- Email: [email protected]
Radioembolization in Patients with Hepatic Metastases from Breast Cancer
Radioembolization in Patients with Hepatic Metastases from Breast Cancer Tobias F. Jakobs, MD, Ralf-Thorsten Hoffmann, MD, Ton Fischer, MD, Hans-Joachim Stemmler, MD, Klaus Tatsch, MD, Christian La Fougere, MD, Ravi Murthy, MD, Maximillian F. Reiser, MD, and Thomas K. Helmberger, MD
PURPOSE: To determine the safety of and survival outcomes associated with single-session, whole-liver radioembolization with Yttrium-90 (90Y)-labelled resin microspheres in patients with nonresectable liver metastases from breast cancer that were refractory to other treatments. MATERIALS AND METHODS: Thirty patients underwent radioembolization with 90Y-labeled resin microspheres infusion in a single-session, whole-liver treatment. All patients had undergone polychemotherapy regimens including at least anthracyclines and taxanes, hormonal therapy, and trastuzumab where applicable. Follow-up data were available for 23 patients. After treatment, the authors assessed tumor response with computed tomography and/or magnetic resonance imaging by using Response Evaluation Criteria in Solid Tumors (RECIST), laboratory and clinical toxicities, and survival. RESULTS: A mean activity of 1.9 GBq of 90Y was delivered. Follow-up at a median of 4.2 months demonstrated partial response, stable disease, and progressive disease in 61%, 35%, and 4% of patients, respectively. With respect to tumor diameters, imaging revealed a maximum and minimum response of ⴚ64.8% to ⴙ23.6%, respectively (mean, 29.2%; median, 39.7%). The median follow-up time was 14.2 months. The median overall survival was 11.7 months. The median survival of responders and nonresponders was 23.6 and 5.7 months, respectively, and the median survival of patients with and patients without extrahepatic disease was 9.6 and 16 months. Clinically significant toxicities with the appearance of increasing transaminase level, increasing bilirubin level, nausea and vomiting, gastric ulcers, and ascites occurred in eight of 30 patients. One patient=s death was attributed to treatment-related hepatic toxicity. CONCLUSIONS: Single-session, whole-liver 90Y radioembolization can be performed with an acceptable toxicity profile in patients with liver metastases from breast cancer. Response to radioembolization in these patients is supported by the decrease in tumor size. Further investigation is warranted to prove survival benefit. J Vasc Interv Radiol 2008; 19:683– 690 Abbreviations:
MAA ⫽ macoaggregated albumin, RECIST ⫽ Response Evaluation Criteria in Solid Tumors
WORLDWIDE, breast cancer is the most frequent cancer in women. According to the National Cancer Institute, approximately 40,500 women will die of metastatic breast cancer in 2007 in the United States. Breast cancer
is responsible for 26.5% of all new cancer cases among women in Europe and 17.5% of cancer deaths (1). Breast cancer has a propensity to spread to bones, lung, and liver. Available data suggest that, although the
From the Departments of Radiology (T.F.J., R.T.H., T.F., M.F.R.), Internal Medicine III (H.J.S.), and Nuclear Medicine (K.T., C.L.F.), Ludwig-MaximiliansUniversity of Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany; the Division of Diagnostic Imaging, the University of Texas M. D. Anderson Cancer Center, Houston, Tex (R.M.); and the Department of Radiology, Klinikum Bogenhausen, Munich, Germany (T.K.H.). Received July 24, 2007; final revision received January 10,
2008; accepted January 13, 2008. Address correspondence to T.F.J.; E-mail: [email protected] T.F.J., R.T.H., K.T., R.M., M.F.R., and T.K.H. have occasionally lectured for Sirtex Medical. Sirtex Medical had no input in this manuscript. © SIR, 2008 DOI: 10.1016/j.jvir.2008.01.009
liver is not a common initial site of distant metastases in breast cancer (it is observed in 5%–20% of patients), almost half of all women with metastatic breast cancer will eventually be diagnosed with liver metastases (2,3). Chemotherapy and hormonal therapy are currently the mainstays of treatment in metastatic breast cancer. Although transient responses are possible with conventional treatment modalities (chemotherapy, hormonal therapy, or local radiation therapy), most patients develop progressive disease within 1–2 years of initiating therapy (4 –7). Thus, chemotherapy in the setting of hepatic metastases from breast cancer delays progression and
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prolongs survival but rarely cures the disease. The median survival is approximately 18 –24 months, and the 5-year survival rate is 22% (8,9). A variety of liver-targeted therapies for metastatic disease are now available, including laser interstitial tumor therapy, radiofrequency or microwave ablation, and cryotherapy. These techniques are applicable only to patients who have limited metastatic liver disease in terms of number and size of tumors (10). Furthermore, liver metastases will ultimately recur in 60%–90% of these patients. For patients with liver metastases that are too large, too numerous, or inaccessible with the aforementioned techniques, transarterial hepatic chemoperfusion or chemoembolization may be more effective. Vogl et al (11) published a series of 162 patients with unresectable liver metastases (predominantly from colorectal cancer) in whom a reduction of tumor size was achieved in 50.6% of the cases by performing repeated transarterial chemoembolization with mitomycin, iodized oil, and microspheres. However, thus far, the efficacy of these treatment options has not been proved in controlled studies. Radiation therapy has become more effective in destroying tumors because of the technologic advances in treatment planning and delivery typically combined with radiosensitizing chemotherapy. However, three-dimensional radiation therapy, intensitymodulated radiation therapy, and stereotactic radiation therapy are limited by the tolerance of normal liver parenchyma to radiation. The maximum acceptable dose to the whole liver of 35 Gy is far below that required to destroy adenocarcinoma metastases, which is estimated to be at least 70–90 Gy. Radioembolization, which combines the effects of interstitial highdose radiation therapy and arterial microembolization, is a promising treatment option for liver metastases. Radioactive microspheres are injected into the hepatic artery, resulting in very high doses of radiation being selectively delivered to metastases via their arterial blood supply. In Europe, SIR-Spheres (Sirtex Medical Limited, Sydney, Australia), which are composed of resin microspheres labelled with the isotope Yttrium-90 (90Y), have been approved for radioembolo-
therapy in patients with nonresectable malignant liver disease. On the basis of the encouraging results obtained with 90Y radioembolization in the treatment of hepatic metastases from colorectal cancer and hepatocellular carcinoma, we used this technique to treat patients with hepatic metastases from breast cancer (12–19). The purpose of our study was to determine the safety of and survival outcomes associated with single-session, whole-liver radioembolization with 90Y resin microspheres in patients with nonresectable liver metastases from breast cancer that were refractory to other treatments.
