Annals of Oncology 15:440-449, 2004
© 2004 European Society for Medical Oncology
Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYXTM/Doxil®) versus conventional doxorubicin for first-line treatment of metastatic breast cancer
,21 Kent Cancer Center, Maidstone, UK; 2 Ichilov Hospital, Tel Aviv, Israel; 3 Oncologia Medica I Ist., Genova, Italy; 4 Frauenklinik der Ruprecht-Karls-Universitat Vosstrasse, Heidelberg, Germany; 5 Oncologia Medica & Ematologie, Istituto Clinico Humanitas, Rozzano (MI), Italy;6 Sha’are Zedek Medical Center, Jerusalem, Israel; 7 Maastricht University Medical Center, Maastricht, The Netherlands; 8 Oncology Clinic, Poznan, Poland; 9 Newcastle Mater Misericordiae Hospital, Waratah, Australia; 10 Hospital Dipreca, Santiago, Chile; 11 Schering-Plough Research Institute, Kenilworth, NJ, USA
Received 26 June 2003; revised 16 October 2003; accepted 16 December 2003
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Background:
This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYXTM [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC).
Patients and methods:
Women (n = 509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose.
Results:
PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR) = 1.00; 95% confidence interval (CI) 0.82–1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR = 3.16; 95%CI 1.58–6.31; P <0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR = 0.94; 95%CI 0.74–1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin.
Conclusions:
In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
Key words: cardiotoxicity, pegylated liposomal doxorubicin
|
Introduction |
|---|
|
TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Anthracyclines used alone or in combination with other chemotherapeutic agents are among the most active therapies for the treatment of MBC. In the adjuvant setting, anthracycline use is also increasing [1]. While combination chemotherapy regimens in advanced disease are prevalent, no difference in overall survival between combination regimens versus sequential single agent therapies in women with MBC has been observed [2, 3]. The median survival after initiation of conventional chemotherapy in patients with MBC is 18–24 months [4].
The clinical usefulness of doxorubicin, the most widely used anthracycline, is limited by toxicity that may preclude adequate dosing and rechallenge on relapse, or lead to drug resistance. High cumulative doses of doxorubicin increase the probability of cardiotoxicity while individual doses are often limited by myelosuppression. Alopecia, severe acute nausea and vomiting, and mucositis are additional adverse effects of doxorubicin that may limit therapy. Doxorubicin analogs such as epirubicin are also associated with cardiotoxicity, alopecia, nausea and vomiting. An anthracycline formulation with comparable efficacy and improved safety would increase the drug’s therapeutic index and enhance its overall clinical benefit.
Pegylated liposomal doxorubicin (PLD; CAELYXTM, Schering-Plough Corp., Kenilworth, NJ, USA/DOXIL", ALZA, Mountain View, CA, USA) is doxorubicin confined in liposomes that have been sterically stabilized by grafting polyethylene glycol onto the surface (Stealth Liposome"). PLD has a circulation half-life of approximately 73.9 h, whereas doxorubicin has a half-life of <10 min [Schering-Plough Research Institute (Kenilworth, NJ, USA), unpublished data]. Prolonged circulation facilitates greater uptake of PLD liposomes by tumor tissue. PLD accumulates selectively in metastatic breast carcinoma tissue, resulting in 10-fold higher intracellular drug concentrations compared with adjacent normal tissue [5]. Pegylated liposomal encapsulation also reduces plasma levels of free doxorubicin and may reduce drug delivery to normal tissue, which may reduce toxicity.
The dosage of PLD selected for this study was based upon the results of phase I and II studies in patients with solid tumors, including breast cancer, and upon a phase III ovarian cancer trial. The results of these trials indicated that a dosage of 50 mg/m2 every 4 weeks is clinically active and well tolerated [6, 7]. In patients with MBC treated with PLD doses of 45–60 mg/m2 every 3 to 4 weeks, a response rate of 31% has been reported [8].
The present study was designed as a noninferiority trial to assess treatment efficacy, measured by progression-free survival (PFS), and to assess whether PLD has a superior cardiac safety profile as compared with doxorubicin in first-line therapy for women with MBC.
|
Patients and methods |
|---|
|
TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Study design
In this open-label, multicenter trial, patients were randomized in a 1:1 ratio by an independent central third party according to a computer-generated randomization program. Patients received either PLD [50 mg/m2 intravenous (i.v.) infusion for up to 60 min every 4 weeks] or doxorubicin [60 mg/m2 i.v. infusion for 60 min every 3 weeks]. The protocol was subsequently amended permitting infusion of PLD up to 90 min if there were infusion reactions. As per protocol, dose modifications of PLD were permitted for palmar-plantar erythrodysesthesia, hematological toxicity, increases in bilirubin levels, stomatitis and other grade 3 and 4 adverse events. Similarly, dose modifications of doxorubicin were permitted for hematological toxicity or other grade 3 or 4 adverse events. Treatment was to be discontinued for disease progression. Supportive care, including analgesics, antiemetics, antibiotics, bone marrow growth factors, and blood and blood products transfusions were provided as clinically indicated and were to be recorded on the case report form.
Patient status was reviewed every 3 weeks (doxorubicin arm) or 4 weeks (CAELYXTM arm) while on study treatment with assessment of physical signs, performance status, adverse events, complete blood count and serum chemistry. After disease progression, patients were followed up at least every 3 months for assessment of subsequent treatment and survival. Patients who discontinued study treatment prior to disease progression had tumor assessments every 12 weeks until progression was documented, and then were followed as above.
