Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma

Evidence of symptom palliation from chemotherapy




Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined.


Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m2 intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m2 iv every 3 weeks. The KS Functional Assessment of HIV (FAHI) quality of life instrument was used before and after every other treatment cycle.


The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P = .024) and swelling (P < .001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P = .49), median progression-free survival (17.5 months vs 12.2 months; P = .66), and 2-year survival rates (79% vs 78%; P = .75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P = .077).


Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the HAART era. Cancer 2010. © 2010 American Cancer Society.

Kaposi sarcoma (KS), a neoplasm caused by the KS-associated herpesvirus (KSHV), is the most commonly diagnosed cancer in individuals infected with the human immunodeficiency virus (HIV).1 Although the introduction of highly active antiretroviral therapy (HAART) has led to a markedly reduced incidence of KS associated with HIV infection and the acquired immunodeficiency syndrome (AIDS),1-7 the disease still develops in approximately 15% of AIDS patients in developed countries and may occur despite well-controlled HIV infection.8, 9 KS incidence remains very high in Sub-Saharan Africa, where coinfection with KSHV and HIV is far more common than in high-income locales and HAART is not as widely available.10, 11 Furthermore, although KS may regress after the initiation of HAART, this has been documented primarily among patients with limited KS, whereas patients with advanced, symptomatic KS generally receive HAART combined with cytotoxic chemotherapy.6

Liposomal anthracyclines are safe and effective for the treatment of AIDS-related KS. Randomized trials conducted before the introduction of HAART found them to be superior to combination therapy with bleomycin and vincristine, with or without nonliposomal doxorubicin.12-14 Furthermore, a trial that compared the combination of pegylated liposomal doxorubicin (PLD) and HAART with HAART alone demonstrated a significantly higher response rate for the combination.15 Paclitaxel has also demonstrated efficacy in phase 2 trials in patients with AIDS-related KS whose disease had progressed after receiving ≥1 chemotherapy regimens.16, 17

Given the single-agent activity of both PLD and paclitaxel, we sought to compare their effectiveness as initial cytotoxic therapy in a phase 3 trial for advanced, symptomatic KS in patients receiving antiretroviral therapy. The primary endpoint was progression-free survival (PFS). As a secondary objective, we sought to compare the regimens with respect to quality of life (QoL). The trial was terminated prematurely because of slow accrual. We report herein the results of the trial in 73 evaluable patients, which provided a sufficient sample size to estimate antitumor efficacy and toxicity for each treatment arm.


Eligibility Criteria

Eligible patients had a serologic diagnosis of HIV infection and biopsy-proven, measurable KS with any of the following features: progressive cutaneous disease; symptomatic oropharyngeal or conjunctival lesions; visceral involvement; or tumor-related lymphedema, ulceration, or pain. Patients had to be aged ≥18 years and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Prior systemic cytotoxic chemotherapy for KS was not permitted. Radiotherapy could not have been delivered to marker lesions and had to be discontinued ≥7 days before randomization. Other requirements included adequate bone marrow function (absolute neutrophil count [ANC] ≥1000/mm3, hemoglobin ≥8 g/dL, and platelet count ≥50,000/mm3), renal function (creatinine ≤2.1 mg/dL), and hepatic function (aspartate aminotransferase or alanine aminotransferase ≤5 times the upper limit of normal [ULN] and bilirubin <1.5 times the ULN [unless isolated elevation of conjugated bilirubin was associated with indinavir administration]). Pregnant or nursing women were excluded and women of childbearing potential and sexually active men were advised to use effective contraception. Other exclusion criteria included a history of cardiac insufficiency (New York Heart Association Functional Classification of II or higher); active, untreated infection; prior or concomitant malignancy (other than curatively treated in situ cervical carcinoma or basal/squamous cell skin carcinoma); or sensitivity to Escherichia coli (E. coli)-derived proteins that would preclude the use of granulocyte–colony-stimulating factor (G-CSF). Patients were required to be receiving a stable antiretroviral drug regimen for at least 14 days before study enrollment.

