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Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2704-2712
Long-Term Results From MOPPEBVCAD Chemotherapy With Optional Limited
Radiotherapy in Advanced Hodgkin's Disease
By
Paolo G. Gobbi,
Carla Pieresca,
Maria L. Ghirardelli,
Nicola DiRenzo,
Massimo Federico,
Francesco Merli,
Emilio Iannitto,
Vincenzo Pitini,
Giovanni Grignani,
Amedea Donelli,
Mario Carotenuto,
Vittorio Silingardi, and
Edoardo Ascari for the Gruppo Italiano per lo
Studio dei Linfomi
From Medicina Interna e Oncologia Medica, IRCCS
Policlinico S. Matteo, Università di Pavia, Pavia, Italy; the
Divisione di Ematologia, Ospedale "Casa Sollievo della
Sofferenza," S. Giovanni Rotondo, Foggia, Italy; the Cattedra e
Divisione di Oncologia, Università di Modena, Modena, Italy; the
Divisione di Ematologia, Ospedale S. Maria Nuova, Reggio Emilia, Italy;
the Divisione di Ematologia con Trapianto di Midollo,
Università di Palermo, Palermo, Italy; the Istituto di Clinica
Oncologica, Università di Messina, Messina, Italy; and the
Divisione di Ematologia, Università di Modena, Modena, Italy.
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ABSTRACT |
The purpose was to verify the 5-year results of the
MOPPEBVCAD chemotherapy regimen with limited radiotherapy in
relation to the promising preliminary data. Mechlorethamine,
vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin,
vinblastine, lomustine, melphalan, and vindesine were delivered
according to a schedule derived through hybridization, intensification,
and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas
that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in
complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were
fully acceptable. Most of the unfavorable prognostic factors lost their
clinical weight. Only age and lymphocyte depletion histologic type were
statistically correlated with major follow-up endpoints; performance
status and bone marrow involvement were subordinate to age. Seven
patients developed a second cancer (including 3 myelodysplasias).
MOPPEBVCAD with selected radiotherapy is a highly effective regimen in
advanced Hodgkin's disease. Early and late toxicity are no more severe
than what would be expected with other alternating or hybrid regimens.
A comparison with ABVD, which is currently considered the standard
regimen for advanced Hodgkin's disease, is needed.
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INTRODUCTION |
IN THE LAST DECADE, increasing evidence
made it clear that the treatment of advanced Hodgkin's disease (HD)
should be based on two distinct chemotherapy (CT) regimens, possibly
combined with variable radiotherapy (RT), ie, MOPP (mechlorethamine,
vincristine, procarbazine, and prednisone) and ABVD (doxorubicin,
bleomycin, vinblastine, and dacarbazine). Both regimens have been
tested on large patient series, both achieve equivalent
results,1,2 both are non-cross-resistant,3 and
both have no better four- or five-drug variants.4-8
However, in the 1980s, clinical application of the mathematical model
of Goldie and Coldman9 to the drug sensitivity of tumor
cells according to their spontaneous mutation rate led many investigators to design CT schedules that alternated some of the most
effective regimens, chiefly MOPP and ABVD. Therefore, together with the
alternating MOPP/ABVD schedule,10 many other similar combinations were designed, such as MOPP/CABS,11
MOP-BAP,12 MOPP-CAVmP,13
BCVPP/ABD,14 LOPP/EVAP,15
ChlVPP/PABIOE,16 but none of them seemed to be superior to
MOPP. In the Cancer and Leukemia Group B randomized trial, MOPP/ABVD
was as effective as ABVD alone and more effective than MOPP with regard
to complete remission rate and failure-free survival, but it did not
show statistically significant better survival.17
The Goldie and Coldman model reached its extreme exploitation in CT
regimens that delivered, within each cycle, all the drugs previously
scheduled in alternating courses. This strategy allowed tumor cells
more exposure to drugs having different mechanisms of action, which
should also contribute to reducing the chance that resistant cell
clones develop and grow. To this aim, the so-called hybrid regimens
were designed, such as MOPP/ABV,18 MA/MA,19
ChlVPP/EVA,20 and BEACOPP.21 So far, such
hybrid protocols have not shown results clearly superior to those
obtained with their alternating counterparts or even with ABVD alone,
which, moreover, proved to be less toxic during a short
follow-up.22
In agreement with the ongoing evolution of CT for advanced HD, in 1987 the Italian Lymphoma Study Group (GISL) designed a shortened,
hybridized, and intensified version of Straus' alternating regimen
CAD/MOPP/ABV23 and combined it with optional use of RT on
very selected and limited areas. The preliminary data on feasibility,
early results, and toxicity of this modified CT program were very
encouraging.24
We report here the final results of this multicenter trial using hybrid
MOPP/EBV/CAD (or, simply, MOPPEBVCAD) CT, with or without limited RT.