MATERIALS AND METHODS Patient and Tumor Characteristics Between 2003 and 2007, radioembolization was performed in 29 women and one man with liver metastases from breast cancer. The mean patient age was 58 years (range, 39 –73 years). The median follow-up time was 14.2 months (mean, 15.7 months; range, 2– 45.1 months). At least one follow-up image was available for 23 patients. Four patients have not undergone their first scheduled follow-up examination, one patient died before undergoing the first follow-up, and two patients were lost to follow-up. Our prospective study protocol was approved by the institutional review board. Informed patient consent was obtained after extensive information had been provided to all patients. Previous Treatments Adjuvant Hormonal Treatment Schedules.—Because of hormone receptor positivity, 24 of the 30 patients (80%) had received antihormonal treatment with tamoxifen, which was replaced with an aromatase inhibitor in 20 patients (66%) during the course of treatment. Six patients did not receive tamoxifen or aromatase inhibitors due to low or negative hormone receptor expression. Chemotherapy Treatment Schedules for Metastatic Disease.—In case of hormone receptor negativity or progression after primary antihormonal treatment, patients underwent the following chemotherapy regimens. Twenty-six patients (87%) received at least one an-
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thracycline-containing regimen. Due to contraindications, four patients (13%) received an anthracycline-free regimen as the first-line treatment of metastatic disease (cyclophosphamide, methotrexate, 5-fluorouracil; CMFscheme). During the course of the disease, 24 patients (80%) received a taxane-based second-line regimen. Furtherline treatment included capecitabine in 15 patients (50%) and vinorelbine in 21 (70%). Six of the 30 patients (20%) showed an overexpression of human epidermal growth factor receptor 2 (DAKO HercepTest score 3⫹ [semiquantitative immunohistochemical assay for determination of human epidermal growth factor receptor 2 protein overexpression] or fluorescence in situ hybridization test positive) and, therefore, received a trastuzumab-based regimen. Radioembolization was offered to patients who either did not respond to chemotherapy or had to abandon chemotherapy because of its toxic effects. Radioembolization was approved for each individual patient by a multidisciplinary team consisting of oncologists, radiation oncologists, surgeons, physicians from nuclear medicine, and interventional radiologists. At radioembolization 17 of the 30 patients (57%) presented with extrahepatic metastatic disease. Ten of those 30 patients (33%) had isolated bone metastases that were not considered to be determining the individual life expectancy. Two of the 30 patients (6.6%) had limited paraaortal lymph node metastases only, and five of the 30 patients (17%) had concomitant osseous and lymph node metastases. There was no evidence of extrahepatic metastases in 13 of the 30 patients (43%). Preprocedural Evaluation For staging, all patients were assessed before radioembolization with combined positron emission tomography (PET) and computed tomography (CT), whole-body magnetic resonance (MR) imaging, and standard blood tests, including testing for tumor-associated markers. All patients who met the primary inclusion criteria of no substantial extrahepatic tumor spread (controlled osseous metastases were not regarded as a contraindication; patients with limited lymph node metastases were treated based on an indi-
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vidual decision) were considered candidates for radioembolization. Because lethal radiation-related injury to the lungs is possible after radioembolization, patients underwent angiography of the celiac axis and hepatic arteries together with a direct hepatic arterial injection of 99mtechnetium (99mTc) macroaggregated albumin (MAA) followed by thoracic and abdominal perfusion scintigraphy to rule out substantial hepatopulmonary shunting. If hepatopulmonary shunts exceeded 20% of the applied 99mTcMAA activity, the procedure was abandoned (20,21). Other exclusion criteria were tumor volume exceeding 70% of the liver, previous external beam irradiation of the liver, recent treatment with capecitabine (within 2 months before study entry), serum bilirubin level of at least 2 mg/dL (34 mol/L), creatinine level of at least 1.8 mg/dL (159 mol/L), platelet count of less than or equal to 50 ⫻ 109/L, treatment refractory coagulopathy, portal vein occlusion accompanied by hepatofugal flow, high risk for ectopic implantation of microspheres due to nonoccludable vessels to other organ regions, and life expectancy of less than 6 weeks (22,23). The presence of regional biliary obstruction was considered a relative contraindication to radioembolization. The detection of life-threatening or dominant extrahepatic disease was regarded as a contraindication to radioembolization. However, in the presence of major liver disease and only minor extrahepatic tumor spread, radioembolization treatment was considered justifiable. Five of the 30 patients had undergone liver-directed therapy before radioembolization. One patient had undergone right hemihepatectomy, and four patients underwent radiofrequency ablation at an earlier stage of disease for local tumor control. Radiation Source and Dosimetry The isotope used for radioembolization was 90Y, an artificial  radiation– emitting isotope. It has a 64.2hour half-life and decays to stable 90 zirconium. The beta radiation of 90Y has an average energy of 0.935 MeV and an average penetration in tissue of approximately 2.5 mm. To facilitate predictable delivery of 90Y, the isotope
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is incorporated in insoluble and nonbiodegradable resin microspheres with a mean diameter of 32 m. The activity (measured in gigabecquerel) of the resin microspheres was titrated to the calculated extent (tumor volume) of the disease (⬍25% liver replacement, 2 GBq; 25%–50% liver replacement, 2.5 GBq; ⬎50% liver replacement, 3 GBq) and was given over a 30 – 45 minute period, including time needed to reposition the catheter. The tip of the catheter was placed exactly corresponding to the positioning during the 99mTc-MAA application. Therapeutic Procedure After completion of the aforementioned tests, whole-liver radioembolization was performed as a single-session treatment in 29 patients. In one patient, only lobar treatment was performed because the patient had previously undergone hemihepatectomy. Prophylactic embolization of the gastroduodenal artery was done routinely. If deemed necessary, coiling of the right gastric artery and other small visceral arteries was performed. A detailed description of the administration procedure has been published previously (13,22,24 –27). Concomitant medication consisting of analgesics, antiemetics, steroids, gastric mucosal protection agents, and prophylactic antibiotics were administered routinely. Approximately 1 hour and 24 hours after radioembolization, Bremstrahlungs scintigraphy was performed to control and document the relative distribution of radiation. Assessment of Response Patients were followed-up repeatedly every 2–5 months after radioembolization. Follow-up included physical examination, combined PET-CT and/or MR imaging (with the same parameters as those used for pretreatment imaging), laboratory tests (including tumor markers), and liver function tests. Tumor response on CT or MR images was assessed by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria (28). Crosssectional imaging changes within the liver were defined as follows: complete remission ⫽ disappearance of the tumor; partial response ⫽ 30% decrease of the tumor size; stable disease
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⫽ criteria for partial response or progressive disease were not met; and progressive disease ⫽ 20% increase in tumor size and complete remission, partial response, or stable disease was not previously documented. Toxicity In compliance with federal law, all patients were treated on an inpatient basis and were kept in a designated ward for at least 48 hours. Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days after treatment) were evaluated in all patients on the basis of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (29). Therefore, all patients were followed up closely until all acute toxicities were resolved and after approximately 3 months to look for possible radiationinduced hepatitis or other toxicities. Statistical Analysis Overall survival rates and survival rates according to response or no response at the first follow-up imaging study and the presence or absence of extrahepatic disease before radioembolization were calculated by using the Kaplan-Meier method. The logrank test was used to compare survival curves and to test the probability of trends in survival scores across groups. If the P value associated with the 2 statistic was less than .05, the conclusion was that, statistically, the two survival curves differ significantly or that the grouping variable has a statistically significant influence on survival time. Furthermore, survival curves were compared by calculating the hazard ratio with its 95% confidence interval. The estimated survival times are biased owing to a number of censored cases. In these cases, the event in question had not been noted by the end of the period of observation. For the purposes of calculating the mean survival time, these cases were treated as if the event had been noted at the end of the observation period. Statistical analyses were performed with software (MedCalc for Windows, version 7.3.0.1; MedCalc Software, Mariakerke, Belgium).
