Annals of Oncology 12 105-108.2001
© 2001 Kltiwer Academic Publishers Primed in the Netherlands
Original article
Cyclophosphamide, adriamycin and dexamethasone (CAD) is a highly
effective therapy for patients with advanced multiple myeloma
H. Szelenyi,1 E. D. Kreuser,2 U Keilholz,1 H. D. Menssen,1 C. Keitel-Wittig,3 J. Siehl,1
W. Knauf1 &E.Thiel'
1
Umversitatsklimkum Benjamin Franklin, Medizimsche Klimk III, Freie Universilat Berlin, Berlin, Krankenhau.s der Bannherzigen Briider,
Regenshurg, 1Onkologische Praxis Dr Keilel-Wiltig, Dr Herrenberger, Berlin, Germany
Summary
Background Patients with advanced multiple myeloma (stage
III or progressive myeloma) received the CAD protocol every
three weeks cyclophosphamide 200 mg/m 2 l v /orally days
1-4, adriamycin 30 mg/m 2 l v on day 1 and dexamethasone
40 mg p o days 1—4
Patients and methods Forty-six patients with a median age
of sixty years (range 34-84 years) were enrolled According to
Dune-Salmon 44 patients were in stage III, 2 in stage II, 6
patients had renal insufficiency (stage B) Twenty-three patients
were pre-treated at least with melphalane/prednisone.
Results Remission rates were as follows complete remission
4%, partial remission 70%, minimal change 11%, no change
11%, progressive disease 4% After an observation time of 14
months the median progression free interval for 33 patients not
treated with subsequent high-dose chemotherapy with stem-cell
support was more than 14 months Overall, treatment was well
tolerated After 209 cycles given febrile neutropenia occurred
in 11% of cycles including one fatal outcome Neutropenia or
thrombocytopenia grade 3—4 WHO was recorded in 18%i and
6%> of the cycles, respectively
Conclusions This study shows that CAD is an effective
regimen with an overall remission rate of 74% The CAD
protocol should be further evaluated in prospective trials
Key words adriamycin, chemotherapy, cyclophosphamide,
dexamethasone, multiple myeloma
Introduction
Patients and methods
Since its introduction in 1969, when Alexanian [1] described the combination of melphalane and prednisone
(MP) to be effective in the treatment of multiple myeloma
(MM), this regimen is regarded as the palliative 'gold
standard'. The MP protocol induces approximately
40%-50% responses with a median survival between 19
and 39 months. A variety of different chemotherapy
regimens, either mono- or polychemotherapy have been
tested for the treatment of this disease since [2] Mainly,
three cytotoxic agents were shown to be effective either
as single compounds or in combination chemotherapy
[3-5]: dexamethasone, alkylating agents (melphalane,
cyclophosphamide) and adriamycin. Dexamethasone
alone induces remissions in 40%-50% of the patients
[6]. Cyclophosphamide, being as effective as melphalane
[7], produces around 25% of remissions in myeloma
patients [5, 8]. Finally, adriamycin given in combination
regimens is associated with a remission rate of up to
50% [9].
Here we report a phase II study of a combination of
the three main active drug groups in MM, namely the
CAD protocol: cyclophosphamide, adriamycin and
dexamethasone.