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MATERIALS AND METHODS |
Patient population.
The criteria for enrollment in the study were (1) unequivocal
histologic diagnosis of HD; (2) age of 15 to 75 years; (3) no previous
treatment; and (4) advanced or unfavorably presenting disease, defined
as stage II B, III B, IV or subdiaphragmatic stage III A with
lymphocyte-depleted nodular sclerosis or lymphocyte-depletion histologic types, or all histologic types of stage III2A.
One hundred and fifty-five patients were entered into the study between January 1, 1988 and September 30, 1993, the date on which the trial was
closed. Ten patients were subsequently excluded from the series: 5 on
account of histologic reevaluation, which changed the diagnosis to
anaplastic large-cell (CD30+) lymphoma (3 cases),
T-cell-rich B-cell lymphoma (1 patient), and undifferentiated
anaplastic carcinoma of the thyroid (1 case), respectively, and 5 because of staging inaccuracy (2 cases with actual stage IIA disease)
or protocol violations (3 patients who received 1 or 2 cycles of
MOPPEBVCAD then continued with either ABVD [2 cases] or MOPP [1
case] for reasons other than clinical, less frequent administration,
distance from the hospital, etc).
Therefore, a total of 145 patients were eligible for the study and
their clinical characteristics are listed in
Table 1. The annual enrollment rate also
reflects the increasing number of institutions that joined the GISL
during the years of this investigation; the enrollment rate was as
follows: 8% (1988), 16% (1989), 19% (1990), 23% (1991), 20%
(1992), and 14% (first 9 months of 1993).
An exact estimate of the expected sample size of the study was not
made, because this protocol was part of a general plan that divided
treatment strategy into three different risk groups.25 A
preliminary report was published on the first 80 patients, who were
evaluable at the end of 1991, regarding the feasibility, tolerability,
and early clinical results of the study.24 At that time,
the advisability of stopping the trial and starting a randomized study
to compare MOPPEBVCAD with one of the best current regimens was clear.
However, the GISL rate of patient accrual was not sufficient to sustain
a randomized study until other groups began to cooperate.
Disease stage was investigated according to the requirements of the
Cotswolds Meeting.26 In particular, staging procedures routinely involved chest roentgenogram, computed tomography of the
thorax and abdomen, ultrasonography of the abdomen, and bone marrow
biopsy. None of the patients was staged with exploratory laparotomy and
splenectomy. Every clinical, radiologic, or laboratory abnormality
found at pretreatment staging was retested at the end of treatment to
evaluate response.
In 1995, pathologists were called on to revise the histologic
assessment of all cases of their own center and to submit equivocal specimens to two external pathologists; 27 cases underwent such intercenter reevaluation.
Chemotherapy.
The criteria for hybridization, dose intensification, and schedule
shortening through which MOPPEBVCAD was derived from the alternating
three-drug combination CAD/MOPP/ABV have already been detailed
elsewhere.24 Six cycles of chemotherapy were planned. Drug
doses and administration schedules are listed in
Table 2, which also reports drug-dose
modifications according to blood counts. Growth factors were not
available until the end of 1991. However, starting in 1992, their use
was very restricted and they were used only in cases of severe febrile
neutropenia. Dose intensity was calculated according to the criteria
reported by Hryniuk27 and the examples and suggestions
offered by DeVita et al.28
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Table 2.
