant per cent of patients experience prolonged disease-free survival, i.e., 38 per cent are alive at five years. When the complete response rate of new combinations exceeds 50 per cent, a marked change in median survival will occur. This group of long-term survivors consists entirely of patients in whom a histologically documented complete remission was achieved. In fact, the survival of patients with a partial response is no different than that of the nonresponders. We have analyzed these cases in detail in order to determine what pretreatment clinical factors predicted a patient’s response to combination chemotherapy. Patients with stage III and stage IV disease have been grouped together in many treatment protocols. Yet this analysis clearly demonstrates that the survival of patients with stage III disease is significantly better than
in
TABLE
V
Complete
Response Rate by Site in
Each Treatment
site Stage IV Bone marrow Gastrolntestlnal Huye mass
tlact
Group
BACOP ~ ~~ ~~~~~
C-MOPP
C-MOPP
No.
%
No.
%
16124 4i24 5124 8124
67 17 21 33
26132 8132 5132 12132
81 25 16 38
Site Stage III + stage lVSkln stage IVM arrow or gasfrolnfesfinal Stage lVOrher
August 1977
rracf
The American Journal of Medicine
BACOP
No.
%
No.
%
8/10 018 3’6
SO 0 50
618 3113 6111
75 23 55
Volume 63
191
PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
the survival of patients with stage IV disease (P = 0.02). Future studies should continue to adequately stage patients with advanced diffuse histiocytic lymphoma and stratify them accordingly. A positive bone marrow biopsy carries the worst prognosis of all the extranodal sites of tumor in this study. Eleven of 12 patients with stage lVMarrowhave already died. Bunn et al. [ 121 reported that in 65 per cent of the patients with diffuse histiocytic or undifferentiated lymphoma with bone marrow involvement, central nervous system lymphoma developed. Prior studies reported a median survival of only three months following the diagnosis of central nervous system lymphoma [ 131. The only other extranodal site in this study associated with a poor chance of long-term survival is the gastrointestinal tract. Often these patients had massive involvement of the bowel and retroperitoneal lymph nodes. Following combination chemotherapy, they frequently had rapid tumor lysis complicated by bowel perforation with sepsis. It must be noted that all these patients had advanced stages of lymphoma. They do not represent patients with localized gastrointestinal disease who may be cured by radiotherapy [ 141. No other extranodal sites statistically affected the chances of long-term survival in this study. The development of central nervous system disease following treatment is well recognized as a poor prognostic indicator [ 131. Since there were only three patients with central nervous system involvement at presentation, no statistically significant effect on response to combination chemotherapy could be detected. Survival was adversely affected by a huge mass of tumor greater than 10 cm in diameter in a single location. Frequently these huge masses were located near vital organs so that
ET AL.
adequate tumoricidal radiation therapy could not be given as the only treatment modality. The response rate and survival curve in patients treated with C-MOPP are identical to those treated with BACOP. Since the C-MOPP and BACOP trials were conducted sequentially, a comparison of the prognostic factors in each group was performed. Although the patients treated with BACOP had a slightly increased incidence of stage IV disease, bone marrow involvement and huge masses, there were no statistically significant differences in the two groups. The preceding analysis permits the division of patients with advanced stages of diffuse histiocytic lymphoma prognostically into three groups of relatively equal size. Patients, who are stage Ill or stage IV by virtue of skin disease only, have a 75 per cent to 80 per cent chance of complete remission with either C-MOPP or BACOP. Because C-MOPP lacks the potential cardiac and pulmonary complications from adriamycin or bleomycin, chemotherapy with C-MOPP can be recommended for these patients. The complete response rate for patients with stage IV Marrow or gastrointestinal tract is only 14 per cent. This suggests that neither regimen is adequate for this population and that new treatment protocols should be developed and investigated. The response rate for all other patients with stage IV disease is 50 per cent. A prospective randomized comparison of C-MOPP and BACOP will be necessary to determine the relative merits of each regimen in larger numbers of patients. Finally, the results achieved by combination chemotherapy in advanced stages of diffuse histiocytic lymphoma provide a rationale for testing the value of combination chemotherapy in patients with stage I or stage II diffuse histiocytic lymphoma.