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dence of progression of the osseous metastases, and one patient (4%) developed a metastasis within the chest wall. Survival Data
Figure 1. Images in a 57-year-old woman with hepatic metastases from breast cancer. (a) T1-weighted three-dimensional gradient-echo gadolinium-enhanced MR image with nearly isotropic resolution and (b) T2-weighted coronal MR image delineate a huge tumor mass within the liver dome. (c, d) Axial (c) and coronal (d) images obtained 4 months after radioembolization show that the tumor diameter has decreased by 64.8%. There is no evidence of contrast-enhanced tissue at the center of the tumor, which is indicative of complete necrosis or scar formation, whereas some contrast enhancement is found at the rim of the tumor.
RESULTS The median follow-up after radioembolization was 14.2 months (mean, 15.7 months; range, 2– 45.1 months). The mean calculated activity was 2,083 MBq (range, 1,750 –2,500 MBq), with a mean activity of 1,896 MBq (range, 1,500 –2,445 MBq) infused. The median activity delivered was 1,900 MBq. In 22 patients, the full calculated activity was administered, whereas in eight patients the infusion was abandoned early due to embolization effects and impending danger of reflux into other organ territories. Imaging Response With use of RECIST, responses for 23 patients were evaluated with either contrast medium– enhanced CT or MR imaging after radioembolization. The median time to the first imaging fol-
low-up was 4.2 months (mean, 3.9 months; range, 1.6 –5.6 months). No complete response was observed. Fourteen of the 23 patients (61%) had a partial response to radioembolization (Fig 1), eight patients (35%) had stable disease or a minor response, and one patient (4%) had progression of disease. With respect to the sum of the tumor diameters, imaging revealed a maximum and minimum response of ⫺64.8% and ⫹23.6%, respectively. The mean and median reductions were 29.2% and 39.7%, respectively. In two of the 23 patients (8.7%), new pulmonary metastases were detected at the first follow-up; one of these patients (4%) also showed evidence of peritoneal carcinomatosis and positive paraaortal lymph nodes. One patient (4%) developed a cerebellar metastasis, and another patient (4%) showed signs of meningiosis carcinomatosa. In three patients (13%), there was evi-
Overall Survival.—Survival curves were evaluated with the Kaplan-Meier method. The median survival time for all patients, with calculation started at the date of radioembolization, was 11.7 months (Fig 2). The mean survival was 9.6 months (range, 3.0 – 45.1 months). At the time of this analysis, 15 patients were dead. Survival Depending on Response.— There was a statistically significant difference in the survival probability of patients with (n ⫽ 14) and patients without (n ⫽ 9) response (P ⫽ .005, log-rank test; 2 test ⫽ 7.8824) (Fig 3). The median survival for patients with and patients without response was 23.6 months (hazard ratio, 3.6; 95% confidence interval ⫽ 1.67, 17.83) and 5.7 months, respectively. Survival Depending on the Presence of Extrahepatic Disease.—We found no significant difference in survival between patients with (n ⫽ 17) and patients without (n ⫽ 13) extrahepatic disease (P ⫽ .077, log-rank test; 2 test ⫽ 3.1248) (Fig 4). The median survival times were 9.6 and 16 months for patients with and patients without extrahepatic disease, respectively. Although this difference was substantial, it was not statistically significant. The calculation of the hazard ratio did not apply. Side Effects and Toxicities Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days after treatment) were recorded for all patients on the basis of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Overall, radioembolization treatment with resin microspheres resulted in an acceptable toxicity profile. Twenty-six patients reported mild to moderate right upper quadrant pain after embolization, which required the administration of non-opiod (n ⫽ 3) or opoid (n ⫽ 15) analgesics. In eight patients, no medication was required. Grade 1 or 2 nausea was reported by 20 patients, and grade 3 nausea was reported by only one patient. Gastroin-
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Figure 2. Graph illustrates the overall survival probability calculated with the Kaplan-Meier method for 30 patients with liver metastases from breast cancer. Calculation was started at the date of the radioembolization procedure. The estimated median survival was 11.7 months.
testinal toxicity with grade 1, 2, and 3 vomiting occurred in three patients, three patients, and one patient, respectively. Two patients developed actinic gastric ulcers, which, in retrospect, were most likely due to ectopic embolization of initially undetected vascular branches into the stomach. Both patients recovered uneventfully with appropriate medication and dietary management after a prolonged time. None of the patients required surgery. No treatment-associated diarrhea was observed. Ascites was noted in four patients and was considered severe in only one patient. Two patients developed lower leg edema during the course of their disease. In one patient, grade 3 toxicity occurred with the appearance of increasing transaminase levels (aspartate aminotransferase and alanine aminotransferase levels 5–20 times above normal) in conjunction with a grade 4 increase in the bilirubin level. This patient developed capillary leakage syndrome (ascites, edema, pleural effusion, hemoconcentration, and decrease in the serum albumin level) approximately 8 –10 weeks after radioembolization and died of hepatorenal failure (grade 5 toxicity) 90 days after the procedure. Twenty-six patients had grade 1 to grade 2 toxicity increases in aspartate aminotransfer-
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Figure 3. Graph illustrates the survival probability calculated with the Kaplan-Meier method on the basis of the presence or absence of initial response to radioembolization. There was a statistically significant difference in the survival probability (P ⫽ .005), with a median survival for patients with (dashed line) and patients without (solid line) response of 23.6 months and 5.7 months, respectively.
ase and alanine aminotransferase levels, and two patients had grade 3 toxicities. In 24 patients, no significant change of the bilirubin level was recorded, in addition to the patient with a grade 4 bilirubin increase, four patients had grade 2 toxicity and one patient had grade 3 toxicity. The four grade 2 bilirubin toxicities and the severe ascites in one patient were attributed to the presence of disease progression. No life-threatening morbidities or treatment-related deaths were observed within a period of 30 days after radioembolization.
DISCUSSION The results of our study show that Y radioembolization of hepatic breast cancer metastases is an effective treatment option, with an acceptable overall toxicity profile. Considering the palliative intent of this treatment after at least first- and second-line chemotherapy had failed, this study shows promising results. Despite the limited number of patients included in this study, there is a trend toward improved survival in patients with an initial response to 90Y radioembolization and no evidence of tumor spread beyond the liver. There are limited data about the use 90
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of radioembolization to treat hepatic metastases from breast cancer. To our knowledge, only two published articles have addressed the treatment of hepatic metastases from breast cancer with 90Y microspheres (30,31). Coldwell et al (30) studied 44 patients with liver-dominant metastatic breast cancer. Comparable to our study cohort, all patients failed anthracycline- or taxol-based chemotherapy regimens, and 66% of patients had extrahepatic disease. Imaging revealed partial response, stable disease or minor response, or progressive disease in 47%, 47%, and 5% of patients, respectively. For patients whose disease did not respond to radioembolization, survival was short (3.6 months), whereas patients who responded to treatment experienced a much longer survival, although with a median follow-up of 14 months, the median survival was not reached. These results correspond well to those obtained in our study. In our study, imaging revealed partial response, stable disease or minor response, or progressive disease in 61%, 35%, and 4% of patients, respectively. Patients with no response had a median survival of 5.7 months, compared to a median survival of 23.6 months for those with response. The overall median survival was 11.7 months.
