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Keywords:

  • liver metastasis;
  • hepatic arterial infusion;
  • paclitaxel;
  • breast carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

Approximately 25% of patients with metastatic breast carcinoma develop hepatic involvement during the course of their disease that further affects their survival. Systemic paclitaxel is safe and has demonstrated good antitumor activity against breast carcinoma. The objective of this prospective study was to determine the safety and antitumor activity of hepatic intra-arterial paclitaxel therapy.

METHODS.

Ten patients with breast carcinoma and dominant liver metastases received monthly, inpatient, 24-hour, continuous hepatic infusions of paclitaxel at 200 mg/m2 through an intra-arterial catheter, which was placed using a percutaneous transfemoral approach.

RESULTS.

The mean patient age at the time of treatment was 51 years. Fifty-six courses of paclitaxel were delivered. The most common treatment-related toxicities were leukopenia, fatigue, nausea, and vomiting. No procedure-related complications were observed. Three patients (30%) attained partial responses that lasted for 6 months, 7 months, and 48 months; and 4 other patients had stable disease for 5 months to 9 months. One patient underwent liver resection after receiving hepatic arterial infusions of paclitaxel and remained disease free for 48 months. Eight patients had received prior systemic taxane therapy alone or with other cytotoxic agents. However, no association between previous taxane exposure and the efficacy of the current regimen was established.

CONCLUSIONS.

Hepatic intra-arterial therapy with paclitaxel at the dose level and on the schedule used in this study was safe and well tolerated and had reasonable antitumor activity against breast carcinoma involving the liver. Previous taxane exposure did not hamper the potential benefit of this approach. This regimen alone or in combination with targeted therapies deserves further investigation in patients with dominant liver metastases from breast carcinoma. Cancer 2007. © 2007 American Cancer Society.

Approximately 25% of patients with metastatic breast cancer develop liver involvement, which substantially may decrease their survival.1 Among patients with hepatic involvement, those with hormone receptor-positive tumors usually live longer than those with hormone receptor-negative tumors (median survival, 11 months and 4 months, respectively).2

Regional hepatic arterial therapy theoretically is an attractive alternative to systemic approaches for breast cancer patients who have liver involvement and a lack of hormone receptor expression or for patients who have large liver metastasis and minor extrahepatic tumor involvement. Approximately 80% of the blood supply to liver metastases derives from the hepatic artery,3 and direct tumor infusions, compared with systemic approaches, result in higher drug concentrations, potentially overcoming tumor resistance.4 Furthermore, the high hepatic extraction rate for some drugs may result in a better systemic toxicity profile while increasing exposure of the tumor bed to the drug.

The use of paclitaxel in hepatic infusions is particularly attractive because of its known antitumor activity against breast carcinoma5 and its suitable pharmacologic properties.6 Systemic administration of paclitaxel alone is effective as first- and second-line therapy for metastatic breast cancer,7 with overall response rates ranging between 21% and 62%.8–10 The cytotoxic activity of paclitaxel is related directly to its plasma concentration,11 and its administration directly into the hepatic artery results in a 95% mean extraction by the liver during the infusion and a 61% mean extraction from 5 to 9 hours after completion of the infusion.6 In addition, substantial antitumor activity was observed in a small series of patients with breast and gastric carcinomas who received hepatic intra-arterial infusions (HAIs) of paclitaxel.12–14 We conducted a pilot study to determine the toxic effects and antitumor activity of monthly, 24-hour HAIs of paclitaxel in patients with breast carcinoma metastatic to the liver.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

Between February 2000 and November 2002, 10 women with chemotherapy-refractory breast carcinoma and predominant liver involvement were enrolled in a pilot clinical trial to evaluate the safety and antitumor activity of HAI paclitaxel. The clinical protocol was reviewed and approved by the Institutional Review Board of the University of Texas M. D. Anderson Cancer Center. All study participants provided written informed consent prior to therapy.

Eligible study participants met the following inclusion criteria: Eastern Cooperative Oncology Group performance status of 0 or 115; normal organ function, including a total bilirubin concentration ≤1.0 mg/dL and a serum creatinine concentration ≤1.5 mg/dL; prothrombin time <13 seconds and activated partial thromboplastin time <30 seconds; and a normal complete blood count (CBC). Patients with evidence of portal hypertension, thrombosis, or secondary ascites were excluded from the study. One patient provided written consent and was treated and monitored in this cohort but was not registered because she had Gilbert syndrome and a total bilirubin concentration >1.0 mg/dL.

