Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I–II trial

Annals of Oncology 13: 1771–1778, 2002 DOI: 10.1093/annonc/mdf303

Original article

Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I–II trial T. S. Yang1, C. H. Wang2*, R. K. Hsieh3, J. S. Chen1 & M. C. Fung4 1 Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei; 2Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung; 3Division of Hematology/Oncology, Mackay Memorial Hospital, Taipei; 4Department of Clinical Research, Eli Lilly and Company Taiwan, Taipei, Taiwan

Received 19 November 2001; revised 22 April 2002; accepted 13 May 2002

response rate and safety profile of gemcitabine (Gem) plus doxorubicin (Dox) in chemonaïve patients with advanced hepatocellular carcinoma (HCC). Patients and methods: Dose escalation was tested over four dose levels in each 21-day cycle: level 1 (Gem 1000 mg/m2 on days 1 and 8, Dox 30 mg/m2 on day 1), level 2 (Gem/Dox 1250/30), level 3 (Gem/Dox 1250/45) and level 4 (Gem/Dox 1250/60). The MTD was further evaluated in phase II. Results: Patients’ characteristics were: 47 men, three women; median age 53 years (range 28–70); Zubrod performance status (PS) scores 0–1 (74%), PS 2 (26%); Okuda stage I (24%) and stage II (76%). Fifteen patients were enrolled in phase I: level 1 (n = 3), level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Level 2 was identified as the MTD. Dose-limiting toxicities included esophageal bleeding, grade 4 neutropenia and neutropenic fever. Of the 34 patients evaluable for response in phase II (of 35 total), there were four (11.8%) partial responses (95% CI, 0.8% to 22.8%) and six (17.6%) minor responses; nine (26.5%) had stable disease and 15 (44.1%) progressed. Sixteen per cent of patients had a decline of ≥50% in α-fetoprotein levels after treatment. Median survival and progression-free survival were 4.6 months (range 0.3–19.2) and 2.5 months (range 0.2–7.8), respectively, for 35 patients. Grade 3/4 hematological toxicities included anemia (45.7%), neutropenia (51.4%), thrombocytopenia (25.7%); febrile neutropenia (11.8%) and non-hematological toxicities were mild to moderate. Conclusions: Gemcitabine plus doxorubicin produces modest activity and moderate toxicity in this cohort of Chinese patients with advanced HCC. Key words: chemotherapy, doxorubicin, gemcitabine, hepatocellular carcinoma

Introduction Hepatocellular carcinoma (HCC) accounts for approximately 8–10% of all malignant neoplasms worldwide [1–3]. It causes approximately 600000 deaths annually and is the third most common cause of cancer mortality in the world, especially in countries with a high prevalence of viral hepatitis. Hepatocellular carcinoma is a major challenge for medical oncologists because of its highly chemoresistant nature. In addition, because of the lack of early symptoms, most patients present with advanced disease for which the outcome has generally been poor. The median survival for patients with advanced disease is only a few months [4].

*Correspondence to: Dr Cheng-Hsu Wang, Department of Internal Medicine, Chang Gung Memorial Hospital, 222 Mai Chin Road, Keelung, Taiwan, Republic of China. Tel: +886-2-24313131; Fax: +886-2-24335342; E-mail: [email protected] © 2002 European Society for Medical Oncology

There are currently no established chemotherapeutic regimens for the treatment of advanced HCC [5–7]. Several chemotherapeutic agents, such as 5-fluorouracil (5-FU), etoposide, doxorubicin and cisplatin, have been previously tested as single-agent or combination therapies in HCC [5–17]. The response rates have varied from 0% to 19%, although these responses were usually short-lived, lasting from only weeks to a few months. The poor therapeutic outcome and the small number of patients tested in these studies preclude the support of any particular regimen to be used routinely for HCC patients. Hence, new treatment strategies need to be examined. Gemcitabine is a pyrimidine antimetabolite that exhibits a broad range of activity against a variety of tumors [18, 19]. Preclinical studies by Graziadei et al. [20, 21] demonstrated activity with gemcitabine in the inhibition of human hepatoma cells in vitro. In our previous phase II trial, treatment of advanced HCC with single-agent gemcitabine over a 28-day schedule produced a 17.8% response rate [22].