Treatment Plan

Patients were randomly assigned to receive either paclitaxel (Taxol; Bristol-Myers Squibb [BMS], Princeton, NJ) at a dose of 100 mg/m2, infused intravenously (iv) over 3 hours every 14 days or PLD (Doxil; Ortho Biotech, Horsham, PA) at a dose of 20 mg/m2, infused iv over 30 to 60 minutes every 21 days. Paclitaxel was provided to the National Cancer Institute (NCI) by BMS, whereas commercially available PLD was used for trial participants. Treatment cycles were repeated if the ANC was at least 1000/uL, the platelet count was at least 50,000/uL, and the patient had satisfactorily recovered from nonhematologic toxicity to grade 1 or less. Dose modifications were required for grade 3 to 4 hematologic, skin, hepatic, and other toxicities. Premedication given before each paclitaxel infusion included dexamethasone (at a dose of 20 mg iv or orally), diphenhydramine (at a dose of 50 mg), and cimetidine (at a dose of 300 mg) or an alternative H2 blocker. Erythropoietin use was allowed. If neutropenia of grade 3 or higher occurred within 24 hours before the scheduled day of treatment, G-CSF was administered in all subsequent cycles (at a dose of 5 μg/kg starting on the day after chemotherapy and continuing until neutrophil recovery). Patients with an absolute CD4-positive (+) count <200 cells/mm3 or <15% CD4+ lymphocytes were required to receive Pneumocystis jirovecii pneumonia prophylaxis. Patients with a complete response (CR) remained on therapy for 2 cycles beyond the first documented CR. Patients with a partial response (PR) or stable disease remained on therapy until KS progressed or unacceptable toxicity developed.

Response and Toxicity Criteria

Tumor responses were graded as CR, PR, stable disease, or disease progression using previously described criteria.18 The NCI Common Toxicity Criteria (version 2.0) were used to evaluate and grade adverse events. KS evaluation and staging were performed as previously described18 at baseline and after every third cycle.

QoL Assessments

The KS Functional Assessment of HIV (FAHI) QoL instrument,19, 20 with 3 supplemental questions addressing pain, swelling, and satisfaction with physical appearance, was used to collect QoL data in 5 categories: physical well-being, emotional well-being, functional and global well-being, social well-being, and cognitive functioning. QoL data were collected before every other cycle. The FAHI is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, which assesses both generic and disease-specific QoL for patients with chronic illnesses including malignancy and HIV and is based on a core instrument, the Functional Assessment of Cancer Therapy (FACT).21 Nine HIV-specific items were subsequently developed using interviews with 5 HIV specialists and 15 patients. QoL assessment was performed at baseline and after every third cycle.

Design and Analysis

Randomization was stratified based on tumor classification (T0 or T1),22 CD4+ count (<150 cells/mm3 or ≥150 cells/mm3), and viral load (<400 copies/mL, >400 to <5000 copies/mL, or ≥5000 copies/mL). The trial was originally designed with PFS as the primary endpoint. PFS was defined as the time from randomization to disease progression, censored at the date of last disease assessment for those patients who had not developed disease progression. On the basis of results of prior studies of PLD and paclitaxel,12-14 we assumed that the median PFS for the patients treated with PLD would be 6 months and would be 9 months for those treated with paclitaxel. The sample size of 216 eligible patients provided an 80% power to detect at least a 3-month difference in the median PFS while allowing for 2 interim (at 35% and 70%, respectively, of the statistical information time) and 1 final analysis. The sample size and power were based on a 2-sided log-rank test using an overall significance level of .05. The group sequential method of O'Brien and Fleming23 was used for the 2-sided test. Secondary endpoints included changes in health-related QoL, overall and complete response rates, toxicity, and effects on HIV infection. On the basis of prior studies demonstrating the overall response rate to PLD to be approximately 70%, 216 patients would provide at least 83% power to detect differences of ≥17% in the overall response rate.