Treatment

All patients underwent angiographic placement of a catheter for HAI. A 3-French microcatheter was placed into the appropriate hepatic branch through a 5-French catheter inserted into the right common femoral artery. A nuclear medicine catheter flow study was performed on all patients using 5-mCi technetium-99m macroaggregated albumin particles to demonstrate the flow distribution within the liver and to exclude the presence of extrahepatic flow to prevent gastrointestinal complications. Then, paclitaxel (200 mg/m2) was administered by 24-hour continuous HAI in the inpatient unit. To prevent hypersensitivity reactions, we administered 10 mg of intravenous (IV) dexamethasone, 50 mg of IV diphenhydramine, and 300 mg of IV cimetidine 30 minutes before each infusion. The regimen was repeated every 4 weeks until tumor progression, withdrawal of consent, or life-threatening toxic effects occurred, such as fulminant hepatitis, bone marrow suppression, or other greater than grade 3 toxicities.

Patient Evaluations During Treatment

The baseline evaluation included a complete medical history, toxicity assessment, physical examination, and abdominal computed tomography (CT) scan with and without injection of contrast material. Laboratory analysis included a CBC, coagulation profile, and measurements of serum tumor markers (CA27-29, carcinoembryonic antigen [CEA], and CA125), serum electrolytes, uric acid, total bilirubin, serum albumin, alkaline phosphatase, aspartate and alanine aminotransferases, lactic dehydrogenase (LDH), blood urea nitrogen, and serum creatinine. Before the second course and each subsequent course of therapy, patients were evaluated with CBCs, liver and renal function tests, and tumor marker measurements. Abdominal CT scans were obtained after every 2 courses of therapy except in patients who had consistent decreases in LDH and/or tumor marker levels; in such instances, abdominal CT scans were obtained only when those levels had reached their nadir, as determined by the principal investigator.

Response Criteria

Our assessment of clinical responses adhered to the World Health Organization tumor assessment guidelines.15 A complete response was defined as the total disappearance of all areas of tumor involvement confirmed by abdominal CT scans and normalization of all liver function test results. A partial response was defined as a reduction ≥50% in the sum of the products of the greatest perpendicular dimensions of all selected measurable lesions. Progression of disease was defined as an increase ≥25% in the sum of the products of the greatest perpendicular dimensions of all measurable lesions. Participation was ended if disease progression (confirmed by abdominal CT scan) or unacceptable toxic effects occurred or when the patient declined further treatment.

Toxicity Assessment

Toxic effects were assessed at patient entry (baseline) and during each inpatient hospital stay according to the National Cancer Institute Common Toxicity Criteria guidelines, version 2.0. CBCs, liver function studies, and serum electrolyte measurements were obtained once between monthly treatments.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

All 10 patients were women who ranged in age from 39 years to 60 years (mean age, 51 years; median age, 45 years). Table 1 summarizes their disease characteristics and prior treatments. Overall, the group had received a median of 4 previous systemic treatment regimens, including adjuvant regimens and therapies for metastatic disease; and 8 patients previously had received systemic taxane either alone or in combination with other cytotoxic agents. Taxanes had been administered to 4 patients as adjuvant therapy and to 4 patients in the metastatic setting.

Table 1. Disease Characteristics (n = 10 Patients)*
CharacteristicNo.
  • ER indicates estrogen receptor; PR, progesterone receptor.

  • *

    Values are numbers of patients unless indicated otherwise.

  • Includes regimens delivered in the adjuvant and metastatic settings.

Histology
 Ductal9
 Lobular0
 Mixed1
ER status, positive/negative/unknown3/5/2
PR status, positive/negative/unknown3/4/3
Her2/neu status, positive/negative/unknown1/8/1
Sites of involvement
 Liver10
 Lungs3
 Bone1
 Brain3
 Lymph nodes1
Mean no. of sites (range)1.8 (1–3)
Mean no. of previous chemotherapy regimens (range)3.8 (1–7)
Previous paclitaxel exposure8

Treatment

In total, 56 infusions were delivered during the study period. The median hospital admission time for all patients during the 56 courses was 3 days (range, 2–16 days; 3 days in 53 of the courses). A prolonged hospital stay occurred in 1 patient who had rapid progression of her disease after therapy.

Toxic Effects

Table 2 lists the most common toxicities. Leukopenia was the most commonly observed side effect, occurring in 8 (14%) of the 56 treatment courses delivered. Three of those episodes were severe (grade 3 or 4). The next most common treatment-related toxicity was grade 1 nausea and vomiting, which also was reported in 8 (14%) of the 56 courses administered. Otherwise, patients tolerated the procedure and therapy well, without significant side effects. There were no catheter-related complications or hypersensitivity reactions to paclitaxel.

Table 2. Clinical Toxicities Observed in 56 Treatment Courses
EventGrade 1Grade 2Grade 3Grade 4
Nausea/vomiting8000
Diarrhea4000
Neuropathy1000
Leukopenia5421
Fever2000
Myalgia/arthralgia3000
Fatigue6100

Response and Outcome

Two patients experienced rapid disease progression after 1 course of therapy, and 2 other patients developed tumor progression after the third and fifth infusions, respectively. Both patients had marked progression in the liver (≥50% increase), and extrahepatic progression developed in 1 of them.