The study was conducted in accordance with International Conference on Harmonization Good Clinical Practice guidelines. An informed consent document and protocol were reviewed and approved by the appropriate local ethics or review boards prior to study initiation.
Study population
Female patients 
18 years of
age with World Health Organization (WHO) performance status 
2 and
measurable or evaluable, stages IIIB or IV MBC [9] were eligible for enrollment. Patients
with measurable disease had tumors with clearly defined margins, as defined
by any of the following: plain X-ray with at least one diameter 1.0 cm
(excluding bone lesions); computed tomography (CT), magnetic resonance
imaging (MRI) or other imaging scan with both diameters 1.0 cm;
palpation with both diameters 2.0 cm; or unidimensionally measurable
disease 1.0 cm. Patients with evaluable disease had tumors with margins
not clearly defined on CT, MRI or X-ray, or with both diameters
1.0 cm, or had palpable masses with either diameter <2.0 cm, or bone
metastases. Prior hormonal or adjuvant anthracycline therapy was permitted
with a cumulative doxorubicin (or doxorubicin-equivalent) dose of 300
mg/m2, and an adjuvant chemotherapy-free interval of >12
months. Normal hematological, hepatic, renal and cardiac [left
ventricular ejection fraction (LVEF) within normal limits] function
was required. Patients with elevated bilirubin concentration and/or
elevated alanine aminotransferase/aspartate aminotransferase were eligible
for inclusion if reduced liver function was secondary to liver metastases.
Bisphosphonate use at the time of study entry was permitted.
Patients who had received prior chemotherapy for metastatic disease, radiation less than 3 weeks before treatment initiation or had symptomatic central nervous system metastasis, uncontrolled systemic infection or were unable to give informed consent were not eligible for participation. Patients were excluded if they had a history of ischemic heart disease or arrhythmia requiring treatment, clinically significant valvular disease or LVEF below the range of normal (less than the lower limit of normal for the institution).
Patient stratification
Patients were
prospectively stratified based on three criteria to balance major
prognostic risk factors between treatment groups:
- prior adjuvant anthracycline exposure;
presence of bone metastases as only site of disease;
presence of at least one cardiac risk factor.
Cardiac risk factors were defined
as prior mediastinal irradiation, age 65 years, history of heart
disease (previous myocardial infarction, arrhythmia or angina, not
requiring treatment) or had hypertension, or diabetes requiring medical
treatment.
Clinical assessments
Primary objectives
were to test whether efficacy (PFS) of PLD was statistically non-inferior
to doxorubicin and whether significantly less cardiotoxicity was observed
with PLD. Tumor evaluations were performed every 12 weeks until disease
progression. PFS was measured from the date of randomization to the date of
disease progression, death (within 4 months of last tumor evaluation
indicating no progression) or last tumor assessment (censored), whichever
was the earliest. Multigated blood-pool imaging (MUGA) scans were performed
to measure LVEF before onset of treatment, after 300 mg/m2
cumulative anthracycline exposure, and after every additional 100
mg/m2 of PLD and every 120 mg/m2 of doxorubicin.
Secondary objectives were to compare treatment effects on overall survival
(OS), overall response rate, tolerability and health care resource
utilization (defined as the proportion of patients in each treatment group
who received antiemetics, growth factors or transfusions during the study).
OS was measured from the date of randomization to the date of death or last
follow-up (censored). Objective tumor responses were assessed according to
World Health Organization criteria [10] with the exception of progressive
disease. For bidimensionally measurable disease, a 50% increase
in the sum of the products of the longest perpendicular diameters or for
unidimensionally measurable disease, a 50% increase in the sum
of the diameters of all lesions was considered evidence of disease
progression. Furthermore, a 25% increase in the size of any
single lesion, appearance of any new lesions or significant worsening of
evaluable, but nonmeasurable, disease was also considered evidence of
disease progression.
Safety assessments
Safety was
monitored by clinical and selected laboratory evaluations. Certified local
laboratories performed hematology and blood chemistry analyses. Patients
also received a 12-lead electrocardiogram at baseline (within 4 weeks of
initiation of study drug) and at the end of the study. The presence of any
pre-existing signs and symptoms of concomitant illness was noted by the
investigator, as were adverse events that occurred during treatment and/or
follow-up. Data on onset and resolution, severity, frequency, impact on
study treatments, and outcome were recorded for adverse events. Adverse
events were rated by investigators using the National Cancer Institute
(NCI)–common toxicity criteria [11]. Alopecia grading was reported as no
loss (grade 0), mild loss (grade 1) or pronounced or total loss (grade 2).
Relationship of an adverse event to treatment was judged by the
investigator to be possibly related, probably related, or
unrelated.
Statistical methodology
Primary
efficacy and all safety analyses were performed on data from all randomized
patients. With enrollment of 500 patients and 390 events (disease
progressions or deaths), the study was designed to test, with at least
80% power and at the 0.025 level of significance (one-sided test),
whether PLD was statistically non-inferior to doxorubicin with respect to
PFS; i.e. PFS for PLD was 80% of that for doxorubicin (lower
boundary of the 95% CI for the hazard ratio [HR] >0.8).