The binomial proportion and its 95% confidence interval (95% CI) were used to estimate the tumor response rate. PFS was analyzed using the Kaplan-Meier method and the median PFS with its 95% CI.24 For each of the 5 categories of the FAHI, the Student t test for paired data was used to evaluate changes from the pretreatment value to the best value observed while the patient received treatment. There were also 3 KS-specific supplemental statements. Agreement with these statements was graded using a Likert scale from 0 to 4, with 0 indicating “not at all” and 4 indicating “very much.” Changes from pretreatment value to the best value observed on treatment for the KS-specific statements were evaluated using the kappa statistic. All P values shown in the analysis were 2-sided.

Informed Consent and Regulatory Approval

The study was reviewed and approved by the Cancer Evaluation Therapy Program of the NCI, and by the institutional review board at each participating institution (Clinical Trials.gov identifier NCT00003350). All patients provided written informed consent, which was reviewed and approved by the local institutional review board.


Patient Characteristics

This trial originated in ECOG, but was later expanded to include enrollment from the AIDS Malignancy Consortium. Of a planned accrual of 240 patients, 89 were accrued at 16 trials sites between November 20, 1998 and May 9, 2002. The ECOG Data Monitoring Committee terminated the trial before reaching its accrual goal because of slow accrual. Eleven patients were ineligible (the majority because they had not been receiving antiretroviral therapy for >14 days), 4 never had therapy initiated, and no data were submitted for 1 patient. Therefore, 73 patients, 36 in the paclitaxel arm and 37 in the PLD arm, were considered analyzable and included in the main analysis. Table 1 shows the characteristics of the 73 analyzable patients. In general, the groups were well balanced and there were no significant differences between the 2 treatment arms. The majority of the patients (97%) were male, and approximately two-thirds had an advanced tumor stage (T1). The median age of the patients was 39 years in the paclitaxel arm and 36 years in the PLD arm. Approximately 50% or more of the patients in each arm were Hispanic or African American. Greater than half of the patients in each arm had a CD4+ count <150 cells/mm3, and 40% of patients in the paclitaxel arm and 46% in the PLD arm had a prior history of opportunistic infection.

Table 1. Patient Characteristics
  1. PLD indicates pegylated liposomal doxorubicin.

No. of patients3637
Median age (range), y39 (25-67)36 (23-59)
 Male35 (97%)36 (97.3%)
 Female1 (3%)1 (2.7%)
 White, non-Hispanic16 (44.4%)15 (41.7%)
 Hispanic7 (19.4%)13 (36.1%)
 Black, non-Hispanic11 (30.6%)7 (19.4%)
 Native American2 (5.6%)
 Other1 (2.8%)
T classification  
 T012 (33.3%)12 (32.4%)
 T124 (67.7%)25 (67.6%)
CD 4 count  
 Median (range)  
 <150/uL20 (55.6%)22 (59.5%)
 ≥150/uL16 (44.4%)15 (40.5%)
Viral load  
 <400 copies/uL11 (30.6%)12 (32.4%)
 <5000 copies/uL10 (27.8%)8 (21.6%)
 ≥5000 copies/uL15 (41.6%)17 (46%)
Prior opportunistic infection14 (38.9%)17 (46%)

At baseline, 53 of the 73 patients were receiving a combination HAART regimen containing either a protease inhibitor (N = 20), a non-nucleoside reverse transcriptase inhibitor without a protease inhibitor (N = 21), or both (N = 12). Approximately 33% of patients had a baseline HIV viral load <400 copies/mL, and >40% had a viral load ≥5000 copies/mL.

Treatment Administration

The median total number of chemotherapy cycles was 8 (range, 0-33 cycles) in the paclitaxel arm. Among the 35 patients in the PLD arm for whom data were available, the median number of treatment cycles was 7 (range, 0-33 cycles). Table 2 summarizes the reasons for discontinuing treatment. The most common reasons in both treatment arms were patient withdrawal (25% in the paclitaxel arm and 29.4% in the PLD arm) and toxicity (25% in paclitaxel arm and 14.5% in the PLD arm).

