Controversies in the Management of Early Stage

CLINICAL REVIEW ARTICLE
Controversies in the Management of Early Stage Hodgkin’s Disease
By Peter M. Mauch
0
VER THE LAST 25 YEARS, there hasbeen great success in the treatment of early stage Hodgkin’s disease
(HD; defined as stage 1-11 for this review). Yet considerable
controversy exists in both the staging and treatment of patients asthe late complicationsof treatment such as the development of second malignant neoplasms have become
more evident. New treatments that aim tomaintain a high
freedom from relapse while reducing long-term adverse
effects are being studied, yet it may be many years before
their effectiveness is known. This review discusses the current controversies in thestaging and treatment of early stage
HD. It examines the role of radiation field size, use of chemotherapy in early HD, influence of prognostic factors on
treatment, indications for staging laparotomy, factors for
development of late complications, and details of ongoing
clinical trials.
HISTORICAL PERSPECTIVE
In his historic paper entitled, “On Some MorbidAppearances of the Exorbant Glands and Spleen” to the Medical
Chirurgical Society in London January IO, 1832, Thomas
Hodgkin briefly described the clinical history and postmortem findings of massive enlargement of lymph nodes and
spleen in six patients and added the description of a seventh
who had been seen by Carswell in 1828.’ For the next 70
years, most of the advances in H D were descriptive. Between 1865 and 1902, Wilks, Pel, Ebstein, and others contributed clinical
and Greenfield, Sternberg,
and Reed provided definition of the microscopic appearance of HD.5-7
The early treatment of HD with crude x-rays in 1901 followed the discovery of x-rays by Roentgen, radioactivity by
Becquerel, and radium by the Curies in the late 1800s. Before this, serum and other biologic preparations, arsenic, iodine, and surgery were all usedin the treatmentof H D with
dismal results. The first reports ofx-ray treatments that
would dramatically shrink enlarged lymph nodes produced
great excitement and premature predictions for the curability of HD.8,9
The development of modern radiation therapy techniques for the treatment of H D began with the work of Gilbert, a Swiss radiotherapist, in 1925.” One of the first physicians to point out certain clinical patterns in the behavior
of HD, he also attempted to adapt his radiotherapy techniques to these patterns. Gilbert began to advocate irradiation to apparently uninvolved adjacent lymph node chains
From the Joint Centerfor Radiation Therapy,Department QfRadiation Therapy, Harvard Medical School, Boston, MA.
Submitted May IO, 1993.-accepted October 6 , 1993.
Address reprint requests to Peter M. Mauch, MD, JCRT,
SO Binney St, Boston, MA 021 I S .
0 1994 by TheAmerican SocietyofHematolo~y.
0006-4971/94/8302-0042$3.00/0
318
that might contain suspected microscopic disease, as well as
to the evident sites of lymph node involvement. This technique was also adapted by Peters at the Princess Margaret
Hospital in the late 1930s and early 1940s. In her historic
report published in the American Journal ofRoentgenology
in 1950, Peters observed that patients with limited H D
could be cured with aggressive radiation therapy that covered involved nodal sites as well as adjacent sites.’
Despite these studies, the concept that early stage H D
might be curable with higher dose and larger field radiation
therapy (RT) was slowto be accepted; before the 1960smost
patients with limited H D were not treatedat all, or only with
small doses of radiation. When in 1963 Easson and Russell
published their report, “The Cure of Hodgkin’s Disease,”
physicians were closer to accepting the effectiveness of radical treatment for this once fatal illness than they were in
1950, the year Peters published her report.’* The development of the linear accelerator, which allowed for higher
doses and larger radiation fields to be used, the proposal of
new classification systems for histologic subtyping13 and
staging,14the pioneering of methods for more precise radiographic and surgical staging (bipedal lymphangiography
and staging lapar~torny),’~,’~ the
anddevelopment of an
effective multi-agent chemotherapy regimen” all contributed to the development of curative treatmentfor early HD.
Because of these advances, the philosophy and practice of
managing early stage H D changed dramatically by the late
1960s from no treatmentto extensive staging and radiation
therapy with wide-fields and high doses.
’
RANDOMIZED CLINICAL TRIALS
Studies of radiation Jield size. Significant advances in
the treatment of early stage H D were made with information obtainedfrom clinical trials first organized in the 1960s.
Both Stanford University Medical School and theEuropean
Organization for the Research and Treatment of Cancer
(EORTC), along with other groups, made significant contributions. Results from prospective randomized trials that
systematically evaluated the role of limited radiation therapy versus extensive radiation therapy are shown in Table
1. Representative trials that have reported large numbers of
patients and long follow-up (greater than 5 years) are emphasized in Table 1.
Two trials have noted significant differences in the freedom from progression” or in disease-free survival” favoring treatment with wide-field versus limited field radiation
therapy. At Stanford University, laparotomy staged (pathological staged [PS]) IA-IIA patients treated with subtotal
nodal irradiation (STLI; including treatment of upper abdominal nodes) or total nodal irradiation (TLI) had
an 83%
freedom from progression versus a 32% freedom from Progression for patients treatedwith involved field (IF) irradiation.” Significant differences were also noted in PS 1-11 patients and in clinically staged (CS) 1-11 patientsin the
Collaborative Clinical Trial favoring STLI over IF irradiaBlood, Vol83, No 2 (January 15). 1994: pp 3 18-329
MANAGEMENT OF EARLY STAGE HODGKIN’S DISEASE
319
Table 1. Wide-Field Radiation Therapy (STLI/TLI) Versus Limited-Field Radiation Therapy
(IF/M)
Study
Stage
Design (no. of patients)
FFR M )
Survival
Stanford University”
Collaborative ClinicalTriaP
BNLI”,*’
EORTC H5 Tria122,23
Collaborative Clinical TriaVg
BNL120~Z’
PS IA-IIA
PS 1-11
PS IA-IIA
PS I-lk
CS 1-11
CS IA-IIA
STLI/TLI (35) vlF (28)
STLl(84) v IF (81)
Regional (1 8 1 ) v IF ( 147)
STLl(98) vM (100)
STLl(98) vlF (88)
Regional (95) v IF (1 14)
80%v32%(15)’
66% ~ 5 2 %
(10)’
48% v 50% (1 2)t
80% v 79%
92% v 87%
78% v 74%
91%v94%
79%v71%
68% v 68%
70% ~ 6 9 %
(9)
(10)’
59% ~ 3 2 %
43% ~ 4 0 %
(12)t
Abbreviations:regional, involvedfield irradiation plusthe immediate adjacent nodal site;FFR, freedom from relapse, also freedom from pregression,
or disease-free survival in some studies.