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Figure 4. Graph displays the survival probability calculated with the Kaplan-Meier method on the basis of the presence or absence of extrahepatic metastatic disease. Statistically, there was no significant difference in survival probability (P ⫽ .077). The median survival was 9.6 months and 16 months for patients with (dashed line) and patients without (solid line) extrahepatic disease, respectively.
Recently, Bangash et al (31) published their results of 90Y radioembolization of breast cancer liver metastases in 27 patients with glass microspheres. In contrast to the singlesession whole-liver treatment we used in our study, treatment was administered to their patients by means of either the right or the left hepatic lobe, depending on the disease presentation. The median delivered activity of 1.7 GBq is comparable to the 1.9 GBq administered in our study. For image evaluation and determination of response, the World Health Organization classification method was used. Partial response, stable disease, and progressive disease were reported in 39%, 52%, and 9% of patients, respectively. Taking into account the fact that partial response is more difficult to achieve with the World Health Organization criteria than with RECIST (a tumor reduction of ⬎50% instead of ⬎30% is required), these results are in alignment with our responses. Bangash et al reported median survival rates from first radioembolization of 6.8 months in the group with a good performance status and 9.4 months for patients with tumor burdens of less than 25% of the liver volume. The latter corresponds well to the overall median survival time of 11.7 months we calculated from our data, especially considering that 23 of our 30 patients
presented with a tumor burden to the liver of less than 25%. The rate of complications in our series, with a number of patients having grade 3 and 4 toxicities, is somewhat higher than that reported by Coldwell et al (30). However, given the fact that treatment was palliative in intent and all patients underwent intense pretreatment regimens, most complications did not seriously interfere with the patients= quality of life and resolved uneventfully with appropriate treatment. One patient in our study died of hepatorenal failure 90 days after treatment. We consider this most likely to be related to the radioembolization. Unfortunately, neither CT nor MR imaging was performed after treatment. However, ultrasonography did not reveal extensive metastatic liver disease. Therefore, hepatic failure was most likely due to radiation-induced liver disease. In retrospect, as revealed with MR imaging 2 weeks before radioembolization, this patient had multiple small metastases (Fig 5), which suggests that the surrounding healthy liver tissue was also irradiated by the implanted microspheres and the remaining liver reserve was not sufficient to support liver function. Although Bangash et al reported no radiation-induced liver disease in their study, three patients had grade 3 bili-
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rubin toxicity related to tumor progression, one patient had peripheral biliary necrosis, and one patient had radiation-induced cholecystitis. Two patients in our study developed gastric ulcers as a result of nontarget embolization by the microspheres via undetected vascular branches into the stomach. These cases occurred near the beginning of our experience with this relatively new treatment option. In retrospect, we identified the vascular branches responsible and found that this severe complication could have been avoided had these vessels been occluded properly. Patient selection and tumor biology appear to be important variables for determining the survival of patients with breast cancer metastases. The optimal therapeutic management of an individual patient is largely determined by the prognostic and/or predictive models that have been established with the evaluation of multiple patient-, tumor-, and disease-related factors (32). A short disease-free interval, young age, negative hormone receptor status, lack of response to previous therapy, presence of visceral involvement, multiple sites of disease, and human epidermal growth factor 2 positivity are among the prognostic factors indicating an unfavorable disease course. It has long been reported that the development of visceral metastases, particularly in the liver, is an ominous sign indicative of a poor disease outcome and a poor response to chemotherapy, endocrine therapy, or both (33–35). Moreover, even with highdose and intensive chemotherapy with stem cell support, liver metastases retain their poor prognosis (36,37). This dire reputation of liver metastases is partly attributable to the other unfavorable prognostic and/or predictive factors that are reported to be commonly associated with the presence of liver metastases (a shorter disease-free interval, negative hormone receptor status, young age, and node-positive disease) (38). Furthermore, the biologic aggressiveness of metastatic disease often reflects that of the primary tumor. In other instances, treatmentinduced mutations in metastatic cells can lead to differences in some prognostic factors (eg, tumor grade, receptor status, and cellular kinetic parameters) in primary and metastatic
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Figure 5. (a, b) Axial T2-weighted fat-saturated turbo spin-echo MR images in a 55-year-old woman with hepatic metastases from breast cancer show multiple, finely distributed metastases all over the liver. This finding indicates that, after implantation of the radioactive microspheres in the tumor, the surrounding normal liver tissue might have been irradiated as well, with the consequence of liver failure 90 days after treatment.
disease. Therefore, fast fatal outcome or relatively prolonged survival may occur in patients with distant metastases from primary tumors with favorable or unfavorable prognosis, respectively. These articles (Bangash et al, Coldwell et al) about the use of radioembolization in the treatment of liver metastases from breast cancer as well as our study describe only relatively small patient cohorts, and all investigators noted considerable heterogeneity in the presentation and progression of metastatic disease. Thus, despite initially promising results, most patients with metastatic breast cancer continue to be treated with systemic chemotherapy alone. In patients who have previously undergone intense pretreatment regimens or those refractory to previous chemotherapy, further-line chemotherapy is palliative and the observed response rate with different agents is low (39); therefore, the improvement of symptoms and the maintenance of a good quality of life are the main aims of treatment. On the basis of our study and others, radioembolization has a potential role in the management of liver metastases from breast cancer. Owing to the excellent initial response, radioembolization might prolong survival. However, these conclusions are based solely on reports from small, heterogeneous, single-institution series, and
the lack of prospective randomized trials demonstrating that this treatment modality might add further benefit to conventional treatment hampers its integration into routine clinical practice. Given the small number of centers experienced in radioembolization, however, a large, multicenter, international collaboration seems mandatory to accomplish this ambitious task.