Table 2. Reasons for Treatment Discontinuation
  1. PLD indicates pegylated liposomal doxorubicin.

Treatment completed4 (12.5%)3 (8.8%)
Progressive disease4 (12.5%)3 (8.8%)
Toxicity8 (25%)5 (14.5%)
Death1 (3%)3 (8.8%)
Withdrawal/refusal8 (25%)10 (29.4%)
Nonprotocol therapy1 (3%)1 (2.9%)
Other complicating disease01 (2.9%)
Other6 (18.8%)8 (23.5%)
Unknown4 (12.5%)3 (8.8%)

Tumor Response

Table 3 presents response by treatment arm. Response information was not available for 12 patients, including 5 in the paclitaxel arm and 7 in the PLD arm. Using an intent-to-treat analysis, the overall CR and PR rate was 56% (95% CI, 39-75%) for the paclitaxel arm and 46% (95% CI, 30-62%) for the PLD arm (P = .486). The CR rate was 8% (95% CI, 7-19%) for the paclitaxel arm and 5% for the PLD arm (95% CI, 0.6-18%) (P = .674). There was no significant difference noted with regard to response rate between patients receiving HAART at study entry and those not receiving HAART.

Table 3. Response Data
  1. PLD indicates pegylated liposomal doxorubicin; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; 95% CI, 95% confidence interval.

CR + PR20 (56%) (95% CI, 39-75%)17 (46%) (95% CI, 30-62%)

Progression-Free Survival

Of the 73 evaluable patients, 4 patients who did not have a disease assessment or progression date were initially included in the analysis using a censored PFS value of 2 months. The median PFS was 17.5 months (95% CI, 12.8-21 months) for the paclitaxel arm and 12.2 months (95% CI, 8.2-33.7 months) for the PLD arm (P = .66) (Fig. 1 Top). If the 4 patients who did not have disease evaluation were excluded from the analysis (1 in the paclitaxel arm and 3 in the PLD arm), the median PFS was 17.5 months (95% CI, 12.8-21 months) for the paclitaxel arm and 12.2 months (95% CI, 8.2-13.9 months) for the PLD arm (P = .653).

Figure 1.

(Top) Progression-free survival is shown (N = 73). (Bottom) Overall survival is shown (N = 73). PLD indicates pegylated liposomal doxorubicin.

There was a marginally significant (P = .0582) difference in time to disease progression favoring patients receiving HAART. The median time to disease progression was 17 months in HAART recipients and only 9 months for those not receiving HAART at the time of study entry.

Overall Survival

The bottom panel of Figure 1 displays overall survival (OS) data for the 73 evaluable patients. The median OS for the paclitaxel arm was 53.6 months (95%CI, 37.7 months to not reached), and that for the PLD arm had not been reached at the time of last follow-up. The 2-year OS rate was 79% (95% CI, 62-96%) for the paclitaxel arm and 78% (95% CI, 56-84%) for the PLD arm (P = .748). The median follow-up time for the 48 surviving patients in both treatment arms was 36 months (range, 0.9-90.9 months).

Adverse Events

Toxicity data were available for 82 patients, and are summarized in Table 4. The most common grade 3 or 4 laboratory abnormalities were low CD4+ counts, lymphopenia, leukopenia, and neutropenia. The overall incidence of grade 3 or greater toxicity was somewhat higher in the paclitaxel arm (84% vs 66%; P = .077), including neutropenia (58% vs 41%; P = .184). Grade 1 to 2 alopecia (57.8% vs 11%; P < .001) and sensory neuropathy (26% vs 9%; P = .045) were found to be significantly more common in the paclitaxel treatment arm compared with the PLD treatment arm. Hematologic toxicity was not associated with the use of zidovudine, which has been reported to be associated with anemia and neutropenia.25 Infection rates were similar (16% in the paclitaxel arm vs 14% in the PLD arm; P = 1). There was 1 toxicity of grade 5 (lethal) in the paclitaxel arm; the patient died of a pulmonary embolism on Day 9.