MOPPEBVCAD Hybrid Regimen: Drug Doses and Time Schedule,
With Dose Reduction According to Blood Cell Counts
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Radiotherapy.
RT was not routinely associated with CT but was administered to a
limited number of patients and only to 1 or 2 selected areas corresponding to previous bulky involvement or to masses that were only
slowly or partially reduced during CT. RT had to be administered after
CT and total doses could not exceed 35 Gy. The decision to treat, which
sites to treat, and which dose to deliver were left to the clinicians
and radiotherapists of each institution. In 4 patients, the extensive
initial involvement of supradiaphragmatic areas required truly
extended-field mantle RT.
Assessment of response and statistical analysis.
Complete remission (CR) was defined as complete regression of measured
lesions and disappearance of all other objective evidence of lymphoma
for at least 3 months. Partial remission (PR) consisted of a decrease
of more than 50% in the sum of the products of the diameters of the
measurable lesions. No response (NR) was anything less than a 50%
decrease in measurable lesions. According to the Cotswolds Meeting
recommendation,26 the category of unconfirmed or uncertain
complete remission (CR[u]) was accepted to denote patients in normal
health with no clinical evidence of HD but with some radiological
abnormality in a site of previous disease. However, uncertainty about
the completeness of such a remission had to be resolved within 6 months
from the end of therapy. The definition of bulky masses met the
criteria coded in the Cotswolds Meeting, ie, for a mediastinal mass,
when its maximum width exceeded one third of the internal transverse
diameter of the thorax at the level of the disc between T5 and T6
vertebrae and, for any extramediastinal mass, when its largest diameter
was greater than 10 cm. A mass was judged to respond slowly when less
than a PR was achieved after the third cycle in patients responding at
least partially at the end of chemotherapy.
The Scotland and Newcastle Lymphoma Group (SNLG) prognostic
index29 and the International Database on Hodgkin's
Disease (IDHD)30 estimate of the probability of surviving
year by year were retrospectively calculated for each patient according
to the investigators' guidelines. These parameters were used as
synthetic risk predictors derived from some of the most recent
systematic investigations directed at selecting the best prognostic
factors in HD.
Toxicity was measured according to standard ECOG
criteria.31
Overall survival (OS) was determined from the date of diagnosis to the
date of last observation or death (from any cause). The same time frame
was used to calculate tumor mortality (TM), with the exception of
censoring deaths occurring in complete remission of HD and not directly
due to therapy. Relapse-free survival (RFS) for complete responders was
measured from the date of therapy completion to the date of last
observation or relapse. Failure-free survival (FFS) was computed from
the start of treatment to one of the following events: death from any
cause, disease progression during treatment, no CR at the end of
treatment, or relapse.
Survival curves were calculated using the method of Kaplan and
Meier.32 Deaths due to causes other than HD or treatment were not censored, except for RFS.33
Many clinical features were scrutinized singly at diagnosis to evaluate
their individual role in discriminating OS, RFS, and FFS. In this
univariate study, the Kaplan and Meier estimate was used for
qualitative variables, whereas a simple linear regression analysis
applied to the proportional hazard model34 was used for
quantitative parameters. A multiple regression analysis was then
performed, within the same proportional hazard model, to select the
best clinical features related to OS, RFS, and FFS, respectively. In
these analyses, the SNLG index and the IDHD estimate of the survival
probability at 5 years were used as single, distinct covariates.
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RESULTS |
Of the 145 eligible patients, 137 (94%) achieved CR, 136 with
chemotherapy alone. Four obtained only a PR (3%) and the other 4 did
not respond at all (3%).
A total of 844 cycles were administered and evaluated; the mean number
of cycles per patient was 5.8 (range, 3 to 8). Six patients received
more than 6 cycles due to slowly responding symptoms or adenomegalies.
All but 1 of them reached CR.
