Download Weekly paclitaxel combined with pegylated liposomal doxorubicin

Original article
Annals of Oncology 15: 1566– 1573, 2004
doi:10.1093/annonc/mdh404
Weekly paclitaxel combined with pegylated liposomal
doxorubicin (Caelyxe) given every 4 weeks: dose-finding and
pharmacokinetic study in patients with advanced solid tumors
E. Briasoulis*, G. Pentheroudakis, V. Karavasilis, E. Tzamakou, D. Rammou & N. Pavlidis
Department of Medical Oncology, University of Ioannina, Ioannina, Greece
Received 2 February 2004; revised 1 July 2004; accepted 2 July 2004
Background: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity
of the combination of pegylated liposomal doxorubicin (PLD; Caelyxe) and weekly paclitaxel
(wPTX), and to investigate pharmacokinetics of PLD in this combination.
Methods: A phase I study was performed with an initial dose of 50 mg/m2 wPTX and 30 mg/m2 PLD.
The paclitaxel dose was escalated in increments of 10 mg/m2 and PLD in increments of 5 mg/m2 until
the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels.
Results: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m2 for
PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar –plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD
was mild: skin toxicity grade 1 – 2 developed at high cumulative doses and vascular thrombotic
events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant
peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete
responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median
53.5% increase of PLD area under the concentration curve (range 4.4%– 219%).
Conclusions: The combination of PLD/wPTX constitutes an active chemotherapy regimen with
mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m2. Patients should be monitored for a potentially increased risk of thromboembolic events.
Key words: combination chemotherapy, liposomal doxorubicin, paclitaxel, phase I
Introduction
The majority of patients with advanced solid tumors receive
palliative chemotherapy. Therefore, the development of effective therapeutic regimens that offer palliation of symptoms
and also respect the quality of life of patients is of great
importance [1, 2].
Doxorubicin and Taxol (paclitaxel formulated in Cremophor EL) are among the most potent cytotoxic drugs in use,
with a definite role in the treatment of a variety of metastatic
tumors. Unfortunately, they both have a poor toxicity profile,
with detrimental effects on the daily life of patients treated.
Myelosuppression and cardiotoxicity are the main side-effects
of anthracyclines [3, 4], while peripheral neuropathy is commonly encountered with paclitaxel [5, 6]. Alopecia is another
unwanted adverse effect shared by both these agents.
*Correspondence to: Dr E. Briasoulis, Department of Medical Oncology,
Medical School, University of Ioannina, Pedini PO Box 434, Ioannina
45500, Greece. Tel/Fax:+30-26510-99394; E-mail: [email protected]
q 2004 European Society for Medical Oncology
Initial trials of the doxorubicin–paclitaxel combination
suggested impressive response rates in metastatic breast cancer, but it failed to prove its merit in multicenter comparative
studies [7, 8]. Moreover, the combination presented unacceptably high cardiac risk [9], substantial myelosuppression,
infectious complications and mucositis, which made its wide
adoption in clinical practice problematic [10].
Encapsulation of doxorubicin into liposomes coated with
methoxypolyethyleneglycol alters favorably the toxicity profile of the active agent, and produces prolonged circulation
and passive trapping in tumor due to an enhanced permeability
and retention effect of tumor vessels [11, 12]. Polyethylene
glycol-coated liposomal doxorubicin (PLD; Caelyxe) has
been shown to be active against a variety of malignancies
with a lower degree of toxicity [13 –15]. On the other hand,
evidence is growing that favors weekly paclitaxel over the
standard administration schedule [16].
The efficacy and mild toxicity of PLD combined with the
well tolerated weekly paclitaxel schedule make the combination an attractive alternative for the treatment of patients
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with metastatic cancer. We undertook this dose escalation
study to identify the maximum tolerated dose (MTD) and
dose-limiting toxicity (DLT) of PLD combined with weekly
paclitaxel (wPTX); data on the antitumor activity of the combination are also reported. This trial was conducted between
April 1998 and September 2000 at the Oncology Department
of the Ioannina University Hospital, Greece. It was approved
by the local institutional review board and was performed in
accordance with the Declaration of Helsinki and its amendments. All patients provided written, informed consent.
