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Use of Yttrium-90 Microspheres in the Treatment of Unresectable Hepatic Metastases From Breast Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 3, pp. 800–804, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.03.056
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USE OF YTTRIUM-90 MICROSPHERES IN THE TREATMENT OF UNRESECTABLE HEPATIC METASTASES FROM BREAST CANCER DOUGLAS M. COLDWELL, PH.D., M.D., F.S.I.R.,* ANDREW S. KENNEDY, M.D., F.A.C.R.O.,y z AND CHARLES W. NUTTING, D.O. * Department of Radiology, University of Mississippi Medical Center, Jackson, MS; y Wake Radiology Oncology, Cary, NC; and z Sky Ridge Medical Center, Lone Tree, CO Purpose: Therapy for patients with unresectable liver metastases from breast cancer that were refractory to multiple treatment regimens was performed using radioactive microspheres. High doses of radiation were delivered to tumors from these permanently implanted yttrium-90 (90Y) microspheres, delivered through the hepatic arterial vessels. Methods and Materials: Women from three institutions were selected for treatment, after screening that demonstrated vascular access to all tumors and after imaging confirmed that microspheres would be implanted only in the liver tumors. All patients were followed with laboratory and imaging studies at regular intervals until death. Toxicities, both acute and late were recorded, and actuarial survival determined. Results: A total of 44 women were treated from April 2002 to April 2005. Median follow-up of these women was 14 months (1–42 months). No treatment-related procedure deaths or radiation related veno-occlusive liver failures were found. Computed tomographic imaging partial response was 47% and positron emission tomographic response 95%. Conclusion: In this group of heavily pretreated patients, radioactive microspheres produced an encouraging median survival, with acceptable toxicity and a significant objective response rate, suggesting that further investigation of this approach is warranted. Ó 2007 Elsevier Inc. Liver, Yttrium, Microsphere, Breast, Brachytherapy.
In the United States in 2006, breast cancer is expected to be diagnosed in an estimated 213,000 patients (1). The percentage of patients who will eventually develop metastatic disease in the liver is less well known but is believed to be at least 60%, or 127,000 individuals (2). Tumors in the liver are approachable by potentially curative surgery in only a select group of these patients who do not have other sites of metastatic disease. However, the disease in the liver is the lifespan-limiting site of disease in most cases, whereas metastases to the brain account for the death of many of the remaining patients. Among those who do undergo curative liver resection, 5-year survival rates range from 25% to 38%; but 60% to 90% of these patients will ultimately develop recurrent liver metastases. Chemotherapy, which for decades was mostly limited to doxorubicin, resulted in poor response
and survival rates when used alone for metastatic disease in the liver. The introduction of taxanes and herceptin now offers a dramatic and long hoped-for improvement against advanced metastatic breast cancer (3–5). Yet despite these significant gains, metastatic breast cancer is almost always fatal, with up to 60% of patients dying of liver failure caused by local effects of hepatic tumors. Surveillance, Epidemiology, and End Results (SEER) data reveal that, once breast cancer is metastasized, the median survival of patients with this disease is 18.5 months, compared with 7.5 months for colorectal cancer and 24.5 months for prostate cancer (6). A number of liver-directed therapies are now available including radiofrequency or microwave ablation, cryotherapy, and direct chemical injection. These techniques are effective only in patients who have a limited number of tumors. For patients with larger numbers, particularly of small tumors, the hepatic arterial therapies of hepatic arterial embolization
Reprint requests to: Douglas M. Coldwell, M.D., 4629 Livingston Avenue, Dallas, TX 75209. Tel: (214) 356-0443; Fax: (214) 350-2957; E-mail: [email protected] Dr. Coldwell is currently affiliated with Coldwell Associates, Dallas, TX. Conflict of interest: D. M. Coldwell, A. S. Kennedy, and C. W.
Nutting have received honoraria for lectures and training provided on microsphere therapy from Sirtex, Inc., which is the manufacturer of the microspheres used in the patients in this report. They do not have any other financial arrangements with Sirtex. Received Jan 16, 2007, and in revised form Feb 22, 2007. Accepted for publication March 31, 2007.
INTRODUCTION
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Yttrium-90 microspheres in hepatic metastases from breast cancer d D. M. COLDWELL et al.
and chemoembolization may be more effective. However, no controlled studies have been performed with these modalities. In addition, in the opinion of the current investigators, these modalities are variably effective, given the nature of the procedure, because they are so operator sensitive and are effective in palliation of symptoms only. Radiotherapy has become more effective in destroying breast tumors, typically with combined chemotherapy (usually 5-fluorouracil [5FU] at doses >50 Gy) because of the technologic advances in treatment planning and delivery. However, three-dimensional radiotherapy, intensity-modulated radiotherapy, and stereotactic radiotherapy 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, estimated at $70 Gy. An alternate approach is implantation of radiation sources into the tumor, i.e., brachytherapy, using yttrium-90 (90Y) microspheres (7–16). This report presents a review of our institutions’ experience, and represents the largest number and longest follow-up of patients treated with 90Y microspheres in liver brachytherapy for metastatic breast cancer.
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uncorrectable delivery to the GI tract; reverse blood flow out of the liver, or complete portal vein thrombosis.