In 18 patients, treatment was stopped before the sixth cycle because of
severe hematological toxicity (14 cases), infection (1 case of
Pneumocystis carinii pneumonia and 1 of B-virus hepatitis), or
patient refusal of further therapy (2 cases). Four of these 18 subjects
died with persisting evidence of disease, whereas another relapsed
after 3 months of CR and died of the disease during salvage treatment.
The remaining 13 achieved stable CR.
CT was administered on an outpatient basis in the great majority of
cases and only 18 subjects had to be hospitalized for complications.
Dose intensity was 0.76 ± 0.12 for the first 3 cycles and
0.72 ± 0.11 over all 6 cycles. According to the criteria
for dose adjustment on the basis of white blood cell and platelet
counts, delaying therapy was preferred to decreasing drug doses if
severe myelosuppression occurred near the beginning of a new cycle,
whereas the opposite strategy was followed when myelosuppression
appeared before completion of the cycle. In 1992, growth factors became available in Italy, but the possibility of further dose intensification was not pursued. Granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage colony-stimulating factor (GM-CSF) were used
strictly on clinical demand, ie, when the neutrophil count decreased to
less than 0.5 × 109/L and fever or other signs of
infection were present. Twenty-four patients in all (16.5%) received
at least a few days of therapy with G-CSF or GM-CSF.
Table 3 shows the toxicity associated with
administration of the drug regimen.
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Table 3.
Maximal Grades of Acute Hematological and
Nonhematological Toxicity Experienced by Patients (Percentages of
145 Cases)
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Hematologic toxicity was more severe (and more frequently
dose-limiting) than nonhematological side effects. Eleven patients (8%) required transfusion of at least 1 U of concentrated
erythrocytes. Thirty-seven febrile episodes were recorded throughout
the treatment of the 30 patients (21%; Table 3) who registered at
least one neutrophil count less than 0.5 × 109/L. In
this regard, the criteria adopted in 1992 for the use of growth factors
helped to limit the length and severity of serious infections in the
second part of the trial, but did not affect their number throughout
the study. One P carinii pneumonia, 1 cytomegalovirus
infection, 1 acute B-virus hepatitis (likely posttransfusional), and 2 cases of thoracic herpes zoster were recorded; interruption of
chemotherapy due to these illnesses had no effect on clinical response.
Seven subjects developed prolonged asymptomatic pancytopenia, presenting a hemoglobin level of less than 10.0 g/dL, a white blood
cell count of less than 2 × 109/L, and a platelet
count of less than 100 × 109/L for 3 months or longer
after the end of therapy.
Nonhematological toxicity was acceptable. Most of the cases of grade
2-3 nausea and/or vomiting were recorded before the
antiserotoninergic receptor drugs became available, so that this side
effect can be considered well controlled. Neurotoxicity required dose
reduction of vincristine and vinblastine in 7 subjects. Mucositis was
always mild. Two cases of pulmonary fibrosis were observed: the first (of grade 2 intensity) occurred during chemotherapy and was related to
the administration of bleomycin (which was promptly stopped); the
second (of grade 3 intensity) became evident 2 months after radiotherapy. One case of probable cardiotoxicity due to anthracycline consisting of a reversible episode of flutter-fibrillation occurred in
a 33-year-old patient during the second cycle. Epidoxorubicin was
omitted from this subject's subsequent cycles.
RT was administered in 47 patients (32%), 46 of whom were evaluated to
be in CR or in CRu after completion of chemotherapy. Patients received
RT with different supervoltage equipment in 13 distinct radiotherapy
units. Dose fractions varied from 0.16 to 0.22 Gy and total doses
ranged from 26 to 42 Gy (median, 35 Gy). The number of irradiated
anatomic sites was 1 in 21 patients, 2 in 12, and 3 in 4. The areas to
be irradiated were selected according to their bulky involvement at
diagnosis or slow or partial response to chemotherapy. Extended-field
radiotherapy was delivered in 10 patients (above the diaphragm in 9 and
below the diaphragm in 1) either because of the extensive and massive
involvement of other lymph node sites besides the one evaluated as
bulky or because chemotherapy interruption (for complications, patient refusal to continue, etc) was anticipated.
