1. No category

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Stages I and I1 Diffuse Large Cell Lymphomas: Prognostic Factors and
Long-Term Results With CHOP-Bleo and Radiotherapy
By William S. Velasquez, Lillian M. Fuller, Sundar Jagannath, Susan L. Tucker, Luceil B. North, Fredrick B. Hagemeister,
Peter McLaughlin, Forrest Swan, John R. Redman, Maria A. Rodriguez, and Fernando Cabanillas
One hundred forty-seven patients with Ann Arbor stages I
and II diffuse large cell lymphoma (DLCL) were treated with
combinationchemotherapy consisting of cyclophosphamide,
doxyrubicin, prednisone, and low-dose bleomycin (CHOPBleo) and involved-fieldradiation (IF XRT) between 1974 and
1984. A complete remission (CR) was attained by 54 of 57
patients with stage I disease and by 78 of 90 patients with
stage II disease. Thirty-five patients had relapsing disease
that occurred within 3 years in 31. The overall 10-year
survival rate, counting all deaths, for patients with stage I
was 72% as compared with 43% for patients with stage II
(P < .01). Determinate survival rates, censoring eight unrelated deaths, were similar to the overall survival rates: 77%
and 51%. respectively. A multivariate analysis identified
three independentprognosticfactors: age, tumor extent, and
serum lactic dehydrogenase (LDH) level. When the combined
effect of tumor extent and LDH level were taken into consideration in the analysis, three risk groups for survival were
identified. The best group, which consists of patients with
minimum tumor and normal LDH levels, had a 10-year
determinate survival of 79%. Patients with extensive tumors
and elevated LDH levels had the poorestsurvival rate of 44%.
An intermediate-risk group with a determinant survival of
62% was composed of patients with either extensivetumors
or elevated LDH levels. These differences demonstrate the
need to develop different treatment strategies based on risk
factors for survival for patients with apparently localizedAnn
Arbor stages 1/11 DLCL.
o 1991 by The American Society of Hematology.
P
Ann Arbor stage.7 In a previous publication, we reported
that age, tumor burden, and LDH level influenced prognosis for patients with stages I11 and IV disease.’ Our purpose
in reporting our long-term results for CHOP-Bleo and
irradiation treatment for stage 1/11 disease is to demonstrate the role of tumor burden and other prognostic factors
for patients with early-stage disease.
ATIENTS WITH Ann Arbor stages I and I1 diffuse
large cell lymphoma (DLCL) represent a significant
proportion of patients with intermediate-grade lymphomas.
The traditional therapeutic approach was to treat this
seemingly localized malignancy with radiation, and although local control was frequently achieved, most patients
had a relapse at distant sites.’.’ When combination chemotherapy regimens proved effective treatment for advanced
stages of DLCL, it became obvious that such treatment
should be tried for early-stage disease either alone or in
combination with radiotherapy. Although initial results
with this approach have been encouraging: few long-term
studies of results of treatment with chemotherapy and
radiotherapy (XRT) for patients with Ann Arbor stage 1/11
DLCL have been published. In some of these reports, bulky
disease and certain other clinical features were identified as
adverse prognostic
In 1974, we initiated for patients with stages I/III DLCL a
combined modality treatment program of cyclophosphamide, Adriamycin, vincristine, prednisone, and bleomycin
(CHOP-Bleo) and involved-field XRT (IF XRT). Patients
with stage IV were treated with CHOP-Bleo ~ n l y . Re~.~
cently, we reported our results for all patients treated
according to this plan and showed that outcome was
influenced more by age and the total extent of disease as
well as the serum lactic dehydrogenase (LDH) level than by
From the Departmentsof Hematology,Radiotherapy,Biomathematics, and Diagnostic Radiology, University of Texas M.D. Anderson
Cancer Center, Houston, TX; and University of Arkansas for Medical
Sciences, Little Rock.
Submitted May 14, 1990; accepted October 24, 1990.
Address reprint requests to William S. Velasquez, MD, Department
of Hematology, Box 68, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 I991 by The American Society of Hematology.