Radioactive material Yttrium-90 is a pure beta emitter, which decays to stable zirconium-90 with an average energy of 0.94 MeV via a half-life of 2.67 days (64.2 h). It is produced by neutron bombardment of 89 Y in a commercial reactor, yielding 90Y beta radiation with a mean tissue penetration of 2.5 mm, and a maximum range of 1.1 cm. A 1-GBq (27 mCi) quantity of 90Y delivers a total dose of 50 Gy/Kg in tissue. Although two commercially available radioactive microspheres are on the market in North America, a glass (TheraSphere, MDS Nordion, Inc., Ontario, Canada) and a resin (SIR-Spheres, SIRTex Medical Limited, Sydney, Australia) product using 90Y that is permanently embedded within the glass or resin structure, only the resin product was used for these patients, as it is the only microsphere product to have full approval from the Food and Drug Administration and consequently can be used on an ‘‘off-label’’ manner. Each resin sphere has a diameter of 32 10 mm, causing them to be permanently embolized in terminal arterioles, that is, within the tumor. No significant amount of 90 Y leaches in the patient from the resin spheres. A standard dose of resin microspheres is 2 GBq containing approximately 50 million microspheres (range, 40–80 million) with a dose per microsphere estimated to be 50 Bq. Radiation treatment planning and dose delivery are identical with that of treatment of other tumor types and have been well described previously (20).
Patient selection Several reports in abstract form have been published regarding delivery of microspheres for colorectal hepatic metastases (11–14, 17–21). This report is limited to resin microspheres that are fully cleared by the Food and Drug Administration (FDA), indicated for colorectal cancer, and used in an off-label fashion, with data collected retrospectively without the institutions following a prescribed protocol. Approval from the institutional review board was obtained for retrospective review of the patient data. It was the intent of the treating team to accept patients for therapy who had already received and failed standard first-, second-, or third-line therapies for their primary tumor and needed intervention to address their liver metastases. Evaluation of patients by Medical Oncology, Radiation Oncology, and Interventional Radiology were completed before acceptance for microsphere treatment. By consensus, they were not candidates for radiofrequency ablation, transarterial chemoembolization, resection, intensity-modulated radiation therapy, or stereotactic radiotherapy. In addition, careful review of screening tests—in particular nuclear medicine and body computed tomography (CT) or magnetic resonance imaging (MRI)—required significant consultations with subspecialist physicians in those disciplines. All patients were selected according to strict inclusion/exclusion criteria. Eligible patients were $18 years of age; of any race; who had a confirmed diagnosis of breast cancer; with measurable unresectable disease predominately involving the liver; who were able to give informed consent; with a European Organisation for Research and Treatment of Cancer (ECOG) performance status score of #2; adequate bone marrow (granulocytes >1500/ml, platelets >60,000/ml); hepatic (total bilirubin #2.0 mg/dl) SGOT/SGPT or alkaline phosphatase <5 times the upper limit of normal; pulmonary function (forced expiratory volume in 1 s [FEV1]>1 L); and no contraindications to angiography and selective visceral catheterization. In addition, absolute contraindications included pulmonary shunt >20% of technetium99m–labeled macroaggregated albumin (99mTc-MAA) or any
Imaging studies All patients were evaluated via chest, abdomen, and pelvic CT scans (MRI was also used but few patients had them) to detect extrahepatic metastases and to determine liver tumor location, size, and number. All scans of the abdomen were three-phase, performed with oral and intravenous contrast, with slice thickness #7 mm through the abdomen. Some patients began undergoing fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning after July 1, 2001, pre- and post-treatment as their insurance coverage and referring physicians would allow. Response to treatment was judged as follows: Complete response (CR): All lesions from the pretreatment CT or MRI were not seen on the 12-week follow-up CT/MRI. For PET scans, all detected accumulations of FDG were eliminated. Partial response (PR): A 50% decrease in tumor number or size by one measurement or necrosis of most lesions as determined by water-equivalent Hounsfield unit values in the center of a lesion. For PET scans, this is a decrease in the most intense area of uptake by 25%. Stable disease: less than 50% response of lesions or less than 25% growth in number or size of lesions. For PET scans, this is less than a 25% decrease in uptake of the most intense lesion. Progressive disease: Growth of more than 25% in number or size of any lesion without necrosis at the 12-week post-treatment follow-up scan. The PET scan response criteria were not uniform but were typically used to evaluate response at 12 weeks post-treatment, compared with a pretreatment study performed within 4 weeks before the treatment. In addition, hepatic arteriography with 99mTc MAA embolization of the liver–lung shunt was performed as well documented elsewhere (20). Pretreatment embolization of the gastroduodenal artery, right gastric artery, and any other artery serving the stomach or duodenum was performed to ensure that any hollow viscus was protected from radioembolization.
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Table 1. Results in study patients
Dosimetry The dose of the 90Y SIR-Spheres was determined by using the body surface area formula given in the user’s manual: Dose ¼ BSA of the patient 0:2 þ % tumor burden: This dose, given in gigabecquerels, is used to treat the entire liver (whole liver treatment dose). For patients in whom a lobar approach is used, the dose is then proportional to the volume of the treated lobe to the entire liver. Such a dose is applied intra-arterially on the treatment date to either the entire liver or to a single lobe, usually 10 to 14 days after the screening arteriogram was obtained. If lobar treatment was used in a patient with bilobar disease, the patient returned for treatment of the other diseased lobe approximately 1 month later.
Toxicity Patients were followed closely until all acute toxicities were resolved, or at least every 2 weeks for 6 weeks, then monthly for 3 months to observe for possible radiation hepatitis or other toxicities. Acute events were those that occurred within 30 days of treatment and late effects were defined as occurring 31 to 90 days post-treatment. The National Cancer Institute’s Common Terminology Criteria for Adverse Events v 3.0 (CTCAE) (22) was used as appropriate.
Statistical analysis Survival was calculated as the number of elapsed days starting from the day of first microsphere treatment until death. Patients who were lost to follow-up were censured as of the day of last follow-up, as were those who received other treatments.