The median follow-up was 66 months (range, 25 to 114 months).
Figure 1 shows the TM and OS and
Fig 2 shows the RFS and FFS recorded
in the eligible study population. Table 4
offers a summary check of CR, PR, and death rates and OS, TM, RFS, and
FFS both in the 145 eligible patients and in the total population of
155 subjects that were recruited and whom we intended to treat.
Differences shown in Table 4 were negligible, and therefore only the
eligible patients were analyzed. Of the 4 PR patients, 2 underwent
high-dose chemotherapy with autologous bone marrow transplantation (1 was rescued and is still alive in CR and 1 did not respond and
subsequently died) and 2 responded poorly to additional therapies as
well and still survive with evidence of disease. The other 4 subjects
with nonresponding or progressive disease during chemotherapy died within 5 months of diagnosis: 1 of complications to therapy and 3 of
the disease.
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Table 4.
Comparison of Results Obtained in the 145 Patients
Eligible for the Study and in the Total Population of Subjects That
Were Recruited and Treated
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Among the 137 CR, 24 relapses were recorded. Five of these 24 patients
underwent high-dose chemotherapy with autologous bone marrow
transplantation: 3 of them died of unresponsive disease, 1 responded
partially and is alive with evidence of disease, and 1 achieved a new
CR. The relapses of the other 19 were treated with different
conventional regimens containing three or four drugs or with
alternating or hybrid ones delivering six drugs or more; 8 patients
obtained a new CR and 6 are still alive (1 died of myelodysplastic
syndrome and 1 died of infections [the subject was human
immunodeficiency virus (HIV)-positive]), 1 responded partially to
several subsequent therapies and is alive with evidence of disease, and
10 died of the disease after little or no response.
A synchronous tumor was diagnosed in 1 patient and metachronous ones
developed in 7 other subjects. The clinical characteristics of these
patients and the types of tumors recorded are listed in
Table 5. These patients shared no definite
clinical features, in particular not high drug dose intensity, frequent
association of RT, or elevated incidence of relapses requiring further
treatment. Both patients who developed small-cell lung carcinoma were
smokers.
In all, 18 patients died: 13 of HD progression after either first-line
CT failure or one or more relapses, 1 of a pulmonary infection from
Klebsiella pneumoniae in second CR (the HIV-positive patient),
1 of severe gastric hemorrhage during CT (to which the disease did not
respond), and 3 of second tumors.
A large list of factors reputed to be important for HD prognosis were
scrutinized in a univariate analysis in relation to OS, RFS, and FFS
and are reported in Table 6. Surprisingly,
some of the best-known and most important prognostic factors in HD, such as stage, presence of bulky disease, extranodal involvement, erythrocyte sedimentation rate, hemoglobin concentration, serum lactate
dehydrogenase, serum albumin level, and treatment with combined
radiotherapy, did not influence any of the survival time parameters.
Those that were found to exert a statistically significant role with
respect to at least one follow-up variable (age, histologic type,
performance status, bone marrow involvement, dose intensity of the
first 3 CT cycles, SNLG prognostic index, and IDHD 5-year OS estimate)
underwent multivariate analysis in the final Cox model, and only age
and histologic type retained good statistical importance for OS and
FFS, with histology being the only decisive factor for RFS
(Table 7). When age was removed from the
model, its prognostic role was replaced by bone marrow involvement and performance status for OS and by performance status alone for FFS.
Practically speaking, patients more than 45 to 50 years of age (or,
alternatively, with involved bone marrow and Karnofsky index  70)
presenting lymphocyte depletion histologic type have a high probability
of poor or short-lasting response.
Systematic calculation of the SNLG index at diagnosis for each patient
led to the identification of 52 subjects who had to be considered at
high risk (ie, with an index >0.5, corresponding to a 60%
probability of dying within 4 years, according to the work of Proctor
et al29). Survival of such high-risk subjects (Fig 3) tended to be shorter than that of
the other patients in the series, but the difference was not
statistically significant and the survival plateaux, rather near each
other, reached by both the curves do not lead us to think that
prolonging the observation time would improve the statistical
difference.
