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Radioembolization of Liver Metastases From Colorectal Cancer Using Yttrium-90 Microspheres With Concomitant Systemic Oxaliplatin, Fluorouracil, and Leucovorin Chemotherapy

Ricky A. Sharma, Guy A. Van Hazel, Bruno Morgan, David P. Berry, Keith Blanshard, David Price, Geoffrey Bower, Jennifer A. Shannon, Peter Gibbs, William P. Steward

From the Department of Radiation Oncology and Biology, University of Oxford, Churchill Hospital, Oxford; Departments of Oncology, Radiology, and Surgery, University Hospitals of Leicester, Leicester, UK; Perth Oncology, Mount Medical Centre, Perth, NSW; Medical Oncology, Nepean Hospital, Sydney; and the Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, Australia

Address reprint requests to Ricky Sharma, MD, PhD, Radiation Oncology and Biology, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; e-mail: ricky.sharma{at}rob.ox.ac.uk

	ABSTRACT

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Purpose Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)—containing the ß-emitter, yttrium-90—into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX).

Patients and Methods A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m²) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity.

Results Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months.

Conclusion The maximum-tolerated dose was 60 mg/m² of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.

	INTRODUCTION

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The development of liver metastases from any solid malignancy heralds a poor prognosis, unless the disease is amenable to surgical resection. For patients diagnosed with colorectal carcinoma (CRC), the majority of deaths are attributable to hepatic metastases.¹ Although significant advances have occurred in surgical techniques, only 10% to 20% of patients with liver metastases from CRC are candidates for potentially curative surgical resection.^2-5

Radioembolization (RE) is a technique that has been developed to target multiple sites of disease within the liver in a single procedure. It has been administered to more than 4,500 patients since 1987. RE involves the vascular injection of embolic particles loaded with radionuclide, such as SIR-Spheres (Sirtex Medical Limited, Sydney, Australia), which contain the pure ß-emitter, yttrium-90. The microspheres, with a mean diameter of 32 µm, lodge in malignant microvasculature.⁶ Since RE delivers high doses of ionizing radiation to the tumor compartment while maintaining radiation exposure of the normal liver to a tolerable level, it can be regarded as a form of brachytherapy, and it also has been termed selective internal radiotherapy.^7,8 The physical half-life of yttrium-90 is 64.1 hours.

A significant advance in the systemic treatment of CRC has been the addition of oxaliplatin to infusional fluorouracil (FU) and leucovorin (LV).^9-11 Oxaliplatin is a diaminocyclohexane-platinum compound that forms bulky, hydrophobic DNA adducts within cells and demonstrates cytotoxic synergy with FU in preclinical models.¹⁰ Large-scale phase III trials of the combination of oxaliplatin, FU, and LV (FOLFOX) as first-line treatment for patients with metastatic CRC have demonstrated median progression-free survival (PFS) of 7 to 9.2 months.^11-14 This combination of drugs is currently an international standard first-line treatment for patients with metastatic CRC.

Like other platinum compounds used routinely in chemoradiation treatment of cancers of the cervix, head, neck, and esophagus, oxaliplatin is a radiosensitizer to cancer cells grown in vitro.^15,16 The combination of FOLFOX and external-beam radiation (total dose 45 to 50.4 Gy) has been assessed in phase I and II studies in rectal cancer and esophageal cancer with documentation of toxicities at dose levels of oxaliplatin more than 60 mg/m².^17-19

Based on data suggesting that the combination of RE and concomitant FU and LV chemotherapy is well-tolerated by patients with metastatic CRC,²⁰ we designed a phase I study to assess the tolerability of RE with concomitant FOLFOX chemotherapy. On account of the risk of radiosensitization of normal tissues by oxaliplatin,^15-19 reduced doses of this drug were used for the first three cycles compared to full-dose FOLFOX4 chemotherapy (see Study Design and Protocol Treatment) in the first two dose levels of the trial.

	PATIENTS AND METHODS

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Patients and Baseline Investigations
Inclusion criteria were as follows: patients with histologically proven adenocarcinoma of the colon or rectum; unequivocal and measurable computed tomography (CT) evidence of liver metastases, which were not treatable by surgical resection or local ablation with curative intent (determined at multidisciplinary team meetings with hepatobiliary surgical representation) at the time of trial entry; age older than 18 years; WHO performance status of 0 to 2; serum bilirubin less than 18 µmol/L; serum albumin more than 30 g/L; and serum creatinine less than 150 µmol/L. Although extrahepatic metastases were permitted, patients with CNS metastases were excluded. Prior chemotherapy for metastatic CRC was not permitted, although patients were permitted to have previously received adjuvant chemotherapy (completed at least 6 months before trial entry) and/or pelvic radiotherapy following resection of the primary cancer. Exclusion criteria were as follows: evidence of ascites, cirrhosis, or portal hypertension; previous radiotherapy to the upper abdomen; and more than 20% arteriovenous shunting from liver to lungs on a technetium⁹⁹-labeled macro-aggregated albumin (MAA) nuclear scan (see Patients and Baseline Investigations).