Statistically significantdifferences; none ofthe trials show significant differences in actuarial survivalrates.
t Numbers estimated from survival curves.
t NS/LP histology,age 5 4 0 years, PS I or PS Il-no med, ESR 570.
ate therole of chemotherapy in the treatment of early stage
tion.” In contrast, differences favoring large field irradiation
HD. Clinically staged 1-11 patients were randomized to rewere not seen for PS or CS patients in the British National
ceive mantle irradiation aloneor combined with velban cheLymphoma Investigation (BNLI) study.20,2’However, this
motherapy. Results were better in patients receiving both
study did not randomize patients by extent of staging, and
mantle irradiation and velban chemotherapy. However, rediffers from the first two reports in thatwide-field irradiation
lapse rates were high in both groups, suggesting that mantle
usually consisted of lessthan a mantle field (compared with
irradiation alone was not adequate treatment for patients
STLI or TLI in the other studies). The smaller field sizes
with CS 1-11 HD and that
velban was only partially effective
used in the BNLI study might explain in partthe high overin eliminating recurrences, many of which occurred below
all relapse rate (approximately 50%)and thehigh recurrence
the d i a ~ h r a g m .Clinically
~ ~ . ~ ~ staged 1-11patients with mixed
rate below the diaphragm (29%) compared with the other
cellularity (MC) histology had a particularly high abdomitwo studies that used prophylactic irradiation to the upper
nal recurrence rate of 40%.
abdominal nodes.
Table 2 lists one additional study in CS 1-11 patients and
To determine therole of prophylactic abdominal irradiafive studies in PS 1-11 patients comparing MOPP (nitrogen
tion inearly stage HD, the EORTC
H-5 trial studiedthe use
mustard, vincristine, procarbazine, prednisone) or MVPP
of mantle and paraaortic-splenic pedicle irradiation (MPA)
(vinblastine substituted for vincristine) chemotherapy and
versus mantle irradiation (M) alone in patients with favorable early stage HD.22,23This study, in contrastto theBNLI
radiation (to involved, mantle, or STLI/TLI fields) versus
M, STLI, or TLI without chem~therapy.’~.~~,~~,~’.~~
Altrial, included only patients with nodular sclerosis (NS) or
lymphocyte predominance (LP) histology, age 40 years or
though numerical differences in the freedom from relapse
(FFR) areseen in all studies favoring MOPP and RT
versus
younger, PS I or PS I1 without mediastinal adenopathy,and
R T alone, these differences reach statistical significance in
an erythrocyte sedimentation rate(ESR) of lessthan 70. No
differences were seen in disease-free survival between the
only two of the five reports of PS patient^.^^.^' The variation
in field sizes in these studies do not provide data to detertwo treatment groups. This select subgroup of patients
treated with mantle irradiation alone had only an 1 1% risk
mine whether significant field size reductioncan
be
of relapsing below the diaphragm.22 Other retrospective
achieved in early stage H D patients receiving CMT. This
studies have demonstrated high relapse rates for unselected
may be an importantissue as there appears
to be some assopatients with CS 1-11 H D treated with mantle irradiation
ciation with the use of large radiation fields and the develalone, but improved results for patients who have a negative
opment of long-term complications such as second maligstaging laparotomy and have favorable prognostic features
nancies. However, two studies have suggested that involved
such as disease limited to a single lymph node region withfield or mantle irradiation without subdiaphragmaticirradiout “ B ’ symptom^.'^
ation may be sufficient for CS 1-11 patients receiving comStudies of chemotherapy in early stage HD. Since the
bined modality therapy with standard ~ h e m o t h e r a p y . ~ ~ , ~ ’
development of effective multi-agent chemotherapy regiNone of the trials for CS or PS patients shown in Tables I
mens for HD, chemotherapy has been used for early stage
or 2 demonstrate an overall survival advantage favoring eiHD. Twenty-two randomized trials of radiation therapy
ther theuse of wide-fieldirradiation versus more limited raalone versus combined radiation therapy and chemotherdiation, or combined chemotherapy and radiation therapy
apy (CMT) have been performed worldwide.25 Many of
versus RT alone, even when significant disease-free survival
these trials have been published with a number showing redifferences are present. One explanation includesthe possilapse-free survival advantages favoring CMT. However,
bility that these studies have not reached the very long folnone of the trials have demonstrated an overall survival
low-up ( 10 to 15 years) needed to see survival differences in
difference between the two treatment approaches.’8*20*23,26-35HD. Alternatively, the effectiveness of salvage chemotherRepresentative trials with large numbers of patients and/or
apy for relapse after radiation therapy alonemay minimize
long follow-up are shown in Table2.