Table 4. Grade 3 to 4 Adverse Eventsa
Adverse EventPaclitaxel (n=38)PLD (n=44)
Grade 3Grade 4Grade 3Grade 4
  • PLD indicates pegylated liposomal doxorubicin; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

  • a

    The National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0) were used to evaluate and grade adverse events.

Hematologic and infectious    
 CD4+ lymphopenia9 (24%)10 (26%)7 (16%)10 (23%)
 Hemoglobin2 (5%)4 (9%)1 (2%)
 Leukopenia8 (21%)4 (11%)13 (30%)2 (5%)
 Lymphopenia13 (34%)12 (27%)
 Neutropenia9 (24%)13 (34%)6 (14%)12 (27%)
 Thrombocytopenia1 (3%)3 (7%)
 Febrile neutropenia1 (3%)2 (5%)1 (2%)
 Infection with grade 3-4 neutropenia2 (5%)1 (3%)1 (2%)1 (2%)
 Infection without grade 3-4 neutropenia1 (3%)3 (7%)
Nonhematologic toxicity    
 Sinus tachycardia1 (3%)
 Hypertension1 (3%)
 Cardiac, other1 (3%)
 Anorexia2 (5%)
 Fatigue2 (5%)2 (5%)
 Fever2 (5%)2 (5%)
 Constipation1 (3%)
 Diarrhea1 (2%)
 Nausea2 (5%)
 Vomiting1 (3%)
 Elevated bilirubin2 (5%)1 (3%)
 Elevated AST1 (3%)2 (5%)
 Elevated ALT2 (5%)
 Hand-foot reaction1 (2%)
 Rash/desquamation1 (3%)
 Stomatitis1 (3%)
 Depression1 (2%)
 Neuropathy, motor1 (3%)1 (2%)
 Neuropathy, sensory1 (3%)
 Pneumonitis/pulmonary infiltrates1 (3%)
 Arthralgia1 (3%)
 Bone pain1 (3%)
 Myalgia1 (3%)
 Pain, other1 (2%)
Worst degree12 (32%)19 (50%)9 (20%)20 (45%)

Quality of Life

Of the 73 analyzable patients in both treatment arms, 56 had FAHI QoL data available at baseline and during treatment, as shown in Table 5. There was no significant change in the global FAHI score noted to be associated with treatment, nor in the physical well-being or emotional well-being subscales; however, there was a trend toward an improved functional and global well-being subscale, and there was significant improvement noted in social well-being and cognitive function. There were also significant differences reported between baseline and treatment values for pain (P = .024) and swelling (P < .001), but not for satisfaction with appearance. Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) had improvement with treatment. Of the 41 patients who reported swelling at baseline, 38 (93%) reported improvement with treatment. None of the QoL measures was found to be correlated with tumor response.

Table 5. Quality of Life Measures
Category Baseline Mean (SD)Treatment Mean (SD)Change Mean (SD)P
  1. SD indicates standard deviation; FAHI, KS [Kaposi Sarcoma] Functional Assessment of HIV [Human Immunodeficiency Virus].

FAHI (Total) 70.7 (29.8)73.0 (33.2)2.4 (20.8).401
FAHI categories     
 Physical well-being 14.6 (10.0)16.0 (10.7)1.42 (9.6).274
 Emotional well-being 18.4 (9.0)18.8 (8.9)0.4 (6.9).661
 Functional and global well-being 24.4 (11.2)26.2 (11.3)1.8 (7.9).094
 Social well-being 9.7 (7.4)12.1 (7.1)2.4 (5.2).001
 Cognitive functioning 3.6 (2.5)4.9 (2.9)1.3 (2.5)<.001
 Pain Has Interfered With My Normal Work or Activities
 Not at AllA Little BitSomewhatQuite a BitVery Much
Baseline20 (36%)1 (2%)13 (23%)8 (14%)14 (25%)
Treatment25 (45%)17 (30%)4 (7%)7 (13%)3 (5%)
 I Am Satisfied With My Physical Appearance
 Not at AllA Little BitSomewhatQuite a BitVery Much
Baseline19 (34%)11 (20%)11 (20%)7 (13%)8 (14%)
Treatment6 (11%)12 (21%)13 (23%)12 (21%)13 (23%)
 I Have Had Swelling in My Face, Arms, or Legs
 Not at AllA Little BitSomewhatQuite a BitVery Much
Baseline15 (27%)8 (14%)5 (9%)12 (21%)16 (29%)
Treatment36 (64%)15 (27%)2 (4%)3 (5%)0