REFERENCES 1.
2.
3.
4. 5.
6.
7.
182
Rappaport H: Atlas of Tumor Pathology, sect II, fast 8, Washington, D.C., Armed Forces Institute of Pathology, 1966. Jones SE, Fuks Z, Bull M, et al.: Non-Hodgkin’s lymphomas. IV. Clinicopathologic correlations in 405 cases. Cancer 31: 806, 1973. Schein PS, Chabner BA, Canellos GP, et al.: Potential for prolonged disease-free survival following combination chemotherapy of non-Hodgkin’s lymphomas. Blood 43: 181, 1974. Jones SE, Fuks Z, Kaplan HS, et al.: Non-Hodgkin’s lymphomas. V. Results of radiotherapy. Cancer 32: 682, 1973. Jones SE, Rosenberg SA, Kaplan HS, et al.: Non-Hodgkin’s lymphomas. II. Single agent chemotherapy. Cancer 30: 31, 1972. DeVita VT, Canellos GP, Chabner B, et al.: Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1: 248, 1975. Schein PS, DeVita VT Jr, Hubbard S, et al.: Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of
August 1977
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8.
9.
10. 11.
12.
13. 14.
Volume 63
advanced diffuse histiocytic lymphoma. Ann Intern Med 85: 417, 1976. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31: 1860.1971. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203, 1965. Cox DR: Analysis of Binary Data. London, Methuen, 1970. p 48. Berd D, Cornog J, DeConti RC, et al.: Long term remission in diffuse histiocytic lymphoma treated with combination sequential chemotherapy. Cancer 35: 1050, 1975. Bunn PA, Schein PS, Banks PM. et al.: Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: leukemia revisited. Blood 47: 3, 1976. Griffin JW, Thomson RW, Mfchiison fvU,et al.: Lymphomatous leptomeningitis. Am J Med 51: 200, 1971. Freeman C. Berg JW, Cutler SJ: Occurrence and prognosis of extranodal lymphomas. Cancer 29: 252, 1972.
Prognostic Factors for Advanced Diffuse Histiocytic Lymphoma Following Treatment with Combination Chemotherapy
RICHARD I. FISHER, M.D. VINCENT T. DeVITA,
Jr., M.D
BONNY L. JOHNSON, B.S.N. RICHARD SIMON, Ph.D. ROBERT C. YOUNG, M.D. Bethesda, Maryland
Combination chemotherapy can dramatically improve the survival of those patients with advanced diffuse histiocytic lymphoma who enter complete remission. The age, sex, stage, constitutional symptoms, sites of disease and tumor mass of 56 consecutive patients with advanced diffuse histiocytic lymphoma were analyzed as prognostic factors. Twenty-four patients received cytoxan, vincristine, procarbazine’and prednisone (C-MOPP) and 32 patients received bleomycin, adriamycin, cytoxan, vincristine and prednisone (BACOP). In 26 of 56 (46 per cent) a complete remission was achieved, in 21 of 56 (36 per cent) a partial remission and in nine of 56 (16 per cent) no response. Median survival with a complete remission was not reached at three years with 82 per cent still alive, but was significantly greater than with a partial remission (7.6 months median) or no response (3.2 months median). Survival of those with a partial remission and no response did not differ statistically. Stage IV disease, bone marrow involvement, gastrointestinal involvement and a tumor mass greater than 10 cm in diameter in a single location were all poor prognostic factors. No other analyzed factor significantly affected survival in this study. Complete response rates and survival curves for patients treated with C-MOPP were similar to those treated with BACOP. Prior to the late 1960’s, the non-Hodgkin’s lymphomas were classified as lymphosarcoma, reticulum cell sarcoma or giant follicular lymphoma. Rappaport [l] suggested that these lymphomas be divided into nodular and diffuse forms with the cellular infiltrates being termed lymphocytic, histiocytic or mixed. Recent clinicopathologic studies have verified the usefulness of these histologic subtypes in defining the natural history and prognosis of patients with non-Hodgkin’s
From the Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Richard I. Fisher, Medicine Branch, Bldg. lO/Rm. 12N226, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted August 24, 1976.