the impact of any increase in relapse on survival and may be
The EORTCH l trial was one of the first studies to evalubalanced by an increased mortality from other complica-
320
PETER M. MAUCH
Table 2. Combined Chemotherapy and Radiation Therapy Versus Wide-Field Radiation Therapy Alone
Study
Standord University'8
Stanford University"
Danish National Study GroupZ6
~
~
0
~
3
4
Manchester Lymphoma Group"
EORTC H5 Trialz3
EORTC H1 Tria123.35
-~
~
~~
~~
Stage
Design (no. of patients)
FFR (yr)
PS IA-IIA
PS 18-118
PS I 4
PS 1-11
PS 1-11
CS 1-119
CS 1-11
IF MOPP (36) vSTLI/TLI (35)
TLI + MOPP (35)TLI
v
(28)
M + MOPP ( 133) v STLI/TLI (128)
IF+MOPP(120)vSTL1(115)
M MVPP (59) v M (56)
MOPP STLI/TLI (152) v TLI ( 144)
M(Y)+Vbl(l36)vM(Y)(152)
83% v 66% (9)
76% ~ 7 3 %
(15)
90% ~ 6 7 %
(7)'t
82% v 71% (8)t
91%v67%(10)'$
83% ~ 6 6 %
(9)'
60% v 38% (1 5)'
+
+
+
Survtval
84%v91%
78% v 79%
92% v 93%
82% v 86%
95% v 90%t
88% v 73%
65% v 58%
~
Abbreviations: regional, involved field irradiation plus the immediate adjacentnodal site; FFR, freedom from relapse, alsofreedom from pregression,
or disease-free survival in some studies; Y, inverted Y irradiation(abdominal-pelvic nodes);Vbl, Velban.
Statistically significant differences; none of the
trials show significant differences In actuarial survival
rates.
t Numbers estimated from survival curves.
t Patients dying of intercurrent causes were censoredfrom the survival curves.
9 PS 111 (CS II),or CS II with MC/LD histology, age >40 years, or ESR >70, or CS II with NS/LP histology and mediastinal disease.
tions (cardiac, second tumors) often seen patients receiving
more intensive initial treatment. A third alternative is that
there are not enough patients in any
single study to show a
small significance difference; megatrials or overviews may
be needed to determine whether differences in relapse-free
survival will result in smaller but significant differences in
overall survival. Such trials are inprogress.
PROGNOSTIC FACTORS DEVELOPED
FROM EARLY TRIALS
Implications for treatment of PS 1-11patients. Prognostic factors have been used to identify subgroups stage 1-11
HD patients who have a potentially higher risk ofrelapse or
worse survival; these factors help individualize treatment to
the extent of disease. Table 3 lists results from three studies
that identify independent prognostic factors in PS 1-11 pat i e n t ~ . ~ 'The
~ ' first two studies evaluatePS IA-IIA patients
treated with STLI/TLI alone. Both report large mediastinal
adenopathy (LMA), defined as a mass greater than one-third
the maximumthoracic diameter on a standing chest radiograph:' as the major factor predicting an increased risk of
relapse.38339
In neither study did LMA predict for a lower
survival rate; however, age 40 years or older and MC/LD
histology were felt to be adverse prognostic factors for survival in the Harvard Joint Center for Radiation Therapy
(JCRT)
The
third
study from the Danish
National
Study Group analyzed PS IA-IIB patients treatedwith either
RT or CMT. Patients with a high tumor burden, treated
sex
Male
with RT alone, or of male sex had an increased
relapse
risk.
Patients age 40 years or older or with an increased tumor
burden had a decreased survival.4oThe presence of B symptoms was not an independent adverse factor in thisstudy. A
fourth study from the Manchester Lymphoma Study Group
of PS 1-11 patients treated with RT or CMT identified low
lymphocyte counts, low serum albumin, and treatment
with
RT alone as independentadverse prognostic factors for relapse." The significance of these identified factors in the
staging and treatmentof patients is discussed in more detail
below.
In addition to the above trials, a number of retrospective
studies have identified LMA as an adverse prognostic factor
for relapse in PS IA-IIB patients treated with radiation ther-
apy a l ~ n e . ~ ~The
. ~ majority
'~*
of relapses in these patients
have been in lymph nodes above the diaphragm or in thoracic extranodal sites, including the pleura, chest wall, or
pulmonary paren~hyma.~~,~'.~~-~'.~~
The routine use of thoracic computed axial tomographic scanning and gallium
scanning has aidedin determination of initial treatment of
patients with LMA.36.50-56
These studies suggest that patients
with pericardial nodes, extensive pericardial involvement,
bulky axillary disease, or significant involvement of the
pleural or lung are probably not suitable for RT alone because of the high risk of relapse and the potential toxicity
associated with the large radiation volumes needed to treat
such extensive HD. These patients canbe quite successfully
treated with 6 cyclesof combination chemotherapy followed by regional or mantle irradiation withoutthe need for
staging laparotomy or abdominal i r r a d i a t i ~ n . ~ ~
Table 3. Prognostic Factors in PS
1-11 Patients
(PValues Adjustedfor Other Factors)
Study
Stage
Adverse Factor
FFR
,002
.04
NS NS
Survival
Stanford
University38
( 109 patients,
RT alone)
PS IA-IIA
LMA
STLl (vTLI)
No. of sites 2 4
Harvard University
5 (31
(JCRT)39
patients, RT
alone)
PS IA-IIA
LMA
Age 240 yr
No. of sites NS
NS
MC/LD histology
<.WO1
NS
NS
NS
NS
NS
,008
Tumor
burden
Age 240 yr
RT alone
histology
B symptoms NS
Male sex
NS
ESR 240
No. of sites NS
<.WO1
NS
<.OW1
.001
.04
NS
NS
Danish
National
Group"
Study
(290 patients,
RTMC/LD
or CMT)
PS 1-11
NS
.01
NS
NS
NS
NS
,001
NS
Abbreviations: FFR, freedom from relapse, also freedom from pregression. or disease-free survivalin some studies; LMA, large mediastinal adenopathy; LD, lymphocyte depletion histology; NS, no significant
difference.
321
MANAGEMENT OF EARLYSTAGEHODGKIN'SDISEASE
Patients age 40 years or older appear tohave a worse survival (but not a worse FFR) both because they may not be
as successfully treated at relapse as younger patient^^^.^^ and
because they may have a greater absolute excess risk of developing long-term complications such as second tumors
and/or cardiac disease.60-62
This argues for the continueduse
of surgical staging (at least for patients under60 years of age)
and radiation therapy alone in this group of patients, with
the goal of maintaining a high disease-free survival while
minimizing the initial extentof treatment.