Patients and methods
End points
Primary end points were to determine the MTD and DLT of the
PLD/wPTX combination. Secondary end points were to assess the spectrum of toxicities associated with its use and describe the pharmacokinetic
profile and interactions of PLD when combined with wPTX. Recording of
the antitumour activity of the combination was deemed appropriate in evaluable cases.
Eligibility criteria
Eligibility criteria for all patients included age >17 years, World Health
Organization (WHO) performance status 0–2, life expectancy of at least
12 weeks, sufficient cardiac function defined by absence of symptoms and
a left ventricular ejection fraction (LVEF) of at least 60%, adequate bone
marrow [white blood cell count (WBC) >3.5 109, absolute neutrophil
count (ANC) >1.5 109, platelet count >100 109), renal (serum creatinine _<150 mmol/l) and hepatic [serum bilirubin <1.25 upper limit of normal (ULN), serum transaminases <2 ULN or <5 ULN in the presence
of liver metastases] functions, and absence of clinically relevant neuropathy, psychiatric illness, pregnancy or lactation. All patients were required
to have histologically or cytologically proven locally advanced or metastatic solid tumors. Any previous chemotherapy should have been discontinued at least 4 weeks (6 weeks for nitrosoureas, melphalan, mitomycin
C) before enrollment. Extended-field radiotherapy should have been
stopped at least 6 weeks prior to study entry, whereas concurrent limited
field radiotherapy was allowed.
Chemotherapy dose-escalation scheme: duration of treatment
PLD was diluted in 250 ml dextrose/water solution and was infused intravenously over 1 h, followed by paclitaxel diluted in 500 ml of normal
saline (NaCl 0.9%) infused over 1 h. Paclitaxel was re-administered on
days 8 and 15. Treatment courses were repeated every 28 days.
Routine anti-allergy medication was always given prior to each treatment. This consisted of 32 mg oral methylprednisolone the day before,
and a triplet of 16 mg dexamethasone, 0.1 mg/kg dimetindene maleate
(antihistamine) and 100 mg ranitidine (H2 blocker) administered intravenously 30 min prior to treatment. Hematopoietic growth factors were only
allowed for the management of complicated febrile neutropenia.
The initial dose levels were 30 mg/m2 for PLD and 50 mg/m2 for
wPXT. The paclitaxel dose was increased by 10 mg/m2 in cohorts of a
minimum of three patients in the absence of major toxicity. In the case of
occurrence of a DLT event during the first two cycles in one patient, a
minimum of six patients were to be treated at that dose level. Dose escalation could continue if no further DLTs were observed in all six patients
(one of six). When two DLTs occurred within a maximum of six patients,
it would be assumed that the MTD had been reached. The dose level
immediately below the MTD level would be considered as the recommended dose for phase II studies. After reaching the paclitaxel MTD
for the 30 mg/m2 dose of PLD, wPTX was to be escalated again in combination with 35 mg/m2 PLD. This dual dose escalation scheme aimed to
comprehensively evaluate this regimen by testing different doses of both
combined drugs.
Patients with measurable or evaluable disease who experience an objective response or clinical benefit continued therapy for a maximum of eight
courses, toxicity permitting. Patients with progressive disease or unacceptable toxicity discontinued treatment and were dropped from the study.
Pharmacokinetics
The pharmacokinetics of PLD were to be studied only in patients treated
at the estimated highest dose levels. For patients who consented to pharmacokinetic analysis, PLD was first given as a single agent and 4 weeks
later was re-administered in combination with paclitaxel.
Each patient was sampled twice: when initially treated with PLD as a
single agent and 4 weeks later when started on the combination. Heparinized blood (5 ml each) was collected from each patient at the following
time points (in h): 0 (pre-dose), +0.15, +0.25, +0.5, +1, +2, +3, +8 and + 24,
and also on the third, seventh, 14th and 21st day post-infusion of PLD.
Blood samples were processed for plasma, centrifuged at 2500 g for
10 min at 48C and stored in a deep freeze at approximately 208C until
analyzed. Samples were analyzed for total plasma doxorubicin at the
Laboratory of Analytical Chemistry, European Environmental Research
Institute, Ioannina, Greece.