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crospheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol 2005; 16:1627–1639. Salem R, Thurston KG. Radioembolization with yttrium-90 microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies: part 3: comprehensive literature review and future direction. J Vasc Interv Radiol 2006; 17:1571–1593. Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol 2007; 25:1099 –1106. Stubbs RS, O’Brien I, Correia MM. Selective internal radiation therapy with 90Y microspheres for colorectal liver metastases: single-centre experience with 100 patients. ANZ J Surg 2006; 76:696 –703. Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998; 40:583–592. Goin JE, Salem R, Carr BI, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities. J Vasc Interv Radiol 2005; 16:205–213. Ho S, Lau WY, Leung TW, Chan M, Johnson PJ, Li AK. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med 1997; 24: 293–298. Liu DM, Salem R, Bui JT, et al. Angiographic considerations in patients undergoing liver-directed therapy. J Vasc Interv Radiol 2005; 16:911– 935. Murthy R, Nunez R, Szklaruk J, et al. Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, technical considerations, and po-
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tential complications. Radiographics 2005; 25(suppl 1):41–55. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007; 68:13–23. Lewandowski RJ, Sato KT, Atassi B, et al. Radioembolization with (90)Y microspheres: angiographic and technical considerations. Cardiovasc Intervent Radiol 2007; 30:571–592. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007; 68:13–23. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. I. Technical and methodologic considerations. J Vasc Interv Radiol 2006; 17:1251–1278. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205–216. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13:176 –181. Coldwell DM, Kennedy AS, Nutting CW. Use of Yttrium-90 microspheres in the treatment of unresectable hepatic metastases from breast cancer. Int J Radiat Oncol Biol Phys 2007; 69:800 – 804. Bangash AK, Atassi B, Kaklamani V, et al. 90Y radioembolization of metastatic breast cancer to the liver: toxicity,
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imaging response, survival. J Vasc Interv Radiol 2007; 18:621– 628. Hortobagyi GN, Smith TL, Legha SS, et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol 1983; 1:776 –786. Perez JE, Machiavelli M, Leone BA, et al. Bone-only versus visceral-only metastatic pattern in breast cancer: analysis of 150 patients: a GOCS study. Grupo Oncologico Cooperativo del Sur. Am J Clin Oncol 1990; 13:294 –298. Leone BA, Romero A, Rabinovich MG, et al. Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis: The GOCS (Grupo Oncologico Cooperativo del Sur) experience. Am J Clin Oncol 1988; 11:618 – 622. Muss HB. Endocrine therapy for advanced breast cancer: a review. Breast Cancer Res Treat 1992; 21:15–26. Rowlings PA, Williams SF, Antman KH, et al. Factors correlated with progression-free survival after highdose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer. JAMA 1999; 282:1335– 1343. Rizzieri DA, Vredenburgh JJ, Jones R, et al. Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stemcell support. J Clin Oncol 1999; 17: 3064 –3074. Pritchard KI. Liver metastases: can our understanding of their biology and prognostic value contribute to a strategy for optimum therapeutic management? Eur J Cancer 1997; 33(suppl 7): S11–14. Mano M. Vinorelbine in the management of breast cancer: new perspectives, revived role in the era of targeted therapy. Cancer Treat Rev 2006; 32: 106 –118.
PURPOSE: To determine the safety of and survival outcomes associated with single-session, whole-liver radioembolization with Yttrium-90 (90Y)-labelled resin microspheres in patients with nonresectable liver metastases from breast cancer that were refractory to other treatments. MATERIALS AND METHODS: Thirty patients underwent radioembolization with 90Y-labeled resin microspheres infusion in a single-session, whole-liver treatment. All patients had undergone polychemotherapy regimens including at least anthracyclines and taxanes, hormonal therapy, and trastuzumab where applicable. Follow-up data were available for 23 patients. After treatment, the authors assessed tumor response with computed tomography and/or magnetic resonance imaging by using Response Evaluation Criteria in Solid Tumors (RECIST), laboratory and clinical toxicities, and survival. RESULTS: A mean activity of 1.9 GBq of 90Y was delivered. Follow-up at a median of 4.2 months demonstrated partial response, stable disease, and progressive disease in 61%, 35%, and 4% of patients, respectively. With respect to tumor diameters, imaging revealed a maximum and minimum response of ⴚ64.8% to ⴙ23.6%, respectively (mean, 29.2%; median, 39.7%). The median follow-up time was 14.2 months. The median overall survival was 11.7 months. The median survival of responders and nonresponders was 23.6 and 5.7 months, respectively, and the median survival of patients with and patients without extrahepatic disease was 9.6 and 16 months. Clinically significant toxicities with the appearance of increasing transaminase level, increasing bilirubin level, nausea and vomiting, gastric ulcers, and ascites occurred in eight of 30 patients. One patient=s death was attributed to treatment-related hepatic toxicity. CONCLUSIONS: Single-session, whole-liver 90Y radioembolization can be performed with an acceptable toxicity profile in patients with liver metastases from breast cancer. Response to radioembolization in these patients is supported by the decrease in tumor size. Further investigation is warranted to prove survival benefit. J Vasc Interv Radiol 2008; 19:683– 690 Abbreviations:
MAA ⫽ macoaggregated albumin, RECIST ⫽ Response Evaluation Criteria in Solid Tumors
WORLDWIDE, breast cancer is the most frequent cancer in women. According to the National Cancer Institute, approximately 40,500 women will die of metastatic breast cancer in 2007 in the United States. Breast cancer
is responsible for 26.5% of all new cancer cases among women in Europe and 17.5% of cancer deaths (1). Breast cancer has a propensity to spread to bones, lung, and liver. Available data suggest that, although the
From the Departments of Radiology (T.F.J., R.T.H., T.F., M.F.R.), Internal Medicine III (H.J.S.), and Nuclear Medicine (K.T., C.L.F.), Ludwig-MaximiliansUniversity of Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany; the Division of Diagnostic Imaging, the University of Texas M. D. Anderson Cancer Center, Houston, Tex (R.M.); and the Department of Radiology, Klinikum Bogenhausen, Munich, Germany (T.K.H.). Received July 24, 2007; final revision received January 10,
2008; accepted January 13, 2008. Address correspondence to T.F.J.; E-mail: [email protected] T.F.J., R.T.H., K.T., R.M., M.F.R., and T.K.H. have occasionally lectured for Sirtex Medical. Sirtex Medical had no input in this manuscript. © SIR, 2008 DOI: 10.1016/j.jvir.2008.01.009
liver is not a common initial site of distant metastases in breast cancer (it is observed in 5%–20% of patients), almost half of all women with metastatic breast cancer will eventually be diagnosed with liver metastases (2,3). Chemotherapy and hormonal therapy are currently the mainstays of treatment in metastatic breast cancer. Although transient responses are possible with conventional treatment modalities (chemotherapy, hormonal therapy, or local radiation therapy), most patients develop progressive disease within 1–2 years of initiating therapy (4 –7). Thus, chemotherapy in the setting of hepatic metastases from breast cancer delays progression and
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prolongs survival but rarely cures the disease. The median survival is approximately 18 –24 months, and the 5-year survival rate is 22% (8,9). A variety of liver-targeted therapies for metastatic disease are now available, including laser interstitial tumor therapy, radiofrequency or microwave ablation, and cryotherapy. These techniques are applicable only to patients who have limited metastatic liver disease in terms of number and size of tumors (10). Furthermore, liver metastases will ultimately recur in 60%–90% of these patients. For patients with liver metastases that are too large, too numerous, or inaccessible with the aforementioned techniques, transarterial hepatic chemoperfusion or chemoembolization may be more effective. Vogl et al (11) published a series of 162 patients with unresectable liver metastases (predominantly from colorectal cancer) in whom a reduction of tumor size was achieved in 50.6% of the cases by performing repeated transarterial chemoembolization with mitomycin, iodized oil, and microspheres. However, thus far, the efficacy of these treatment options has not been proved in controlled studies. Radiation therapy has become more effective in destroying tumors because of the technologic advances in treatment planning and delivery typically combined with radiosensitizing chemotherapy. However, three-dimensional radiation therapy, intensitymodulated radiation therapy, and stereotactic radiation therapy are limited by the tolerance of normal liver parenchyma to radiation. The maximum acceptable dose to the whole liver of 35 Gy is far below that required to destroy adenocarcinoma metastases, which is estimated to be at least 70–90 Gy. Radioembolization, which combines the effects of interstitial highdose radiation therapy and arterial microembolization, is a promising treatment option for liver metastases. Radioactive microspheres are injected into the hepatic artery, resulting in very high doses of radiation being selectively delivered to metastases via their arterial blood supply. In Europe, SIR-Spheres (Sirtex Medical Limited, Sydney, Australia), which are composed of resin microspheres labelled with the isotope Yttrium-90 (90Y), have been approved for radioembolo-
therapy in patients with nonresectable malignant liver disease. On the basis of the encouraging results obtained with 90Y radioembolization in the treatment of hepatic metastases from colorectal cancer and hepatocellular carcinoma, we used this technique to treat patients with hepatic metastases from breast cancer (12–19). The purpose of our study was to determine the safety of and survival outcomes associated with single-session, whole-liver radioembolization with 90Y resin microspheres in patients with nonresectable liver metastases from breast cancer that were refractory to other treatments.