0006-4971I91/7705-O027$3.OOJO
942
MATERIALS AND METHODS
Between 1974 and 1984,147 adult patients with Ann Arbor stage
1/11 DLCL were treated in this study with chemotherapy and
radiotherapy. Prerequisites were that patients agreed to give
informed consent and that no contraindication existed to their
receiving the prescribed treatment.
Staging procedures included complete blood cell count, serum
chemistry analysis, posteroanterior and lateral chest roentgenograms, bilateral lymphangiography, and liver scans. After 1978,
abdominal computed tomography (CT) was performed routinely.
Bone marrow (BM) biopsies were performed in all patients.
Additional radiologic studies were performed, when indicated, to
investigate specific areas of suspected disease. Before 1978, 11
patients had staging laparotomies as part of the protocol design.
After 1978, staging laparotomywas not used.
Treatment
All patients received CHOP-Bleo9 and IF XRT. Between 1974
and 1978, 37 patients with peripheral nodal or extranodal disease
were first treated with XRT. This was followed by eight cycles of
CHOP-Bleo and then four cycles of cyclophosphamide, vincristine,
and prednisone (COP). Patients with mediastinal or abdominal
disease presentations initially received four cycles of CHOP-Bleo
before XRT to one or more involved regions. The number of
disease sites radiated depended on location and extent of involvement. XRT was followed by another four cycles of CHOP-Bleo;
XRT was then administered to any previously unirradiated sites of
disease. Treatment was completed with four cycles of COP. After
1978, all patients were treated in this way regardless of location or
extent of disease. This decision was based on our observation that
DLCL disseminated rapidly after initial treatment with XRT in
some patients. This was particularly true of patients who had bulky
initial disease.
XRT fields and doses. XRT treatment was administered with
“CO or 6 MV using linear accelerator equipment. The fields were
Blood, Vol77, No 5 (March 1). 1991: pp 942-947
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943
LARGE CELL LYMPHOMA STAGE 1-11 PROGNOSTIC FACTORS
designed to cover the initial gross disease with minimal margins.
Prophylactic treatment was not administered to adjacent lymph
node-bearing regions. Tumor doses depended on whether XRT
was given before or after chemotherapy and on the response to
chemotherapy. For most patients who obtained complete remission (CR) during chemotherapy, the irradiation doses were -40
Gy. Patients initially treated with XRT for peripheral presentations or who had residual disease after chemotherapy received
slightly higher doses (-50 GY). Treatment to these upper torso
presentations was initiated at a daily dose rate of 200 cGY. For
patients with lower torso disease, treatment was administered at a
daily dose rate of 150 cGY. After a tumor dose of 30 GY, the
treatment field size was reduced to 40 GY before treatment was
completed.
Estimation of Extent of Disease in Involved Sites
The extent of disease in both nodal and extranodal sites was
recorded during the initial assessment for each patient. Usually
tumor extent could be measured either directly or from radiographic images. Retrospectively, measurable disease was classified
as extensive if it measured 2 7 cm rather than the 10-cm criterion
used by other investigators! Our decision to use 2 7 cm was based
on a preliminary analysis in which we compared results for bulky
and nonbulky disease using both 7 and 10 cm. Differences were
apparent when we used 2 7 cm to classify the extent of nodal
disease. To measure abdominal disease, we used 2 7 cm, but
patients with radiographic evidence of disease in both the paraaortic and the pelvic nodes were also considered to have extensive
disease (Table 1).
Estimating the extent of mediastinal disease from posteroanterior and lateral chest roentgenograms proved to be less accurate, as
shown by CT and diagnostic thoracotomy findings, which usually
demonstrated more extensive involvement. This observation may
explain the fact that any involvement in the mediastinum detected
in a routine anteroposterior chest roentgenogram proved to be an
unfavorable prognostic feature. Thus, for the purpose of this
analysis, we elected to categorize any mediastinal involvement as
extensive.
Because extranodal head presentations tend to infiltrate surrounding structures, they are frequently difficult to measure with
any degree of accuracy. Based on our previously reported findings
and those of other investigators demonstrating that the prognosis
for patients with stage 1/11extranodal head and neck presentations
was related to the TNM AJCIo classification, we used this staging
system for denoting the extent of extranodal head and neck
disease. Thus, T3and T, extranodal head lesions were categorized
as extensive.