lymphomas [2,3]. Diffuse histiocytic lymphoma has been considered one of the most rapidly progressive and invariably fatal types of non-Hodgkin’s lymphoma. Less than 20 per cent of all patients with diffuse histiocytic lymphoma treated during the 1960’s were alive at five years [2]. Radiation therapy has led to a significant percentage of long-term survivors only in patients with stage I diffuse histiocytic lymphoma [4]. In only 5 per cent of patients with advanced disease has complete remission been achieved with single agent chemotherapy [ 51. However, recent studies of combination chemotherapy have demonstrated
August 1977
The American Journal of Medicine
‘Volume 63
177
PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
TABLE
I
Clinical Characteristics of Patient with Diffuse Histiocytic Lymphoma
Characteristics
NO.
Total patients Males Females
%
56 36 20
Age (yr) Median Range Stage IIE III IV Constitutional symptoms* A B Prior therapy Radiation Single agent chemotherapy Treatment regimen C-MOPP BACOP
$4 36
50 20-74 2 12 42
21 75
4
26 30
46 54
15 3
27 6
24 32
43 57
NOTE: C-MOPP = cytoxan, vincristine, procarbazine and prednisone. BACOP = bleomycin, adriamycin, cytoxan, vincristine and prednisone. *Fever, night sweats or loss of 10 per cent of total body weight.
that long-term survival can be achieved in from 37 to 48 per cent of patients with advanced stages of diffuse histiocytic lymphoma [6,7] We have analyzed 56 consecutive cases of diffuse histiocytic lymphoma in order to determine the clinical factors that influenced the response to combination chemotherapy and ultimately the survival of these patients. The insights gained from this analysis may lead to a more rational selection of existing combination chemotherapy for certain groups of these patients and may define certain patient populations for whom new modalities of treatment need to be developed. PATIENTS AND METHODS Fifty-six consecutive patients with advanced stages of diffuse histiocytic lymphoma were treated by the Medicine Branch of the National Cancer Institute between 1966 and 1975. Several clinical features of these cases are outlined in Table
TABLE
II
Extranodal Diffuse
178
Sites of Involvement
Histiocytic
by
Lymphoma
Site
No.
%
Bone marrow Skin Bone Gastrointestinal tract Pleura Lwer Lung Kidney Central nervous system Other
12 12 11 10 7 6 5 4 3 9
21 21 19 18 13 11 9 7 5 16
August 1977
The American Journal of Medicine
ET AL.
I. There were 36 men and 20 women. The median age of the patients was 50 years with a range of 20 to 74 years. The patients’ extent of disease was staged as outlined by the Ann Arbor Conference [ 81. Staging procedures before treatment included chest roentgenogram, lymphangiography, bone roentgenograms and scans, liver-spleen scans, bilateral iliac crest bone marrow aspirations and biopsy, and routine laboratory studies. Laparotomies were not routinely performed. Since 197 1, percutaneous liver biopsies were performed; if negative, the patient underwent peritoneoscopy with multiple liver biopsies. Lumbar punctures were performed in patients with a clinical presentation suggesting meningeal or central nervous system involvement. An x-ray series of the upper and lower gastrointestinal tract was carried out in the presence of abdominal pain, obstruction or extensive intra-abdominal lymph node involvement. Two patients were stage IIE, 12 patients were stage Ill, and 42 patients were stage IV. Fifty-four per cent had “B” symptomatology consisting of fever, sweats or loss of 10 per cent of total body weight. The extranodal sites of involvement prior to chemotherapy are shown in Table II. The bone marrow, skin, bone and gastrointestinal tract were each involved in approximately 20 per cent of the patients with diffuse histiocytic lymphoma. Less commonly involved sites were pleura, liver, spleen, lung, kidney and central nervous system. Between July 1966 and July 1972 patients with advanced stages of diffuse histiocytic lymphoma were routinely treated with a combination chemotherapy regimen referred to as C-MOPP [6]. This consisted of cyclophosphamide (650 mg/m2 given