RESULTS Patients A total of 44 women were treated in this study. Their mean age was 58 years (range, 42–71 years). All had documented metastatic breast cancer in their liver that was symptomatic. Symptoms of hepatic metastases included right upper quadrant pain, hepatomegaly, lethargy, and mass effect from the enlarged liver. In all, 29 patients (66%) had disease elsewhere, in either the nodes or bone, but none had brain metastases. Of the patients with extrahepatic metastases, 20 had nodal metastases and 16 osseous metastases, and 7 had both. The patients with extrahepatic metastases had liverdominant disease with the metastases documented in the nodes or bones via PET scanning (Table 1). All patients had received doxorubicin and docetaxel in prior treatment. Twelve (27%) were reported to be positive for human epidermal growth factor 2, with 10 of these patients having received trastuzumab. In all, 31 patients (70%) were positive for estrogen receptors and had received hormonal therapy. A total of 32 patients had failed chemotherapy, having had at least three lines of chemotherapy with recurrent and intractable disease. Of these 32 patients, 8 had failed to respond to trastuzumab. The remaining 12 patients had received one or two chemotherapeutic regimens and needed treatment of liver metastases while on a treatment break from chemotherapy.
Total patients 44 Age (y) 58 (range, 42–71) Patients receiving whole-liver treatments 23 Patients receiving sequential lobar treatments 21 Total treatments 63 HER2 positive 12 Trastuzumab received 10 Estrogen-receptor positive 31 Failed three lines of chemotherapy 32 Had trastuzumab 8 Chemotherapy hiatus with development of liver 12 metastases Had trastuzumab 2 Alive at mean follow-up of 14 months 38 Dead at mean follow-up of 14 months 6 Failed chemotherapy 5 Had trastuzumab 1 Chemotherapy hiatus 1 Estrogen-receptor positive 2 Liver-exclusive disease 15 Liver-dominant disease 29 Extrahepatic disease Nodal metastases 20 Osseous metastases 16 Both 7 Imaging 12-week CT scans available 36 6- or 12-week PET scans available 40 Response CT scan at 12 weeks CR in liver 0 PR in liver 17 (47%) Stable disease in liver 17 (47%) Progressive disease in liver 2 (6%) PET scan at 12 weeks CR in liver 7 (17%) PR in liver 23 (58%) Stable disease in liver 8 (20%) Progressive disease in liver 2 (5%) Survivors Extrahepatic metastases 24 (63%) Nodal metastases 18 (47%) Osseous metastases 12 (32%) Both 6 (16%) Abbreviations: CR = complete response; CT = computed tomography; HER2 = human epidermal growth factor 2; PET = positron emission tomography; PR = partial response.
After signing informed consent, all patients received at least lobar infusion, with 23 receiving whole-liver treatment. The other 21 patients received sequential lobar infusions of the radioactive embolic therapy. Radiation There was a wide range of delivered activities for lobar and whole-liver treatments, with a median 2.1 GBq activity delivered. Early in the experience with microspheres (11–14), sequential treatment of the right lobe followed by the left lobe in 30 days was preferred in an attempt to decrease acute toxicity. However it has now become common to deliver whole-liver treatment initially to any patient with bilobar disease.
Yttrium-90 microspheres in hepatic metastases from breast cancer d D. M. COLDWELL et al.
Toxicity Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days post-treatment) were evaluated for all patients based on the CTCAE criteria. All patients reported mild to moderate postembolization syndrome of nausea, vomiting, fever, and mild right upper quadrant pain, which was treated symptomatically. Eight patients (18%) were hospitalized for 1 night, whereas 36 (86%) were treated as outpatients. There were no occurrences of veno-occlusive disease or occlusion of the portal vein. Grade 3 gastrointestinal toxicity occurred in 7 patients with the appearance of nausea or vomiting. Two patients had documented stomach ulcers, which resolved on medical therapy. No patient required surgery. Imaging response All patients underwent a three-phase abdominal CT scan post-treatment to measure response to therapy. Because this was not a prospective trial and a number of imaging centers across the US were used, unavoidable heterogeneity in the quality and scanning parameters was present. Bi-dimensional measurements of the largest tumors were made and the Response Evaluation Criteria for Solid Tumors (RECIST) applied. Among the 44 patients, CT scans at week 12 post microspheres were available for review in 36 patients (82%), and PET scans at either week 6 or week 12 post-therapy in 40 (91%). Partial responses were found on CT in 17 (47%), stable disease or minor response in 17 (47%), and progressive disease in 2 patients (5%) at 12 weeks post-treatment. The PET scans showed response in 42 (95%) and no response or progression in 2 (5%). The CT scans were available for review at 6 and 12 months post-treatment in 29 and 20 patients, respectively. On sequential review of these available CT scans, it was noted that the maximal response occurred, similar to the treatment of colorectal metastases, at 12 weeks post-treatment, with no new or significant tumor reduction or responses developing in the previously documented lesions beyond that time. The bi-dimensional measurements of the largest tumors of each patient were unchanged after the 12-week mark. Also, no additional late side effects occurred (i.e., ascites, portal hypertension, or occlusion) beyond 12 weeks in the absence of tumor progression in the liver or abdomen. Survival In the 6 patients who did not experience a measurable response in PET or CT scan by 6 weeks post-treatment, survival was short (median, 3.6 months). However responders and those with slowly progressing tumors experienced a longer survival, which, with a follow-up of 14 months (range, 1–42 months), has not yet reached the mean survival. A total of 38 patients (86%) are alive at 14 months, with the six deaths caused by brain metastases in 5 patients (11%) and recurrent liver metastatic disease in 3 (7%). Simultaneous brain and liver metastases were present in 2 of the patients who died. Of patients who died, 5 had failed chemotherapy and 1 had failed trastuzumab. Two of these 6 deceased patients were also estrogen receptor negative. Of the patients in the