A true HR of 1.06 for doxorubicin relative to PLD was assumed. Having
demonstrated non-inferiority with respect to PFS, differences in cumulative
anthracycline dose at first cardiac event would be analyzed. The study had
80% power at an overall 5% significance level to show
statistical significance (adjusted for one interim analysis) if the HR for
cardiac toxicity was 1.76 or higher.
PFS and cumulative
anthracycline dose at first protocol-specified cardiac event were estimated
for each treatment group using the Kaplan–Meier method; the
stratified log-rank test was utilized to compare treatment groups. A
protocol-specified cardiac event was defined as a decrease of
20% from baseline if the resting LVEF remained in the normal
range, or a decrease of 10% if the LVEF became abnormal (less
than the institutional lower limit of normal). Patients were also assessed
for signs and symptoms of congestive heart failure. The differential
diagnosis of congestive heart failure (CHF) required the presence of a
constellation of signs and symptoms (such as dyspnea upon exertion,
peripheral edema, orthopnea or tachypnea) requiring treatment specific for
CHF. In addition, the investigator’s discretion was accepted as the
determination of whether symptoms were specific to CHF rather than disease
progression. Patients who discontinued treatment without experiencing
cardiotoxicity were censored at the cumulative dose received at the time of
discontinuation.
Analyses of cardiotoxicity included comparison of the proportion of patients in each treatment group who developed cardiotoxicity (by protocol-specified cardiac event) at any time during the study, as well as a comparison of the mean percentage change in LVEF from baseline by cumulative anthracycline dose for each treatment group.
OS was estimated for each treatment group using the Kaplan–Meier method; the stratified log-rank test was utilized to compare treatment groups. The effect of prognostic factors (in addition to treatment) on PFS and OS was examined in supplementary analyses using Cox’s Proportional Hazards Model. Overall response to treatment (complete plus partial response) in patients with measurable disease at study entry was tabulated.
|
Results |
|---|
|
TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Patient demographics
From June 1998 to August 2000, 509 women with MBC were enrolled at 68 international centers. Both the PLD and doxorubicin groups were comparable with respect to demographic and disease characteristics, including WHO performance status, age, menopausal status, previous adjuvant anthracycline therapy, sites of metastatic disease and the presence of cardiac risk factors (Tables 1 and 2). Nearly 60% had visceral disease and 30% had more than two metastatic sites. Fifteen per cent of PLD-treated patients and 16% of doxorubicin-treated patients had received prior adjuvant anthracyclines.
|
|
Efficacy results
PFS
The median duration of therapy in all patients was similar in both treatment groups: PLD, 149 days (5.3 cycles); doxorubicin, 133 days (6.3 cycles). Of the 509 patients, 81% (410/509) progressed at a median of 6.9 months in the PLD group and 7.8 months in the doxorubicin group. The HR for PFS was 1.00 (95% CI for HR 0.82–1.22); consistent with non-inferiority of PLD compared with doxorubicin (Figure 1). Subgroup analysis (according to various known prognostic factors) was consistent with PFS for all randomized patients (Figure 2). The treatment HR, when adjusted for potential imbalances in prognostic factors using a Cox regression analysis, was 0.99 (95% CI 0.81–1.20), consistent with the unadjusted treatment HR.
|
|
Cardiotoxicity
Compliance with the protocol on performing MUGA evaluations was high. Of the 283 patients who reached doses
300 mg/m2 cumulative
anthracyclines, all but 20 patients (nine PLD, 11 doxorubicin) had a
baseline MUGA evaluation and at least one follow-up MUGA evaluation during
treatment. Overall, 339 patients (152 PLD and 187 doxorubicin) had electronic MUGA scan data for evaluation of cardiotoxicity (baseline and at least one scan during treatment) and were included in the analysis. Patients in the PLD arm had a median cumulative anthracycline dose of 398 mg/m2 (including prior anthracycline exposure). Patients in the conventional doxorubicin arm had a median cumulative anthracycline dose of 421 mg/m2 (including prior anthracycline exposure). Fifty-eight patients (10 PLD, 48 doxorubicin) met the protocol-defined LVEF criteria for cardiotoxicity during treatment and/or follow-up (Table 3). The risk of developing cardiotoxicity was significantly higher for patients receiving doxorubicin than for those receiving PLD (P <0.001, HR = 3.16 for comparison of cumulative anthracycline dose at the first, protocol-specified, cardiac event). The increase in risk of developing cardiotoxicity on doxorubicin versus PLD was observed in all subgroups analyzed, including those at high risk for developing CHF [12] (Table 4). In the subgroup that received prior adjuvant anthracycline therapy, the risk of developing cardiotoxicity was seven-fold higher with doxorubicin than with PLD. None of the 10 PLD-treated patients who had cardiotoxicity by LVEF criteria developed clinical signs or symptoms of CHF, whereas 10 of 48 doxorubicin-treated patients who had cardiotoxicity by LVEF criteria developed signs or symptoms of CHF. Two patients in each group developed clinical CHF but did not have a corresponding decrease in LVEF.
|
|
As expected with doxorubicin, the mean percentage change from baseline in LVEF was positively correlated with the increase in cumulative anthracycline dose (Figure 3; Table 5). However, with PLD, only a 2–3% mean decrease in LVEF was observed as the cumulative anthracycline dose increased. At cumulative doses at or above 450 mg/m2, a seven-fold greater mean percentage decrease in LVEF was observed with doxorubicin versus PLD (–17.2% versus –2.3%; mean percentage change from baseline in LVEF in doxorubicin-treated and PLD-treated patients, respectively).