Overall Tumor Extent
Stage
Characteristics
I
II
Total
57
90
147
31
26
33
6
34
43
47
40
14
39
74
73
73
20
73
41
16
48
42
89
58
30
27
24
66
54
93
All patients
Age
< 56 (y)
t 56
Males
Constitutionalsymptoms (6)
Extranodal presentations
Serum LDH
Normal
High
Tumor extent
Minimum
Extensive
resection of all bulky nodal or extranodal disease and were
subsequently considered to have minimum involvement. All others
were considered to have extensive disease.
Data Analyses
The Kaplan-Meier" method was used to calculate overall,
determinate survival, and relapse-free survival curves. Overall
survival curve was calculated from the date of admission to the date
of death regardless of the cause. Deaths due to other than
lymphoma or treatment-related causes were censored in the
determinate survival plot. Relapse-free survival curves were calculated from date of documented CR to the date of last follow-up or
relapse. CR was defined as the disappearance of all clinical
evidence of disease, with normalization of radiographs and laboratory values that had been abnormal before therapy. Partial remission (PR) was defined as the reduction of measurable disease
250% for at least 1 month. When we calculated the CR rate, we
considered 2 patients to be nonresponders because they died
within 4 weeks of beginning Chemotherapy.
The generalized Wilcoxon'2test was used to compare differences
in determinate survival and in disease-free survival curves for
distinct patient groups. The proportional hazards model of Cox"
was used to determine the prognostic significance of age, sex,
constitutional symptoms, Ann Arbor stage, nodal and extranodal
presentations, tumor burden, LDH level, and initial type of
treatment. Possible synergistic effects were investigated by including interaction terms in the model. Fisher's exact test was used to
compare frequencies in 2 x 2 tables.
RESULTS
We classified tumor extent as minimal or extensive. Patients
were considered to have minimal involvement if they did not have
either extensive nodal or extranodal disease. Fourteen of these
patients had a debulking procedure with a greater than 80%
Table 1. Criteria for Delineating Extensive Nodal Disease
Regions
Criteria
Peripheral
Abdominal or pelvic
Mass t 7 cm; includes tight clusters 2 7 cm
Any palpable mass or any mass 5 7 cm organ
displacement or concomitant involvement
of paraaortic and pelvic nodes"
Any mass visualized by routine chest roentgenograms
Mediastinal
Table 2. Patient Characteristics by Ann Arbor Stage
*Determined clinically or by imaging techniques.
Patient characteristics have been correlated with extent
of disease in Table 2. Patients with stage I1 disease had a
higher incidence of both constitutional B symptoms and
abnormal serum LDH levels than those with stage I disease.
Less than half of the patients with stage I disease had
73% of patients with
extensive involvement, whereas
stage I1 presentations were categorized as having extensive
disease. Seventy-three, or slightly less than half of our
patients, had extranodal presentations, and approximately
half of these patients had involvement of associated lymph
node regions. In 29 patients with extranodal disease, the
total extent of disease was categorized as minimum. The
other 44 patients were considered to have extensive involvement; however, the incidence of extensive extranodal pre-
-
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944
VELASOUEZ ET AL
1.o
sentations was approximately equally distributed among
both stages.
Response to Treatment
A CR occurred in 53 (93%) of 57 patients with stage I
disease and in 78 (87%) of 90 patients with stage I1 disease.
Approximately 70% of the patients who received initial
chemotherapy achieved CR before receiving XRT. Eight
patients achieved PR. Six patients failed to respond to
either chemotherapy or XRT. Two others died of complications immediately after initial chemotherapy before restaging; these patients were classified as nonresponders.
The median follow-up for all patients who are alive has
been more than 8 years. During that time, four patients
developed second malignancies: one fibrohistiocytoma in
the lung and pleura, one colon carcinoma, one breast
carcinoma, and one testicular seminoma. The patient who
developed fibrohistiocytoma of the left chest has received
radiation to the mediastinal area previously. No cases of
bladder carcinoma were found.