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Background: We determined the maximum tolerated dose (MTD) and then further evaluated the

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Patients and methods Eligibility Chemonaïve (no intra-arterial or systemic chemotherapy) patients with a histological diagnosis of inoperable HCC not amenable to curative surgery (TNM stage IVA/IVB) were enrolled. Unidimensionally and/or bidimensionally measurable Okuda stage I/II disease was required [4]. Lesions were either pathologically proven or measurable lesions, as demonstrated by imaging studies, that were highly suggestive of HCC, with elevated α-fetoprotein (α-FP) levels >400 ng/ml. Patients were to have received no other form of therapy, such as radiation, transcatheter arterial chemoembolization (TACE) or percutaneous ethanol injection (PEI), for at least 3 weeks prior to enrollment; prior radiation was allowed provided that the irradiated area was not the only source of measurable disease. Patients were also required to be between 18 and 70 years of age and have a Zubrod performance status of 0 to 2 and an anticipated life expectancy of at least 8 weeks. Additional eligibility criteria included adequate renal (serum creatinine level ≤2.0 mg/dl) and bone marrow function (leukocyte count >3500/µl, platelet count >100 000/µl). Because many patients with HCC also had viral hepatitis, there was no specific restriction for baseline transaminase levels. Patients with liver dysfunction were enrolled based on the clinical judgement of whether they could tolerate the therapy, but the serum level of total bilirubin for inclusion was set as ≤3.0 mg/dl. No patients were on anti-viral treatment although this was not specifically prohibited.

Study design The first stage of the study was a dose-escalation, dose-finding phase (phase I) to identify the MTD. After the MTD was identified, accrual was resumed for a subsequent phase II evaluation (in 35 additional patients) using a two-stage design to allow for early termination for lack of efficacy [23]. There were 14 patients evaluated initially. If two or less of the 14 patients responded to therapy, accrual was to be stopped and the conclusion was to be drawn that the regimen was probably not worthwhile for further consideration for this indication or this patient population. If three or more patients responded to therapy, then an additional 21 patients were to be enrolled (for a total of 35 patients in phase II) to provide a sufficient number of patients to evaluate the safety and efficacy of the regimen. The above design ensured a 65% chance of terminating enrollment early at the end of the first stage of phase II if the true response rate was <15%, and an 8% chance of stopping early if the true response rate was as high as 35%. If enrollment continued through the end of the second stage of phase II, the procedure allowed a sufficiently accurate estimate of the true tumor response rate.

Treatment All patients received gemcitabine 1000–1250 mg/m2 diluted in 100 ml normal saline infused over 30 min on days 1 and 8, followed by doxorubicin 30–60 mg/m2 on day 1 as an intravenous bolus every 3 weeks. Treatment was continued until one of the following criteria was met: disease progression, unacceptable toxicity, patient refusal, chemotherapy delay for >2 weeks or completion of six courses of therapy. Treatment was stopped after six courses of therapy even if patients continued to respond. Patients who were refractory to this combination regimen were allowed to receive salvage chemotherapy at the investigator’s discretion. In the dose-finding phase of the study, four dose levels were tested: level 1 (gemcitabine/doxorubicin 1000/30 mg/m2), level 2 (1250/ 30 mg/m2), level 3 (1250/45 mg/m2), and level 4 (1250/60 mg/m2). Three patients were enrolled in each new dose level. The total number of patients in each level depended on the occurrence of dose-limiting toxicity (DLT) (grade 4 hematological toxicity for >7 days, grade 3/4 non-hematological toxicity or grade 3 neutropenia with sepsis). If none of the first three patients developed DLT at a particular level, the dose was escalated to the next level. If one or more of three patients developed DLT, another three patients were added to that dose level. If two or less of these six total patients developed DLT, the treatment dose was escalated to the next higher level. If two or more of six patients experienced DLT, that dose level was considered intolerable and the phase II portion of the study was started at the next lower dose level (the MTD). To minimize the potential of nausea and emesis, ondansetron 8 mg was routinely administered before chemotherapy administration. Once toxicity was demonstrated in any patient during a cycle, prophylactic medication was allowed in subsequent cycles. This generally included antihistamine/steroid for skin rash and nonsteroidal anti-inflammatory medication (naproxen) for drug fever. However, granulocyte colonystimulating factor was not recommended for prophylaxis of neutropenia.