|
|
Overall survival
Overall survival (current as of December 2001) was comparable with both treatments (Figure 4; median: PLD, 21 months versus doxorubicin, 22 months; HR = 0.94; 95% CI 0.74–1.19). At the time of the analysis, approximately 56% of patients in each group had died. When adjusted for potential imbalances in prognostic variables using the Cox regression analysis, the HR was 0.94 (95% CI 0.75–1.19), similar to the unadjusted treatment HR.
|
Objective response
Ninety-nine patients (45 PLD, 54 doxorubicin) entered the study with non-measurable disease and were therefore not evaluable for objective tumor response. Of the 410 patients (209 PLD, 201 doxorubicin) with measurable disease, overall response rates (complete plus partial) were similar with PLD (33%) or doxorubicin (38%). Twenty-five per cent of patients in each group had stable disease. On PLD, 18% of patients progressed compared with 11% of patients on doxorubicin. The median duration of response was comparable between the two groups: 7.3 months for PLD-treated patients and 7.1 months for doxorubicin-treated patients. Twenty-five per cent of patients in both groups had no radiographic assessment of response and therefore were counted as non-responders; in the majority of these cases, the patients were on study for <12 weeks and although followed clinically, radiographic assessments were not required, as specified in the protocol.
Safety
Both drugs were
administered on schedule, at or near the defined dose. The mean cycle
length for PLD was 29.6 days and the mean dose of drug per cycle was 48.3
mg/m2. For doxorubicin, the mean cycle length was 22.3 days and
the mean dose of drug per cycle was 58.0 mg/m2. In both groups,
24% of patients discontinued due to toxicity (adverse event or
cardiac toxicity). Among PLD patients, 56 (22.0%) discontinued due
to an adverse event and six (2.4%) discontinued due to cardiac
toxicity, whereas among doxorubicin patients 24 (9.4%) discontinued
due to an adverse event and 36 (14.1%) discontinued due to cardiac
toxicity. PPE was the most common adverse event associated with PLD
(48%); PPE was reported in five (2%) doxorubicin patients
(Table 6). The
incidence of grade 3 PPE was 17% on PLD and there was no grade 4
(life-threatening) PPE. PPE resulted in treatment discontinuation in
7% of PLD-treated patients.
|
Nausea and vomiting of any severity were less often associated with PLD than with doxorubicin treatment (Table 6). Grade 3 vomiting was reported in two patients treated with PLD versus 11 patients treated with doxorubicin. Antiemetic use overall was more common in the doxorubicin group (83%) compared with PLD (72%), as was the use of 5-HT3 receptor antagonists (54% versus 46%). Mucositis and stomatitis were more commonly associated with PLD (23% and 22%, respectively) than with doxorubicin (13% and 15%, respectively). However, the incidence of grades 3 and 4 mucositis (PLD, 4%; doxorubicin, 2%) and stomatitis (PLD, 5%; doxorubicin, 2%) were low in both groups.
Alopecia was markedly less frequent with PLD (20%) than with doxorubicin (66%). Pronounced or total hair loss was reported in 7% of PLD-treated patients compared with 54% of doxorubicin patients.
The incidence of grades 3 and 4 hematological toxicities (anemia, leukopenia, neutropenia and thrombocytopenia) was low in both groups (Table 6). Grades 3 and 4 anemia occurred in 1–2% of patients in both groups, and grade 4 thrombocytopenia occurred in one doxorubicin-treated patient. The occurrence of grades 3 and 4 leukopenia was higher among doxorubicin-treated patients (9%) than PLD-treated patients (1%). Neutropenia was more commonly reported as an adverse event with doxorubicin (all grades, 10%; grade 3 and 4, 7%) than with PLD (all grades, 4%; grade 3 and 4, 2%). Eight doxorubicin patients compared with two PLD patients developed concomitant fever and neutropenia during the study. The use of blood product support (8.2% versus 5.5%) and hematopoietic growth factor support (8.6% versus 5.1%) were higher on doxorubicin than PLD.
Infusion reactions were more common with PLD than with doxorubicin (13% versus 3%). Allergic reactions (14 PLD versus two doxorubicin) and flushing (7 PLD versus zero doxorubicin) were the most common reactions. The majority were mild to moderate and did not limit treatment; 84% of these patients were successfully rechallenged and tolerated therapy for two to 14 subsequent cycles. Four PLD-treated patients discontinued due to infusion reactions.
There were 30 (PLD, 14; doxorubicin, 16) deaths that occurred during study treatment or within 30 days after patients completed treatment; 50% occurring within the context of disease progression. Adverse events causing death in five patients (two PLD-treated patients and three doxorubicin-treated patients) were considered to be related to treatment. The three patients on conventional doxorubicin died due to neutropenic sepsis. Of the two patients on the PLD arm, one died due to cardiac arrest. This patient had pre-existing bone, liver, lung and pleural involvement. She received two cycles of PLD before being discontinued due to severe dyspnea. The second patient had pre-existing cardiac insufficiency requiring medication, as well as pre-existing liver disease and was therefore not eligible for enrollment (protocol violation). She received a reduced dose of PLD at cycle 1 (12 mg/m2) and died due to cardiac failure within 5 days of receiving the first dose. These PLD patients are those listed as developing signs and symptoms of CHF in Table 3.
|
Discussion |
|---|
|
TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
PLD offers an alternative to doxorubicin for women with metastatic breast cancer. In this large randomized phase III trial of PLD versus doxorubicin in first-line treatment of women with metastatic breast cancer, PLD and doxorubicin were broadly comparable in efficacy, but PLD had a different safety profile, with significantly reduced cardiac toxicity as compared with doxorubicin.