MATERIALS AND METHODS Patient and Tumor Characteristics Between 2003 and 2007, radioembolization was performed in 29 women and one man with liver metastases from breast cancer. The mean patient age was 58 years (range, 39 –73 years). The median follow-up time was 14.2 months (mean, 15.7 months; range, 2– 45.1 months). At least one follow-up image was available for 23 patients. Four patients have not undergone their first scheduled follow-up examination, one patient died before undergoing the first follow-up, and two patients were lost to follow-up. Our prospective study protocol was approved by the institutional review board. Informed patient consent was obtained after extensive information had been provided to all patients. Previous Treatments Adjuvant Hormonal Treatment Schedules.—Because of hormone receptor positivity, 24 of the 30 patients (80%) had received antihormonal treatment with tamoxifen, which was replaced with an aromatase inhibitor in 20 patients (66%) during the course of treatment. Six patients did not receive tamoxifen or aromatase inhibitors due to low or negative hormone receptor expression. Chemotherapy Treatment Schedules for Metastatic Disease.—In case of hormone receptor negativity or progression after primary antihormonal treatment, patients underwent the following chemotherapy regimens. Twenty-six patients (87%) received at least one an-
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thracycline-containing regimen. Due to contraindications, four patients (13%) received an anthracycline-free regimen as the first-line treatment of metastatic disease (cyclophosphamide, methotrexate, 5-fluorouracil; CMFscheme). During the course of the disease, 24 patients (80%) received a taxane-based second-line regimen. Furtherline treatment included capecitabine in 15 patients (50%) and vinorelbine in 21 (70%). Six of the 30 patients (20%) showed an overexpression of human epidermal growth factor receptor 2 (DAKO HercepTest score 3⫹ [semiquantitative immunohistochemical assay for determination of human epidermal growth factor receptor 2 protein overexpression] or fluorescence in situ hybridization test positive) and, therefore, received a trastuzumab-based regimen. Radioembolization was offered to patients who either did not respond to chemotherapy or had to abandon chemotherapy because of its toxic effects. Radioembolization was approved for each individual patient by a multidisciplinary team consisting of oncologists, radiation oncologists, surgeons, physicians from nuclear medicine, and interventional radiologists. At radioembolization 17 of the 30 patients (57%) presented with extrahepatic metastatic disease. Ten of those 30 patients (33%) had isolated bone metastases that were not considered to be determining the individual life expectancy. Two of the 30 patients (6.6%) had limited paraaortal lymph node metastases only, and five of the 30 patients (17%) had concomitant osseous and lymph node metastases. There was no evidence of extrahepatic metastases in 13 of the 30 patients (43%). Preprocedural Evaluation For staging, all patients were assessed before radioembolization with combined positron emission tomography (PET) and computed tomography (CT), whole-body magnetic resonance (MR) imaging, and standard blood tests, including testing for tumor-associated markers. All patients who met the primary inclusion criteria of no substantial extrahepatic tumor spread (controlled osseous metastases were not regarded as a contraindication; patients with limited lymph node metastases were treated based on an indi-
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vidual decision) were considered candidates for radioembolization. Because lethal radiation-related injury to the lungs is possible after radioembolization, patients underwent angiography of the celiac axis and hepatic arteries together with a direct hepatic arterial injection of 99mtechnetium (99mTc) macroaggregated albumin (MAA) followed by thoracic and abdominal perfusion scintigraphy to rule out substantial hepatopulmonary shunting. If hepatopulmonary shunts exceeded 20% of the applied 99mTcMAA activity, the procedure was abandoned (20,21). Other exclusion criteria were tumor volume exceeding 70% of the liver, previous external beam irradiation of the liver, recent treatment with capecitabine (within 2 months before study entry), serum bilirubin level of at least 2 mg/dL (34 mol/L), creatinine level of at least 1.8 mg/dL (159 mol/L), platelet count of less than or equal to 50 ⫻ 109/L, treatment refractory coagulopathy, portal vein occlusion accompanied by hepatofugal flow, high risk for ectopic implantation of microspheres due to nonoccludable vessels to other organ regions, and life expectancy of less than 6 weeks (22,23). The presence of regional biliary obstruction was considered a relative contraindication to radioembolization. The detection of life-threatening or dominant extrahepatic disease was regarded as a contraindication to radioembolization. However, in the presence of major liver disease and only minor extrahepatic tumor spread, radioembolization treatment was considered justifiable. Five of the 30 patients had undergone liver-directed therapy before radioembolization. One patient had undergone right hemihepatectomy, and four patients underwent radiofrequency ablation at an earlier stage of disease for local tumor control. Radiation Source and Dosimetry The isotope used for radioembolization was 90Y, an artificial  radiation– emitting isotope. It has a 64.2hour half-life and decays to stable 90 zirconium. The beta radiation of 90Y has an average energy of 0.935 MeV and an average penetration in tissue of approximately 2.5 mm. To facilitate predictable delivery of 90Y, the isotope
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is incorporated in insoluble and nonbiodegradable resin microspheres with a mean diameter of 32 m. The activity (measured in gigabecquerel) of the resin microspheres was titrated to the calculated extent (tumor volume) of the disease (⬍25% liver replacement, 2 GBq; 25%–50% liver replacement, 2.5 GBq; ⬎50% liver replacement, 3 GBq) and was given over a 30 – 45 minute period, including time needed to reposition the catheter. The tip of the catheter was placed exactly corresponding to the positioning during the 99mTc-MAA application. Therapeutic Procedure After completion of the aforementioned tests, whole-liver radioembolization was performed as a single-session treatment in 29 patients. In one patient, only lobar treatment was performed because the patient had previously undergone hemihepatectomy. Prophylactic embolization of the gastroduodenal artery was done routinely. If deemed necessary, coiling of the right gastric artery and other small visceral arteries was performed. A detailed description of the administration procedure has been published previously (13,22,24 –27). Concomitant medication consisting of analgesics, antiemetics, steroids, gastric mucosal protection agents, and prophylactic antibiotics were administered routinely. Approximately 1 hour and 24 hours after radioembolization, Bremstrahlungs scintigraphy was performed to control and document the relative distribution of radiation. Assessment of Response Patients were followed-up repeatedly every 2–5 months after radioembolization. Follow-up included physical examination, combined PET-CT and/or MR imaging (with the same parameters as those used for pretreatment imaging), laboratory tests (including tumor markers), and liver function tests. Tumor response on CT or MR images was assessed by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria (28). Crosssectional imaging changes within the liver were defined as follows: complete remission ⫽ disappearance of the tumor; partial response ⫽ 30% decrease of the tumor size; stable disease
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⫽ criteria for partial response or progressive disease were not met; and progressive disease ⫽ 20% increase in tumor size and complete remission, partial response, or stable disease was not previously documented. Toxicity In compliance with federal law, all patients were treated on an inpatient basis and were kept in a designated ward for at least 48 hours. Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days after treatment) were evaluated in all patients on the basis of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (29). Therefore, all patients were followed up closely until all acute toxicities were resolved and after approximately 3 months to look for possible radiationinduced hepatitis or other toxicities. Statistical Analysis Overall survival rates and survival rates according to response or no response at the first follow-up imaging study and the presence or absence of extrahepatic disease before radioembolization were calculated by using the Kaplan-Meier method. The logrank test was used to compare survival curves and to test the probability of trends in survival scores across groups. If the P value associated with the 2 statistic was less than .05, the conclusion was that, statistically, the two survival curves differ significantly or that the grouping variable has a statistically significant influence on survival time. Furthermore, survival curves were compared by calculating the hazard ratio with its 95% confidence interval. The estimated survival times are biased owing to a number of censored cases. In these cases, the event in question had not been noted by the end of the period of observation. For the purposes of calculating the mean survival time, these cases were treated as if the event had been noted at the end of the observation period. Statistical analyses were performed with software (MedCalc for Windows, version 7.3.0.1; MedCalc Software, Mariakerke, Belgium).