PLD and paclitaxel are both active cytotoxic agents for the treatment of advanced, symptomatic KS. Because KS treatment is considered palliative rather than curative, and because each agent has a different spectrum of toxicity, we sought to compare the effectiveness and toxicity of these 2 agents as initial therapy for patients with advanced KS. We evaluated not only objective response and time to disease progression, but also used the FAHI QoL instrument to capture symptomatic improvements that might be afforded by each therapy.

The assumptions made in designing the trial were based on data obtained before the widespread introduction of HAART. However, by the time the trial began to accrue patients in late 1998, several such combination antiretroviral regimens had been available for 1 to 2 years. Although declines in the incidence of HIV-associated KS had been noted before the availability of HAART, a more precipitous decline occurred after HAART became widely used in clinical practice.1-7 In addition, some patients with established KS demonstrated spontaneous tumor regression after the initiation of HAART therapy, and HIV-associated KS was more frequently associated with an indolent clinical course in the presence of HAART.26-31 These factors contributed to the slow accrual in our trial. In addition, the subjects enrolled in both arms of the current trial were found to have a much longer median PFS compared with those treated in the pre-HAART era.12, 13, 17 In fact, in both treatment arms, the median PFS was approximately twice what was anticipated when the protocol was designed. For the observed difference (17.5 months for the paclitaxel arm and 12.2 months for the PLD arm) to have been statistically significant would have required 340 patients (ie, 170 patients per group), suggesting that the concomitant administration of HAART to the majority of patients led to the observed increases.

Although this trial did not meet its prespecified accrual goal, several conclusions may be drawn. First, both paclitaxel and PLD are active agents for patients with advanced, symptomatic KS treated in the HAART era, with response rates in the range of 50% to 60%. Second, these agents have somewhat different toxicity profiles, with paclitaxel being associated with more grade 3 to 4 hematologic toxicity and more alopecia and sensory neuropathy. Third, although we found no correlation between objective response and relief of tumor-associated symptoms, the majority of patients who reported pain or tumor-associated edema at baseline demonstrated improvement in these symptoms, and overall social well-being and cognitive functioning were found to improve with treatment. These findings suggest that even among those individuals not meeting the criteria for objective tumor response, chemotherapy may provide clinical benefits with respect to KS-related symptoms, but they also may reflect the long-term benefits of coadministered HAART. These results also confirm earlier findings by Osoba et al,32 who reported significant improvements in pain and energy/fatigue, and possible improvements in general health, social functioning, and overall QoL in patients with AIDS/KS treated with PLD in the pre-HAART era. However, in that study, the investigators used a different instrument to assess health-related QoL and associations with objective response were not sought. Lastly, approximately 75% of patients were alive at 2 years irrespective of the initial chemotherapy treatment given. This suggests that each treatment may be an acceptable option, although the administration of HAART during and/or after the receipt of chemotherapy likely made a major contribution to OS.

In conclusion, PLD and paclitaxel appear to be active first-line agents for the treatment of advanced, symptomatic KS, producing comparable clinical outcomes but with somewhat different adverse event profiles.


Supported in part by grants from the Department of Health and Human Services and the National Institutes of Health CA23318 to the Eastern Cooperative Oncology Group (ECOG) statistical center, CA66636 to the ECOG data management center, CA21115 to the ECOG coordinating center and chairman's office, and U01 CA121947 to the AIDS Malignancy Consortium.