We used a reversed-phase high-performance liquid chromatography
assay developed by Gabizon to quantify doxorubicin, the active component of PLD, as described previously [17, 18].
Pharmacokinetics of PLD were determined by non-compartmental
analysis using the WinNonlin computer program, version 2.1 (Pharsight
Corporation, Palo Alto, CA, USA). For statistical analysis the Prism 4 for
Windows program (Graph Pad Software Inc., San Diego, CA) was used.
Pharmacokinetic values obtained during single PLD administration and
with the combination were compared for differences using the paired
t-test.
Evaluation of toxicity
Toxicity was graded according to the National Cancer Institute Common
Toxicity Criteria. Full blood count, biochemical analysis and clinical toxicity assessment were performed weekly during all treatment courses.
Potential cardiotoxicity was monitored by echocardiographic evaluation of
LVEF at baseline and every four cycles of treatment, or at any time upon
clinical suspicion. Dose escalation and determination of DLT and MTD
were performed on the basis of toxicity occurring during all cycles of
chemotherapy.
DLT was defined as febrile neutropenia (fever >388C with grade 3 or 4
neutropenia), neutropenia grade _>2 resulting in a treatment delay of >2
weeks, any grade 4 thrombocytopenia or grade 3 thrombocytopenia
associated with bleeding disorders, a relative decline of the LVEF by
>20% and any grade 3 or 4 non-hematological toxicity except alopecia,
nausea or vomiting.
The MTD was defined as the dose-level at which DLTs occurred in at
least one-third of a six-patient cohort. Patients who did not complete a full
course of treatment (one PLD infusion along with three weekly pulses of
paclitaxel) for reasons not related to toxicity (withdrawal of consent, rapid
disease progression) were replaced in the determination of DLT and
MTD, but were included in all toxicity analyses.
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Treatment modification and delays
Dose and/or schedule modifications were allowed to a limited extent on
the basis of toxicity. Chemotherapy was only given in the presence
of appropriate hematological reserves (WBC >3.0 109 with ANC
>1.0 109, platelet count >75 109) and recovery of significant nonhematological toxicity. If this was not the case, treatment was delayed
until hematological recovery, resolution of other organ toxicity or for a
maximum of 2 weeks. In the case of a patient experiencing a DLT or
other clinically significant toxic effects and further treatment being considered beneficial, therapy could be continued off-protocol at the next
lowest dose level, based on the clinical judgment of the investigator.
Evaluation of response
Patients completing at least two cycles of treatment with at least one
follow-up tumor assessment were considered evaluable for response. An
initial tumor assessment for all patients was performed within 4 weeks
prior to treatment initiation and thereafter every two cycles while on
therapy and every 2 months thereafter until progression of disease. Chest
X-rays, computed tomography scans, ultrasound imaging studies and clinical measurements were used as appropriate. Response was documented
using the WHO response criteria for solid tumors [19]. For characterization of complete response (CR), total disappearance of all measurable
and assessable disease was required; for partial response (PR) a >50%
reduction in the size of all lesions as measured by the product of the greatest length and width of measurable lesions was required. Confirmation of
objective responses was required in all cases at a minimum time interval
of 4 weeks. Duration of response was calculated from the time the objective response was documented until the date of disease progression. Stable
disease was measured from the start of the treatment until the criteria for
progression were met, taking as reference the smallest measurements
recorded after the treatment started.
Results
Forty-four patients with a variety of metastatic solid tumors
were enrolled and received a total of 154 treatment cycles
(one treatment cycle equals one infusion of PLD and three
weekly pulses of paclitaxel) at different dose levels. The
mean/median number of chemotherapy cycles administered
per patient was 3.5/3, with >50% of the patients receiving at
least three treatment cycles. Detailed study demographics are
shown in Table 1.
In three subMTD dose levels more than six patients (seven,
seven and nine) were treated. This was in accordance with the
protocol design aiming to carry out a more reliable analysis of
toxicity and obtain pharmacokinetics in consented patients.