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dence of progression of the osseous metastases, and one patient (4%) developed a metastasis within the chest wall. Survival Data
Figure 1. Images in a 57-year-old woman with hepatic metastases from breast cancer. (a) T1-weighted three-dimensional gradient-echo gadolinium-enhanced MR image with nearly isotropic resolution and (b) T2-weighted coronal MR image delineate a huge tumor mass within the liver dome. (c, d) Axial (c) and coronal (d) images obtained 4 months after radioembolization show that the tumor diameter has decreased by 64.8%. There is no evidence of contrast-enhanced tissue at the center of the tumor, which is indicative of complete necrosis or scar formation, whereas some contrast enhancement is found at the rim of the tumor.
RESULTS The median follow-up after radioembolization was 14.2 months (mean, 15.7 months; range, 2– 45.1 months). The mean calculated activity was 2,083 MBq (range, 1,750 –2,500 MBq), with a mean activity of 1,896 MBq (range, 1,500 –2,445 MBq) infused. The median activity delivered was 1,900 MBq. In 22 patients, the full calculated activity was administered, whereas in eight patients the infusion was abandoned early due to embolization effects and impending danger of reflux into other organ territories. Imaging Response With use of RECIST, responses for 23 patients were evaluated with either contrast medium– enhanced CT or MR imaging after radioembolization. The median time to the first imaging fol-
low-up was 4.2 months (mean, 3.9 months; range, 1.6 –5.6 months). No complete response was observed. Fourteen of the 23 patients (61%) had a partial response to radioembolization (Fig 1), eight patients (35%) had stable disease or a minor response, and one patient (4%) had progression of disease. With respect to the sum of the tumor diameters, imaging revealed a maximum and minimum response of ⫺64.8% and ⫹23.6%, respectively. The mean and median reductions were 29.2% and 39.7%, respectively. In two of the 23 patients (8.7%), new pulmonary metastases were detected at the first follow-up; one of these patients (4%) also showed evidence of peritoneal carcinomatosis and positive paraaortal lymph nodes. One patient (4%) developed a cerebellar metastasis, and another patient (4%) showed signs of meningiosis carcinomatosa. In three patients (13%), there was evi-
Overall Survival.—Survival curves were evaluated with the Kaplan-Meier method. The median survival time for all patients, with calculation started at the date of radioembolization, was 11.7 months (Fig 2). The mean survival was 9.6 months (range, 3.0 – 45.1 months). At the time of this analysis, 15 patients were dead. Survival Depending on Response.— There was a statistically significant difference in the survival probability of patients with (n ⫽ 14) and patients without (n ⫽ 9) response (P ⫽ .005, log-rank test; 2 test ⫽ 7.8824) (Fig 3). The median survival for patients with and patients without response was 23.6 months (hazard ratio, 3.6; 95% confidence interval ⫽ 1.67, 17.83) and 5.7 months, respectively. Survival Depending on the Presence of Extrahepatic Disease.—We found no significant difference in survival between patients with (n ⫽ 17) and patients without (n ⫽ 13) extrahepatic disease (P ⫽ .077, log-rank test; 2 test ⫽ 3.1248) (Fig 4). The median survival times were 9.6 and 16 months for patients with and patients without extrahepatic disease, respectively. Although this difference was substantial, it was not statistically significant. The calculation of the hazard ratio did not apply. Side Effects and Toxicities Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days after treatment) were recorded for all patients on the basis of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Overall, radioembolization treatment with resin microspheres resulted in an acceptable toxicity profile. Twenty-six patients reported mild to moderate right upper quadrant pain after embolization, which required the administration of non-opiod (n ⫽ 3) or opoid (n ⫽ 15) analgesics. In eight patients, no medication was required. Grade 1 or 2 nausea was reported by 20 patients, and grade 3 nausea was reported by only one patient. Gastroin-
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Figure 2. Graph illustrates the overall survival probability calculated with the Kaplan-Meier method for 30 patients with liver metastases from breast cancer. Calculation was started at the date of the radioembolization procedure. The estimated median survival was 11.7 months.
testinal toxicity with grade 1, 2, and 3 vomiting occurred in three patients, three patients, and one patient, respectively. Two patients developed actinic gastric ulcers, which, in retrospect, were most likely due to ectopic embolization of initially undetected vascular branches into the stomach. Both patients recovered uneventfully with appropriate medication and dietary management after a prolonged time. None of the patients required surgery. No treatment-associated diarrhea was observed. Ascites was noted in four patients and was considered severe in only one patient. Two patients developed lower leg edema during the course of their disease. In one patient, grade 3 toxicity occurred with the appearance of increasing transaminase levels (aspartate aminotransferase and alanine aminotransferase levels 5–20 times above normal) in conjunction with a grade 4 increase in the bilirubin level. This patient developed capillary leakage syndrome (ascites, edema, pleural effusion, hemoconcentration, and decrease in the serum albumin level) approximately 8 –10 weeks after radioembolization and died of hepatorenal failure (grade 5 toxicity) 90 days after the procedure. Twenty-six patients had grade 1 to grade 2 toxicity increases in aspartate aminotransfer-
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Figure 3. Graph illustrates the survival probability calculated with the Kaplan-Meier method on the basis of the presence or absence of initial response to radioembolization. There was a statistically significant difference in the survival probability (P ⫽ .005), with a median survival for patients with (dashed line) and patients without (solid line) response of 23.6 months and 5.7 months, respectively.
ase and alanine aminotransferase levels, and two patients had grade 3 toxicities. In 24 patients, no significant change of the bilirubin level was recorded, in addition to the patient with a grade 4 bilirubin increase, four patients had grade 2 toxicity and one patient had grade 3 toxicity. The four grade 2 bilirubin toxicities and the severe ascites in one patient were attributed to the presence of disease progression. No life-threatening morbidities or treatment-related deaths were observed within a period of 30 days after radioembolization.