Patients with other serious or uncontrolled concurrent medical conditions or with brain metastases were excluded from the study, as were patients with active, or history of, second malignancy (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin), peripheral neuropathy or significant neurological/psychiatric disorders. During the study, no other chemotherapy, hormonal therapy (excluding contraceptives), radiation therapy or experimental medication was permitted.

Dose modification

Appropriate ethical review board approval was obtained at each site before study initiation and written informed consent was obtained from all patients according to the requirements of the individual institutions. The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki or the applicable guidelines on good clinical practice.

The gemcitabine drug dose on day 8 was reduced by 50% within a cycle if the lowest absolute neutrophil count (ANC) was 500–1500/µl, the lowest platelet count was 50 000– 100 000/µl, or if any grade 3 nonhematological adverse reaction (except nausea/vomiting and alopecia) was observed. Any worse hematological counts or grade 4 nonhematological toxicities resulted in withholding of the day 8 dose. For subsequent cycles, the doses

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Doxorubicin, a topoisomerase II inhibitor, is one of the most active agents in HCC, with single-agent response rates of 0–15% in advanced HCC [14–17]. The demonstrated singleagent activities of both doxorubicin and gemcitabine, in addition to their different mechanisms of action and safety profiles, suggest that these agents may prove to be an attractive combination in these patients. Thus, we added doxorubicin to gemcitabine in the treatment of advanced HCC. The objectives of this multicenter study were to first determine the maximum tolerated dose (MTD) of gemcitabine plus doxorubicin using a dose-escalating phase (phase I), and to further evaluate the response rate and safety of this combination in a subsequent phase (phase II) in chemonaïve patients with advanced HCC.

1773 were reduced by 25% if the lowest ANC was 1000–1500/µl, the lowest platelet count was 75 000–100 000/µl or if any grade 3 non-hematological toxicities were detected in the previous cycle. Treatment was withheld if ANC counts were <1000/µl and/or grade 4 non-hematological toxicities were seen. Doses missed for any reason, including toxicity, were not administered at a later time. Liver toxicity was difficult to assess because almost all of the patients presented with impaired liver function at baseline. Thus, it was difficult to differentiate the etiologies of elevated transaminases that were due to toxicities of the chemotherapy, viral hepatitis exacerbation or disease progression. Patients who had transaminase elevation during treatment may or may not have had doses modified based on the clinical discretion of the investigators.

calculated from the start of therapy until tumor progression or death. Survival time was calculated from the start of therapy to the date of death, and survival curves were established by using the Kaplan–Meier method [25]. A multivariate analysis using logistic regression was conducted to test the statistical correlation between objective response (CR+PR), tumor growth control (CR+PR+MR+SD) and tumor marker response (50% α-FP reduction) against patient age, gender, Childs’ stage, Okuda stage, PS score, size of tumor, presence of metastases and portal thrombosis, to determine whether any of these variables might be of prognostic value.