Patients
Between July 1995 and May 1999 all consecutive patients with MM
were offered enrolment into the study if they met the following criteria
histologicaly proven MM. stage III disease according to SalmonDune irrespectively of renal involvement or stage II with progressive
monoclonal protein, Karnofsky score >60%, adequate hjematological
and organ function (leukocyte count > 2000/ul, platelet count
>50,000/ul, except lower levels due to myeloma infiltration of bone
marrow, SGOT, SGPT, alkaline phosphdtase, bilirubin < 2 times
upper limit) Main exclusion criteria were hemodialysis and severe
cardiac disease ( > N Y H A 11)
Pre-treatment evaluation included a complete medical history,
physical examination including performance status and vital signs,
bone marrow aspirate and biopsy, electrophoresis and immunofixation
of serum or urine, complete blood count including differential and
platelets, ESR, LDH, p2-microglobulin, CRP, routine serum chemistry
parameters to assess renal and hepatic function. ECG, and a chest
X-ray
Treatment
The treatment regimen consisted of cyclophosphamide 200 mg/m 2
p o or l v day 1-4, adriamycin 30 mg/m 2 I v on day I and dexamethasone 40 mg p o day 1-4 (CAD) Treatment was repeated every three
weeks Treatment was stopped in case of complete remission, in case of
no further reduction in monoclonal-protein or in case of progressive
disease Patients scheduled for high dose chemotherapy received four
106
cycles of CAD Treatment was mostly given in an outpatient setting In
case of grade 3 or 4 leuko- or thrombocytopenia further treatment was
postponed until resolution
The protocol had been approved by the local ethics committee
Prior to study entry, written informed consent was obtained from every
patient
Responses
Responses were classified according to the criteria of the EBMTIBMT-ABMT [10] Complete response was defined as complete disappearance of monoclonal protein (m-protein) in immunofixation for
at least six weeks, a bone marrow infiltration by plasma cells of < 5%
and no increase in size or number of osteolytic lesions For partial
response a reduction of more than 50% of the pre-treatment value of
the m-protein for at least six weeks or a reduction of > 90% in urinary
light chain excretion and no increase in size or number of osteolytic
lesions was required Minimal response was defined as a reduction of
more than 25% of the pre-treatment value of the m-protein for at least
six weeks or a reduction of > 50% in urinary light chain excretion and
no increase in size or number of osteolytic lesions Progressive disease
was defined as an increase of more than 25% of the pre-treatment value
of the monoclonal protein or in urinary light chain excretion, hypercalcacmia not attributable to any other cause or an increase in size or
number of osteolytic lesions Any other state was classified as no change
Time to progression was defined as time from reaching objective
remission to progression Survival time was defined as time from start
of study entry to death
Monitoring, loxicity
For monitoring the disease status of myeloma electrophoresis and
immunofixdtion of serum or urine were performed before start of
therapy, after every second cycle, and after end of treatment
Evaluation of toxicity, classified according to the criteria of the
WHO [II] included physical examination prior to every cycle of therapy,
a complete blood cell counts and serum assessment of renal and hepatic
function In case of complete disappearance of m-protein bone marrow aspirate was repealed
Each patient after having at least one dose of protocol therapy, was
evaludble for toxicity Each patient with more than two cycles was
evaluated for efficacy Analysis was performed on an intent to treat
basis
Results
Patient characteristics (Table 1)
Since July 1995 46 patients were treated: 13 female and
33 male. Median age was 60 years (range 34-84 years)
Myeloma subtypes were. IgG 28 patients, IgA 11 patients,
IgM 2 patients, light chain disease 5 patients. According
to Dune-Salmon 44 patients were stage III, 2 stage II
and 6 patients had stage B (renal insufficiency). Plasmoblastic disease was found in three patients. The median
level of p2-microglobulin was 2 6 mg/dl (range 1 1-5.6
mg/dl). Of 46 patients 21 had relapsing disease after
chemotherapy with MP, three patients relapsed after
additional VAD and one patient after high-dose chemotherapy. In seven patients more than one chemotherapy
regimen had been given prior to study entry.
A total of 209 cycles have been administered with a
median of 4 cycles per patient (range 1-7 cycles)
Table I Patient characteristics
Number of patients
Sex
Male
Female
Age (years)
Median
Range
Immunoglobuline
IgG
IgA
IgM
Light chain
Stage
III
II
B
P2 microglobulin median (mg/dl)
Pretreatment
Radiation
MP
VAD
High-dose chemotherapy
More than one chemotherapy
Time from first diagnosis to
CAD (months)
Median
Range
All
" (%)
Newly
diagnosed
n (%)
Relapsed
" (%)
46
25(54)
21(46)
33
13
19
6
14
7
60
35-84
57
35-79
63
45-84
28(60)
11 (24)
2(4)
5(12)
15(60)
5(20)
1(4)
4(16)
13(62)
44(96)
2(4)
6(12)
2 6"
24 (96)
1(4)
2(8)
26
20 (96)
1(4)
4(16)
30
7(15)
23(50)
3(6)
7(15)
2(8)
0(0)
0(0)
0(0)
0(0)
5(24)
21(100)
3(14)
1 (4)
7(33)
7
1-240
2
1-72
35
8-240
K2)
6(30)
1(4)
1 (4)
Range 1 1 - 5 6
Toxicity
All patients were evaluated for toxicity. Myelosuppression
and consecutive febrile episodes was the predominant
toxicity Leukopenia or thrombocytopenia grade 3 or 4
was observed in 18% and 6% of all treatment cycles,
respectively. Febrile neutropenia occurred in 11% of
cycles with one fatal outcome. Another patient died due
to infection in week 4 after the last chemotherapy. Four
patients presented with pneumonia, one patient with
meningitis during chemotherapy. Two patients died due
to progressive disease after one and three cycles of CAD,
respectively.