The mean time from initiation of therapy to tumor progression was 5.7 months. The mean duration of antitumor responses for the 3 patients who attained a partial response was 7.6 months. All patients eventually developed tumor progression in the liver, and 2 patients also experienced progression at extrahepatic sites. All 3 patients who attained partial responses had received prior systemic paclitaxel, and 2 of them received it in the adjuvant setting in combination with doxorubicin and cyclophosphamide. However, because of the limited number of patients, an association between previous taxane exposure and clinical benefit was not observed. Table 3 provides details on antitumor activity. Below, we describe the 3 patients who attained partial antitumor responses during therapy.

Table 3. Clinical Characteristics and Treatment Outcome
PatientAge, yER/PR statusHer2/neu statusSite(s) of disease at time of study regimenAdjuvant and neoadjuvantFor metastatic diseaseSite of disease progressionNo. of HAIsBest antitumor responseMost recent status
  1. ER indicates estrogen receptor; PR, progesterone receptor; HAIs, hepatic arterial infusions; AWD, alive with disease; IL-2, interleukin 2; GM-CSF, granulocyte-macrophage colony-stimulating factor.

151Positive/negativeNegativeLungs, liverFluorouracil, doxorubicin, cyclophosphamideTamoxifen; LY353381; anastrozole; fluoxymesterone; targretin; capecitabineLungs, liver3Stable; discontinued because of lack of objective response.AWD
242Negative/negativePositiveLiverDoxorubicin, cyclophosphamide, paclitaxelNoneBone, liver9Partial responseDeceased
338Negative/positiveNegativeLiver, lungs, brainNoneFluorouracil; doxorubicin, cyclophosphamide; doxetaxel; capecitabine; vinorelbine; gemcitabine; doxorubicin, cyclophosphamide; whole-brain radiation therapyLiver1ProgressionDeceased
466Negative/negativeNegativeLiverNoneCarboplatin, cyclophosphamide (ovarian carcinoma 11 y earlier); paclitaxel 175mg/m2 × 6 (severe cardiomyopathy)Liver5Stable diseaseDeceased
556Positive/positivePositiveLiver, lungs, boneDoxorubicin, cyclophosphamide × 3; modified radical mastectomy, radiation therapy, doxorubicin, cyclophosphamide × 3Paclitaxel × 8 (until progression); tamoxifen, anastrozole; capecitabine; gemcitabine, vinorelbineLiver, brain1ProgressionDeceased
644Negative/negativeNegativeLiverCyclophosphamide, methotrexate, fluorouracilPaclitaxel × 4, external-beam radiation therapy (1st recurrence)Liver6Partial responseAWD
767Unknown/unknownNegativeLiver, brainCyclophosphamide, methotrexate, fluorouracil; tamoxifenFluorouracil, doxorubicin, cyclophosphamide, paclitaxel; fluorouracil, leucovorin, vinorelbine, herceptin; cyclophosphamide, methotrexate, fluorouracilLiver6Stable diseaseDeceased
852Positive/positiveNegativeLiver, supraclavicular lymph Nodes Adriamycin, tamoxifen; mitoxantrone, 5FU, leucovorin × 3 (mammary infusion 1996), IL-2, GM-CSF, tumor-associated antigens; capecitabine, letrozole; HAI mitomycin C; adriamycin, mitoxantrone; HAI mitomycin C, 5FU, leucovorinBrain9Stable diseaseDeceased
960Positive/unknownUnknownLiverDoxorubicin, cyclophosphamide, paclitaxel; tamoxifen  9Stable diseaseDeceased
1039Negative/negativeNegativeLiverDoxorubicin, cyclophosphamide, paclitaxelNoneLiver8Partial responseAWD

Patient 2 developed liver metastases 1 year after completing adjuvant radiation for an estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, Her2/neu-negative, T2N3M0 infiltrating ductal carcinoma of the left breast. Adjuvant therapy had included paclitaxel. Baseline CT scans demonstrated bilobar liver disease. The CA27-29 level was 446.8 U/mL, the CEA level was 19.7 ng/mL, and the CA125 level was 95.3 U/mL. After 9 courses of therapy, a 90% reduction in the hepatic tumor burden was confirmed along with a decline in the serum CA27-29 level to 47 U/mL and normalization of the serum CEA and CA125 levels. The patient discontinued therapy and remained free of disease progression for 3 months until CT scans demonstrated progression of bilobar lesions and a substantial increase in the serum tumor marker levels was recorded. Subsequently, she received 4 courses of HAI paclitaxel outside the protocol, and tumor regression occurred at each site in the liver. She was given a second break from therapy for 6 months and then 4 more therapy courses until definitive disease progression occurred after the last infusion.