Thirty-five patients experienced relapse; frequently with
widely disseminated involvement that included previously
uninvolved and uninvolved nodal sites, bone marrow, skin,
and brain. Only two patients developed a local recurrence
in an irradiated site as the only evidence of disease,
however. In another three patients, the areas of relapse
included previously unradiated sites contiguous to the
initial site of involvement. Most relapses occurred within 3
years after treatment was started; however, in four patients
relapse occurred at 42,48, 87, and 88 months. The 5-year
relapse rate for the 54 patients with minimum tumors who
achieved CR was 20%. In contrast, the relapse rate of
patients with extensive tumors was 35%. All patients who
failed to achieve a CR and those who had a relapse, with
two exceptions, have died of lymphoma. In addition, five
patients died while in CR of treatment-related causes: 2
died of sepsis, 1 died of bleomycin-induced pulmonary
fibrosis, and 2 died of cardiomyopathy probably related to
Adriamycin. Another eight patients died of apparently
unrelated causes while in unmaintained CR between 20
and 121 months. These deaths were included in the overall
survival analysis, but they were censored in the determinate
survival calculations and in the prognostic factor analyses.
Causes of death in these patients were related to degenerative heart disease in 5, hemorrhage from a peptic ulcer in 1,
colon cancer in 1, and a fatal accident in 1.
At 10 years, the overall survival rate of 73% for patients
with stages I or IE disease was significantly better than that
of 43% for patients with stages I1 or IIE disease (P < .01)
(Fig 1). Similarly, although the determinate survival rates
were slightly higher (77% and 51%, respectively), the
differences between stages remained highly significant (Fig
1).The comparison between overall and determinate survival plots in each stage did not show any significant
difference. Relapse-free survival rates for patients who
achieved CR were 79% for those with stages I or IE disease
and 66% for those with stages I1 or IIE (P = .OS).
Univariate analysis showed that age, serum LDH level,
stage, and tumor extent were significant factors for both
0.a
0.6
c
5
r
6)
n
0.4
Survival
Stage
I
II
0 Determlnate I
A Determinate II
0.2
0 Overall
0 Overall
0.0
Pts.
57
90
57
90
Dead
15
47
13
a0
100
41
r
20
1
40
60
120
140
160
Months
Fig 1. Survival of patients with stages 1/11 DLCL comparing overall
and determinate survival by each stage. A significant (P < .01)
difference was noted between stage 1/11 patients. In each stage,
however, the overall and determinate survival were similar.
overall and determinate survival (P < .01) (Table 3). Neither gender, constitutional symptoms, extranodal disease,
nor sequencing of chemotherapy and XRT influenced
survival significantly. The influence of tumor extent on
determinate survival was observed for patients with stage
1/11 disease; however, the effect of disease extent was more
apparent in patients with stage I presentations. The 10-year
survival rate for patients with minimum stage I disease was
93%, whereas the survival rate for patients with extensive
disease was 59%. The difference in survival rates for
patients with minimum and extensive stage I1 disease was
less significant (Fig 2), indicating the influence of other
prognostic factors, particularly higher frequency of elevated
serum LDH levels.
A multivariate analysis demonstrated that three factors
were independently related to prognosis at the P < .02
Table 3. Prognostic Factors in 147 PatientsWith Stage 1/11 DLCL
Factor
Age (Y)
< 56
t 56
Stage I
Stage II
Serum LDH
Normal
Elevated
Tumor extent
Minimum
Extensive
Survival (10 y) ( O h )
78
47
77
54
PValue
< ,001
< ,006
70
51
< ,003
79
53
< ,001
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945
LARGE CELL LYMPHOMA STAGE 1-11 PROGNOSTIC FACTORS
1.o
0.8
0.6
0.4
Stage
I
0 I
A II
TB Pts
Min 30
Ext 27
Min 24
Ext 66
0
0.0
1.o
0.9
0.8
0.7
.-c0
0.5
2
n
0.4
0.3
4
PrcgnosticGroups
pts
0 LowRisk
38
67
A
Intermediate
0 HighRisk
I Alive
Dead
7
24
42 23
Low Risk
>
pc0.02
p < 0.01
0.1
High Risk
0
24
48
72
96 120
Months
1
0
level: tumor extent, LDH level, and age. When tumor
extent and LDH level were correlated, three distinct
prognostic groups were identified (Fig 3). The most favorable group (10-year determinate survival rate of 79%)
consisted of patients with minimum tumor and normal
LDH levels. An intermediate group (10-year survival rate of
62%) had either extensive disease or elevated LDH levels.