The identification of MC histology as an adverse factor
for survival but not for FFR in PS IA-IIA patients in the
sex
Male
JCRT study has notbeen universally accepted. The investigators initially determined that PS IA-IIA patients with MC
histology were more likely to relapse below the diaphragm,
often with bulky nodal disease, and suggested that this might
have accounted for less success with salvage chemotherIn a subsequent study, PS IA-IIIB patients with MC
histology who relapsed after initial radiation therapy had
lower second CR rate, lower freedom from second relapse,
and decreased survival after salvage chemotherapy compared with patients with NS or LP histology. This was independent of bulk of disease at relapse.59In contrast, others
have failed to identify histology at relapse as a prognostic
fa~tor.~~,~'.~~
The Danish National StudyGroup analysis did not identify B symptoms as anindependent adverse prognostic factor.40 A large retrospective study combining data of PS IBIIB patients treated at Stanford University and the JCRT
suggested that patients with night sweats without other B
symptoms treatedwith RT alone had aprognosis similar to
patients with PS IA-IIA disease. However, the presence of
fevers, weight loss, LMA, or age 40 or older all independently predicted for an increased risk of relapse, and survival was impaired in patientswho had the presence of both
fevers and weight loss.64Treatment with CMT was suggested for patients with adverse prognostic factors.
Implications for treatment of CS I-11 patients. Table 4
lists representative studies that have evaluated adjusted
prognostic factors in clinically staged patient^.^^.^^.^^ Two of
the three studies evaluate patients treated with either RT
or CMT, and thethird uses data from patients treated with
chemotherapy (CT)or CMT.Adverse factors for relapse include male sex (in 1 of 2 studies), large number of sites involved (in 2 of 3 studies), age (in 2 of 3 studies), high ESR
(in 2 of 2 studies), MC/LD histology (in 1 of 2 studies), involved field RT (in 1 of 1 study), and LMA (in I of 1 study).
Other studies have also identified these adverse prognostic
f a ~ t o r s . Many
~~.~~
of the factors, including B symptoms
(similar to ESR), male sex, number of sites of involvement,
and, toa lesser extent, age, have predicted for an increased
risk ofoccult abdominal involvement inCS 1-11patients and
may explain in part why these factors are identified for CS
patients but usually not for PS patients. Prognostic factors
for survival in Table 4 include age in all three studies, and
male sex, high ESR, MC/LD histology, number of sites of
involvement, and large mediastinal involvement in one of
three studies. Identification of adverse prognostic factors is
essential for determining treatment of CS 1-11 patients in
Table 4. Prognostic Factorsin PS 1-11 Patients
(PValues Adjusted for Other Factors)
Study
Stage
Adverse Factor
FFR
Survival
EORTCZ3(1,392 CS 1-11 sex
Male
,006 .01
patients, RT or
Age 240 yr
NS
<.0001
CMT)
ESR 250 (A) or 230 (B) < . O O O l
NS
,0006
NS
MC/LD histology
<.OW1 .005
No. of sites 24
Princess Margaret CS 1-11
Hospital" (250
No.patients,
or RT
CMT)
FundaleP
(277patients,
CT orNo.
CMT)
Age 250 yr
MC/LD histology
of sites
NS
IF RT (v M/STLI)
ESR 2 4 0
CS 1-11 LMA
Age 245 yr
of sites 23
,0005
.0005
.08
,004
NS NS
NS
.024
NS
,001
.03
,005
<.W1
<.001
<.001
<.m1
NS
Abbreviations: FFR, freedom from relapse, also freedom from pregression, or disease-free survival in some studies; LD, lymphocyte depletion histology; NS, no significant difference.
centers that do not routinely use staging laparotomy and
splenectomy. Some of the ways in which these factors help
determine treatmentfor CS 1-11patients arepresented at the
end of the next section.
STAGING LAPAROTOMY AND SPLENECTOMY:
IMPACT ON TREATMENT
Staging laparotomy remains the most precise way to determine thepresence and extent of abdominal involvement
in
patients
presenting with supradiaphragmatic HD.
Twenty to 30%of CS IA-IIA and 35% of CS IB-IIB patients
with H D will have occult splenic or upper abdominal nodal
involvement not detected by bipedal lymphangiography,
computed axial tomography, magnetic resonance imaging,
or gallium imaging.70.7'These radiographic studies have not
been successful at visualizing H D in the spleen and often
miss lymph node involvement in the upper abdomen.72 A
number of studies have evaluated the ability of selected
prognostic factors to predict for occult abdominal involveSelected subgroups of CS Iment in CS 1-11
I1 patients, including CS IA females, CS IIA females 26 years
old or younger, and CS IA males with lymphocyte predominant histology, appear to be at lowest risk for occult abdominal involvement (6%to 9%).The remainder of CS IIA
and all CS IB-IIB patients, who make up about75% to 80%
of all CS 1-11 patients, remain at substantial risk for H D in
the spleen or abdominal nodes (24%to 36%).70,7'
There have been a number of arguments for and against
the routine use of diagnostic staging laparotomy and splenectomy in the management of patients with HD. Arguments for the use of surgical staging are that it (1) improves
staging accuracy over the use of clinical prognostic factors,
allowing treatment to be tailored to the extent of disease.
Surgical staging allows for selection of early stage patients to
receive radiation therapy alone and reduces the overall need
322
for ~hemotherapy.~'
(2) Laparotomy and splenectomy allow for the use of smaller radiation fields with less riskto the
heart, lungs, and kidneys. If treatment with STLI is needed,
the volume of abdominal tissue irradiated is significantly reduced with the prior removal of the spleen. In patients with
early HD, a negative laparotomy may allow treatment with
mantle field radiation a10ne.23,24,76,77
This approachrequires
only 4 to 5 weeks of treatment and is quite successful in
selected PS IA-IIA patients, but is too risky for most patients
who do not undergo surgical ~ t a g i n g . ' ~ , ~ ~ , ~ ~
Arguments against the routineuse of staging laparotomy
and splenectomy are that it (1) delays initial treatment by 2
to 3 weeks, requires 5 to 7 days in the hospital, and is associated with potential morbidity and mortality. In centers
that routinely perform surgical staging, the mortality risk
should be well under 0.5%.70,7'We have seen only a 3% risk
of major morbidity from wound abscess, subphrenic abscess, and small bowel o b s t n ~ c t i o nHowever,
.~~
others have
reported higher major complication
(2) After splenectomy, patients are at increased risk for bacterial sepsis.