Previous studies have shown that the
incidence of anthracycline-induced CHF increases in relation to total dose
of drug administered [13], and that the risk of
anthracycline-induced cardiotoxicity is increased for patients 65 years
of age, those who received previous adjuvant anthracycline therapy, and
those with one or more cardiac risk factor [12]. The results of this trial clearly
demonstrated that there was less risk of developing cardiotoxicity with PLD
than with doxorubicin in all subgroups analyzed, including those subgroups
at increased risk of developing a cardiac event.
In the short-term, there was a higher incidence of skin toxicity (PPE) with PLD; but unlike cardiotoxicity, this side-effect is not life threatening, and is reversible and manageable with appropriate supportive care measures. Measures such as advising patients to wear loose-fitting clothing and to avoid exposure to heat and vigorous exercise may minimize PPE. Published reports also suggest that concomitant medication with pyridoxine and/or dexamethasone may alleviate the symptoms of PPE [14–16], although this has not been established in randomized trials. More recent phase II studies have reported a significantly lower incidence of grade 3 PPE (<10%) [17–19] than that reported in this randomized study, most likely the result of improved awareness among clinicians of this side-effect and improved implementation of supportive care or dosing modification measures.
Patients treated with PLD experienced less alopecia, nausea, vomiting and myelosuppression than those treated with doxorubicin. Pronounced or total hair loss was reported in 54% of patients treated with doxorubicin but in only 7% of patients treated with PLD. Nausea, vomiting and myelosuppression occurred less frequently with PLD even though there was greater use of supportive care including 5-HT3 antagonists, growth factors and transfusions among patients treated with doxorubicin.
The cardiac
safety of PLD demonstrated in this study is supported by a previous
retrospective analysis of cardiac safety among patients treated with PLD
for solid tumors [20]. Among 34
patients who had received doses of PLD from 500 to 1450 mg/m2
(median 654 mg/m2) and who had not received conventional
anthracyclines, the median change in LVEF was –1%. Only two
patients (6%) experienced a drop in LVEF of 10%, and none
of the patients developed clinical congestive heart failure.
PLD should be explored as an alternative to non-anthracycline based adjuvant therapies in elderly women with breast cancer. In addition, the use of PLD in combination with trastuzumab for HER2+ breast cancer might offer an efficacious anthracycline-based regimen without the known associated cardiotoxic morbidity of conventional anthracyclines plus trastuzumab. These avenues should be investigated in clinical trials in the near future.
Doxorubicin analogs, such as epirubicin, demonstrate less cardiac toxicity than doxorubicin on an equimolar basis [21], but as with conventional doxorubicin, the cardiac risk increases with increased cumulative dose [22, 23]. Another option to conventional anthracyclines is TLC-D99, a nonpegylated liposomally encapsulated formulation of doxorubicin [24, 25]. In a randomized phase III trial of TLC-D99 versus conventional doxorubicin for first-line MBC, overall response rates were similar (26%), but there was a trend in favor of doxorubicin with respect to overall survival [24]. In another randomized phase III trial, TLC-D99 in combination with cyclophosphamide provided comparable antitumor efficacy and better cardiac safety as compared with conventional doxorubicin in combination with cyclophosphamide [24, 25]. However, TLC-D99 in combination with cyclophosphamide did not offer a safety advantage with respect to alopecia, nausea, vomiting or myelosuppression.
For patients with MBC who are at increased cardiac risk (the elderly, patients with specific cardiac risk factors, and patients who have been previously treated with anthracyclines) PLD is an important new therapeutic option. In addition, for individual patients with MBC who wish to minimize some of the short-term side-effects of conventional anthracyclines, or who seek the convenience of a once-monthly dosing schedule, PLD is a rational therapeutic choice.
