| Japanese Journal of Clinical Oncology | Pages |
A Phase I/II Study of Continuous Intra-arterial Chemotherapy Using an Implantable Reservoir for the Treatment of Liver Metastases from Breast Cancer: A Japan Clinical Oncology Group (JCOG) Study 9113
Introduction
Patients and methods
Results
Discussion
Acknowledgments
References
A Phase I/II Study of Continuous Intra-arterial Chemotherapy Using an Implantable Reservoir for the Treatment of Liver Metastases from Breast Cancer: A Japan Clinical Oncology Group (JCOG) Study 9113
Methods: A hepatic arterial catheter with an access port was inserted into the proper hepatic artery. Patients received 30 mg/m2 adriamycin on days 1 and 8 and 100 mg/m2 5-fluorouracil at level 1, 200 mg/m2 at level 2, 300 mg/m2 at level 3 and 400 mg/m2 at level 4 continuously from day 1 through day 14 every 28 days. At least two cycles were required before evaluation. Twenty-eight patients were entered into this study and 26 patients were evaluable. Seventeen patients had hepatic metastasis only, although nine patients had additional metastasis to other sites.
Results: Dose-limiting toxicity of thrombocytopenia and neurotoxicity occurred at level 4. Leukocytopenia (ECOG grade 3-4) was observed in five (19%), thrombocytopenia in three (12%) and anemia in two (8%) patients. There were 11 catheter-related complications which were not dose dependent. Seven out of 13 evaluable patients (54%) responded at level 3. The median duration of response was 5.8 months (range, 1-23+) and median survival was 25.3 months (range, 6.2-54.7+).
Conclusion: Hepatic arterial infusion therapy appears to be safe and effective but catheter-related complications must be overcome before starting a phase III trial.
Introduction
Patients with liver metastasis of breast cancer show poor prognosis, with a median survival of 6-11 months (1). Once liver metastasis appears, it may be fatal, as is shown by the fact that liver metastasis is recognized in a high frequency of autopsy cases of breast cancer patients (2). Cancer patients with liver metastasis may be able to live longer if the liver metastasis is controlled and changing the life-threatening site from the liver to another organ. The response rate to intravenous chemotherapy in patients with liver metastasis has not been satisfactory (3,4). Intra-arterial route chemotherapy obtained good response rates in patients with liver metastasis from colon cancer (5,6). These results may be due partly to higher hepatic concentrations of anti-cancer drugs achieved by intra-arterial infusion compared with intravenous administration (7). Recent advances in treatment using an access port make it possible to perform intra-arterial chemotherapy repeatedly with few restrictions in daily life (i.e. the patient can take a bath, it can be performed in outpatient clinics, etc.). These facts led us to attempt to carry out a phase I/II trial of hepatic intra-arterial infusion chemotherapy. There are some reports showing good response rates of hepatic metastasis from breast cancer achieved by hepatic intra-arterial infusion chemotherapy (8,9), although no phase I trial including pharmacokinetic analysis has yet been reported.
Patients and methods
Major eligibility criteria for patient enrollment were: age between 15 and 70 years; existence of measurable lesions including those in the liver; performance status 0-3; liver function GOT/GPT <2.5 × normal limit; leukocyte count [ge]4000/mm3; platelet count [ge]10 × 104/mm3; hemoglobin [ge]10 g/dl; ejection fraction [ge]50%; and life expectancy >2 months. Between October 1992 and December 1995, 28 breast cancer patients with hepatic metastasis without other critical organ metastasis, including lymphangitis, pulmonary metastasis or brain metastasis, and who satisfied the above criteria were entered in this trial. All patients had previously received surgery for breast cancer. The mean age was 48 years with 15 premenopausal patients and the median disease-free interval was 23.5 months. All patients had received previous chemotherapy either as adjuvant therapy or due to metastasis or both. The initial site of metastasis was the liver in 19, soft tissue in seven and bone in six. Hepatic metastasis was limited to one lobe in 13 patients while it extended to two lobes in 13 patients (Table 1).
After obtaining informed consent, an arterial catheter was inserted into the proper hepatic artery either by an operative procedure or by Seldinger's method. The catheter was then connected to an access port which was buried in subcutaneous tissue. From day 1 through 14, 120 mg/m2/day 5-fluorouracil (5-FU) continuous infusion and a bolus injection of 30 mg/m2 adriamycin on days 1 and 8 of every 28 day cycle were carried out in level 1. After assessment of safety, the dose of 5-FU was increased to 200 mg/m2/day in level 2, 300 mg/m2/day in level 3 and 400 mg/m2/day in level 4.