Toxicity
Hematological toxicity
Hematological toxicity was mild (Tables 2 and 4) and consisted primarily of uncomplicated grade 3 neutropenia. In
three cases it was characterized as DLT for causing a >2 week
delay in chemotherapy re-administration. Febrile neutropenia
occurred in three patients treated, respectively, at
(PLD/wPTX) 30/70, 30/80 and 35/70 mg/m2.
The median duration of all grade 3 uncomplicated neutropenic episodes was 5 days (range 1–8), whereas that of febrile
Table 1. Study characteristics (n = 44)
n
2
PLD 30 mg/m , wPTX escalated
27
PLD 35 mg/m2, wPTX escalated
17
Gender
Female
Male
Age, years [median (range)]
23
21
60 (29–85)
WHO performance status
1
5
2
32
3
7
Previous therapies
Chemotherapy
22
1 regimen
9
_>2 regimens
13
Radiotherapy
13
No treatment
18
Other (thalidomide, immunotherapy, radiodrug)
3
Tumor types
Unknown primary
12
NSCLC
5
Ovarian
3
Thyroid
2
Breast
9
SCLC
3
Sarcoma
2
Mesothelioma
2
Renal, head and neck, melanoma, bladder,
lachrymal gland, hepatoma
1
No. cycles administered [median (range)]
3 (1–10)
PLD, pegylated liposomal doxorubicin; wPTX, weekly paclitaxel;
NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer.
neutropenic events was 3 days (range 1 –5). Overall, no major
ablative effect was observed in the erythropoietic or thrombopoietic blood lineages.
Non-hematological toxicity
The five most common non-hematological side-effects
observed in this patient population were mucositis, nausea/
vomiting, neurotoxicity, palmar –plantar erythrodysesthesia and
fatigue. However, the majority of these events were mild and
easy to manage, if treatment was needed at all. No cardiac
toxicity was seen with repeat echocardiogram, and alopecia
was negligible without the use of a scalp cooling system.
Detailed data on the non-hematological toxicity profile are
depicted in Table 3.
Serious non-hematological reactions were seen in three
patients, who developed thromboembolic events not directly
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Table 2. Hematological toxicity events recorded in all cycles (granulocyte colony-stimulating factor was given only in three
patients for FN)
PLD (mg/m2)
30
wPTX (mg/m2)
50
60
70
80
90
50
60
70
80
Cycles (total 154)
14
18
24
22
3
9
33
25
6
Grade 1
2
2
5
5
2
2
4
2
1
Grade 2
0
2
2
3
1
0
2
1
1
Grade 3–4
0
0
0
0
0
0
0
0
0
Grade 1
2
1
4
2
1
0
1
2
2
Grade 2
0
0
1
1
1
0
0
1
0
35
Anemia
Neutropenia
Grade 3 (No DLT)
0
5
2
2
0
1
1
2
1
Grade 3 plus FN (DLT)
0
0
1
1
0
0
0
1
0
Grade 3 plus treatment delay (DLT)
0
0
0
0
1
0
0
0
1
Grade 4
0
0
0
0
0
0
0
0
0
Grade 1
0
0
0
0
0
0
1
0
0
Grade 2–4
0
0
0
0
0
0
0
0
0
Thrombocytopenia
PLD, pegylated liposomal doxorubicin; wPTX, weekly paclitaxel; DLT, dose-limiting toxicity; FN, febrile neutropenia.