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longer survival group, 24 (63%) have either nodal or osseous metastases. DISCUSSION Treatment of hepatic metastases predominantly from gastrointestinal tumors has a long history of using brachytherapy. There are early reports using implanted isotopes from a number of sources but, only recently, has the treatment begun to rely more on the intra-arterial delivery of the particles or spheres. Early data demonstrated the safety of using 90Y as the treating agent, with more recent data obtained from reports written in the last 5 years (11–21). The authors of the current report were the first to use both yttrium-based microsphere products; however, only the resin-based product (SIRSpheres, Sirtex, Inc., Sydney, Australia) were used in the treatment of the patients reported herein. The incidence of liver metastases found during laparotomy on patients with breast cancer is reported to be 35% (23). Autopsy studies and examination of large patient registries also arrive at an incidence of hepatic metastases in 35% to 61% of patients developing these tumors (24, 25) However the presence of liver metastases at the time of first diagnosis is less common, observed in 5% to 20% of cases (25). Treatment of these metastatic deposits is usually through the use of systemic chemotherapy with hormone receptor positive patients responding better to treatment (24). Even though the loco-regional approach to the treatment of hepatic metastases from breast cancer is not widely used, Eichbaum et al. demonstrated that the implantation of hepatic pumps for intra-arterial infusion of chemotherapy after hepatic resection for these tumors results in improvement in survival (26–28). Patients receiving either loco-regional or systemic treatment also developed brain, nodal, and osseous metastases over time. All these metastases were noted on angiography to be hypervascular. Because they are also relatively slow growing, these tumors should be ideal candidates for 90Y microsphere therapy. Previous experience with both metastatic colorectal carcinoma and neuroendocrine tumors has shown that these two characteristics are likely to obtain the best results (14, 20). Patients who are candidates to receive 90Y SIR-Spheres were those having liver-dominant but not necessarily liverexclusive disease. The patients receiving the 90Y SIR-Spheres showed an improvement in their symptoms; and because the survival of patients with advanced breast cancer with standard chemotherapy is 14 months (the median follow-up with this series), it is expected that these patients will demonstrate an increase in their overall survival, as they have not reached their median survival even at 14 months. The complications were few in this series, with a small number of patients having Grade 3 toxicity but with no surgery or deaths resulting. All of these gastrointestinal complications resolved on medical therapy and did not seriously interfere with the patients’ quality of life. Follow-up of treatment in these patients has been predominantly via cross-sectional imaging with CT and use of the RECIST criteria. Because this is an anatomic imaging
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modality, not a functional one, the response of the tumor is underestimated when the CT is compared with the FDG-PET scanning. In addition, these imaging response criteria do not take into account the rapidity of the cell death and the time lag for remodeling of the liver, which also results in underestimation of the response. Consequently, the authors believe that an accurate evaluation of the response of the tumor to this therapy is best obtained using FDG-PET scanning, which demonstrated a high degree of response and appears to be well demonstrated by the survival of the patients in this series. This is a promising new therapy that has demonstrated utility in the treatment of many differing histologies of tumor. Use of 90Y microspheres in the treatment of hepatic tumors
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from breast cancer was expected to be efficacious because the tumors are uniformly hypervascular and usually slow growing. This combination of factors promotes efficacy in this therapy, as there are more tumor arterioles in which the spheres can lodge, and the dose administered to the tumor is consequently larger. CONCLUSION In conclusion, this small series demonstrates the efficacy of this therapy when applied to breast cancer metastases, both in chemotherapy-refractory disease and during a treatment hiatus, and warrants further investigation.
REFERENCES 1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30. 2. Viadana E, Bross IDJ, Pickren JW. An autopsy study of some routes of dissemination of cancer of the breast. Br J Cancer 1973;27:336. 3. Goldberg RM, Gill S. Recent phase III trials of fluorouracil, irinotecan, and oxaliplatin as chemotherapy for metastatic colorectal cancer. Cancer Chemother Pharmacol 2004;54(Suppl. 1): S57–S64. 4. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30. 5. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil–leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–1214. 6. Kato I, Severson RK, Schwartz AG. Conditional median survival of patients with advanced carcinoma: Surveillance, Epidemiology, and End Results data. Cancer 2001;92:2211–2219. 7. Gray BN, Anderson JE, Burton MA, et al. Regression of liver metastases following treatment with yttrium-90 microspheres. Aust N Z J Surg 1992;62:105–110. 8. Stubbs RS, Cannan RJ, Mitchell AW. Selective internal radiation therapy (SIRT) with 90Yttrium microspheres for extensive colorectal liver metastases. Hepato-Gastroenterology 2001;48: 333–337. 9. Lau WY, Leung WT, Ho S, et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: A phase I and II study. Br J Cancer 1994;70:994–999. 10. 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. 11. Kennedy AS, Murthy R, Sarfaraz M, et al. Outpatient hepatic artery brachytherapy for primary and secondary hepatic malignancies. Radiology 2001;221P:468. 12. Kennedy AS, Murthy R, Van Echo DA. Preliminary results of outpatient hepatic artery brachytherapy for colorectal hepatic metastases. Eur J Cancer 2001;37:289. 13. Van Echo DA, Kennedy AS, Coldwell D. TheraSphere (TS) at 143 Gy median dose for mixed hepatic cancers; feasibility and toxicities. Am Soc Clin Oncol 2001;260a:1038. 14. Coldwell D, Kennedy AS, Van Echo DA, et al. Feasibility of treatment of hepatic tumors utilizing embolization with yttrium-90 glass microspheres. J Vasc Interv Radiol 2001;12: S113.