DISCUSSION The results of our study show that Y radioembolization of hepatic breast cancer metastases is an effective treatment option, with an acceptable overall toxicity profile. Considering the palliative intent of this treatment after at least first- and second-line chemotherapy had failed, this study shows promising results. Despite the limited number of patients included in this study, there is a trend toward improved survival in patients with an initial response to 90Y radioembolization and no evidence of tumor spread beyond the liver. There are limited data about the use 90
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of radioembolization to treat hepatic metastases from breast cancer. To our knowledge, only two published articles have addressed the treatment of hepatic metastases from breast cancer with 90Y microspheres (30,31). Coldwell et al (30) studied 44 patients with liver-dominant metastatic breast cancer. Comparable to our study cohort, all patients failed anthracycline- or taxol-based chemotherapy regimens, and 66% of patients had extrahepatic disease. Imaging revealed partial response, stable disease or minor response, or progressive disease in 47%, 47%, and 5% of patients, respectively. For patients whose disease did not respond to radioembolization, survival was short (3.6 months), whereas patients who responded to treatment experienced a much longer survival, although with a median follow-up of 14 months, the median survival was not reached. These results correspond well to those obtained in our study. In our study, imaging revealed partial response, stable disease or minor response, or progressive disease in 61%, 35%, and 4% of patients, respectively. Patients with no response had a median survival of 5.7 months, compared to a median survival of 23.6 months for those with response. The overall median survival was 11.7 months.
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Figure 4. Graph displays the survival probability calculated with the Kaplan-Meier method on the basis of the presence or absence of extrahepatic metastatic disease. Statistically, there was no significant difference in survival probability (P ⫽ .077). The median survival was 9.6 months and 16 months for patients with (dashed line) and patients without (solid line) extrahepatic disease, respectively.
Recently, Bangash et al (31) published their results of 90Y radioembolization of breast cancer liver metastases in 27 patients with glass microspheres. In contrast to the singlesession whole-liver treatment we used in our study, treatment was administered to their patients by means of either the right or the left hepatic lobe, depending on the disease presentation. The median delivered activity of 1.7 GBq is comparable to the 1.9 GBq administered in our study. For image evaluation and determination of response, the World Health Organization classification method was used. Partial response, stable disease, and progressive disease were reported in 39%, 52%, and 9% of patients, respectively. Taking into account the fact that partial response is more difficult to achieve with the World Health Organization criteria than with RECIST (a tumor reduction of ⬎50% instead of ⬎30% is required), these results are in alignment with our responses. Bangash et al reported median survival rates from first radioembolization of 6.8 months in the group with a good performance status and 9.4 months for patients with tumor burdens of less than 25% of the liver volume. The latter corresponds well to the overall median survival time of 11.7 months we calculated from our data, especially considering that 23 of our 30 patients
presented with a tumor burden to the liver of less than 25%. The rate of complications in our series, with a number of patients having grade 3 and 4 toxicities, is somewhat higher than that reported by Coldwell et al (30). However, given the fact that treatment was palliative in intent and all patients underwent intense pretreatment regimens, most complications did not seriously interfere with the patients= quality of life and resolved uneventfully with appropriate treatment. One patient in our study died of hepatorenal failure 90 days after treatment. We consider this most likely to be related to the radioembolization. Unfortunately, neither CT nor MR imaging was performed after treatment. However, ultrasonography did not reveal extensive metastatic liver disease. Therefore, hepatic failure was most likely due to radiation-induced liver disease. In retrospect, as revealed with MR imaging 2 weeks before radioembolization, this patient had multiple small metastases (Fig 5), which suggests that the surrounding healthy liver tissue was also irradiated by the implanted microspheres and the remaining liver reserve was not sufficient to support liver function. Although Bangash et al reported no radiation-induced liver disease in their study, three patients had grade 3 bili-
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rubin toxicity related to tumor progression, one patient had peripheral biliary necrosis, and one patient had radiation-induced cholecystitis. Two patients in our study developed gastric ulcers as a result of nontarget embolization by the microspheres via undetected vascular branches into the stomach. These cases occurred near the beginning of our experience with this relatively new treatment option. In retrospect, we identified the vascular branches responsible and found that this severe complication could have been avoided had these vessels been occluded properly. Patient selection and tumor biology appear to be important variables for determining the survival of patients with breast cancer metastases. The optimal therapeutic management of an individual patient is largely determined by the prognostic and/or predictive models that have been established with the evaluation of multiple patient-, tumor-, and disease-related factors (32). A short disease-free interval, young age, negative hormone receptor status, lack of response to previous therapy, presence of visceral involvement, multiple sites of disease, and human epidermal growth factor 2 positivity are among the prognostic factors indicating an unfavorable disease course. It has long been reported that the development of visceral metastases, particularly in the liver, is an ominous sign indicative of a poor disease outcome and a poor response to chemotherapy, endocrine therapy, or both (33–35). Moreover, even with highdose and intensive chemotherapy with stem cell support, liver metastases retain their poor prognosis (36,37). This dire reputation of liver metastases is partly attributable to the other unfavorable prognostic and/or predictive factors that are reported to be commonly associated with the presence of liver metastases (a shorter disease-free interval, negative hormone receptor status, young age, and node-positive disease) (38). Furthermore, the biologic aggressiveness of metastatic disease often reflects that of the primary tumor. In other instances, treatmentinduced mutations in metastatic cells can lead to differences in some prognostic factors (eg, tumor grade, receptor status, and cellular kinetic parameters) in primary and metastatic
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Figure 5. (a, b) Axial T2-weighted fat-saturated turbo spin-echo MR images in a 55-year-old woman with hepatic metastases from breast cancer show multiple, finely distributed metastases all over the liver. This finding indicates that, after implantation of the radioactive microspheres in the tumor, the surrounding normal liver tissue might have been irradiated as well, with the consequence of liver failure 90 days after treatment.
disease. Therefore, fast fatal outcome or relatively prolonged survival may occur in patients with distant metastases from primary tumors with favorable or unfavorable prognosis, respectively. These articles (Bangash et al, Coldwell et al) about the use of radioembolization in the treatment of liver metastases from breast cancer as well as our study describe only relatively small patient cohorts, and all investigators noted considerable heterogeneity in the presentation and progression of metastatic disease. Thus, despite initially promising results, most patients with metastatic breast cancer continue to be treated with systemic chemotherapy alone. In patients who have previously undergone intense pretreatment regimens or those refractory to previous chemotherapy, further-line chemotherapy is palliative and the observed response rate with different agents is low (39); therefore, the improvement of symptoms and the maintenance of a good quality of life are the main aims of treatment. On the basis of our study and others, radioembolization has a potential role in the management of liver metastases from breast cancer. Owing to the excellent initial response, radioembolization might prolong survival. However, these conclusions are based solely on reports from small, heterogeneous, single-institution series, and
the lack of prospective randomized trials demonstrating that this treatment modality might add further benefit to conventional treatment hampers its integration into routine clinical practice. Given the small number of centers experienced in radioembolization, however, a large, multicenter, international collaboration seems mandatory to accomplish this ambitious task.
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