|
Acknowledgements |
|---|
This work was supported by Schering-Plough Research Institute (Kenilworth, NJ, USA). Participating institutions and investigators are as follows: Ernst Kubista, Gynecological Unic. Clinic, Vienna; Johannes Schuller, Krankenanstalt Rudolfstiftung, Vienna, Austria; Federico Coppola, Hospital Aleman, Buenos Aires; Reinaldo Chacon, Instituto ‘Alexander Fleming’, Buenos Aires; Adrian Hannois, Hospital Interzonal Eva Peron, Buenos Aires; Justina Martinez, Hospital Britanico, Buenos Aires, Argentina; Juan G. Restrepo, Instituto de Oncologia Carlos Ardila Lulle, Santafe de Bogota, Colombia; Luis Eduardo Garcia Quiros, Clinica Aguilar Bonilla Indecon, San Jose, Costa Rica; Jorge Bolivar Moncayo Cervantes, Hospital of Iess: ‘Dr. Teodoro Maldonado Carbo’, Guayaquil, Ecuador; Wolfgang Eiermann, Frauenklinik vom Roten Kreuz, Munich, Germany; Mario Fredy Sandoval Castaneda, Instituto de Cancerologia (INCAN), Guatemala, Guatemala; Carlo Barone, Ist. Medicina Interna e Geriatria, Universita Catiolica Sacro Cuore, Rome; G. Brignone, Servizio di Senologia Ospedale Civico Benfratelli, Palermo; L. Repetto, Oncologia Medica I Ist., Genova, Italy; Alberto Eugenio Palomo Gonzalez and Ignacio Garcia Tellez, Servicio de Oncologia, Merida, Yuc.; Nicolas Ramirez Torres, IMSS Centro Medico La Raza, Hospital de Gineco-Obstetricia 3, Mexico, D.F., Mexico; Enrique Diaz Correa, Instituto Oncologico, Nacional de Panama, Panama, Republica de Panama; Ondina Campos and Conceicao Canha, Centro Hospitalar de Coimbra, Coimbra; Maria Helena Gervasio, Instituto Portugues de Oncologia, Coimbra, Portugal; Emilio Alba Conejo, Hospital Universitario Virgen de la Victoria, Malaga; Alejandro Tres Sanchez, Hospital Clinico Universitario, Zaragoza, Spain; Maria Dolores Juana Menendez Prieto, Hospital Xeral Basico de Conxo, A Coruna, Spain; Mats Broberg, Danderyd Hospital, Danderyd, Sweden; Henrik Lindman, Akademiska Hospital, Uppsala, Sweden; Margareta Palm-Sjovall, University Hospital of Lund, Lund, Sweden; Robert Laing, Royal Surrey County Hospital, Guildford, Surrey, UK; Aura A. Erazo Valle Solis, Centro Medico Nacional, Mexico; Luis Martignon, Hospital Regional de Puebla, Puebla, Pue., Mexico; Paul Sevelda, Krankenhaus d. Stadt Wien Lainz, Vienna, Austria; Michael George Boag Smylie, Cross Cancer Institute, Edmonton, Alberta, Canada; W.E. Aulitzky, Robert-Bosch-Krankenhaus GmbH Hamatologie/Onkologie, Stuttgart, Germany; D. Skarlos, Athens Medical Center, Maroussi-Athens; Papakostas, ‘Hippokration’ General Hospital, Athens, Greece; V. Georgoulias, Univ. Hospital of Heraklion, Heraklion, Crete, Greece; Vito Spataro, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Francisco Arcia-Romero, Policlinica Santiago de Leon, Caracas, Venezuela; James Gowing and Dr. Pierre Major, Cambridge Memorial Hospital, Cambridge, Ontario, Canada; Shailendra Verma, Ottawa Regional Cancer Center Ottawa General Hospital, Ottawa, Ontario, Canada; Juan Carlos Cervellino, Hospital ‘Prof. Bernardo Houssay’, Florida-BS.AS., Argentina; Arie Figer, Rabin Medical Center, Petach Tikva; Dr. Wigler, Ichilov Hospital, Tel Aviv, Israel; Abraham Kuten, Rambam Medical Center, Haifa, Israel; Jane M. Beith, Concord Repatriation General Hospital, Concord, Australia and Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, Australia; M. Findlay, Wellington Hospital, Wellington South, New Zealand; Joseph Prendiville, Queen Mary’s Hospital, Kent, UK; Paul Ellis, King’s College Hospital, London, UK; J.P. Jordaan, Addington Hospital, Durban, South Africa; Bortz, Lake & Partners, St. Augustines Hospital, Durban; Bortz, Lake & Partners, Entabeni Hospital, Durban, South Africa; M. Friedlander, Prince of Wales Hospital, Randwick, Australia and Tamworth Base Hospital, Tamworth, Australia and Grafton Base Hospital, Grafton, Australia; David Wyld, Royal Brisbane Hospital, Herston, Australia; Annika Malmstrom, University Hospital, Linkoping, Sweden; Lubomir Petruzelka, U nemocnice 2, Prague; Katarina Petrakova, Masaryk Memorial Institute of Oncology, Brno, Czech Republic; Tamas Nagykalnai, Uzsoki Hospital, Budapest; Katalin Moskovits, Szent Imre Hospital, Budapest, Hungary; Waldemar Banasiak, Military Hospital, Wroclaw, Poland; Luigi Manzione, Unita Operativa Oncologia Medica, Potenza, Italy; Mitchell Chipman, Austin & Repatriation Medical Center, Heidelberg Vic, Australia and Warringal Private Hospital, Heidelberg Vic, Australia; Russell Basser, Western Hospital, Footscray Vic, Australia; Michael Green, The Royal Melbourne Hospital, Parkville Vic, Australia.
|
FOOTNOTES |
|---|
* Correspondence to: Dr Mary O’Brien, Consultant Medical Oncologist, Royal Marsden Hospital Sutton, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8661-3278; E-mail: maryo{at}icr.ac.uk
M. E. R. O’Brien and N. Wigler contributed equally to this work
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
1. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998; 352: 930–942.[CrossRef][Web of Science][Medline]
2. Joensuu H, Holli K, Heikkinen M et al. Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial. J Clin Oncol 1998; 16: 3720–3730.
3. Chlebowski RT, Smalley RV, Weiner JM et al. Combination versus sequential single agent chemotherapy in advanced breast cancer: associations with metastatic sites and long-term survival. The Western Cancer Study Group and The Southeastern Cancer Study Group. Br J Cancer 1989; 59: 227–230. [Web of Science][Medline]
4. Smith G, Henderson IC. New treatments for breast cancer. Semin Oncol 1996; 23: 506–528. [Web of Science][Medline]
5. Symon Z, Peyser A, Tzemach D et al. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 1999; 86: 72–78. [CrossRef][Web of Science][Medline]
6. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19: 3312–3322.
7. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54: 15–21.
8. Ranson MR, Carmichael J, O’Byrne K et al. Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185–3191.[Abstract]
9. Fleming I, Cooper J, Henson D et al. AJCC Cancer Staging Manual, 5th edition. Philadelphia, PA: Lippincott-Raven 1997.
10. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[CrossRef][Web of Science][Medline]
11. Common Toxicity Criteria, version 2.0. Bethesda, MA: National Cancer Institute 1998.
12. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998; 339: 900–905.
13. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–717.
14. Titgan M. Prevention of palmar-plantar erythrodysesthesia associated with liposome-encapsulated doxorubicin (Doxil) by oral dexamethasone. Proc Am Soc Clin Oncol 1997; 16: 288a.
15. Vail DM, Chun R, Thamm DH et al. Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model. Clin Cancer Res 1998; 4: 1567–1571.[Abstract]
16. Honecker F, Mayer F, Hilger R et al. Reduction of skin toxicity of pegylated lipsomal doxorubicin (PLD) by concomitant administration of dexamethasone and pyridoxine (PYR) in patients (PTS) with anthracycline-sensitive malignancies: a phase I/II trial. J Cancer Res Clin Oncol 2002; 128 (Suppl): 848.
17. Baas P, van Meerbeeck J, Groen H et al. Caelyx in malignant mesothelioma: a phase II EORTC study. Ann Oncol 2000; 11: 697–700.
18. Israel VP, Garcia AA, Roman L et al. Phase II study of liposomal doxorubicin in advanced gynecologic cancers. Gynecol Oncol 2000; 78: 143–147. [CrossRef][Web of Science][Medline]
19. Muggia FM, Blessing JA, Sorosky J et al. Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2002; 20: 2360–2364.
20. Safra T, Muggia F, Jeffers S et al. Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000; 11: 1029–1033.
21. Torti FM, Bristow MM, Lum BL et al. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986; 46: 3722–3727.
22. Jain KK, Casper ES, Geller NL et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 1985; 3: 818–826.
23. Epirubicin-based chemotherapy in metastatic breast cancer patients: role of dose-intensity and duration of treatment. J Clin Oncol 2000; 18: 3115–3124.
24. Harris L, Batist G, Belt R et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002; 94: 25–36.[CrossRef][Web of Science][Medline]
25. Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 2001; 19: 1444–1454.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. J. Jakubowiak, T. Kendall, A. Al-Zoubi, Y. Khaled, S. Mineishi, A. Ahmed, E. Campagnaro, C. Brozo, T. Braun, M. Talpaz, et al. Phase II Trial of Combination Therapy With Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone in Patients With Newly Diagnosed Myeloma J. Clin. Oncol., October 20, 2009; 27(30): 5015 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. WEBER, A. LORTHOLARY, F. MAYER, H. BOURGEOIS, H. ORFEUVRE, M. COMBE, C. PLATINI, J. CRETIN, D. FRIC, D. PARAISO, et al. Pegylated Liposomal Doxorubicin and Carboplatin in Late-relapsing Ovarian Cancer: A GINECO Group Phase II Trial Anticancer Res, October 1, 2009; 29(10): 4195 - 4200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Sparano, A. N. Makhson, V. F. Semiglazov, S. A. Tjulandin, O. I. Balashova, I. N. Bondarenko, N. V. Bogdanova, G. M. Manikhas, G. P. Oliynychenko, V. A. Chatikhine, et al. Pegylated Liposomal Doxorubicin Plus Docetaxel Significantly Improves Time to Progression Without Additive Cardiotoxicity Compared With Docetaxel Monotherapy in Patients With Advanced Breast Cancer Previously Treated With Neoadjuvant-Adjuvant Anthracycline Therapy: Results From a Randomized Phase III Study J. Clin. Oncol., September 20, 2009; 27(27): 4522 - 4529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. de la Fouchardiere, R. Largillier, Y. Goubely, A.-C. Hardy-Bessard, B. Slama, J. Cretin, H. Orfeuvre, D. Paraiso, T. Bachelot, and E. Pujade-Lauraine Docetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLE Ann. Onc., June 25, 2009; (2009) mdp231v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Moreno-Aspitia and E. A. Perez Treatment Options for Breast Cancer Resistant to Anthracycline and Taxane Mayo Clin. Proc., June 1, 2009; 84(6): 533 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barrett-Lee, J. M. Dixon, C. Farrell, A. Jones, R. Leonard, N. Murray, C. Palmieri, C. J. Plummer, A. Stanley, and M. W. Verrill Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk Ann. Onc., May 1, 2009; 20(5): 816 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cortes, S. Di Cosimo, M. A. Climent, H. Cortes-Funes, A. Lluch, P. Gascon, J. I. Mayordomo, M. Gil, M. Benavides, L. Cirera, et al. Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study Clin. Cancer Res., January 1, 2009; 15(1): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Katsumata, Y. Fujiwara, T. Kamura, T. Nakanishi, M. Hatae, D. Aoki, K. Tanaka, H. Tsuda, S. Kamiura, K. Takehara, et al. Phase II Clinical Trial of Pegylated Liposomal Doxorubicin (JNS002) in Japanese Patients with Mullerian Carcinoma (Epithelial Ovarian Carcinoma, Primary Carcinoma of Fallopian Tube, Peritoneal Carcinoma) Having a Therapeutic History of Platinum-based Chemotherapy: A Phase II Study of the Japanese Gynecologic Oncology Group Jpn. J. Clin. Oncol., November 1, 2008; 38(11): 777 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. von Mehren, R. J. Schilder, J. D. Cheng, E. Temmer, T. M. Cardoso, F. G. Renshaw, E. Bayever, P. Zannikos, Z. Yuan, and R. B. Cohen A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies Ann. Onc., October 1, 2008; 19(10): 1802 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Rayson, D. Richel, S. Chia, C. Jackisch, S. van der Vegt, and T. Suter Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies Ann. Onc., September 1, 2008; 19(9): 1530 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Bjelogrlic, J. Radic, S. Radulovic, M. Jokanovic, and V. Jovic Effects of Dexrazoxane and Amifostine on Evolution of Doxorubicin Cardiomyopathy In Vivo Experimental Biology and Medicine, December 1, 2007; 232(11): 1414 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Lorusso, A Di Stefano, V Carone, A Fagotti, S Pisconti, and G Scambia Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome) Ann. Onc., July 1, 2007; 18(7): 1159 - 1164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verma and M. Clemons First-Line Treatment Options for Patients with HER-2 Negative Metastatic Breast Cancer: The Impact of Modern Adjuvant Chemotherapy Oncologist, July 1, 2007; 12(7): 785 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lichtman, H. Wildiers, E. Chatelut, C. Steer, D. Budman, V. A. Morrison, B. Tranchand, I. Shapira, and M. Aapro International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of Chemotherapy in Older Patients--An Analysis of the Medical Literature J. Clin. Oncol., May 10, 2007; 25(14): 1832 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Andreopoulou, D Gaiotti, E Kim, A Downey, D Mirchandani, A Hamilton, A. Jacobs, J. Curtin, and F Muggia Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil(R)): Experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer Ann. Onc., April 1, 2007; 18(4): 716 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tada, H. Higuchi, T. M. Wanatabe, and N. Ohuchi In vivo Real-time Tracking of Single Quantum Dots Conjugated with Monoclonal Anti-HER2 Antibody in Tumors of Mice Cancer Res., February 1, 2007; 67(3): 1138 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S Beslija, J Bonneterre, H Burstein, V Cocquyt, M Gnant, P Goodwin, V Heinemann, J Jassem, W. Kostler, M Krainer, et al. Second consensus on medical treatment of metastatic breast cancer Ann. Onc., February 1, 2007; 18(2): 215 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Cooley, D. Henry, M. Tonda, S. Sun, M. O'Connell, and W. Rackoff A Randomized, Double-Blind Study of Pegylated Liposomal Doxorubicin for the Treatment of AIDS-Related Kaposi's Sarcoma Oncologist, January 1, 2007; 12(1): 114 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fujisaka, A. Horiike, T. Shimizu, N. Yamamoto, Y. Yamada, and T. Tamura Phase 1 Clinical Study of Pegylated Liposomal Doxorubicin (JNS002) in Japanese Patients with Solid Tumors Jpn. J. Clin. Oncol., December 1, 2006; 36(12): 768 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Kleiter, D. Yu, L. A. Mohammadian, N. Niehaus, I. Spasojevic, L. Sanders, B. L. Viglianti, P. S. Yarmolenko, M. Hauck, N. A. Petry, et al. A Tracer Dose of Technetium-99m-Labeled Liposomes Can Estimate the Effect of Hyperthermia on Intratumoral Doxil Extravasation. Clin. Cancer Res., November 15, 2006; 12(22): 6800 - 6807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chia, M. Clemons, L.-A. Martin, A. Rodgers, K. Gelmon, G. R. Pond, and L. Panasci Pegylated Liposomal Doxorubicin and Trastuzumab in HER-2 Overexpressing Metastatic Breast Cancer: A Multicenter Phase II Trial J. Clin. Oncol., June 20, 2006; 24(18): 2773 - 2778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Mamot, D. C. Drummond, C. O. Noble, V. Kallab, Z. Guo, K. Hong, D. B. Kirpotin, and J. W. Park Epidermal Growth Factor Receptor-Targeted Immunoliposomes Significantly Enhance the Efficacy of Multiple Anticancer Drugs In vivo Cancer Res., December 15, 2005; 65(24): 11631 - 11638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Laginha, S. Verwoert, G. J.R. Charrois, and T. M. Allen Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors Clin. Cancer Res., October 1, 2005; 11(19): 6944 - 6949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mirchandani, H. Hochster, A. Hamilton, L. Liebes, H. Yee, J. P. Curtin, S. Lee, J. Sorich, C. Dellenbaugh, and F. M. Muggia Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer Clin. Cancer Res., August 15, 2005; 11(16): 5912 - 5919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Allen, D. R. Mumbengegwi, and G. J.R. Charrois Anti-CD19-Targeted Liposomal Doxorubicin Improves the Therapeutic Efficacy in Murine B-Cell Lymphoma and Ameliorates the Toxicity of Liposomes with Varying Drug Release Rates Clin. Cancer Res., May 1, 2005; 11(9): 3567 - 3573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hamilton and G. Hortobagyi Chemotherapy: What Progress in the Last 5 Years? J. Clin. Oncol., March 10, 2005; 23(8): 1760 - 1775. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||