Following institutional ethics committee approvals, patients were enrolled at four centers between July 2002 and March 2005: University Hospitals of Leicester (Leicester, UK), Mount Hospital (Perth, Australia), Nepean Hospital (Sydney, Australia), and Epworth Hospital (Melbourne, Australia). All patients were fully informed of the nature of the trial and signed an informed consent document. Treatment was approved by the UK Medicines Control Agency (London, United Kingdom) and the Administration of Radioactive Substances Advisory Committee. The trial conformed to the Australian National Health and Medical Research Council (Canberra, Australia) statement on human experimentation and to the World Medical Association Declaration (Helsinki, Finland).

Patients were required to have screening investigations performed within 29 days of protocol treatment. In addition to clinical examination and blood tests (full blood count, serum renal and liver function tests and carcino-embryonic antigen [CEA]), all patients underwent contrast-enhanced CT scanning, hepatic arteriography, and subsequent abdominal scintigraphy of the liver and lungs with technetium⁹⁹-labeled MAA. Based on a particle size similar to the resin microspheres, several studies have suggested that the MAA scan can predict the risk of radiation pneumonitis occurring after RE.^6,21,22 Accordingly, the radiation dose calculated from the formula provided later was decreased by 20% for liver-lung shunting of 11% to 15% (one patient) and decreased by 40% for shunting of 16% to 20% (two patients).

Study Design and Protocol Treatment
The study design was an open-label, nonrandomized phase I clinical trial with escalation of the oxaliplatin dose administered for the first three cycles (Table 1). All patients received a full dose of FU and LV as per the FOLFOX4 dose schedule,¹² and the full dose (85 mg/m²) of oxaliplatin was administered to patients at all dose levels from cycle 4 onward. Patients were serially recruited to the dose levels. Patients received a maximum of 12 cycles of protocol chemotherapy; each cycle was 14 days. A summary timescale for the first four cycles is presented in Table 2. Patients received oxaliplatin (30-85 mg/m² in 250 mL glucose 5%, administered as 2-hour IV infusion) on day 1 of each cycle. LV (200 mg/m² in 250 mL glucose 5%, administered as 2-hour IV infusion) was administered concurrently with the oxaliplatin infusion via a separate intravenous line on days 1 and 2 of each cycle. As soon as the LV infusion was complete, a bolus of FU (400 mg/m²) was administered followed immediately by a 22-hour continuous infusion (600 mg/m²) via a long intravenous catheter. Patients received ondansetron (8 mg orally twice daily) and dexamethasone (8 mg orally twice daily) for the first 3 days of every cycle.

(Equation 1:)

The percentage of tumor involvement was calculated from the baseline contrast-enhanced CT scan by a radiologist as the volume of tumor divided by the volume of liver (including tumor), based on a reproducible method.²³ The liver was scanned using helical CT after intravenous contrast bolus and images were reconstructed with 5 mm slices at 5 mm intervals. Using a CT workstation (Philips EasyVision, Philips Medical Systems, Reigate, United Kingdom), regions of interest (ROI) were created for each slice covering the whole liver and all visible tumor deposits for each imaged slice containing liver. The surface area of the whole liver ROI and the tumor ROIs were multiplied by the slice thickness and then summated for all liver slices to permit calculation of the percentage of tumor involvement.

Chemotherapy treatment was continued until dose-limiting toxicity (DLT) was experienced, disease progression was established, or consent was withdrawn. Patients were followed until death, unless consent was withdrawn. Toxicity was classified using the NCI Common Toxicity Criteria (version 3). DLT was defined as the occurrence of grade 3 or 4 toxicity in approximately 25% more patients than would be expected from FOLFOX4 chemotherapy alone (see Discussion). The maximum-tolerated dose was defined as the dose level immediately below the dose level at which DLT was observed. Empirical dosage modifications to chemotherapy in line with standard clinical care were permitted at the discretion of the investigators. Physical examination and blood tests were repeated every 2 weeks, except CEA measurement, which was performed every 4 weeks. CT scanning of chest, abdomen, and pelvis was repeated every 12 weeks. Response was measured by Response Evaluation Criteria in Solid Tumors Group criteria²⁴ and verified by an external, independent radiologist in a blinded fashion. In the retrospective review, splenic volume was estimated from CT scans by taking the product of the maximum diameter in the axial plane and the maximum diameters perpendicular to this plane.