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| Fig 3.
Survival comparison between the 52 patients having a SNLG
index greater than 0.5, ie, absolutely the best prognosis according to
Proctor et al,29 and the remaining 93 members of the study population.
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Moreover, the IDHD estimate of the probability of surviving at any
given time was computed for each subject and made it possible to
calculate the expected median survival of the whole population for any
given year with a ±1 standard deviation confidence interval. As
shown in Fig 4, it is clear that the
MOPPEBVCAD protocol allows patients to survive longer than expected,
all clinical patient characteristics of the patients being equal, with
respect to the experience of the 1970s and 1980s.
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| Fig 4.
Survival curve of the 145 study patients together with a
band of ±1 SD around the expected median survival, which was
estimated in the same patient series according to IDHD clinical
experience and computation techniques.30
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DISCUSSION |
The basic idea that underlay the formulation of the MOPPEBVCAD CT
regimen, optionally combined with limited RT, for advanced HD was to
try to improve an already existing treatment program, which had to be
well known as widely tested and highly effective, by introducing
selected changes. In 1987, the GISL chose Straus' alternating
regimen23 as the original reference model, because, in the
middle 1980s, it showed some of the relatively best figures for CR and
RFS, associated with less frequent nausea and vomiting (which were
serious clinical problems in those years). Importantly, these results
seemed to agree fully with the theoretical models of drug
sensitivity related to cell kinetics. Thus, hybridization of the
drugs of the alternating CAD/MOPP/ABV into the MOPPEBVCAD schedule offered closer compliance with the Goldie and Coldman theory.9
Contemporary intensification of doses was obtained by administering in
6 cycles approximately the same cumulative drug dosage delivered with 9 cycles of the alternating CAD/MOPP/ABV and by reducing the cycle length
from 35 to 28 days. The resulting planned intensification, according to
the criteria reported by Hryniuk,27 was 1.54. Therefore,
the average relative dose intensity actually delivered in our series
with the hybrid regimen, which was 0.72, corresponded to 1.10 of the
projected doses in the first 6 cycles of the reference regimen. Because
the average observed-to-expected total drug delivery ratio during the
initial 6 months with the alternating regimen proved to be
0.81,23 a true dose intensification of about 36% was
actually reached with the hybridized CT regimen.
Conversely, to minimize early and late toxicity without compromising
results, CT intensification was coupled with a marked reduction in the
RT program. Whereas irradiation of all nodal regions initially involved
was provided between the sixth and seventh cycle of the alternating
CAD/MOPP/ABV regimen, only lesions evaluated as bulky at diagnosis or
slowly or partially responding during CT (which are the sites with the
highest probability of clinical failure) were irradiated after hybrid
MOPPEBVCAD. The consequence of this decision was that about two thirds
of our patients did not undergo RT and, where it was used, only one or two anatomic sites (rarely more) were irradiated.
Clinical results regarding the unfavorable subset of HD patients are
interesting, because consistently excellent figures for CR rate, TM,
OS, RFS, and FFS were achieved. Table 8
lists the results of some of the major and recently reported series on
advanced HD. Even though true and exact comparisons cannot be made
among series with differences in patient composition, length of
follow-up, therapy duration (mainly, number of cycles), and supportive
care, our data seem to be similar to or better than those from the best protocols with alternating or hybrid chemotherapy. Only 2 of the 24 relapses in our study were recorded after 36 months of follow-up and
none after 43 months; thus, our initial reserve about long-term results
can be removed.
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Table 8.