The risk depends on intensity of treatment; it is very lowin
patients receiving radiation therapy alone (l%), but is increased by as much asIO-fold in patients treated with intensive radiation therapy (ie, TNI) andchemotherapy.82 Vaccination against meningococcus and pneumococcus or
administration of prophylactic antibiotics reduces the risk
of sepsis in some patients." (3) Patients may have a small
(approximately 2-fold) increased risk ofleukemia after splenectomy. This is in contrast to the 60- to 120-fold relative
risk conferred by exposure to MOPP-like chemotherapy.
This increased risk after splenectomy is not seen in all studies, iscomplicated by confounding variables, and is difficult
to explain epidemiologically, suggestingthat further evaluation is
Patients are candidates for diagnostic staging laparotomy
and splenectomy only if the outcomeinfluences treatment.
This approach continues to be used by some centers in the
United States and is based on thephilosophy that aggressive
staging minimizes the treatment needed. Patients with extensive mediastinal involvement, multiple "B" symptoms,
or obvious CS 111 disease require chemotherapy as part of
their management and should not undergo surgical staging.
For patients at very low riskfor abdominal involvement(CS
IA females and CS IA males with lymphocyte predominant
histology), optionsinclude STLI and splenic irradiation
without a staging laparotomy or mantle irradiation alone
after a negative laparotomy. For the remainder of CS 1-11
patients, recurrence rates are low after a negative laparotomy and treatment with extended field irradiation (or mantle irradiation alone in selected patients). This staging and
treatment approach canbe supported even for patients with
mixed cellularity histology, age 40 years or older, or with 4
sites or greater above the diaphragm. These patients have a
long-term FFR of 75% to 82% after a negative laparotomy
and treatment with MPA.
An alternative approach favored in many of the recent
clinical trials uses prognostic factors in clinically staged patients without a staging laparotomy (common in Europe,
Canada, and South America). Treatment is determined by
PETER M. MAUCH
the presence of adverse prognostic factors that predict for
likelihood of occult disease in the abdomen and for the
effectiveness of treatment (usually radiation therapy alone)
to prevent relapse (see previous discussion). Based on the
number ofadverse factors, patients are placed into favorable
or unfavorable prognostic groups. The most favorable patients are treated with mantle or extended field irradiation
alone.23,65.76
Patients with a less favorable prognosis receive
chemotherapy combined with involved or regional field irradiation. The type of chemotherapy and the number
of cycles delivered (often as partof ongoing clinical trials) is also
determined by the presence of adverse factors. Two recent
EORTC trials illustrate this approach. In the EORTC H6 trial, CS 1-11 patients with favorable prognostic features
(number of sites = 1 or 2 , and ESR 4 0 without B symptoms or<30 with B symptoms)were randomized to receive
either STLI without a laparotomy or a staging laparotomy
followed by mantle irradiation (forNS or LP histology, lap
negative), STLI (for MC histology, lap negative), or combined CT and RT (lap positive). As longer follow-up data
become available, this trial should help determine the influence of staging laparotomy on outcome in favorable CS
1-11 patients whose treatment is modified by the findings at
s ~ r g e r y . ~In
~ , the
' ~ ongoing EORTC H-7 trial, CS 1-11 patients are divided into very favorable, favorable, or unfavorable groups. None of the patients is to receive a staging laparotomy.Mantlealone
is thetreatment
for the very
favorable group (only about6% of the totalgroup), which is
restricted to CS IA women with NS or LP histology and an
ESR less than 50. Patients in the favorable group are randomized to receive either six cyclesof modified chemotherapy (EBVP; epirubicine, bleomycin, vinblastine, and prednisone@) followed by involved field irradiation or subtotal
lymph node and splenic irradiation. Patients inthe unfavorable group are randomized to receive either six cycles of
MOPP/ABV89 followed by involved field irradiation or 6
cycles of EBVP and involved field irradiation. Thistrial was
started in 1988 and is discussed in more detail later in this
review.
LONG-TERMOUTCOME OF TREATMENT
FOR EARLY STAGE HD
Much of the long-term follow-up data for early stage H D
is derived from the treatmentof patients with radiation therapy alone. Large, single institutional studies show greater
than an 80%actuarial 10- to 15-year freedom from relapse
and less than a 10% mortality from H D after STLI for PS
IA-IIA patient^.^'^^^^^^ These results have been achieved
through careful delineation of extent of involvement (including staging laparotomy and splenectomy), adherence to
the precise use of radiation therapy (including treatment
simulation, individually contoured divergent blocks, equal
doses from front and back, and machine generated verification film^),^'.^^ and the successful treatment of patients
who relapse with multiagent chemotherapy.58x59
The treatmentof early stage H D has becomeso successful
that at15 to 20 years the overall mortality fromcauses other
than tumor mortality may approach that seen from H D itself.93-95A Stanford University Medical School study pro-
MANAGEMENT OF EARLY STAGE HODGKIN'S DISEASE
323
observed to expected ratio of developingacute nonlymphovides some of the most detailed information. The report
cytic leukemia after treatment with chemotherapy has
evaluates PS IA-IIIB patients treated on clinical trials either
ranged between 100 to 1 to approximately 200 to 1 in three
with radiation therapy alone or with CMT. A total of 107of
large ~ t u d i e s . ~ ~Despite
~ ~ ~ ~ this
. " ' high observedto expected
326 patients had died at the time of the study. Causes of
risk, the low background incidence of leukemia results in an
death included 41% from HD, 26% from second cancers,
overall risk of developing
leukemia within 10 years ofinitial
and 16% from cardiovascular events.94These three causes
chemotherapy of as low as 2% insome studies to 5% to 6%
of death are discussed indetail below.