intravenously on days 1 and 8) vincristine (1.4 mg/m* given intravenously on days 1 and 8), procarbazine (100 mg/m* given orally for 14 days) and prednisone (40 mg/m* daily given orally for 14 days). After the two weeks of chemotherapy the patients received no therapy for 14 days and then the cycle was repeated. Eighteen patients were treated with C-MOPP. Six patients were treated with the MOPP regimen in which nitrogen mustard (6 mg/m* given intravenously on days 1 and 8) was substituted for cyclophosphamide. Since the complete response rates to MOPP and C-MOPP were identical [6], patients treated with either of these two regimens have been grouped together for the purpose of this study. Thus, 24 patients were treated with C-MOPP or MOPP; in this paper they are termed the C-MOPP treatment group. Between August 1972 and December 1975, 32 patients received a regimen termed BACOP [7]. Cyclophosphamide 650 mg/m*, adriamycin 25 mg/m* and vincristine 1.4 mg/m* were each given intravenously on days 1 and 8. Bleomycin 5 U/m* was given intravenously on days 15 and 22, and prednisone 60 mg/m* was given orally on days 15 through 29. The cycle was then repeated. All patients receiving either C-MOPP or BACOP were treated for a minimum of six cycles or two cycles following clinical remission. Therapy was then stopped, and one month later each patient was restaged for evidence of residual tumor. Restaging included repeat physical examination, laboratory studies, lymphangiogram and biopsy of all previously involved extranodal sites. Only those patients with no evidence of residual tumor at restaging have been called complete responders. No maintenance therapy was given. Those in whom there was a 50 per cent decrease in tumor
Volume 83
PROGNOSTIC FACTORS FOR ADVANCED
TOTAL 66
DEAD 32
l
DIFFUSE HISTIOCYTIC
LYMPHOMA-FISHER
ALL PATIENTS
TOTAL
0’
’ 6
1 12
16
24
30
36
42
ET AL.
46
54
0
60
6
12
DEAD
OCR
26
41
API? l NR
21 9
19; 9,P’
18
30
24
P6 001
36
16
48
42
54
60
MONTHS
MONTHS
fgure 1. Survival of a// patients with diffuse histiocytic lymphoma treated with combination chemotherapy.
igwe 2. Survival of patients with diffuse histiocytic phoma accozdjns to response to chemotherapy.
lym-
size and those attaining a complete clinical remission with microscopic disease present at restaging were considered partial responders. All other patients are classified as nonresponders. Survival was calculated from the start of therapy and plotted by the life table method. Survival curves were analyzed by the generalized Wilcoxon test [9]. Response rates were compared statistically by the Fisher exact test [ lo]. No patients were excluded because of toxicity, incomplete therapy or insufficient data.
The median survival of the 12 patients whose disease was in stage Ill, as shown in Figure 3, is not reached at three years with 66 per cent alive, but it is significantly greater than that of the 42 patients whose disease is in stage IV, with a median of 9.5 months (P = 0.02). Bone marrow involvement carries the worst prognosis of all the sites of disease in this series (Figure 4). All but one of the 12 patients with a positive bone
RESULTS The survival curve for all 56 patients with diffuse histiocytic lymphoma treated with combination chemotherapy is shown in Figure 1. The median survival is 11.4 months with 38 per cent of all patients alive at five years. The achievement of a histologically confirmed complete remission is the single most important determinant of survival as shown in Figure 2. Twenty-six patients or 46 per cent of the total group had complete remissions. Only four patients have had a relapse. Thus, the median survival of complete responders is not reached at three years with 82 per cent still alive but receiving no maintenance therapy. Twenty-one patients (38 per cent) had partial remissions with a median survival of 7.6 months. Nine patients had no response to chemotherapy and survived 3.2 months median. Survival of patients with a complete response is significantly better than those with either a partial response or no response at P
August
5
L--i_ 10
15
20
25
30
I 35
I~_~_.