attributable to the protocol treatment. Interestingly, two of
these patients had predisposing factors for vascular thrombosis. A 56-year-old female patient with metastatic thyroid cancer treated at the 30/50 cohort developed subclavicular venous
thrombosis at a site of pre-existing extensive infiltration by
malignant disease. The event occurred at cycle 3 and, although
a serious adverse event, it was attributed to the underlying primary tumor and was not characterized as a DLT. In the 30/70
cohort a 74-year-old female with metastatic breast cancer and
long-standing atrial fibrillation developed a thromboembolic
Table 3. Non-hematological toxicity per patient summed and ranked by frequency
Escalation steps
Totals
PLD (mg/m2)
wPTX (mg/m2)
30
50
60
70
80
No. patients treated
3
6
9
7
1
2
3
Rash/desquamation (1–2)
0
2
Nail changes (1–2)
0
0
90
35
50
60
70
80
2
3
5
7
2
3
1
2
0
1
2
0
0
0
0
0
1
1
1
0
0
0
0
0
0
Toxicity (highest grade)
Mucositis (1–2)
15
Dermatology/skin
15
PPE (1–2)
1
3
0
0
0
1
2
2
0
PPE (3)
0
0
0
0
0
0
0
0
1a
Nausea/vomiting (1– 2)
0
4
2
0
0
0
1
2
1
10
Neurotoxicity (1)
0
1
2
2
0
0
2
3
0
10
Fatigue (1–2)
1
1
0
2
0
0
2
2
0
8
Diarrhoea (1–2)
2
0
1
0
0
0
0
1
0
4
Thrombosis (3–4)
1
0
1
0
1a
0
0
0
0
3
Infection (1–2)
0
0
1
0
0
0
1
0
1
3
Alopecia (1)
0
0
1
1
0
0
0
1
0
3
a
Dose-limiting toxicity.
PLD, pegylated liposomal doxorubicin; wPTX, weekly paclitaxel; PPE, palmar–plantar erythrodysesthesia.
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Table 4. DLTs per cohort
Dose (mg/m2)
No. patients
treated
DLTs
PLD
wPTX
30
50
3
0
60
6
1
Treatment delay (grade 3), cycle 1
70
9
1
FN, cycle 1
80
7
1
FN, cycle 3
90
2
2
Treatment delay (grade 3), cycle 2; DVT, cycle 1
50
3
0
60
5
0
70
7
1
FN, cycle 1
80
2
2
PPE (grade 3), cycle 4; treatment delay (grade 3), cycle 2
35
No. events
Description
PLD, pegylated liposomal doxorubicin; wPTX, weekly paclitaxel; DLT, dose-limiting toxicity; FN, febrile neutropenia;
DVT, deep venous thrombosis; PPE, palmar–plantar erythrodyesthesia.
occlusion of the right popliteal artery 2 months after her last
chemotherapy course. An amputation below the knee was
carried out. In view of her past medical history and the echocardiographic evidence of a left atrial thrombus, this serious
adverse event was not considered treatment-related. Further
chemotherapy was given uneventfully off-study in the form of
carboplatin plus paclitaxel. One patient in the 30/90 dose level
developed thrombosis of the internal jugular vein which was
characterized as a DLT.
in 20 out of 154 chemotherapy courses (13%). Sixteen patients
were dropped from the study at some time during their management for reasons other than progressive disease or clinical
deterioration, including patient’s request (four), completion of
therapy (three), toxicity related to chemotherapy (six) or
adverse events thought to be unrelated to treatment (three).
Chemotherapy had to be delayed by one or more weeks in 46
out of 462 weekly pulses of chemotherapy (10%).
Efficacy
DLT and MTD
The dose escalation, number of patients included in each
cohort, the DLTs and serious adverse events are concisely presented in Table 4.
DLTs consisted of protracted grade 3 neutropenia, febrile
neutropenia and thromboembolic event spread over the entire
escalation range. In all cases, patients developing a DLT were
taken off protocol treatment.
MTDs were determined to be dose levels 30/90 and
35/80 mg/m2 (for PLD/wPTX). Two patients who received
treatment at the dose level 30/90 developed DLTs: the first
a grade 3 neutropenia at cycle 2 delaying treatment for
>2 weeks, and the second a jugular deep venous thrombosis at
first cycle. The thrombotic event was characterized as a DLT
since it occurred in the absence of local tumor infiltration or
compression.
In addition, two patients treated at 35/80 developed a DLT.
The first developed grade 3 palmar–plantar erythrodysesthesia
at cycle 4. The skin reaction improved after 8 days and the
patient received off-study therapy for another two uneventful
cycles at lower doses. The second patient had a protracted
grade 3 neutropenia delaying treatment for >2 weeks at cycle
2. The patient elected not to receive further chemotherapy.
Thirty-four patients were evaluable for tumor response. Three
CRs and nine PRs were documented among 34 evaluable
cases. Another 15 patients had disease stabilization, and only
five exhibited progressive disease from the outset despite
treatment. The median duration both of CR and PR was
5 months, while that of stable disease was 3 months. The
three CRs had metastatic breast, bladder and ovarian cancer.