Critical toxicity was defined as grade 3 or more of the Eastern Cooperative Oncology Group (ECOG) toxicity criteria, except for bone marrow and liver toxicity. Critical bone marrow toxicity was defined as grade 3 toxicity for 7 days or more or grade 4 toxicity for 3 days. Critical liver toxicity was defined as more than 7 days of grade 4 toxicity. The stopping rule was defined using the multi-step method, assessing the numbers of patients who experienced critical toxicity. Catheter-related events were not considered in assessing critical toxicity but were described independently. After the phase I study, nine patients were included in the phase II study. Patients were required to perform more than two courses of this therapy, apart from the patients with hepatic lesions showing progressive disease or extrahepatic lesions showing progressive disease considered to be life-threatening. In eight patients in phase I, blood samples were obtained to analyze the pharmacokinetics of adriamycin and 5-FU. Plasma concentrations of adriamycin and 5-FU were measured by high-performance liquid chromatography and pharmacokinetic parameters were calculated using Automated Pharmacokinetic Analysis System software (Nanko-Do, Tokyo).
Table 1. Patients' characteristics
| Age (years) | |
| Median | 48 |
| Range | 29-63 |
| Menopausal status | |
| Pre | 16 |
| Post | 12 |
| Performance status | |
| 0 | 22 |
| 1 | 6 |
| 2 | 0 |
| Stage | |
| 1 | 1 |
| 2 | 17 |
| 3a | 3 |
| 3b | 1 |
| 4 | 5 |
| Estrogen recepton | |
| Positive | 10 |
| Negative | 11 |
| Unknown | 7 |
| Adjuvant therapy | |
| Chemoendrocrine | 14 |
| Chemotherapy | 7 |
| Endocrine | 3 |
| None | 4 |
| Disease-free interval (months) | |
| Mean | 26 |
| Median | 22 |
| Range | 0-82 |
| Initial site of metastasis | |
| Bone | 6 |
| Soft tissue | 7 |
| Liver | 21 |
| Lung | 1 |
| Pleura | 0 |
| Others | 0 |
| Number of organs involved | |
| 1 | 17 |
| 2 | 9 |
| 3 | 2 |
| 4 | 0 |
| Prior systemic therapy after recurrence | |
| Yes | 9 |
| No | 19 |
| Hepatic metastases | |
| H1 | 13 |
| H2 | 5 |
| H3 | 8 |
Extramural review was performed and the responses were assessed according to the WHO criteria. This protocol was approved by the clinical trial review committee of the Japan Clinical Oncology Group (JCOG) and was periodically assessed by its monitoring committee. This protocol was also approved by the institutional review board of each institution.
Results
Four patients were enrolled in level 1, six in level 2, six in level 3, three in level 4 and nine in phase II. In total, 28 patients were enrolled and 98 courses were given. Toxicity was evaluated in all patients except one, who refused to enter this trial after registration before any chemotherapy. Response was evaluable in 25 patients and not evaluable in two patients because of the shortness of the observation period.