Pretreatment and follow-up evaluation

A total of 50 Chinese patients were enrolled (15 in phase I, 35 phase II) from November 1999 to September 2000. Detailed demographic data and various tumor-related pretreatment characteristics are depicted in Table 1. The study population consisted of 47 men and three women, with a median age of 53 years (range 28–70 years). Zubrod performance status scores were 0 in 10%, 1 in 64% and 2 in 26% of patients. A majority of the patients (74%) had tumors >10 cm, while only 38% underwent various prior treatments (surgery, PEI and TACE). Regarding tumor status, 12% of patients had ascites, 78% had either portal vein or inferior vena cava thrombosis and 44% had distant metastases. Approximately half (52%) of the patients had elevated α-FP >10 000 ng/ml at baseline.

Patient characteristics

Response and toxicity assessments All eligible patients who received one cycle of treatment were considered evaluable for response. Complete response (CR) was defined as the disappearance of all radiological and clinical evidence of tumor for a minimum of 4 weeks, during which period the patient was also free of all cancer-related symptoms. Partial response (PR) was defined as a ≥50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions appearing and none progressing for at least 4 consecutive weeks. If the reduction was between 25% and 49%, the response was classified as a minor response (MR). A patient was considered to have progressive disease if any new lesion appeared, if the tumor size increased by ≥25% over pretreatment measurements or if the patient experienced deterioration in the clinical status consistent with disease progression. A patient who failed to meet the definition of CR, PR or MR, or progressive disease, but remained on the study for at least 2 months was classified as having stable disease (SD). For patients with partial or CR, a second radiological assessment was required 4 weeks later to confirm the response. In addition, all tumor measurements in patients who responded were reviewed and confirmed by an independent radiologist. All patients who received at least one dose of treatment were considered evaluable for safety. Toxicity was evaluated weekly in accordance with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria.

Statistical methods Response rates were calculated separately for phase I and phase II and 95% confidence intervals (CIs) were included [24]. Duration of response was calculated from the onset of the best response until evidence of disease progression was identified. The time to disease progression was

Maximum tolerated dose A total of 15 patients were enrolled in three institutions in the initial phase I dose-escalation portion of the study: level 1 (n = 3), level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Because no patient had a DLT in level 1 (gemcitabine/doxorubicin 1000/30 mg/m2), dose escalation proceeded to level 2 (gemcitabine/doxorubicin 1250/30 mg/m2). As one of the first three patients developed DLT at level 2 (esophageal varices bleeding), three additional patients were tested at this level. An additional patient (for a total of 2/6 patients) experienced DLT (grade 4 neutropenia) at level 2, allowing further dose escalation to level 3 (gemcitabine/doxorubicin 1250/45 mg/m2). Three of the six patients at level 3 experienced DLT (two patients with grade 4 neutropenia and one with neutropenic fever), establishing the next lower dose level, gemcitabine/ doxorubicin 1250/30 mg/m2, as the MTD. Thirty-five additional patients were treated at this dose level for the phase II portion of the study, for a total of 50 patients. Table 2 summarizes the toxicities of maximum severity for the subjects at each dose level in phase I.

Dose delivery Dose intensity for each dose level in phase I and phase II are provided in Table 3. A total of 182 cycles of therapy were delivered and the median number of cycles was three (range 1–6) for the entire study (phase I and II combined). The

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Pretreatment and follow-up evaluations included a complete medical history, physical examination, vital signs, blood chemistry, urinalysis, chest X-ray, electrocardiogram, cardiac echocardiogram, dynamic liver computerized tomography (CT) scan, hepatitis screen (hepatitis B surface antigen, antihepatitis C virus) and prothrombin time. Performance status assessment, Childs’ criteria evaluation, TNM staging and Okuda staging were also conducted at baseline. Complete blood counts with differential counts were determined weekly. Liver and renal function and α-FP were measured every 3 weeks. Body weight, performance status and toxicity assessments were performed every week. Computerized tomography scans for response evaluation were conducted every 9 weeks, with objective tumor assessments performed according to standard World Health Organization criteria at every cycle.