15. Andrews JC, Walker SC, Ackermann RJ, et al. Hepatic radioembolization with yttrium-90 containing glass microspheres: Preliminary results and clinical follow-up. J Nucl Med 1994; 35:1637–1644. 16. Dancey JE, Shepherd FA, Paul K, et al. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y microspheres [in process citation]. J Nucl Med 2000;41: 1673–1681. 17. Murthy R, Kennedy AS, Coldwell D, et al. Technical aspects of TheraSphere (TS) infusion. J Vasc Interv Radiol 2002;13:S2. 18. Murthy R, Kennedy AS, Tucker G, et al. Outpatient trans arterial hepatic ‘low dose rate’ (TAH-LDR) brachytherapy for unresectable hepatocellular carcinoma. Proc Am Assoc Cancer Res 2002;43:485. 19. Murthy R, Line BR, Kennedy AS, et al. Clinical utility of Brehmstralung scan (BRM-Scan) after TheraSphere (TS). J Vasc Interv Radiol 2002;13:S2. 20. Kennedy A, Coldwell D, Nutting C, et al. Resin 90Y microsphere brachytherapy for unresectable colorectal liver metastases: Modern USA experience. Int J Radiat Oncol Biol Phys 2006;65:412. 21. Coldwell DM, Sewell PE. The expanding role of interventional radiology in the supportive care of the oncology patient: From diagnosis to therapy. Semin Oncol 2005;32:169–173. 22. Cancer Therapy Evaluation Program. December 12, 2003. Available at: http://ctep.cancer.gov. Accessed February 1, 2007. 23. Nemato T, Dao TL. Significance of liver metastases in women with disseminated breast cancer undergoing endocrine ablative surgery. Cancer 1966;19:421. 24. Jardines L, Callans LS, Torosian MH. Recurrent breast cancer: Presentation, diagnosis, and treatment. Semin Oncol 1993;20: 538–547. 25. Pentheroudakis G, Fountzilas G, Bafaloukos D, et al. Metastatic breast cancer with liver metastases: A registry analysis of clinicopathologic, management and outcome characteristics of 500 women. Breast Cancer Res Treatment 2005;97:237–244. 26. Eichbaum MHR, Kaltwasser M, Bruckner T, et al. Prognostic factors for patients with liver metastases from breast cancer. Breast Cancer Res Treat 2006;96:53–62. 27. Elias D, Maisonnette F, Druet-Cabanac M, et al. An attempt to clarify indications for hepatectomy for liver metastases from breast cancer. Am J Surg 2003;185:158–164. 28. Vlastos G, Smith DL, Singletary E, et al. Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases. Ann Surg Oncol 2004;11:869–874.
doi:10.1016/j.ijrobp.2007.03.056
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USE OF YTTRIUM-90 MICROSPHERES IN THE TREATMENT OF UNRESECTABLE HEPATIC METASTASES FROM BREAST CANCER DOUGLAS M. COLDWELL, PH.D., M.D., F.S.I.R.,* ANDREW S. KENNEDY, M.D., F.A.C.R.O.,y z AND CHARLES W. NUTTING, D.O. * Department of Radiology, University of Mississippi Medical Center, Jackson, MS; y Wake Radiology Oncology, Cary, NC; and z Sky Ridge Medical Center, Lone Tree, CO Purpose: Therapy for patients with unresectable liver metastases from breast cancer that were refractory to multiple treatment regimens was performed using radioactive microspheres. High doses of radiation were delivered to tumors from these permanently implanted yttrium-90 (90Y) microspheres, delivered through the hepatic arterial vessels. Methods and Materials: Women from three institutions were selected for treatment, after screening that demonstrated vascular access to all tumors and after imaging confirmed that microspheres would be implanted only in the liver tumors. All patients were followed with laboratory and imaging studies at regular intervals until death. Toxicities, both acute and late were recorded, and actuarial survival determined. Results: A total of 44 women were treated from April 2002 to April 2005. Median follow-up of these women was 14 months (1–42 months). No treatment-related procedure deaths or radiation related veno-occlusive liver failures were found. Computed tomographic imaging partial response was 47% and positron emission tomographic response 95%. Conclusion: In this group of heavily pretreated patients, radioactive microspheres produced an encouraging median survival, with acceptable toxicity and a significant objective response rate, suggesting that further investigation of this approach is warranted. Ó 2007 Elsevier Inc. Liver, Yttrium, Microsphere, Breast, Brachytherapy.
In the United States in 2006, breast cancer is expected to be diagnosed in an estimated 213,000 patients (1). The percentage of patients who will eventually develop metastatic disease in the liver is less well known but is believed to be at least 60%, or 127,000 individuals (2). Tumors in the liver are approachable by potentially curative surgery in only a select group of these patients who do not have other sites of metastatic disease. However, the disease in the liver is the lifespan-limiting site of disease in most cases, whereas metastases to the brain account for the death of many of the remaining patients. Among those who do undergo curative liver resection, 5-year survival rates range from 25% to 38%; but 60% to 90% of these patients will ultimately develop recurrent liver metastases. Chemotherapy, which for decades was mostly limited to doxorubicin, resulted in poor response
and survival rates when used alone for metastatic disease in the liver. The introduction of taxanes and herceptin now offers a dramatic and long hoped-for improvement against advanced metastatic breast cancer (3–5). Yet despite these significant gains, metastatic breast cancer is almost always fatal, with up to 60% of patients dying of liver failure caused by local effects of hepatic tumors. Surveillance, Epidemiology, and End Results (SEER) data reveal that, once breast cancer is metastasized, the median survival of patients with this disease is 18.5 months, compared with 7.5 months for colorectal cancer and 24.5 months for prostate cancer (6). A number of liver-directed therapies are now available including radiofrequency or microwave ablation, cryotherapy, and direct chemical injection. These techniques are effective only in patients who have a limited number of tumors. For patients with larger numbers, particularly of small tumors, the hepatic arterial therapies of hepatic arterial embolization
Reprint requests to: Douglas M. Coldwell, M.D., 4629 Livingston Avenue, Dallas, TX 75209. Tel: (214) 356-0443; Fax: (214) 350-2957; E-mail: [email protected] Dr. Coldwell is currently affiliated with Coldwell Associates, Dallas, TX. Conflict of interest: D. M. Coldwell, A. S. Kennedy, and C. W.