Other side effects like nausea, hair loss and gastrointestinal toxicity were mild (WHO grade 2 or less).
Response
Responses rates for the patients are given in Table 2. The
objective response rate (OR = complete and partial
response) was 74% for the whole study population.
Since patients numbers are to small subgroup analysis
has only descriptive value. CAD is slightly more effective
in newly diagnosed patients than in relapsed patients
(OR 80% vs. 67%). The subgroup of patients intended to
be treated with high dose chemotherapy (HDT) had the
best response rate (OR 85%). Four of the six patients
with renal insufficiency showed a partial response, lasting
107
Table 2 Treatment efficacy
Number of patients
Response
Complete remission
Partial remission
Objective response
Minimal response
No change
Progression
Median decrease in monoclonal
protein (%)
Range
CAD followed by high-dose
chemotherapy
All
n (%)
Newly
diagnosed
n (%)
Relapsed
n (%)
46
25
21
2(4)
32(70)
0(0)
14(67)
5(11)
5(11)
2(4)
2(8)
18(72)
20 (SO)
2(8)
2(8)
1(4)
56
0-100
62
0-100
55
17-80
13
13
0
34 (74)
14 (67)
3(14)
3(14)
<u
K5)
between three and twenty-one months. In patients relapsing after MP, response rate was high, irrespective
whether patients initially responded to MP (11 patients,
OR 72%) or were progressive to initial MP (10 patients,
OR 60%). All three patients treated with CAD after
VAD (4, 6 and 20 months after last VAD) reached PR.
Two patients relapsing eight and twelve months after
CAD were effectively retreated with CAD.
Stem-cell mobilisation
After completing 4 cycles of CAD, 15 patients entered an
autologous stem-cell mobilisation protocol with cyclophosphamide 4 g and G-CSF 5 ug/kg.
In all 15 patients a median of 3.5 x 106 CD34+ cells/kg
could be harvested on days 11-13 suggesting that pretreatment with CAD did not impair the stem-cell pool
Thirteen of the later patients were treated with HDT.
Progression-free interval/survival
Survival and time to progression was calculated for the
33 patients without subsequent HDT.
Of the 23 patients having reached an objective remission, 8 patients relapsed after a median of 10 months
(range 3-23 months). With 17 patients still alive, median
survival was also not reached after a median follow-up
of 14 months (range 4-50 months). Figure 1 shows a
Kaplan-Meier plot for time to progression.
Discussion
Over the past thirty years, several chemotherapy regimens have been tested for treatment of multiple myeloma. However MP (melphalane, prednisone) remained
the standard palliative therapy for advanced myeloma.
Unfortunately, only a minority (30%-40%) of patients
achieve an objective response with a short duration of
less than one year (reviewed in [3, 5]). The introduction
of VAD [12] (vincristine, adriamycin, dexamethasone)
Figure I Kaplan-Meier plot for time to progression (33 patients not
treated with high-dose chemotherapy)
proved to be more effective with response rates as high
as 50%-84%. However, in the early VAD studies only a
minority of patients were in advanced stages II and III
[13, 14] and subsequent studies showed no major benefit
in terms of survival [13, 14] Adding infusional vincristin
to the combination therapy is associated with toxicity
and the therapeutic value is small [5]. Other multidrug
protocols such as VMBCP [15], ABCM [16] or alternating
VMCP-VBAP [17] were found to have substantial efficacy in selected patients, but not for the whole group of
myeloma patients.