As seen in Table 5, objective responses occurred at almost all
Table 5. Antitumor activity (evaluable patients = 34)
Dose (mg/m2)
No. evaluable
patients
CR
PR
PLD
WPTX
30
50
3
1 (breast)
1 (thyroid)
60
4
0
1 (CUP)
70
4
0
0
80
7
0
2 (ovarian, CUP)
90
1
0
0
50
2
0
1 (CUP)
60
4
0
2 (both CUP)
70
7
2 (bladder,
ovarian)
2 (breast)
80
2
0
0 (breast)
34
3
9
35
Dose modifications and delays
Total
Dose reductions due to treatment-related toxic effects were
made based on medical judgment in eight out of 44 patients,
PLD, pegylated liposomal doxorubicin; wPTX, weekly paclitaxel; CR,
complete response; PR, partial response; CUP, cancer of unknown primary.
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Figure 1. Mean area under the concentration curve (AUC1) values
(columns) of pegylated liposomal doxorubicin (PLD) when given as single
agent (grey bar) and in combination with paclitaxel (wPTX) (black bars)
(n = 7). Error bars represent standard error of the mean.
Table 6. Median values ± SD of PLD pharmacokinetics as single agent
and in combination with wPXT
Parameter
PLD only
PLD + wPTX
AUC ( ± SD) (mg h/l)
1427 ± 589
2316 ± 886
Clearance ( ± SD) (ml/h)
24 ± 10
16 ± 5
t1/2lz ( ± SD) (h)
75 ± 18
115 ± 83
SD, standard deviation; PLD, pegylated liposomal doxorubicin; wPTX,
weekly paclitaxel; AUC, area under the concentration curve; t1/2lz,
terminal half life.
dose levels, whereas patients treated at the recommended
doses of 30/80 and 35/70 derived a similar benefit.
Pharmacokinetic analyses
Pharmacokinetic sampling was performed in seven patients,
one each at 35/50, 35/60, 35/70 and 30/80, and three at 30/70.
The median area under the concentration curve (AUC) of liposomal doxorubicin at single administration of PLD was 1427
[±589 standard deviation (SD)], whereas the median AUC of
the drug in combination was 2316 (±886 SD) (Figure 1). The
observed difference was statistically significant (paired t-test
P = 0.03), with a median 53.5%, mean 77.3% increase of PLD
AUC at the combined administration. A similar difference
was also observed in the plasma clearance of PLD, which was
decreased in the combination in comparison with the singleagent administration. Pharmacokinetic data are summarized in
Table 6.
Discussion
Preserving the quality of life of cancer patients with metastatic, incurable disease who are offered palliative cytotoxic
chemotherapy is of principal importance [20].
Taxanes and anthracyclines produce toxicities that preclude
prolonged use and even compromise the quality of life of treated patients. Doxorubicin has been in clinical use for more
than two decades in cancer treatment and has established
lasting landmarks in the treatment of several malignancies,
such as lymphomas, breast cancer and sarcomas. However, the
classical cumulative dose-related cardiotoxicity sets an upper
limit for its safe clinical use [21]. To reduce cardiomyopathy,
administration schedules producing low peak plasma drug
concentrations have been adopted and novel liposomal formulations have been attempted [22]. The antimicrotubule agent
Taxol (paclitaxel formulated in Cremophor EL) has been evaluated in clinical trials for over 10 years and is currently being
used in the treatment of certain tumor types, including breast,
ovarian and non-small-cell lung cancer [23]. The combination
of these two drugs is a potent chemotherapy regimen against a
number of solid tumors. However, initial reports pointed to an
alarming rate of cardiotoxicity along with poorly tolerated toxicity [24, 25]. The increased occurrence of toxicities with the
combination is partially attributed to reduced clearance of
doxorubicin in the presence of paclitaxel [26].