40
45
5i-
5k
-6Od5
MONTHS I
Figure 3. Survival of patients with diffuse hisphoma according to stage.
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179
PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
ET AL
Total Dead
i/,i,, 0
5
10
15
20
25
30
,
,
,
,
/,
35
40
45
50
55
, 60
10 0
65
0
" 5
10
" 15
20
' 25
' 30
" 35
40
" 45
50
" 55
60
' 65
MONTHS
MONTHS
,
igure 4. Survival of patients with diffuse histiocytic lymphoma according to presence or absence of marrow involvement.
igure 5. Survival of patients with diffuse histiocytic Iymphoma without marrow involvement according to presence or absence of gastrointestinal disease.
marrow are dead. Median survival with a positive bone marrow is 7.6 months versus 36 months for all other patients (P = 0.004). The only other site associated with a significantly shorter survival is the gastrointestinal tract (Figure 5). Excluding those patients with a positive bone marrow, the median survival of those with gastrointestinal disease is 9.5 months versus 50.8 months in those without it (P <0.05). There is no statistical correlation between age, sex or constitutional symptoms and response to chemotherapy. Likewise, no significant adverse effect on survival is detected from any other extranodal or nodal sites of disease. Survival of the patients previously treated with radiation therapy did not differ statistically from that in the previously untreated group. An attempt was made to determine the effect of tumor mass on the response to combination chemotherapy. There is no correlation between the total number of sites of nodal or extranodal tumor involvement and survival. However, there is a correlation between the size of a patient’s largest lesion and the prognosis. A huge mass was defined as a single site of tumor measuring greater than 10 cm in diameter. The complete response rate of the 20 patients whose largest lesion was greater than 10 cm in diameter is 25 per cent. This is significantly less than the 58 per cent complete response rate achieved in all other patients (P <0.025). The preceding data allow us to classify patients with
diffuse histiocytic lymphoma into three groups of approximately equal size as shown in Table III. Eighteen of the 56 patients presented with stage III disease or
160
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The American Journal of Medicine
stage IV disease by virtue of skin involvement only. The complete response rate for this group is 78 per cent. Twenty-one patients had stage IV disease involving the marrow or gastrointestinal tract. Their complete response rate is only 14 per cent. The remaining 17 patients had stage IV disease in other extranodal sites. Complete remissions are found in 53 per cent. All patients with advanced stages of diffuse histiocytic lymphoma were treated with C-MOPP between 1966 and 1972. From 1972 to the present time, BACOP has been utilized. In 46 per cent of the patients treated with C-MOPP and in 47 per cent of those treated with BACOP complete remission was achieved. Figure 6 demonstrates that the survival curves of the patients treated with the two regimens are identical. Therefore we have attempted to determine whether the prognostic factors are similar in each group. Table IV illustrates the number of patients in each TABLE
III
Complete Response Rate of Patients with Diffuse Histiocytic Lymphoma by Sites of Involvement Involvement
stage III + stage IVSki” Stage IVM arrow or gastrointestinal Stage 1VOther
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tract
No.
%
14118 3121 9117
78 14 53
PROGNOSTIC FACTORS FOR ADVANCED
DIFFUSE HISTIOCYTIC
LYMPHOMA---FISHER
ET AL.
tients with stage II or III diffuse histiocytic lymphoma was only 25 per cent, and there were no survivals with Total
Dead
24
15
‘1 CMOPP
32
17
- BACOP
I
rp=8g
20
10
---2.
15
20
25
30
_L~_~
35
40
45
50
-l55
--.a
60
/
65
MONTHS
I
Figure 6. Survival of patients with diffuse histiocytic phoma treated with C-MOPP or BACOP.
Iym-
treatment group with a poor prognostic factor. Stage IV disease, bone marrow involvement and huge bulk disease are slightly more common in the patients treated with BACOP, although the differences are not statistically significant. Table V shows that there is no difference in the complete remission rate of patients classified as having stage Ill or stage IVskin, stage h/other they were or stage lVhnarrow or gastrointestinal tract whether treated
with C-MOPP or BACOP.