This study was designed to evaluate a combination of
cytotoxic drugs with proven efficacy in the treatment of
myeloma. This combination has been tested previously
[18], but the dosages applied were relatively low (adriamycin 25 mg/m 2 on day 1, cyclophosphamide 100 mg/m 2
and prednisone 60 mg/m 2 days 1-4) resulting in a
remission rate of only 39%. Therefore we combined the
same compounds in higher dosages in this study: cyclophosphamide 200 mg/m 2 p.o. or I.V. days 1-4, adriamycin
30 mg/m 2 i.v. on day 1 and dexamethasone 40 mg p.o.
days 1-4 for the so-called CAD regimen.
The data of our study shows high efficacy of this
combination in patients with advanced multiple myeloma
In newly diagnosed patients, an objective response rate
(OR = partial and complete responses) of 80% was
observed In patients relapsing after MP, response rate
was high, irrespective whether patients initially responded
to initial MP (11 patients, OR 72%) or were progressive to
MP (10 patients, OR 60%). Also all anthracycline (VAD)
pre-treated patients reached an OR Out of 6 patients with
renal insufficiency four reached a partial response. The
two patients having relapsed after 6 and 10 months after
CAD were again successfully treated with CAD.
The objective remission rate achieved with CAD in
our study population is in the upper part of published
phase II and III data reported for VAD, VMBCP.
ABCM or VMCP-VBAP [2, 5, 15-17, 19]. Since reaching
CR might be of most importance for long-time survival
in myeloma CAD with a CR rate of only 4% per se is
only palliative.
Stem-cell mobilisation in each out of 15 patients was
108
good. Thus, CAD seems to be also a suitable pretransplant regimen for high-dose chemotherapy programme
combining good efficacy with rather low stem-cell toxicity
CAD is a well tolerated chemotherapy regimen which
can be given on an outpatient basis. Main toxicity was
myelosuppression However, one fatal infection occurred
in patients presenting with progressive septicaemia to our
clinic after having two days of neutropenic fever. Severe
thrombocytopenia did not compromise the treatment if
treatment intervals were prolonged to four weeks. It
remains unclear whether the high frequency of pneumonia (4 patients) is due to CAD or myeloma itself.
In comparison to the widely used VAD there are
several considerations in favour of CAD. VAD may be
complicated by side effects either through the need for a
central venous line or the prolonged administration of
dexamethasone. The prevalence of catheter related sepsis
and thrombosis has been documented in up to 25% of
patients receiving VAD [13] and attempts to administer
VAD on an outpatient basis were associated with considerable complications [20]. Prolonged infusion of vincnstin
is associated with an increased rate of sensory polyneuropathy and paralytic ileus [21]. Side effects of prolonged dexamethasone therapy such as peptic ulcer disease, diabetes, psychosis and promotion of osteoporosis
have to be considered as well.
After a median follow-up of 14 months median survival time is not reached in this study. However, clinical
trials have shown that a high remission rate of more
than 70% may translate into improved survival [22]. As
MP is the only chemotherapy regimen besides high-dose
chemotherapy proven to be of survival benefit the effect
of CAD on progression-free and overall survival has to
be tested in a comparative trial against MP.
Treatment of multiple myeloma still is palliative.
Therefore new therapies should be effective in reducing
the m-protein without significant side effect, given on an
outpatient basis. They should not impair stem cell to keep
the option of high-dose chemotherapy with autologous
stem-cell support.
In conclusion, CAD is an active treatment regimen in
the treatment of MM. Because of its low toxicity profile it
is a suitable protocol for outpatient treatment Prospective, randomised trials are warranted to evaluate the
effects of CAD on survival
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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Received 5 June 2000, accepted 11 October 2000
Correspondence to
Prof Dr U Keilholz
Universitatsklinikum Benjamin Franklin
Medizinische Klinik III
(Hamatologie/Onkologie/Transfusionsmedizin)
Hindenburgdamm 30
12200 Berlin
Germany
E-mail szelenyi@zedat fu-berhn de