in ~ t h e r s . ~ ~ . 'The
~ ' , ~excess
~ ' risk of developing ANLL apThe most common cause of death in patients after treatpears to be confinedto the first 10 yearsafter treatment."'
ment for HD is tumor-related mortality. Its relative freNearly all cases of
NHL occurring after HD are of interquency is greater inpatients with more advanced stage dis~ ' ~his~~'~~~~~~
mediate-grade or high-grade h i ~ t o l o g y . ~ ~The
ease, and there is a correlation between increased relapse
tologies represented are similar to lymphomas seen in pafrequency and decreased survival. The absolute excess risk
tients with immunodeficiency diseases or under chronic
of mortality in 5-year intervals over the first 20 years after
immunosuppression for organ transplantation or autoimtreatment for HD is constant with earlymortality caused by
mune disorders. From several largestudies, the observed to
HD and later mortality caused by second malignant tumors
expected ratios for developingNHL vary between8 to 1 and
or myocardial infarction.
31 to l.853"2-"4 In the Tucker et al"' and Abrahamsen et
Patients who developrecurrent HD are more likely to be
studies, the observed to expected ratios were the same
cured with chemotherapy if their initial treatment was RT
for the patients who received radiation alone or radiation
versus CT or CMT. The 10-year actuarial survival of pawith adjuvant chemotherapy. In the van Leeuwen et als5
tients initially treated with radiation therapy alone after restudy, the observed to expected ratio for developing NHL
lapse and treatment with multi-agent chemotherapy is 57%
was lower after radiation alone than with combined radiato 62%.58*59
Results are significantly worse forpatients with
tion and chemotherapy. In all three series there continues
HD who relapse after initial CT or CMT. Treatment with
to be an increased observed to expected risk 10 years after
similar or alternative non-cross-resistant CT regimens
treatment and b e y ~ n d . ~ ~ ~ " ~ ~ " ~
yields 5-yearactuarial disease-free survival
rates of only 22%
The increased observedto expected ratios for developing
to 38% for thesepatient^.^^-'^ Patients who have a diseasesecond primary cancers are of much lower magnitude than
free interval of 12 months or longer before relapse,or who
for ANLL or NHL. However, because the overall backrelapse exclusively in nodal sites, appear to have a greater
ground risk of developing
a solid tumor is high, the absolute
likelihood of survival than those who havea shorter time to
Because
of
the
excess risk of developing a solid tumor is greater than the
relapse or recur in extranodal
poor overall prognosis of patients who relapse after initial
absolute excess risk of developing leukemia or NHL after
chemotherapy, many are now considered candidates for
treatment for HD. Solid tumors constituted 55% ofthe second malignancies in the Tucker et al"' study, and 64% in
high-dose chemotherapy and autologous bone marrow rescue. Althoughthe results ofsuch treatment are still prelimi- the van Leeuwen et aIE5study. As seen with HNL, the obnary, the 3-year disease-free
survival,which has ranged from
served to expected ratios for developinga second malignant
27% to 45%, suggests that this approach may be no better
tumor continues to be elevated beyond I O years after treatthan second-line combination c h e m ~ t h e r a p y . ' ~ lIt- ' ~ap~
ment. The observed to expected ratios for developinga solid
pears that salvage of PS IA-IIAHD patients after initial CT
tumor in the Tucker et al'" study with time from treatment
may be no better than for patients initially treated with CT
increased from 1.9to 1 within the first 5 years, to 4.9 to l in
the second 5 years, to 6.3 to 1 in patients out 10 years or
for advanced disease.Io4The results of salvage of patients
more. Although additional numbers are needed, the risk of
relapsing after treatment with RT and modified CT regideveloping a solid tumor after treatment for HD has been
treatmens (modified drugs or reduced number of cycles of
ment) remains to be determined. All these data suggest that,
primarily reported in patients treated with initial radiation
when CT or CMT are used as initial treatment for patients
therapy or combined RT and CT. Few cases have been rewith HD, treatment should be designed ina manner so as to ported with CT alone; however, there remains little data on
minimize relapse.
the follow-up of patients treated with chemotherapy alone
Many yearsafter chemotherapy and/or radiation therapy,
who are at risk 15 years or beyond. Very little is known of
HD patients have an increased risk of developing
acute nonthe association between radiation volume or dose and delymphoblastic leukemia (ANLL), non-Hodgkin's lymvelopment of a second solid tumor."' In some studies, the
phoma (NHL), and second solidt ~ m ~ r This
~ . in-~ ~ combination
~ ~ ~ .of ~radiation
~ ~ therapy
- ~ ~and~chemotherapy may
creased risk isprobably multifactorial, resulting in part from
result in a higher risk than with radiation therapy alone.lL2
the immunologic deficits associated with HD and/or its
In other studies, this does not appear to be the case.85The
treatment and partly fromthe carcinogenic effectsof radiaobserved to expected ratios for developing a solid maligtion therapy or chemotherapy. Certain cytotoxic agents,
nancy in two large
studies varies between 2.5to 1 and 2.8 to
especially those contained in the MOPP and ChlVPP (chlor1 .85,112 In these two
studies, the highest observedto expected
ambucil, vinblastine, procarbazine, and prednisone) regiratios were for lung cancer (between 4.9 to 1 and 7.7 to 1);
m e n ~ , ~are
' . ~associated
~~
with a marked increase in risk of
however, there were also modest increases in the risk of
developing ANLL.There does not appear to be an increased
stomach cancer, in melanoma, and in tumors of the bone
risk of developing ANLLafter radiation therapy alone. The
and connective tissue."* More recently, an age-dependent
324
PETER M. MAUCH
at treatment increased risk of breast cancer has been noted,
with the highest risk being in patients under 20 at the time
of treatment."' Young females may be at particularly high
risk for other second malignant neoplasms as well."'