COMMENTS Diffuse histiocytic lymphoma has often been considered a rapidly progressive and invariably fatal disease. Before the Rappaport classification, these patients were included in the literature under reticulum cell sarcomas. Such studies are now difficult to interpret since diffuse histiocytic lymphoma only comprised about 55 per cent of the reticulum cell sarcomas [2]. Jones et al. ]4] obtained a five year survival of 65 per cent for patients with stage I diffuse histiocytic lymphoma treated by radiotherapy. However, their five year survival in paTABLE
IV
Poor Prognostic
Factors
Each Treatment
Group
stage IV disease. Patients with diffuse histiocytic lymphoma, who had failed prior radiotherapy or presented initially with stage IV disease, were treated with single agent chemotherapy at Stanford. The median survival was six months, and less than 20 per cent were alive at two years [ 51. In contrast, combination chemotherapy for patients with advanced stages of diffuse histiocytic lymphoma can lead to a significant percentage of complete remissions with long-term survival. DeVita et al. 161 reported a 4 1 per cent complete response rate in 27 patients with advanced diffuse histiocytic lymphoma treated with MOPP or C-MOPP. Thirty-seven per cent were alive and free of disease with no maintenance chemotherapy at five years. Schein et al. [ 71 obtained a 48 per cent complete response rate in 25 previously untreated patients with the BACOP regimen. None of the complete responders had a relapse with a median follow-up in excess of one year. Using cyclophosvincristine, phamide, methotrexate and cytosine arabinoside, Berd et al. [ 111 obtained six complete remissions in eight patients with diffuse histiocytic lymphoma. These patients were followed for up to five years with only one relapse among the complete responders. The median survival of the 56 patients in the study is 11.4 months. However, of more importance is the fact that a significant per cent of patients experience prolonged disease-free survival, i.e., 38 per cent are alive at five years. When the complete response rate of new combinations exceeds 50 per cent, a marked change in median survival will occur. This group of long-term survivors consists entirely of patients in whom a histologically documented complete remission was achieved. In fact, the survival of patients with a partial response is no different than that of the nonresponders. We have analyzed these cases in detail in order to determine what pretreatment clinical factors predicted a patient’s response to combination chemotherapy. Patients with stage III and stage IV disease have been grouped together in many treatment protocols. Yet this analysis clearly demonstrates that the survival of patients with stage III disease is significantly better than
in
TABLE
V
Complete
Response Rate by Site in
Each Treatment
site Stage IV Bone marrow Gastrolntestlnal Huye mass
tlact
Group
BACOP ~ ~~ ~~~~~
C-MOPP
C-MOPP
No.
%
No.
%
16124 4i24 5124 8124
67 17 21 33
26132 8132 5132 12132
81 25 16 38
Site Stage III + stage lVSkln stage IVM arrow or gasfrolnfesfinal Stage lVOrher
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BACOP
No.
%
No.
%
8/10 018 3’6
SO 0 50
618 3113 6111
75 23 55
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PROGNOSTIC FACTORS FOR ADVANCED DIFFUSE HISTIOCYTIC LYMPHOMA-FISHER
the survival of patients with stage IV disease (P = 0.02). Future studies should continue to adequately stage patients with advanced diffuse histiocytic lymphoma and stratify them accordingly. A positive bone marrow biopsy carries the worst prognosis of all the extranodal sites of tumor in this study. Eleven of 12 patients with stage lVMarrowhave already died. Bunn et al. [ 121 reported that in 65 per cent of the patients with diffuse histiocytic or undifferentiated lymphoma with bone marrow involvement, central nervous system lymphoma developed. Prior studies reported a median survival of only three months following the diagnosis of central nervous system lymphoma [ 131. The only other extranodal site in this study associated with a poor chance of long-term survival is the gastrointestinal tract. Often these patients had massive involvement of the bowel and retroperitoneal lymph nodes. Following combination chemotherapy, they frequently had rapid tumor lysis complicated by bowel perforation with sepsis. It must be noted that all these patients had advanced stages of lymphoma. They do not represent patients with localized gastrointestinal disease who may be cured by radiotherapy [ 141. No other extranodal sites statistically affected the chances of long-term survival in this study. The development of central nervous system disease following treatment is well recognized as a poor prognostic indicator [ 131. Since there were only three patients with central nervous system involvement at presentation, no statistically significant effect on response to combination chemotherapy could be detected. Survival was adversely affected by a huge mass of tumor greater than 10 cm in diameter in a single location. Frequently these huge masses were located near vital organs so that
ET AL.