Nutting have received honoraria for lectures and training provided on microsphere therapy from Sirtex, Inc., which is the manufacturer of the microspheres used in the patients in this report. They do not have any other financial arrangements with Sirtex. Received Jan 16, 2007, and in revised form Feb 22, 2007. Accepted for publication March 31, 2007.
INTRODUCTION
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Yttrium-90 microspheres in hepatic metastases from breast cancer d D. M. COLDWELL et al.
and chemoembolization may be more effective. However, no controlled studies have been performed with these modalities. In addition, in the opinion of the current investigators, these modalities are variably effective, given the nature of the procedure, because they are so operator sensitive and are effective in palliation of symptoms only. Radiotherapy has become more effective in destroying breast tumors, typically with combined chemotherapy (usually 5-fluorouracil [5FU] at doses >50 Gy) because of the technologic advances in treatment planning and delivery. However, three-dimensional radiotherapy, intensity-modulated radiotherapy, and stereotactic radiotherapy 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, estimated at $70 Gy. An alternate approach is implantation of radiation sources into the tumor, i.e., brachytherapy, using yttrium-90 (90Y) microspheres (7–16). This report presents a review of our institutions’ experience, and represents the largest number and longest follow-up of patients treated with 90Y microspheres in liver brachytherapy for metastatic breast cancer.
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uncorrectable delivery to the GI tract; reverse blood flow out of the liver, or complete portal vein thrombosis.
Radioactive material Yttrium-90 is a pure beta emitter, which decays to stable zirconium-90 with an average energy of 0.94 MeV via a half-life of 2.67 days (64.2 h). It is produced by neutron bombardment of 89 Y in a commercial reactor, yielding 90Y beta radiation with a mean tissue penetration of 2.5 mm, and a maximum range of 1.1 cm. A 1-GBq (27 mCi) quantity of 90Y delivers a total dose of 50 Gy/Kg in tissue. Although two commercially available radioactive microspheres are on the market in North America, a glass (TheraSphere, MDS Nordion, Inc., Ontario, Canada) and a resin (SIR-Spheres, SIRTex Medical Limited, Sydney, Australia) product using 90Y that is permanently embedded within the glass or resin structure, only the resin product was used for these patients, as it is the only microsphere product to have full approval from the Food and Drug Administration and consequently can be used on an ‘‘off-label’’ manner. Each resin sphere has a diameter of 32 10 mm, causing them to be permanently embolized in terminal arterioles, that is, within the tumor. No significant amount of 90 Y leaches in the patient from the resin spheres. A standard dose of resin microspheres is 2 GBq containing approximately 50 million microspheres (range, 40–80 million) with a dose per microsphere estimated to be 50 Bq. Radiation treatment planning and dose delivery are identical with that of treatment of other tumor types and have been well described previously (20).
Patient selection Several reports in abstract form have been published regarding delivery of microspheres for colorectal hepatic metastases (11–14, 17–21). This report is limited to resin microspheres that are fully cleared by the Food and Drug Administration (FDA), indicated for colorectal cancer, and used in an off-label fashion, with data collected retrospectively without the institutions following a prescribed protocol. Approval from the institutional review board was obtained for retrospective review of the patient data. It was the intent of the treating team to accept patients for therapy who had already received and failed standard first-, second-, or third-line therapies for their primary tumor and needed intervention to address their liver metastases. Evaluation of patients by Medical Oncology, Radiation Oncology, and Interventional Radiology were completed before acceptance for microsphere treatment. By consensus, they were not candidates for radiofrequency ablation, transarterial chemoembolization, resection, intensity-modulated radiation therapy, or stereotactic radiotherapy. In addition, careful review of screening tests—in particular nuclear medicine and body computed tomography (CT) or magnetic resonance imaging (MRI)—required significant consultations with subspecialist physicians in those disciplines. All patients were selected according to strict inclusion/exclusion criteria. Eligible patients were $18 years of age; of any race; who had a confirmed diagnosis of breast cancer; with measurable unresectable disease predominately involving the liver; who were able to give informed consent; with a European Organisation for Research and Treatment of Cancer (ECOG) performance status score of #2; adequate bone marrow (granulocytes >1500/ml, platelets >60,000/ml); hepatic (total bilirubin #2.0 mg/dl) SGOT/SGPT or alkaline phosphatase <5 times the upper limit of normal; pulmonary function (forced expiratory volume in 1 s [FEV1]>1 L); and no contraindications to angiography and selective visceral catheterization. In addition, absolute contraindications included pulmonary shunt >20% of technetium99m–labeled macroaggregated albumin (99mTc-MAA) or any
Imaging studies All patients were evaluated via chest, abdomen, and pelvic CT scans (MRI was also used but few patients had them) to detect extrahepatic metastases and to determine liver tumor location, size, and number. All scans of the abdomen were three-phase, performed with oral and intravenous contrast, with slice thickness #7 mm through the abdomen. Some patients began undergoing fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning after July 1, 2001, pre- and post-treatment as their insurance coverage and referring physicians would allow. Response to treatment was judged as follows: Complete response (CR): All lesions from the pretreatment CT or MRI were not seen on the 12-week follow-up CT/MRI. For PET scans, all detected accumulations of FDG were eliminated. Partial response (PR): A 50% decrease in tumor number or size by one measurement or necrosis of most lesions as determined by water-equivalent Hounsfield unit values in the center of a lesion. For PET scans, this is a decrease in the most intense area of uptake by 25%. Stable disease: less than 50% response of lesions or less than 25% growth in number or size of lesions. For PET scans, this is less than a 25% decrease in uptake of the most intense lesion. Progressive disease: Growth of more than 25% in number or size of any lesion without necrosis at the 12-week post-treatment follow-up scan. The PET scan response criteria were not uniform but were typically used to evaluate response at 12 weeks post-treatment, compared with a pretreatment study performed within 4 weeks before the treatment. In addition, hepatic arteriography with 99mTc MAA embolization of the liver–lung shunt was performed as well documented elsewhere (20). Pretreatment embolization of the gastroduodenal artery, right gastric artery, and any other artery serving the stomach or duodenum was performed to ensure that any hollow viscus was protected from radioembolization.