Complications related to cardiacirradiation(arrhythmias, myocardial infarction and coronary artery disease,
pericarditis, myocarditis, pericardial effusion, and tamponade) have been carefully documented after radiation therapy to the m e d i a s t i n ~ m ~ ' ~ In
~ 'many
~ ' ~ ~of~the
~ ~earlier
'~~
studies these complications were related to treatment techniques that resulted in a high radiation dose to theanterior
mediastinum and heart (lower energy machinery, anterior
weighted fields, doses per fraction of greater than 200 cGy,
and treatment with one field per day). Current practice,
which restricts the dose to the whole heart, blocks the subcarina1 region partway into treatment, delivers treatments
equally from front and back, and uses less radiation dose
and volume by the use ofpreradiation chemotherapyin patients with LMA, has yielded more satisfactory results. In
the Stanford study, despite
16% ofthe deaths occurringfrom
cardiac disease, no observed to expected increase in cardiac
death was seen.94In contrast, a recent report by Boivin et
allz4demonstrateda small age-adjusted significantly increased risk of death from myocardial infarction (RR, 2.56;
CI, 1.1 1 to 5.93) after mediastinal irradiation. This risk did
not differ by age at treatment or by time from treatment,
but, when analyzed by year of diagnosis of H D the risk was
much greater for patientstreated 1966 or earlier (RR, 6.33;
CI, 1.73 to 23.16) compared with 1967 or later (RR, 1.97;
CI, 0.75 to 5.17), suggesting an important role for modern
treatment techniques inreducing the risk ofcomplications.
REDUCTION OF STAGING OR TREATMENT:
ONGOING AND COMPLETED STUDIES
Over the past decade, there has been increasing concern
for the long-term consequences of treatment, with many patients surviving long periods of time after treatmentfor early
stage HD. This has prompted some
investigators to reexamine the aggressive approaches developed for the staging and
treatment of early stage H D in the 1960sand 1970s.A number of studies have been developed in an attempt toreduce
the long-term complications of treatment without increasing mortality from HD. These include studies that evaluate
( 1 ) treatment with chemotherapy alone,( 2 )the reduction of
radiation field sizes, (3) elimination of staging laparotomy
and splenectomy, and (4) use of modified chemotherapy or
shorter courses of standard chemotherapy combined with
radiation therapy. Representative studies are listed below.
Most studies have relatively short follow-up and would not
be expected to demonstrate survival differences. High relapse rates (ie, greater than 30% to 40%)or significant acute
toxicity are used to measure adverse outcome.
Standard chemotherapy alone versus MPA(PSI-II).
Two randomized studieshave evaluated treatment with radiation therapy alone versus MOPP chemotherapy alone,
both with median follow-up times of 7.5 to 8 years (Table
5). In the NCI study, patients with PS IIA, IIB, and IllA
H D were randomized to 6 months of MOPP or radiation
therapy (M, MPA, or TNI). Recognizing that patients with
massive mediastinal involvement or PS IIIA disease were
not optimal candidates for RT alone, the randomization criteria were changed while the studywas ongoing. When these
patients are removed from the analysis, no differences in
disease-free or overall survival are seen."' In the Italian
Prospective Randomized Study, PSIA-IIA patients were
randomized to receive either 6months ofMOPPorSTLI.IW
There areno differences in freedom from progression. However, survival was significantly higher in patients treated
with STLI (93%) comparedwith those treated with MOPP
(56%). The difference in survival was attributed to the inability to salvage patients relapsing after MOPP chemotherapy, a situation similarto patients relapsing after combination
chemotherapy
for advanced HD. Both studies
demonstrated greater acute toxicities in patients receiving
MOPP chemotherapy. In the Longo et all2' study, more
than 50% of patients receiving MOPP had at least one hospital admission for fever and neutropenia. Several small retrospective studies have also reported high relapse
and poor survival'31after treatment with MOPP alone.
Mantle irradiation alone (PSIA-IIA). The use of mantle
irradiation alone for early stage H D i s attractive because all
treatment is completed within 5 weeks, patients avoid the
long-term risks of radiation to the upper abdomen (second
tumors and small bowel obstruction), and the potential for
salvage with combinationchemotherapy is notcompromised. Results with mantle alone in unselected CS 1-11 patients aredisappointing, with the FFR atl0 to 15 years ranging from 38% to 54%23.76
and a survival of only 58% at 15
years.23Improved results with 10- to 15-year FFR of 58% to
81% were seen in selected patients with CS IA d i ~ e a s e . ~ ~ . ~ "
The EORTC H-7 trial is studying treatment with mantle
irradiation alone in CS IA female patients with NS or LP
histology, age less than 40 years, and a low ESR. These patients would be expected to have a risk of occult abdominal
involvement of lessthan 10%.
The role ofprophylactic abdominal irradiationin selected
PS 1-11 patients (stage IA disease, or stage IIA disease without
mediastinal involvement, NS or LP histology, an ESR <70,
and age 1 4 0 years) wasstudied in therandomized EORTC
H-5 trial. Disease-free and overall survivals were identical
for patients treated with mantle or MPA
These excellent results with mantle irradiation alone have
been corroborated in other retrospective s t ~ d i e s .At
~ ~the
,~~
Harvard Longwood area hospitals we are prospectively
studying the treatment of mantle radiation alone inPS IAIIA patients with NS or LP histology. Patients with PS IIA
disease with mediastinal involvement limited to above the
canna areincluded in the study. Patients with MC histology,
with B symptoms. or with more extensive mediastinal involvement are not eligible for this treatment. Preliminary
analysis suggest results similar to treatment with MPA.132
Because of the increased riskof abdominal relapse after
mantle irradiation alone, negative
a
staging laparotomy and
splenectomy and careful radiographic follow-up with monitoring of the abdominal-pelvic nodes after treatment are
essential components of the trial.
Six sycles oj'mod$ed chemotherapy and regional radiution therapy versus subtotal nodal and splenic irradiution.