Results of Some of the Main Alternating or Hybrid
Multiple-Drug CT Regimens in the Treatment of Advanced HD
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Furthermore, some of the most important and strongest prognostic
factors seemed to be mitigated or even eliminated by this therapy:
stage, bulky disease, involvement of the spleen or extranodal sites, B
systemic symptoms, high levels of LDH and/or ESR, and low
hemoglobin and/or serum albumin concentration proved to have no
more influence on response to therapy, survival, or probability of
relapse in patients treated with MOPPEBVCAD. This was particularly clear when outcome data were tested while considering two powerful composite prognostic systems, the IDHD survival estimate and the SNLG
prognostic index. The survival of patients treated with the MOPPEBVCAD
protocol exceeded the IDHD estimation of an expected survival band of 1 standard deviation around the median. Among patients treated with
MOPPEBVCAD, there were no longer clear differences in survival (and RFS
or FFS) between those with a SNLG prognostic index greater than 0.5 (whose probability of dying within 48 months should be
60%29) and those with a lower index value.
With MOPPEBVCAD therapy, only two clinical factors retain a crucial
prognostic role: age and lymphocyte depletion histologic type. However,
in practice, it is clinically rather difficult to use age to select
those patients who are probably destined to fail to respond to
MOPPEBVCAD therapy for a program of alternative experimental treatment.
As a matter of fact, nearly the same age limits that would identify
higher-risk patients should contraindicate such treatment options.
Excluding age from the prognostic evaluation and accepting that it
should simply discriminate otherwise selected high-risk patients only
on the grounds of the technical feasibility of probably investigational
therapy, the second and third most unfavorable prognostic factors for
patients treated with MOPPEBVCAD become performance status
and bone marrow involvement at diagnosis. Performance status can be
accepted as a sufficiently useful factor because, first, it is not
necessarily in conflict with other treatment options, even
transplantation (being subject to pre-therapy improvement, if
necessary) and, second, its highest discriminant effect is placed
between 70 and 80 of the Karnofsky scale (ECOG, 1 to 2). Therefore,
apart from age greater than 45 to 50 years, patients with lymphocyte
depletion histologic type, bone marrow involvement, and/or
Karnofsky index 70 (or ECOG grade 2) should enter clinical trials
to compare one of the best chemotherapy regimens developed so far with
one of the most promising experimental treatments available. Caution is
needed when considering these prognostic results, despite the highly
significant statistical levels reached, because they actually derive
from a low number of observed failures. These results require further
confirmation.
It is likely that the development of treatment protocols with
increasing effectiveness in HD will require a search for particular prognostic factors related to a given CT regimen. Consideration of
these features, according to the specific treatment one intends to use,
would be important for early selection of patients with a definite risk
for specifically designed clinical trials.
A few comments are needed on results and toxicity.
Acute nonhematological toxicity has to be considered fully acceptable
and comparable with that of many alternating or hybrid regimens
containing seven to eight drugs or more. Hematological toxicity was
remarkable but controllable. First of all, only 1 toxic death was
recorded, from gastrointestinal hemorrhage, in a man who did not show a
response and presented severe thrombocytopenia after the second cycle
of therapy. Second, growth factors, which became available during the
last 2 years of the trial, were used only on demand in a strict
minority of patients (16%). It is likely that moderate and intelligent
use of them can contribute to reducing the consequences of
myelotoxicity, particularly those related to heavy neutropenia.
Finally, as for intermediate and late toxicity, 1 case of nonsevere
pulmonary fibrosis, 1 of mild cardiotoxicity (recurrent accesses of
atrial fibrillation), and 7 second cancers (3 of which were fatal) were
diagnosed during the follow-up. Although this series might not be
considered completely mature in this regard, the absolute incidence per
type of cancer appears to be lower than what is generally expected when
dealing with MOPP and MOPP derivatives and probably higher than that
recorded with ABVD. Staging without splenectomy, shortening the time of
CT administration, reducing cumulative individual drug doses scheduled
in the original alternating regimen from which MOPPEBVCAD derives, and
eliminating RT in the majority of patients (with a reduction of the
irradiated areas in the remaining ones) are all factors that
potentially lower the relative risk of second cancer. Actually, the
planned dose intensity for each drug in MOPPEBVCAD CT is not absolutely high when compared with what is commonly delivered in other popular CT
regimens for HD. For example, the 6-cycle cumulative dose of mechlorethamine and vincristine is 25% and that of procarbazine 50%
of what is provided in 6 cycles of the MOPP regimen1; the
total dose of vinblastine and epidoxorubicin (assumed to be equivalent
to a 40% lower dose of doxorubicin35) is 50% and that of
bleomycin is 75% of what is planned in 6-cycle ABVD
therapy2; CCNU doses are 50% of those delivered in the
CVPP regimen36 or 66% of those in CEP37 CT.