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Table 1. Results in study patients
Dosimetry The dose of the 90Y SIR-Spheres was determined by using the body surface area formula given in the user’s manual: Dose ¼ BSA of the patient 0:2 þ % tumor burden: This dose, given in gigabecquerels, is used to treat the entire liver (whole liver treatment dose). For patients in whom a lobar approach is used, the dose is then proportional to the volume of the treated lobe to the entire liver. Such a dose is applied intra-arterially on the treatment date to either the entire liver or to a single lobe, usually 10 to 14 days after the screening arteriogram was obtained. If lobar treatment was used in a patient with bilobar disease, the patient returned for treatment of the other diseased lobe approximately 1 month later.
Toxicity Patients were followed closely until all acute toxicities were resolved, or at least every 2 weeks for 6 weeks, then monthly for 3 months to observe for possible radiation hepatitis or other toxicities. Acute events were those that occurred within 30 days of treatment and late effects were defined as occurring 31 to 90 days post-treatment. The National Cancer Institute’s Common Terminology Criteria for Adverse Events v 3.0 (CTCAE) (22) was used as appropriate.
Statistical analysis Survival was calculated as the number of elapsed days starting from the day of first microsphere treatment until death. Patients who were lost to follow-up were censured as of the day of last follow-up, as were those who received other treatments.
RESULTS Patients A total of 44 women were treated in this study. Their mean age was 58 years (range, 42–71 years). All had documented metastatic breast cancer in their liver that was symptomatic. Symptoms of hepatic metastases included right upper quadrant pain, hepatomegaly, lethargy, and mass effect from the enlarged liver. In all, 29 patients (66%) had disease elsewhere, in either the nodes or bone, but none had brain metastases. Of the patients with extrahepatic metastases, 20 had nodal metastases and 16 osseous metastases, and 7 had both. The patients with extrahepatic metastases had liverdominant disease with the metastases documented in the nodes or bones via PET scanning (Table 1). All patients had received doxorubicin and docetaxel in prior treatment. Twelve (27%) were reported to be positive for human epidermal growth factor 2, with 10 of these patients having received trastuzumab. In all, 31 patients (70%) were positive for estrogen receptors and had received hormonal therapy. A total of 32 patients had failed chemotherapy, having had at least three lines of chemotherapy with recurrent and intractable disease. Of these 32 patients, 8 had failed to respond to trastuzumab. The remaining 12 patients had received one or two chemotherapeutic regimens and needed treatment of liver metastases while on a treatment break from chemotherapy.
Total patients 44 Age (y) 58 (range, 42–71) Patients receiving whole-liver treatments 23 Patients receiving sequential lobar treatments 21 Total treatments 63 HER2 positive 12 Trastuzumab received 10 Estrogen-receptor positive 31 Failed three lines of chemotherapy 32 Had trastuzumab 8 Chemotherapy hiatus with development of liver 12 metastases Had trastuzumab 2 Alive at mean follow-up of 14 months 38 Dead at mean follow-up of 14 months 6 Failed chemotherapy 5 Had trastuzumab 1 Chemotherapy hiatus 1 Estrogen-receptor positive 2 Liver-exclusive disease 15 Liver-dominant disease 29 Extrahepatic disease Nodal metastases 20 Osseous metastases 16 Both 7 Imaging 12-week CT scans available 36 6- or 12-week PET scans available 40 Response CT scan at 12 weeks CR in liver 0 PR in liver 17 (47%) Stable disease in liver 17 (47%) Progressive disease in liver 2 (6%) PET scan at 12 weeks CR in liver 7 (17%) PR in liver 23 (58%) Stable disease in liver 8 (20%) Progressive disease in liver 2 (5%) Survivors Extrahepatic metastases 24 (63%) Nodal metastases 18 (47%) Osseous metastases 12 (32%) Both 6 (16%) Abbreviations: CR = complete response; CT = computed tomography; HER2 = human epidermal growth factor 2; PET = positron emission tomography; PR = partial response.
After signing informed consent, all patients received at least lobar infusion, with 23 receiving whole-liver treatment. The other 21 patients received sequential lobar infusions of the radioactive embolic therapy. Radiation There was a wide range of delivered activities for lobar and whole-liver treatments, with a median 2.1 GBq activity delivered. Early in the experience with microspheres (11–14), sequential treatment of the right lobe followed by the left lobe in 30 days was preferred in an attempt to decrease acute toxicity. However it has now become common to deliver whole-liver treatment initially to any patient with bilobar disease.