Statistical Evaluation
Adverse events were recorded from baseline to such time as an alternative treatment was commenced after the conclusion of protocol chemotherapy. The adverse event profiles reported represent all clinical adverse events recorded in the case report forms. Comparison of splenic volumes was performed using Student's paired t test version 11 (SPSS Inc, Chicago, IL).

	RESULTS

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Twenty patients were enrolled onto the study. The characteristics of the study population are summarized in Table 3.

All patients who underwent angiographic evaluation were deemed suitable for RE. Details of RE procedures are presented in Table 4.

Of the nine patients treated at dose level 3, two suffered neither leukopenia nor neutropenia during protocol chemotherapy. Six patients developed grade 3 to 4 neutropenia within the first 6 weeks of therapy, not associated with sepsis. A seventh patient developed grade 4 neutropenia after the fourth cycle of protocol chemotherapy. The nadir in median neutrophil count (1.8 cells x 10⁹/L) occurred 2 weeks from commencement of protocol treatment. Significant lymphopenia was observed in median values 2 to 5 days after RE, with normalization of median values by the fourth week of protocol therapy.

On account of the potential for radiation hepatitis, changes in serum liver function tests and contrast-enhanced CT scans were analyzed. A transient reduction of attenuation coefficient related to a reduction in hepatic density was observed in one patient, without clinical sequelae. Analysis of splenic volume on CT scans after 6 months of protocol treatment demonstrated an increase of 92.4% ± 28.8% (mean ± standard deviation) compared to pretreatment baseline scans (P < .0001; N = 13). Transient grade 1 to 2 changes in liver function tests were observed in eight patients in dose levels 2 and 3 (Table 5). Eleven weeks into protocol therapy, one patient at dose level 3 developed transient elevation of ALTs and ASTs (both grade 3) with grade 1 hyperbilirubinemia. These levels returned to baseline over a 2-week period, and chemotherapy was continued.

Response to Treatment
Target lesions were measured on contrast-enhanced CT scans using Evaluation Criteria in Solid Tumors Group criteria. After 12 weeks of protocol treatment, partial responses were measured in 18 patients and stable disease in two patients. One patient had a complete response in liver metastases and a partial response in lung metastases. All patients with elevated serum CEA levels at baseline had decreases observed during protocol therapy; median levels decreased from 470 ng/mL pretreatment to 9 ng/mL after 6 months.

After 12 cycles of protocol chemotherapy, two patients were sufficiently downstaged to consider surgical resection of residual lesions evident on CT scans. One patient underwent a left lateral sectionectomy and a segmentectomy 6 from the right liver.²⁵ At the time of operation, splenomegaly and new collateral vessel formation were observed around the spleen, although there were no definite signs of increased portal pressure or ascites. Microscopic histological examination revealed fibrosis, dystrophic calcification, and mild chronic inflammation (Fig 1A). The other patient underwent right hepatectomy and segmentectomy 3 from the left liver (Fig 1B). There were no signs of portal hypertension. With regard to the detection of viable tumor cells on microscopic examination, the closest resection margins were 0.7 mm and 1.0 mm for the first and second patients, respectively. There were no postoperative clinical complications.

View larger version (123K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Microscopic pathology from two patients who underwent partial hepatic resection following radioembolization and 12 cycles of chemotherapy. (A) Hematoxylin and eosin (H&E) stain, 100 x magnification; figure shows microspheres in vascular spaces and fibrosed areas of hepatic parenchyma (left) with small amounts of viable adenocarcinoma (right). Inset: 250 x magnification; demonstrates fibrosis with mild chronic inflammation characterized by foamy macrophages. (B) H&E stain, 25 x magnification; figure shows hepatic parenchyma on right, microspheres with adjacent fibrosis (arrow) and residual tumor above. Inset: 100 x magnification; dense fibrosis and microspheres are demonstrated in close proximity to viable adenocarcinoma.

	DISCUSSION

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The data presented herein represent the first clinical experience of combination treatment with radiosensitizing oxaliplatin chemotherapy and RE in the first-line treatment of metastatic CRC. The results show that combined modality treatment is generally well-tolerated by this patient group.

Large-scale phase III trials of FOLFOX4 chemotherapy as first-line treatment for patients with metastatic CRC have documented its principal toxicities.^11-14 The most common grade 3 and 4 toxicities reported have been neutropenia (40% to 50%), leukopenia (approximately 20%), diarrhea (10% to 15%), nausea (5% to 10%), and neuropathy (15% to 25%). Although the degree of myelosuppression observed at the first two dose levels in the trial reported here equate to the levels reported in these phase III trials, the occurrence of grade 3 to 4 neutropenia in almost 80% and leukopenia in 44% of patients at the highest dose level is greater than one would expect from FOLFOX4 chemotherapy in this patient group. With consideration of the statistical constraints of phase I trials due to small sample size, the proportion of patients developing neutropenia fulfills the criterion defined above for DLT. It is therefore concluded that the maximum-tolerated dose for systemic FOLFOX4 chemotherapy with concomitant RE is 60 mg/m² of oxaliplatin for the first three cycles.