Figure 1. Serum adriamycin concentration after injection of adriamycin. T1/2 [alpha] is 4.12 min and T1/2 [beta] is 70.26 min. AUC was calculated as 15.88 µg/ml. Figure 2. Serum 5-FU concentration after the injection of 5-FU. Pharmacokinetics of adriamycin and 5-FU are shown in Figs 1 and 2, respectively. The plasma concentrations of adriamycin 1, 5, 10, 30, 60, 120 and 360 min after injection were 1.31 ± 0.53, 0.59 ± 0.26, 0.24 ± 0.08, 0.048 ± 0.026, 0.0273 ± 0.008, 0.022 ± 0.008 and 0.011 ± 0.004 µg/ml, respectively. The half-concentration time of adriamycin for the alpha phase was 4.12 min and that for the beta phase was 70.26 min, analyzed by the two-compartment model. The area under the curve (AUC) was calculated as 15.88 µg/ml. The values of 5-FU concentration varied and the sample numbers for each level were low. The steady-state concentration (Css) of 5-FU was 9.59 ng/ml for level 1, 28.0 ng/ml for level 2 and 37.6 ng/ml for level 3. Table 2. Relationship between levels and toxicity
Toxicity mainly involved bone marrow suppression and gastrointestinal tract symptoms. Stomatitis was seldom seen. Toxicity other than the factors listed in Table 2 were diarrhea, epigastralgia and hematuria, although the grade of all these toxicities was mild. Cardiac dysfunction did not occur. Severe thrombocytopenia occurred in two patients in level 4 and grade 3 neurotoxicity in one patient in level 4. This patient experienced dizziness, convulsions and syncope. Thus level 4 was considered to indicate the maximum tolerated dose (MTD) according to the stopping rule (all the first three patients experienced critical toxicities) and the recommended dose for the phase II trial was decided as level 3. Catheter-related events were not dose dependent (Table 3). The most frequent event was thrombosis (five patients). Perforation of the duodenal wall occurred in one patient but the catheter was extracted without any complication after 30 days. Gastric ulcer and duodenal ulcer occurred in one patient each. The former was treated surgically and the latter conservatively. Cholecystitis also occurred in one patient and was treated without operation. Response was observed in 63% of the patients in level 3, which was the recommended dose; however there was no patient with CR. Response rate did not correlate with dose level (Table 4). The survival curve after intrahepatic arterial chemotherapy is shown in Fig. 3. Median survival was 25.3 months and three out of 25 cases are alive. Eighteen out of 22 cases died of liver metastasis. The longest survival period after starting intra-arterial chemotherapy was 54.7 months. Table 3. Catheter-related events
Table 4. Relationship between levels and response
Figure 3. Cumulative survival curve after the initiation of intra-arterial chemotherapy. (Kaplan-Meier method).
Liver metastasis is generally fatal within a short time once it appears in a breast cancer patient (1). Controlling liver metastasis may therefore contribute to the prolongation of survival time. Goldberg et al. (10) reported a case which suggested the usefulness of local chemotherapy compared with systemic chemotherapy. Our study also suggested the usefulness of intrahepatic arterial infusion chemotherapy. The drugs used in this trial were 5-FU and adriamycin. The most appropriate drug for intrahepatic arterial infusion chemotherapy is 5-fluorodeoxyuridine in terms of pharmacokinetics (7), although it can have severe side-effects including sclerosing cholangitis (11). Because 5-fluorodeoxyuridine is not available in Japan, we used 5-FU instead. 5-FU is also considered to be a suitable drug for intrahepatic arterial infusion chemotherapy, because the extraction rate and total body clearance (perfusion rate) are high. We adopted continuous infusion of 5-FU because a high response rate (12) and less leukocytopenia (13) were reported by this method compared with a bolus injection. In contrast to 5-FU, arterial infusion of adriamycin has little benefit in terms of pharmacokinetics, but it is considered to be a key drug for treating breast cancer patients and a high affinity to the perfused tissue may also be a benefit of intra-arterial infusion therapy (14). Adverse effects were basically the same as in intravenous chemotherapy. The grade of toxicity was not severe (Table 2). Bone marrow toxicity tended to become more severe as the dose of 5-FU increased and thrombocytopenia was the dose-limiting toxicity. Catheter-related events also occurred, but since they did not occur dose dependently, the high complication rate of this study may be ascribed to the skill of the operator. The frequency of such events may decrease as