Finally, the cumulative dose of melphalan represents 70% of what is
administered to patients with multiple myeloma over the same period at
a current dosage of 0.25 mg/kg/d for 4 days every 6 weeks. On the other
hand, a relatively high proportion of elderly patients (21% >50
years of age), advanced stage disease, increased dose intensity,
association of several, albeit different, and potentially leukemogeneic
drugs can be factors favoring the onset of a second cancer.
Unfortunately, the majority of the available studies on second cancer
incidence among HD patients either involve too long a period of
recruitment to reach a sufficient number of participants and
unavoidably collect heterogeneously treated patients or are focused on
relative risk with respect to a control population. The information we
need for each trial (and for each arm of randomized studies) is
represented by the number of second cancers actually recorded (or their
cumulative incidence) and by the actual median follow-up length, but
the availability of both in the literature is not common.
Indeed, our incidences of second myelodysplasia (2.1%), truly
secondary lung cancer (0.7%), and colorectal cancer (1.4%) are similar to those of Viviani et al19 after alternating or
hybrid MOPP/ABVD with or without RT, ie, 2.6%, 0.9%, and 0.5%,
respectively. The experience of the Royal Marsden Hospital
investigators38 after MOPP or MOPP-derived regimens also
seems to be comparable, because the cumulative incidence at 5 and 10 years is 0.6 and 1.9 for second leukemia and related disorders, 0.2 and
1.3 for lung cancer, and 1.7 and 2.3 for other solid tumors, excluding skin cancers, respectively. The data on actuarial risk for second leukemia, lung cancer, and solid tumors that can be extrapolated from
the study by Abrahamsen et al,39 on a population of
patients with all disease stages, and from that by Martinelli et
al,40 on advanced-stage patients only, are fully
comparable, too. Thus, MOPPEBVCAD does not carry a higher risk of
secondary tumors than what is observed in other series of patients
treated with other alternating or hybrid drug combinations.
Only 2 patients in our series had relapsed before the onset of second
cancer, so a role for extended administration of potentially oncogenic
drugs as salvage therapy can be claimed in a minority of patients.
Similarly, only the patient who developed lung cancer and the one who
suffered a unifocal eosinophilic granuloma were treated with both CT
and RT; therefore, this combined therapy cannot be considered a major
causative factor.
Fertility was not specifically studied in these high-risk patients.
Nevertheless, it is known to have been preserved in some of them. A
26-year-old woman and a 35-year-old man generated normal offspring 29 and 38 months, respectively, after treatment.
In conclusion, MOPPEBVCAD CT with optional limited RT can be considered
a highly effective protocol for advanced HD. Its early hematologic
toxicity is equivalent to that of other alternating or hybrid seven- or
eight-drug regimens and might be better controlled with a limited use
of growth factors. Its late toxicity is at least no greater than that
of other alternating or hybrid regimens, particularly those including
MOPP drugs. Randomized studies are needed and two are currently under
way to compare other popular regimens with MOPPEBVCAD and to explore a
less toxic version of it.
| |
FOOTNOTES |
Submitted August 26, 1997;
accepted November 20, 1997.
Supported in part by grants from the Associazione Italiana Ricerche sul
Cancro, Milano, and the Fondazione Adolfo Ferrata and Edoardo Storti,
Pavia, Italy.
Address reprint requests to Paolo G. Gobbi, MD, Medicina Interna e
Oncologia Medica, Università di Pavia, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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.
| |
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Abstract
Introduction
Abstract