Results

1774 Table 1. Patient characteristics Phase I

Phase II

Overall

Total no. of patients

15

35

50

Male/female, n

13/2

34/1

47/3

Median age, years (range)

58 (35–69)

51 (28–70)

53 (28–70)

Performance status 0/1/2, n Okuda stage I/II, n

1/10/4

4/22/9

5/32/13

5/10

7/28

12/38

Child classification A/B/C, n

13/2/0

27/7/1

40/9/1

HBsAg (+), n (%)

29 (83)

42 (84)

3 (20)

8 (23)

11 (22)

Alcohol abuse, n (%)

4 (27)

12 (34)

16 (32)

Surgery

1 (7)

2 (6)

3 (6)

Percutaneous ethanol injection

3 (13)

0

3 (6)

Transcatheter arterial chemoembolization

5 (33)

8 (22)

13 (26)

Biopsy

9 (60)

13 (37)

22 (44)

Cytology

1 (7)

4 (11)

5 (10)

α-FP + imaging

5 (33)

18 (51)

23 (46)

<400

6 (40)

9 (26)

15 (30)

400–10 000

2 (13)

7 (20)

9 (18)

>10 000

7 (47)

19 (54)

26 (52)

Liver tumor >10 cm

9 (60)

28 (80)

37 (74)

Ascites

1 (7)

5 (14)

6 (12)

Portal vein thrombosis

7 (47)

25 (71)

32 (64)

Inferior vena cava thrombosis

2 (13)

5 (14)

7 (14)

Distant metastasis

9 (60)

13 (37)

22 (44)

Previous treatment, n (%)

Diagnosis, n (%)

α-FP (ng/ml), n (%)

Tumor status, n (%)

weekly dose intensity was 1169 mg/m2 for gemcitabine (93.6% of the planned dose) and 26.6 mg/m2 for doxorubicin (88.7% of the planned dose for phase II and 1000/30 (level 1), 1102/28.7 (level 2) and 993.6/41.1 (level 3) for the three dose levels of gemcitabine and doxorubicin in phase I, respectively. On day 1, 13 patients needed a 25% dose reduction of gemcitabine and doxorubicin, which occurred in 29 of the 182 cycles delivered. On day 8, 27 patients required a 50% reduction in the gemcitabine dose, which occurred in 54 cycles of therapy. All dose reductions were caused by hematological toxicity.

Response Among the 35 patients who entered phase II, one patient was not evaluable for response (refused further treatment after one course, before measurement of objective response). Overall, no CRs were observed, but four patients experienced PR. Thus, the overall response rate was 11.8% (95% CI 0.8% to 22.8%). There were six (17.6%) additional patients who

achieved a MR, with a 25–49% shrinkage of the tumor. In addition, nine (26.5%) patients had SD and 15 (44.1%) patients progressed. Overall, tumor growth control (PR+MR+SD) was achieved in 19 patients (55.9%, 95% CI 39.0% to 72.8%). The median duration of response was 5.1 months (range 4.4–5.9). Sixteen per cent of patients had a decline of ≥50% in α-FP levels after treatment. Multivariate analyses by logistic regression showed no statistical correlation between objective response, tumor growth control or tumor marker response against any of the potential prognostic variables tested (i.e. patient age, gender, Childs’ stage, Okuda stage, PS score, size of tumor, presence of metastases or portal thrombosis). Thus, none of these factors were found to have any prognostic value.

Survival At the time of this analysis, 31 of 35 enrolled patients in phase II have died. The median survival was 4.6 months (range 0.3– 19.2) for all patients and 10.2 months for those who achieved a PR. The median progression-free survival was 2.5 months

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13 (87)

Anti-HCV (+), n (%)