the operator becomes accustomed to the procedure. Improvement of the catheter material may also reduce the frequency of catheter-related complications. Few patients showed response discrepancy between liver and other metastatic sites. Progressive disease at a site of metastasis other than the liver metastasis was seen in only one patient. The lymph node of this patient showed progressive disease although the liver metastasis revealed a minor response. The low response discrepancy may be because the major metastatic site other than the liver was bone, which had static disease during the study period. Although there has been no report assessing the extraction rate of adriamycin with hepatic arterial infusion, Takatsuka et al. (14) speculated that there was a high extraction rate because of the large difference between peak plasma concentrations of intra-arterial and intravenous infusion. Our results also revealed a low peak plasma concentration of adriamycin compared with that of intravenous infusion reported by Fujiwara (15) (2.24 ± 0.266 vs 1.31 ± 0.527 µg/ml). However, the plasma concentration of adriamycin when given by the intra-arterial route is not lower than that when given by the intravenous route except immediately after the injection (for example, plasma concentrations of adriamycin 10 and 60 min after intra-arterial injection are 0.24 ± 0.08 and 0.0273 ± 0.008 µg/ml, respectively, compared with 0.34 ± 0.03 and 0.020 ± 0.009 µg/ml after intravenous injection). It is speculated that metastatic sites other than the liver may also respond to intra-arterial chemotherapy. We did not perform pharmacodynamic analysis because the 5-FU concentration varied and the numbers at each level were low. The response rate of 60% in this study is relatively high compared with intravenous chemotherapy using adriamycin. Lorenz et al. (16) reported a high response rate of regional therapy, but it did not lead to survival benefit. The median survival of 25.3 months in this study is longer than in previous reports (1,17), but the main cause of death was liver metastasis in this study. This means that intra-arterial chemotherapy could not sufficiently control liver metastasis. To eliminate selection bias, a prospective randomized trial comparing intra-arterial and systemic chemotherapy is needed. In the phase III study, bolus adriamycin injection at 30 mg/m2/day on days 1 and 8 and continuous infusion of 300 mg/m2/day 5-FU from day 1 through 14 every 28 days are recommended. Before starting a phase III study, improvement of catheter materials to improve the compliance of intra-arterial chemotherapy is mandatory. We thank Dr H. Fukuda of the JCOG statistical center for suggestions on statistical analysis. We are grateful to Professor J.P. Barron for revision of the manuscript. This study was supported by Grants-in-Aid for Cancer Research (2S-1,5S-1, 8S-1) from the Ministry of Health and Welfare.
Parameter
Category*
Level 1
Level 2
Level 3
Level 4
Phase II
Level 3 (total)
WBC count
0
1
2
0
0
1
1
1
2
1
3
1
1
4
2
0
1
1
1
6
7
3
1
2
1
0
0
1
4
0
0
0
1
0
0
Granulocyte count
0
2
2
0
0
2
0
1
1
0
3
0
1
4
2
0
3
1
2
5
6
3
0
0
0
0
0
0
4
1
1
1
1
0
1
Platelet count
0
3
4
4
1
6
10
1
1
2
0
0
1
1
2
0
0
1
0
0
1
3
0
0
0
0
0
0
4
0
0
0
2
1
1
Hemoglobin concentration
0
1
3
2
0
6
6
1
0
2
0
1
2
3
2
2
1
2
2
0
2
3
1
0
1
0
0
1
4
0
0
0
0
0
0
GOT
0
1
4
3
1
4
6
1
2
1
2
1
3
6
2
1
1
0
1
1
1
3
0
0
0
0
0
0
4
0
0
0
0
0
0
Nausea and vomiting
0
1
2
1
0
0
1
1
0
1
3
0
3
6
2
2
3
0
0
3
3
3
1
0
1
2
2
3
4
0
0
0
1
0
0
Stomatitis
0
3
6
5
2
7
12
1
1
0
0
0
1
2
0
0
0
1
0
1
3
0
0
0
0
0
0
4
0
0
0
0
0
0
Alopecia
0
0
2
3
0
3
6
1
3
1
2
1
4
6
2
1
3
0
2
1
1
3
0
0
0
0
0
0
4
0
0
0
0
0
0
Fever
0
1
3
2
1
6
8
1
3
3
2
1
2
4
2
0
0
1
1
0
1
3
0
0
0
0
0
0
4
0
0
0
0
0
0
Level
Events
Level 1
Arterial thrombosis
Level 2
Perforation
Arterial thrombosis
Arterial thrombosis
Arterial thrombosis
Level 3
Arterial thrombosis, gastric ulcer
Catheter infection
Cholecystitis
Level 4
None
Phase II (level 3)
Epigastralgia
Duodenal ulcer
Epigastralgia
Response*
Level 1
Level 2
Level 3
Level 4
Phase II (level 3)
Level 3 (Total)
PR
3
3
2
1
5
7
NC
1
2
2
1
2
4
PD
0
0
1
1
1
2
NE
1
1
RR (%)
75
60
40
33
63
54
Discussion
Acknowledgments
References
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Last modification: 22 Feb 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
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D. Coradini, S. Zorzet, R. Rossin, I. Scarlata, C. Pellizzaro, C. Turrin, M. Bello, S. Cantoni, A. Speranza, G. Sava, et al.
Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But
Clin. Cancer Res.,
July 15, 2004;
10(14):
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