adequate tumoricidal radiation therapy could not be given as the only treatment modality. The response rate and survival curve in patients treated with C-MOPP are identical to those treated with BACOP. Since the C-MOPP and BACOP trials were conducted sequentially, a comparison of the prognostic factors in each group was performed. Although the patients treated with BACOP had a slightly increased incidence of stage IV disease, bone marrow involvement and huge masses, there were no statistically significant differences in the two groups. The preceding analysis permits the division of patients with advanced stages of diffuse histiocytic lymphoma prognostically into three groups of relatively equal size. Patients, who are stage Ill or stage IV by virtue of skin disease only, have a 75 per cent to 80 per cent chance of complete remission with either C-MOPP or BACOP. Because C-MOPP lacks the potential cardiac and pulmonary complications from adriamycin or bleomycin, chemotherapy with C-MOPP can be recommended for these patients. The complete response rate for patients with stage IV Marrow or gastrointestinal tract is only 14 per cent. This suggests that neither regimen is adequate for this population and that new treatment protocols should be developed and investigated. The response rate for all other patients with stage IV disease is 50 per cent. A prospective randomized comparison of C-MOPP and BACOP will be necessary to determine the relative merits of each regimen in larger numbers of patients. Finally, the results achieved by combination chemotherapy in advanced stages of diffuse histiocytic lymphoma provide a rationale for testing the value of combination chemotherapy in patients with stage I or stage II diffuse histiocytic lymphoma.
REFERENCES 1.
2.
3.
4. 5.
6.
7.
182
Rappaport H: Atlas of Tumor Pathology, sect II, fast 8, Washington, D.C., Armed Forces Institute of Pathology, 1966. Jones SE, Fuks Z, Bull M, et al.: Non-Hodgkin’s lymphomas. IV. Clinicopathologic correlations in 405 cases. Cancer 31: 806, 1973. Schein PS, Chabner BA, Canellos GP, et al.: Potential for prolonged disease-free survival following combination chemotherapy of non-Hodgkin’s lymphomas. Blood 43: 181, 1974. Jones SE, Fuks Z, Kaplan HS, et al.: Non-Hodgkin’s lymphomas. V. Results of radiotherapy. Cancer 32: 682, 1973. Jones SE, Rosenberg SA, Kaplan HS, et al.: Non-Hodgkin’s lymphomas. II. Single agent chemotherapy. Cancer 30: 31, 1972. DeVita VT, Canellos GP, Chabner B, et al.: Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1: 248, 1975. Schein PS, DeVita VT Jr, Hubbard S, et al.: Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of
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advanced diffuse histiocytic lymphoma. Ann Intern Med 85: 417, 1976. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31: 1860.1971. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203, 1965. Cox DR: Analysis of Binary Data. London, Methuen, 1970. p 48. Berd D, Cornog J, DeConti RC, et al.: Long term remission in diffuse histiocytic lymphoma treated with combination sequential chemotherapy. Cancer 35: 1050, 1975. Bunn PA, Schein PS, Banks PM. et al.: Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: leukemia revisited. Blood 47: 3, 1976. Griffin JW, Thomson RW, Mfchiison fvU,et al.: Lymphomatous leptomeningitis. Am J Med 51: 200, 1971. Freeman C. Berg JW, Cutler SJ: Occurrence and prognosis of extranodal lymphomas. Cancer 29: 252, 1972.