1775 Table 2. Maximum grade of toxicity for phase I (n = 15) Toxicity

NCI-CTC toxicity grade Level 1 (n = 3) (1000/30)a

Level 2 (n = 6) (1250/30)b

Level 3 (n = 6) (1250/45)c

Grade 1/2

Grade 3/4

Grade 1/2

Grade 3/4

Grade 1/2

Grade 3/4

Leukopenia

3/3

–

1/6

2/6

2/6

4/6

Neutropenia

2/3

–

1/6

2/6

2/6

3/6

Anemia

1/3

2/3

3/6

2/6

5/6

1/6

Thrombocytopenia

2/3

1/3

2/6

3/6

1/6

1/6

Nausea/vomiting

2/3

–

3/6

–

4/6

–

Mucositis

–

–

3/6

1/6

2/6

1/6

Diarrhea

1/3

–

1/6

–

2/6

–

Alopecia

3/3

–

5/6

–

6/6

–

Liver

2/3

1/3

2/6

2/6

1/6

3/6

Skin rash

–

–

1/6

–

2/6

–

Fatigue

1/3

–

2/6

–

1/6

–

Infection

–

–

2/6

1/6

–

2/6

Drug fever (non-neutropenic)

–

–

1/6

–

1/6

–

Neutropenic fever

–

–

–

1/6

–

1/6

Bleeding

–

–

1/6

1/6

–

–

Hematological

Non-hematological

Level 1, gemcitabine (Gem) 1000 mg/m2 days 1 and 8, doxorubicin (Dox) 30 mg/m2 day 1. Level 2, Gem/Dox 1250/30. c Level 3, Gem/Dox 1250/45. NCI-CTC, National Cancer Institute-Common Toxicity Criteria. b

Table 3. Response and dose intensity Dose intensity (%)

n

Response

ORR

CR

PR

MR

SD

PD

NE

Phase I Level 1 (1000/30)a

100/100

3

0

2

0

0

1

0

2/3

Level 2 (1250/30)

88.2/95.7

6

0

3

1

1

1

0

3/6

Level 3 (1250/45)

79.5/91.3

Overall phase I

6

0

0

2

0

4

0

0/6

15

0

5

3

1

6

0

5/15 (33.3%)

35

0

4

6

9

15

1

4/34b (11.8%)

Phase II Level 2 (1250/30)

93.6 / 88.7

a

Gemcitabine/doxorubicin dose (mg/m2). For evaluable patients only. n, number of patients; CR, complete response; MR, minor response; NE, nonevaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.

b

(range 0.2–7.8). Figure 1 illustrates the overall survival curve for these patients.

Toxicity Table 4 summarizes the toxicities of maximum severity for the 35 patients in phase II. Grade 3/4 toxicity was mainly hemato-

logical. These included neutropenia in 51.4% of patients, anemia in 45.7% of patients and thrombocytopenia in 25.7% of patients. Febrile neutropenia was infrequent (11.8% of patients). Among the nine patients with grade 3/4 thrombocytopenia, bleeding occurred in three patients, of whom one patient required platelet transfusion. Grade 3/4 non-hemato-

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a

1776 logical toxicities were mild, with liver toxicity reported most frequently (40% of patients); however, almost all patients (96%) had viral hepatitis at baseline. This was followed by gastrointestinal toxicity [mucositis (8.6%), nausea/vomiting (2.9%), diarrhea (2.9%)], infection (8.6%) and bleeding (8.6%).

Discussion

Figure 1. Overall survival curve.

MTD was reached at a relatively low dosage level (level 2: gemcitabine 1250 mg/m2/doxorubicin 30 mg/m2), which could have compromised the overall response observed. Despite this, the current overall response rate of 11.8% (95% CI 0.8% to 22.8%) for the phase II portion of the current study is similar to the response rate [17.8% (95% CI 2.7% to 32.9%)] observed in our earlier phase II study of chemonaïve patients with advanced HCC using gemcitabine alone (at a different dosing schedule of 28-day cycles) [22].