We developed a novel combination regimen of these two
active agents with the primary aim of ameliorating toxicity.
For each drug we used the most suitable pharmacological
approach with regard to producing the most favorable toxicity
profile. For doxorubicin, this is the novel PLD (Caelyxe) formulation, and for paclitaxel it is the weekly schedule [27, 28].
PLD, primarily developed to optimize pharmacokinetics and
abrogate unacceptable clinical toxicity of doxorubicin, is now
gaining acceptance as a useful alternative to non-encapsulated
standard doxorubicin for its favorable clinical profile [13, 14].
In our study, the favorable clinical profile of each of the
drugs was maintained in the combination. Myelosuppression
was minimal and well tolerated. Grade 3–4 neutropenia
occurred in 19 of 154 treatment cycles (12%) and was uncomplicated. Only three episodes of febrile neutropenia, of short
duration, occurred (2%). There was no relevant anemia or
thrombocytopenia. Alopecia, neurotoxicity, diarrhea and
mucositis were mild, a striking finding for a pre-treated patient
population receiving a combination of anthracyclines plus
taxane. Although palmar –plantar erythrodysesthisa is a common side-effect associated with PLD, it was less common in
our study. A grade 1–2 palmar–plantar erythrodysesthisa was
encountered in treated patients in 15 of 154 treatment cycles
(10%), the difference probably being explained by the lower
PLD doses administered and the non-overlapping toxicity with
paclitaxel. There was no evidence of clinically manifested
heart failure. Admittedly, some concern may be raised by the
occurrence of three cardiovascular events in our study. Careful
examination of the clinical setting and patient’s past medical
history in two of these events implies that they were not
related to the study treatment, and implicates past medical history and progressive disease as main causative factors. Still,
as one event was not otherwise explained and in view of possible ‘synergy’ between the chemotherapy being studied, we
must consider further a possible procoagulant activity of this
combination. Increasing clinical experience with the study
chemotherapy will allow safe conclusions to be drawn on the
importance and causes of this phenomenon.
The pharmacokinetics of PLD are characterized by a very
long circulating half-life, slow plasma clearance and a reduced
1572
volume of distribution compared with conventional liposomal
doxorubicin or free doxorubicin. In keeping with the already
published evidence for the conventional doxorubicin and
paclitaxel combination regimens [26, 29], PLD clearance was
reduced by weekly paclitaxel, resulting in a significant
increase of systemic tissue exposure. Yet the mechanism of
the observed drug to drug interaction is not known. It should
be emphasized that this finding should not be interpreted
by merely projecting what is known about conventional
doxorubicin plus paclitaxel combinations. In the case of PLD,
circulating doxorubicin is mostly found in the form of
liposome-encapsulated drug, which is primarily untaken in
peripheral and tumor tissues [30, 31].
An observed objective response rate of 35% lasting a
median of 5 months is promising, and supports existing evidence of enhanced activity of both PLD and weekly taxanes.
Although premature conclusions about the antitumour efficacy
of the regimen should not be drawn in view of the significant
number of patients who were either chemonaı̈ve or not previously exposed to anthracyclines/taxanes, it does indicate a
need for assessment to continue in phase II studies. Supporting
indirect evidence for the efficacy of the regimen is also provided by the presence of major or minor responses in patients
treated at all dose levels, as well as in patients with ‘chemotherapy-resistant’ tumors such as renal, thyroid, cancer of
unknown primary site and mesothelioma.
Based on toxicity, response and pharmacokinetic data, no
superiority for either of the two recommended dosing regimens could be established from this study. In conclusion, we
suggest that Caelyx given every 4 weeks in combination with
three weekly pulses of paclitaxel at doses of either 30/80 or
35/70 mg/m2 is a safe and active combination that may offer
patients with advanced cancer an optimized palliative chemotherapeutic option. Further evaluation in phase II studies
in patients with specific tumor types and survival-efficacy
primary end points is warranted.
Acknowledgements
The authors would like to thank Ms Olga Siarabi for excellent
work in the data management for this study. The preliminary
results of this study were presented at the ASCO Annual
Meeting, New Orleans, LA, USA, 2000 (Abstract 803).
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