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Toxicity Acute toxicity (within 30 days of treatment) and late toxicity (31–90 days post-treatment) were evaluated for all patients based on the CTCAE criteria. All patients reported mild to moderate postembolization syndrome of nausea, vomiting, fever, and mild right upper quadrant pain, which was treated symptomatically. Eight patients (18%) were hospitalized for 1 night, whereas 36 (86%) were treated as outpatients. There were no occurrences of veno-occlusive disease or occlusion of the portal vein. Grade 3 gastrointestinal toxicity occurred in 7 patients with the appearance of nausea or vomiting. Two patients had documented stomach ulcers, which resolved on medical therapy. No patient required surgery. Imaging response All patients underwent a three-phase abdominal CT scan post-treatment to measure response to therapy. Because this was not a prospective trial and a number of imaging centers across the US were used, unavoidable heterogeneity in the quality and scanning parameters was present. Bi-dimensional measurements of the largest tumors were made and the Response Evaluation Criteria for Solid Tumors (RECIST) applied. Among the 44 patients, CT scans at week 12 post microspheres were available for review in 36 patients (82%), and PET scans at either week 6 or week 12 post-therapy in 40 (91%). Partial responses were found on CT in 17 (47%), stable disease or minor response in 17 (47%), and progressive disease in 2 patients (5%) at 12 weeks post-treatment. The PET scans showed response in 42 (95%) and no response or progression in 2 (5%). The CT scans were available for review at 6 and 12 months post-treatment in 29 and 20 patients, respectively. On sequential review of these available CT scans, it was noted that the maximal response occurred, similar to the treatment of colorectal metastases, at 12 weeks post-treatment, with no new or significant tumor reduction or responses developing in the previously documented lesions beyond that time. The bi-dimensional measurements of the largest tumors of each patient were unchanged after the 12-week mark. Also, no additional late side effects occurred (i.e., ascites, portal hypertension, or occlusion) beyond 12 weeks in the absence of tumor progression in the liver or abdomen. Survival In the 6 patients who did not experience a measurable response in PET or CT scan by 6 weeks post-treatment, survival was short (median, 3.6 months). However responders and those with slowly progressing tumors experienced a longer survival, which, with a follow-up of 14 months (range, 1–42 months), has not yet reached the mean survival. A total of 38 patients (86%) are alive at 14 months, with the six deaths caused by brain metastases in 5 patients (11%) and recurrent liver metastatic disease in 3 (7%). Simultaneous brain and liver metastases were present in 2 of the patients who died. Of patients who died, 5 had failed chemotherapy and 1 had failed trastuzumab. Two of these 6 deceased patients were also estrogen receptor negative. Of the patients in the
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longer survival group, 24 (63%) have either nodal or osseous metastases. DISCUSSION Treatment of hepatic metastases predominantly from gastrointestinal tumors has a long history of using brachytherapy. There are early reports using implanted isotopes from a number of sources but, only recently, has the treatment begun to rely more on the intra-arterial delivery of the particles or spheres. Early data demonstrated the safety of using 90Y as the treating agent, with more recent data obtained from reports written in the last 5 years (11–21). The authors of the current report were the first to use both yttrium-based microsphere products; however, only the resin-based product (SIRSpheres, Sirtex, Inc., Sydney, Australia) were used in the treatment of the patients reported herein. The incidence of liver metastases found during laparotomy on patients with breast cancer is reported to be 35% (23). Autopsy studies and examination of large patient registries also arrive at an incidence of hepatic metastases in 35% to 61% of patients developing these tumors (24, 25) However the presence of liver metastases at the time of first diagnosis is less common, observed in 5% to 20% of cases (25). Treatment of these metastatic deposits is usually through the use of systemic chemotherapy with hormone receptor positive patients responding better to treatment (24). Even though the loco-regional approach to the treatment of hepatic metastases from breast cancer is not widely used, Eichbaum et al. demonstrated that the implantation of hepatic pumps for intra-arterial infusion of chemotherapy after hepatic resection for these tumors results in improvement in survival (26–28). Patients receiving either loco-regional or systemic treatment also developed brain, nodal, and osseous metastases over time. All these metastases were noted on angiography to be hypervascular. Because they are also relatively slow growing, these tumors should be ideal candidates for 90Y microsphere therapy. Previous experience with both metastatic colorectal carcinoma and neuroendocrine tumors has shown that these two characteristics are likely to obtain the best results (14, 20). Patients who are candidates to receive 90Y SIR-Spheres were those having liver-dominant but not necessarily liverexclusive disease. The patients receiving the 90Y SIR-Spheres showed an improvement in their symptoms; and because the survival of patients with advanced breast cancer with standard chemotherapy is 14 months (the median follow-up with this series), it is expected that these patients will demonstrate an increase in their overall survival, as they have not reached their median survival even at 14 months. The complications were few in this series, with a small number of patients having Grade 3 toxicity but with no surgery or deaths resulting. All of these gastrointestinal complications resolved on medical therapy and did not seriously interfere with the patients’ quality of life. Follow-up of treatment in these patients has been predominantly via cross-sectional imaging with CT and use of the RECIST criteria. Because this is an anatomic imaging
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modality, not a functional one, the response of the tumor is underestimated when the CT is compared with the FDG-PET scanning. In addition, these imaging response criteria do not take into account the rapidity of the cell death and the time lag for remodeling of the liver, which also results in underestimation of the response. Consequently, the authors believe that an accurate evaluation of the response of the tumor to this therapy is best obtained using FDG-PET scanning, which demonstrated a high degree of response and appears to be well demonstrated by the survival of the patients in this series. This is a promising new therapy that has demonstrated utility in the treatment of many differing histologies of tumor. Use of 90Y microspheres in the treatment of hepatic tumors
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from breast cancer was expected to be efficacious because the tumors are uniformly hypervascular and usually slow growing. This combination of factors promotes efficacy in this therapy, as there are more tumor arterioles in which the spheres can lodge, and the dose administered to the tumor is consequently larger. CONCLUSION In conclusion, this small series demonstrates the efficacy of this therapy when applied to breast cancer metastases, both in chemotherapy-refractory disease and during a treatment hiatus, and warrants further investigation.
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