MANAGEMENT OF EARLY STAGE HODGKIN‘S DISEASE
325
Table 5 . CT Alone Versus Wide-Field RT ISTLITTLI)
Studv
Stage
Design (no. of patients)
FFR ( v )
Survival (yr)
National CancerInstitute’29
Italian Pros Randomized Study”
PS IE, IIA, 116
PS IA-IIA
MOPP(41) vSTLl(41)
MOPP (44) v STLl(45)
82% v 74% (8)’
64% v 76% (8)
90%~ 8 5 %
(8)
56% ~ 9 3 %
(8)t
~
Numbers estimated from survival curves.
t Statistically significantdifferences, P < .001.
With the objective of reducing the acute toxicity and
chronic morbidity (sterility and increased risk of leukemia),
Homing et
developed a relatively “nontoxic”chemotherapy regimen, VBM (vinblastine, methotrexate, bleomycin), which was tested in a randomized trial of PS IA-IIB
and PS IIIA patients comparing STLI/TLIversus VBM and
IF irradiation. The freedom from progression data at5 years
favored IF VBM (95%)versus STLI (70%) (P= .09). No
differences were seen in overall survival. Based on these favorable results, a follow-up Stanford University trial is underway. Patients with CS IA-IIA H D (staging laparotomy
and splenectomy were eliminated) are being treated either
with STLI (and splenic irradiation) or with 6 cycles of VBM
and regional irradiation. This ongoing program is one of a
number of studies developed to test less toxic chemotherapy
for CS IA-IIA patients and define whether modified CT is
sufficient treatment for the 25% of patients who statistically
will have occult abdominal involvement.
Preliminary results in CS 1-11 patients with unfavorable
characteristics (having at least one of the following features:
age 250 years, 2 4 nodal regions involved, large mediastinal
adenopathy. or a combination of B symptoms and elevated
ESR) in the EORTC H7 trial raise concern for the routine
use of non-MOPP or non-ABVD chemotherapy regimens
in the management of patients with poor prognosis, early
stage HD. Patients randomized to receive 6 cycles of EBVP
and involved field irradiation had a significantly lower freedom from relapse than patients treated with 6 cyclesof
MOPP/ABV and involved field irradiation (73% v 91%,respectively; P = .0003), causing this portionof the H7trial to
be d i s ~ o n t i n u e d .Further
’~~
information is needed to determine which subgroups of CS 1-11 patients are suitable for
modified chemotherapy and radiation therapyapproaches.
Shortened courses of chemotherapy and radiation therzpy. The M.D. Anderson Hospital tested the role of two
:ycles of adjuvant MOPP, and mantle with low-dose lung
irradiation in patientswith “unfavorable” PS IA-IIB HD.L35
The study is prospective and nonrandomized. The early results are promising, but the median follow-up is only 26
months. A similar trialby the Cancer and Leukemia Group
B (CALGB) testing three cycles of VP-16, adriamycin, and
velban (EVA) and mantleor MPA irradiation in CS and PS
[A-IIBand in PS IIIA patients hasjust been completed.
Straus et al”‘ reported a randomized trial comparing 4
:ycles of MOPP andmantle RT versus 4 cycles of thiotepa,
deomycin, and vinblastine (TBV) and mantle RT for paients with CS IA-IIA disease. With a median follow-up time
If 64 months,the 5-year freedom from progression was 89%
’or MOPP and RTversus 8 1 % for TBV and RT. Similarly,
.he Southwest Oncology Group and the
CALGB have initi-
+
ated a randomized trial evaluating the role of 3 cycles of
adjuvant Doxorubicin and Vinblastine to subtotal nodal
and splenic irradiation in CS IA-IIA H D patients. All these
trials should helpto determine the continued role of staging
laparotomy and limited radiation therapy in selected early
stage patients. Studies using radiation therapy and modificationsinchemotherapyshould
also help to determine
whether a reduced number of cyclesof standard or modified
chemotherapy can effectively substitute for staging laparotomy or abdominal irradiation.
RECOMMENDATIONS
The treatmentof H D has become more complicated
over
the past 10 years. The development of standards for both
radiation therapyand chemotherapy have made it more feasible to treat H D in community practice settings. Yet, initial
treatment decisions may have profound long-term effects
on patients who are young
and likely to have a long survival.
Whenever possible, routine cases should be treated along
guidelines of standard accepted practice, and physicians
should refer to major centers for the management of more
complicated cases. There is hope that less toxic chemotherapy will be effective in curing occult microscopic disease,
perhaps eventually obviating the need for staging laparotomy and splenectomy. Yet, for now, there are little longterm data defining specifics of treatment or the long-term
efficacy or toxicity of such regimens. Thus, at present, the
management of patients with H D in ways that donot adhere
to standard practice, such as modifying standard radiation
therapy or chemotherapy, should be strongly discouraged
outside of controlled clinical trials.
Diagnostic staging laparotomy and splenectomy is not
routinely performed outside the continental United States.
Academic centers in Canada, Great Britain, Europe, and
South America have identified prognostic factors to aid in
determining treatment for clinically staged patients. Patients with favorable characteristics receive RT alone with
RT and CT
used for the remainder ofpatients. However, on
average, without the information obtained at staging laparotomy, patients require moretreatment, either with larger
radiation fields or with the more frequentuse of chemotherapy.
In many parts of the United States there is still a general
acceptance of staging laparotomy and splenectomy as a
means to aggressively stage patients to minimize treatment.
Patients who are likely to need chemotherapy because of a
high risk of relapse (LMA or extensive B symptoms) or high
risk for having abdominal involvement (morethan onepositive abdominal radiographic test) should not undergo a
staging laparotomy. In addition, there may be special cir-
PETER M. MAUCH
326
cumstances in which chemotherapy and limited field irradiation is preferred (ie, for pediatric patients). For theremainder of patients surgical staging should still be considered in
the routine managementof early stage HD. The majority of
patients with PS IA-IIA HD will be cured with RT alone,
thus sparing the toxicity of combined CT and RT and
preserving the effectiveness ofCT in case of relapse.
ACKNOWLEDGMENT
Geraldine S. Pinkus, MD, and Madeleine D. Kraus, MD, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, generously provided thephotomicrographs reproduced on the cover of this issue.
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