The mechanism by which multimodality treatment may be causing neutropenia is not clear. Prolonged lymphopenia has been noted by researchers^27-29 involved in RE treatment of patients with hepatocellular carcinoma (HCC) using glass microspheres (TheraSpheres; MDS Nordion, Ottawa, Canada). This effect may occur within 2 days of RE, and it has been documented to last more than a year.³⁰ In contrast, significant neutropenia has not been reported in a detailed study of the administration of glass microspheres to 80 patients with unresectable HCC,³¹ nor in studies of resin microspheres alone or in combination with hepatic arterial chemotherapy in patients with metastatic CRC.^32-35 It should be noted, however, that in a small randomized phase II trial studying the combination of SIR-Spheres and the Mayo regime of systemic FU/LV chemotherapy as first-line treatment for patients with metastatic CRC, three out of 11 patients treated with combined modality treatment developed neutropenia (grade 3), of whom one died from neutropenic sepsis.²⁰ Although it is conceivable that blood is irradiated as it passes through the liver,³⁶ it also is possible that low levels of microspheres or free yttrium-90 may be deposited in bone marrow. On account of the timeframe of the leukopenia, it is unlikely that the splenomegaly observed resulted in hypersplenism. With regard to the mechanism of splenomegaly, RE and hepatic arterial chemotherapy have been linked with portal hypertension,³⁷ although it also should be noted that oxaliplatin-based combination chemotherapy may lead to sinusoidal obstruction syndrome, which has been associated with portal hypertension.³⁸

Regardless of the mechanism of leukopenia, current clinical data suggest that this adverse effect may have clinical sequelae when RE is used in combination with systemic treatment with radiosensitizers, such as FU or oxaliplatin. Since SIR-Spheres and TheraSpheres are currently being administered in more than 80 centers worldwide, careful consideration of this potential interaction is mandatory.

The lack of hepatotoxicity demonstrated in the trial reported here is encouraging for the clinical advancement of a multimodality approach. The surgical results presented earlier demonstrate the feasibility of this approach in patients with metastatic CRC, as indicated in a series of 49 patients with unresectable HCC who were downstaged for surgery by chemotherapy, RE or combined modality treatment.³⁹ The results shown in Figure 1A and 1B supplement the published data from four patients whose livers were explanted following RE, in which the investigators estimated that the cumulative absorbed dose to tumor was 100 to 3,000 Gy.⁸

Although the radiological responses must be interpreted with caution due to the small sample size, the data presented earlier are impressive when compared to equivalent statistics for FOLFOX4 chemotherapy alone in this patient group.^11-14 The data on PFS presented for the subset of seven patients with liver only disease, reinforced by the differential responses seen on CT scans, lead us to suggest that phase II and III evaluation of this chemoradiation treatment should focus on patients with liver dominant metastatic disease.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: Guy A. Van Hazel, Sirtex Honoraria: Guy A. Van Hazel, Sirtex; Peter Gibbs, Sirtex Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Ricky A. Sharma, Guy A. Van Hazel, William P. Steward

Provision of study materials or patients: Ricky A. Sharma, Guy A. Van Hazel, Keith Blanshard, David Price, Geoffrey Bower, David P. Berry, Jennifer A. Shannon, Peter Gibbs, William P. Steward

Collection and assembly of data: Ricky A. Sharma, Guy A. Van Hazel, David Price, Geoffrey Bower, Bruno Morgan, David P. Berry, Jennifer A. Shannon, Peter Gibbs, William P. Steward

Data analysis and interpretation: Ricky A. Sharma, Guy A. Van Hazel, Keith Blanshard, David Price, Geoffrey Bower, Bruno Morgan, Jennifer A. Shannon, Peter Gibbs, William P. Steward

Manuscript writing: Ricky A. Sharma, Guy A. Van Hazel, William P. Steward

Final approval of manuscript: Ricky A. Sharma, Guy A. Van Hazel, Keith Blanshard, David Price, Geoffrey Bower, Bruno Morgan, David P. Berry, Jennifer A. Shannon, Peter Gibbs, William P. Steward

	ACKNOWLEDGMENTS

 
We thank the 20 patients who participated, Sirtex Medical Limited (Michael Tapner, David Cade, David Turner, and Bruce Gray for provision of SIR-Spheres and advice), sanofi-aventis for providing oxaliplatin, and S. Khanna, MD, M. Early, MD, T. Vermeulen, MD, A.C. Wotherspoon, MD, and K.A. Vallis, MD, for specialist advice.

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 24, 2006; accepted December 8, 2006.

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