The third group (10-year survival rate of 44%) consisted of
patients with both extensive involvement and abnormal
‘Ig
a
0.2
Fig 2. Determinate survival in stage 1/11 DLCL in
relationship to tumor extent. In each stage, there is a
difference in survival between patients with minimum tumor extent and patients with extensive tumors. This difference is less significant (P = .3) in
stage II in which serum LDH and age may play a
significant role.
144
168
192
Fig 3. Determinate survival in stage 1/11 DLCL according to tumor
extent and serum LDH levels. Low-riskpatients have minimum tumor
and normal LDH; high-risk patients have extensive tumors and
elevated LDH. An intermediate-risk group of patients have either
extensive tumor or elevated serum LDH. A significant difference
(P < ,011was noted among the subgroups.
I
I
I
24
48
72
II
I
I
96
120
Months
Dead
2
11
8
32
I
I
144
168
LDH levels. The differences in prognoses among these
three groups were highly significant (Fig 3).
DISCUSSION
Multiagent chemotherapy has proved effective treatment
for stage 1/11 DLCL. Despite excellent CR rates, however,
the incidence of relapse at local sites has been significant,
particularly in patients who have bulky disease
Although XRT is useful for preventing local recurrence,
our experience and that of other investigators has been that
it should not be given before chemotherapy because of the
tendency for early dissemination, particularly in patients
with extensive disease presentation^.'^.'^
This study concerns 147 patients with stage 1/11 DLCL
who were treated uniformly with CHOP-Bleo and XRT to
achieve a CR rate of 89%. Ten-year determinate survival
rates were better than had been reported for patients
treated with XRT only. This combined modality approach
was well tolerated in terms of treatment-related deaths and
long-term serious sequelae. In agreement with reports of
other investigators, survival for patients treated with CHOPBleo and XRT was influenced by stage; it was better for
patients with stages I or IE disease than for patients with
stages I1 or IIE. When all deaths, including those owing to
causes unrelated to lymphoma or its therapy, are considered for an overall survival (Fig l), similar results are
obtained, although distinct plateaus cannot be identified.
Among possible pretreatment prognostic characteristics,
age, stage, tumor extent, and LDH level proved statistically
significant by univariate analysis for both overall and
determinate survivals. In keeping with our experience for
stage III/IV disease, multivariate analysis demonstrated
that the major independent factors for survival were age,
tumor extent, and LDH level. Thus, we conclude that these
three factors are important biologic features of this disease,
regardless of stage.
Although tumor burden is a recognized biologic factor
for prognosis after treatment of patients with DLCL, it has
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946
VELASQUEZ ET AL
not been accounted for in any of the four stages of the Ann
Arbor staging system. Tumor extent was originally recognized as an important prognostic indicator for patients with
extranodal head and neck DLCL stage IE/IIE who were
treated with irradiation only.1oMore recently, significant
differences in survival have been demonstrated between
patients with large tumor masses and those with small
tumors, regardless of treatment.lX6Our study has confirmed
the concept that tumor extent is an important prognostic
factor even for patients with localized presentations of
DLCL.
This study also demonstrated, even for Ann Arbor stage
1/11 disease, that survival was more closely related to the
combination of tumor burden and LDH level than to Ann
Arbor stage and that within each stage survival was influenced by tumor volume and LDH level. This was particularly true of patients with stage I1 disease in which bulky
tumors and increased LDH levels are more frequent. When
tumor extent and LDH level were considered jointly, three
prognostic subgroups could be defined: one, minimum
tumor and normal LDH levels; two, either extensive diseases or elevated LDH levels; and three, extensive disease
and elevated LDH levels. The first group included patients
who underwent a surgical resection (“debulked”), which
served as a downstaging procedure before chemotherapy or
XRT.