Table 4. Maximum grade of toxicity for phase II (n = 35) Toxicity

NCI-CTC toxicity grade 0

1

2

Leukopenia

10

3

9

Neutropenia

12

1

4

4

3/4 (%)a

7

6

37.1

11

7

51.4

3

Hematological

Anemia

2

6

11

11

5

45.7

16

5

5

6

3

25.7

Nausea/vomiting

20

9

5

1

0

2.9

Mucositis

21

3

8

2

1

8.6

Diarrhea

27

2

5

1

0

2.9

Alopecia

7

6

22

0

0

0

Liver

7

4

10

9

5

40.0

Skin rash

22

3

9

1

0

2.9

Fatigue

24

7

4

0

0

0

Infection

23

6

3

2

1

8.6

Drug fever (non-neutropenic)

18

7

10

0

0

0

0

0

0

3

1

11.8

24

4

4

3

0

8.6

Thrombocytopenia Non-hematological

Neutropenic fever Bleeding a

Percentage of patients with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) toxicity grades 3 and 4.

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The antitumor activities of a number of chemotherapeutic agents against HCC, a chemoresistant tumor, have yielded poor results, with no single or combination agents giving response rates >25% [26]. Furthermore, these response rates are often not reproducible and the impact of systemic chemotherapy on survival has been negligible. This is further complicated by the fact that the vast majority of patients with advanced HCC are poor candidates for curative surgery or local therapy, leaving supportive care as the only option for many patients [6]. It is, therefore, essential to develop more effective systemic chemotherapies to improve the prognosis of these patients. In this study, we evaluated whether the addition of doxorubicin to gemcitabine might demonstrate further treatment benefits for patients with advanced HCC by first assessing the MTD in a dose-escalation phase, and then further assessing the efficacy and safety of this combination in a subsequent phase (phase II), using a 21-day cycle. Unfortunately, the

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Acknowledgements This study was sponsored by Eli Lilly and Company, Taipei, Taiwan. This work was presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, May 12–15, 2001.

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The lower than expected dose-level escalation in the present study was mainly due to an increase in dose-limiting hematological toxicities. Overall, grade 3/4 hematological toxicities were observed about two to three times more with the combination in the current study than in our earlier singleagent gemcitabine study [22]. This was further reflected by the high number of patients who required dose reduction, especially on day 8 of therapy. One possible explanation for this might be that cirrhotic patients typically had impaired liver function and thrombocytopenia, which in turn may have made them unable to tolerate adequate doses of the cytotoxic agents. The apparent lack of improvement in other efficacy parameters for this gemcitabine/doxorubicin doublet when compared with gemcitabine as a single-agent regimen in our earlier trial might be in part explained by the low dose intensity achieved. The weekly dose intensity achieved in phase II of this study was 1169 mg/m2 for gemcitabine (93.6% of the planned dose) and 26.6 mg/m2 for doxorubicin (88.7% of the planned dose) in a 21-day cycle schedule. In contrast, the dose intensity of the single-agent regimen was 1188 mg/m2 (95% of the planned dose) administered on days 1, 8 and 15 in a 28-day cycle schedule. Thus the contribution of this low (possibly subtherapeutic) level of doxorubicin might not have differed much from a slightly higher dose level of gemcitabine administered in a more frequent 28-day schedule as a single agent. In conclusion, the MTD in this cohort of Chinese patients with advanced HCC was gemcitabine 1250 mg/m2 on days 1 and 8 plus doxorubicin 30 mg/m2 on day 1 of a 21-day cycle. This combination regimen resulted in modest activity and a moderate toxicity profile. A preliminary study of gemcitabine (1250 mg/m2 on days 1 and 8) combined with cisplatin (70 mg/m2 on day 1) using a 21-day cycle schedule in a similar patient population of 30 patients produced a comparatively high overall response rate of 30.4% (in 23 evaluable patients) [27]. Given the difficulty of reproducing response rates in advanced HCC, however, larger studies may be needed to confirm these data. Future studies should continue to explore cytotoxic treatment combinations (such as gemcitabine plus cisplatin, 5-FU or etoposide) or biological therapies.

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