Patient 6 initially was diagnosed with an infiltrating ER-negative, PR-negative, Her2/neu-negative carcinoma of the left breast in 1996. Initial therapy included 6 courses of cyclophosphamide, methotrexate, and fluorouracil. Three years later, a chest wall recurrence developed, and a complete excision was performed followed by 4 courses of paclitaxel and external beam radiotherapy. Approximately 7 months later, liver involvement was documented. The patient enrolled in our study and received a total of 6 courses of HAI paclitaxel. Almost complete disappearance of the lesions was attained at the end of therapy. Subsequently, she underwent tamoxifen therapy for 1 year, after which, the lesions were excised. One of the lesions was sterile, and the second was consistent with metastatic carcinoma. The patient remained disease free for 4 more years and currently is receiving systemic palliative therapy for tumor recurrence.

Patient 10 was diagnosed with bilobar liver metastases3.5 years after initial treatment of an ER-negative, PR-negative, Her2/neu-negative, T1N1M0 invasive ductal carcinoma in 1998. Soon after HAI therapy with paclitaxel was started, the patient attained a partial response, which lasted for 8 consecutive cycles, at which time, disease progression in the liver was noted (Fig. 1). The patient currently remains alive and is receiving other forms of regional therapy. No residual toxicities were reported, and the disease has remained confined to the liver.

thumbnail image

Figure 1. Computed tomography scans showing antitumor response in patient 10. (A) Tumor before hepatic arterial infusion (HAI) of paclitaxel and (B) after 8 monthly HAIs. Arrows indicate tumor implants (Tomographic cuts with the greatest dimensions of residual lesions are depicted.).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The results of our study suggest that 24-hour HAIs of paclitaxel given monthly to patients with breast carcinoma metastatic to the liver are tolerated well and result in substantial antitumor activity. The most frequent treatment-related toxicities were grade 1 and 2 leukopenia and grade 1 nausea and vomiting. There was 1 episode of grade 4 neutropenia in a patient who had received extensive prior cytotoxic therapy. Hence, the toxicities observed with our regimen were minimal and were in line with those observed after systemic IV administration of this agent.16

Previous studies of regional HAIs using vinblastine17 and cisplatin18 resulted in objective antitumor responses of 36% and 19%, respectively, among patients with breast carcinoma metastatic to the liver. However, when the 2 agents were combined, their substantial antitumor activity was compromised by excessive toxicity.19

All 3 patients in our study who attained a partial response had received previous treatment with taxanes either in the adjuvant setting or to treat recurrence of their breast carcinoma. It has been demonstrated that high doses and/or prolonged exposure of the tumor to paclitaxel may overcome resistance to the drug20; thus, as also demonstrated in preclinical tumor models, increased exposure (hour, dose, and duration) of the tumor bed to paclitaxel by the 24-hour IA route of administration may overcome tumor resistance and confer a clinical advantage over the IV route while minimizing systemic toxicities.

The liver, as a site of dominant metastatic disease, is a well-recognized, critical factor of poor prognosis (short survival) among patients with either colorectal or breast carcinoma. The proof of principle using liver-directed IA chemotherapy as a modality superior to the systemic IV route in colorectal cancer recently was demonstrated by Kemeny et al.21 A recent update of that study with median follow-up of 10 years22 indicated not only that the median survival was significantly longer for the IA group compared with the IV group but that the 10-year survival was 41% for the IA group and 27% for the IV group, emphasizing the long-lasting effect of the IA route.

The efforts in the same therapeutic direction continue with the emergence of new, more effective agents, such as irinotecan and oxaliplatin, either as IV adjuncts to the IA 5-fluoro-2′-deoxuidine deoxyuridine (5FUDR) with ever higher tumor responses reaching 90%,23 or as agents delivered IA per se replacing 5FUDR altogether.24–26

Tumor responses to IA chemotherapy sometimes can be dramatic and may render patients candidates for liver resection with curative intent. Ducreux et al. described this phenomenon in 5 of 26 patients with colorectal carcinoma after they received IA oxaliplatin.25 One of our patients with breast carcinoma (Patient 6) underwent liver resection with curative intent, which resulted in a 4-year disease-free interval before her tumor reoccurred in the liver.

The recent experience with regional intraperitoneal paclitaxel in patients with ovarian carcinoma demonstrated significant survival advantage compared with IV (systemic) paclitaxel.27 Although this may be encouraging news, further studies will be needed to document whether a similar advantage may be conferred with regional, IA paclitaxel administration to women suffering from breast carcinoma and dominant liver metastases.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We are grateful for the thorough editorial assistance of Christopher J. Yeager in the Scientific Publications office of M. D. Anderson Cancer Center.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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