Chemotherapy for DLCL continues to evolve. The goal is
to improve the effectiveness by combining agents and by
administering all the drugs at the highest dose levels
compatible with systemic and local tolerance. When newer
more intensive programs are considered, the increased risk
of more severe myelosuppression over that associated with
less toxic regimens must be balanced against the prospect of
a better prognosis. For this reason, we and other investigators have proposed that such intense regimens should be
reserved for patients who have a predictably low expectation for survival and that conventional chemotherapies such
as CHOP-Bleo should be used for patients with better
prognoses. Carrying this concept a step further, Connors et
al demonstrated that the number of courses of CHOP used
in combination with XRT can be limited to three cycles for
predictably good prognosis (nonbulky stage IA/IIA presentations) to achieve similar results to those obtained with
eight or more courses of chemotherapy.” In combining
their data for this treatment approach, investigators from
Vancouver and Tucson recently reported a series of patients with stage 1/11DLCL. In this study, the 5-year survival
was 80%; the corresponding relapse-free survival for patients who achieved CR was 82%.18The majority of patients
in this study (84%) had favorable presentations, and only
one had constitutional symptoms.
Ultimately, the value of any retrospective analysis must
be assessed by results of prospective studies. At present,
very little information is available on the results of more
intensive chemotherapy for patients with stage 1/11 DLCL,
other than for a small cohort of the patients with bulky
stage I1 presentation who were included in a report of a
larger series of patients with stage III/IV disease.19320
A
recent report by Longo et al indicated an excellent survival
>90% for 47 evaluable patients with stage I DLCL who
were treated with a modified PROMACE MOPP (prednisone, methotrexate, and leukovorin rescue; hydroxydaunomycin; cyclophosphamide; etoposide/mechlorethamine;vincristine; prednisone; and procarbazine) and XRT program.21
Virtually all patients in this series had favorable presentations, whereas only a few patients had B symptoms (1
patient), high LDH levels (3 patients), or bulky tumors (2
patients). The median age of the entire group was 48 years.
The 5-year survival rates for this series is the same as ours
(90%) for a similar group (Fig 3). The fact that no relapses
occurred among the patients reported by Longo et al during
a median follow-up of 4 years is encouraging. Whether this
type of chemotherapy will be effective for patients with
unfavorable presentations who would be at a higher risk of
relapse if treated by more conventional chemotherapy
remains to be seen.
The role of XRT in management of patients with
extensive stage 1/11 DLCL presentations has not been
clearly defined. Because of a high recurrence rate in
patients with bulky disease who were treated with CHOPBleo, Cabanillas suggested that consolidation radiation
might be of benefit.3 In a retrospective study by Schipp et
aI2*of patients treated with methotrexate, bleomycin, Adriamycin, cyclophosphamide, oncovin, and dexamethasone
(M-BACOD) with or without radiation, the relapse rate in
21 patients with bulky disease who achieved a CR was low,
however. In a relatively short median follow-up time of 18
months, none of the 6 patients who received consolidation
radiation had a local recurrence, whereas 1 of 15 nonirradiated patients did develop a local recurrence.22Although
isolated recurrences in previously irradiated sites were also
rare in our patients, relapses did occur more frequently in
unpredictable distant sites that were not irradiated. This
indicates a need for more effective systemic therapy,
particularly for patients with bulky tumor or with increased
serum LDH level who are at higher risk of relapse. In such a
setting of a more intensive systemic treatment, consolidation by radiation for initial bulky disease could be beneficial
to avoid local recurrence.
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1991 77: 942-947
Stages I and II diffuse large cell lymphomas: prognostic factors and
long-term results with CHOP-bleo and radiotherapy
WS Velasquez, LM Fuller, S Jagannath, SL Tucker, LB North, FB Hagemeister, P McLaughlin, F
Swan, JR Redman and MA Rodriguez
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