A prospective evaluation of treatment with Selective Internal Radiation Therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy
© Lim et al; licensee BioMed Central Ltd. 2005
Received: 04 February 2005
Accepted: 15 October 2005
Published: 15 October 2005
To prospectively evaluate the efficacy and safety of selective internal radiation (SIR) spheres in patients with inoperable liver metastases from colorectal cancer who have failed 5FU based chemotherapy.
Patients were prospectively enrolled at three Australian centres. All patients had previously received 5-FU based chemotherapy for metastatic colorectal cancer. Patients were ECOG 0–2 and had liver dominant or liver only disease. Concurrent 5-FU was given at investigator discretion.
Thirty patients were treated between January 2002 and March 2004. As of July 2004 the median follow-up is 18.3 months. Median patient age was 61.7 years (range 36 – 77). Twenty-nine patients are evaluable for toxicity and response. There were 10 partial responses (33%), with the median duration of response being 8.3 months (range 2–18) and median time to progression of 5.3 mths. Response rates were lower (21%) and progression free survival shorter (3.9 mths) in patients that had received all standard chemotherapy options (n = 14). No responses were seen in patients with a poor performance status (n = 3) or extrahepatic disease (n = 6). Overall treatment related toxicity was acceptable, however significant late toxicity included 4 cases of gastric ulceration.
In patients with metastatic colorectal cancer that have previously received treatment with 5-FU based chemotherapy, treatment with SIR-spheres has demonstrated encouraging activity. Further studies are required to better define the subsets of patients most likely to respond.
Colorectal cancer (CRC) is the most common GI malignancy accounting for 4718 deaths in Australia  and almost 437,000 deaths worldwide annually making it the most third most common malignancy in the developed world . Around fifty to sixty percent of these patients will develop liver metastases, and in approximately 20% of cases the liver is the only site of disease at death. Surgical resection of all apparent disease is possible in selected patients, however for the majority of patients with metastatic CRC the standard approach remains systemic chemotherapy.
Selective Internal Radiation (SIR) spheres (Sirtex Medical, Sydney, Australia) are a new radiotherapeutic treatment for liver metastases. These resin microspheres contain yttrium, a high energy beta-emitting isotope, and are embolised into the hepatic artery where they become lodged within the microvasculature of the tumour. The treatment is relatively selective as hepatic tumours derive their blood supply almost exclusively from the hepatic artery whereas normal liver parenchyma is supplied predominantly by the portal circulation. Animal studies suggest that SIR spheres allow on average 200–300 Gy to be delivered to liver tumours . In contrast the delivery of standard external beam radiation therapy to the whole liver is limited by the ability of the normal parenchyma to tolerate only 30–35 Gy, an insufficient dose to produce a significant anti-tumour effect .
Encouraging results have been reported following previous studies of SIR spheres in metastatic colorectal cancer. In a series of 21 chemonaive patients with colorectal liver metastases who were randomised to receive intravenous 5FU alone or intravenous 5FU plus SIR spheres, the combination demonstrated a higher response rate and significantly improved progression free survival compared to chemotherapy alone . In a larger study of 74 patients combining SIR-spheres with hepatic artery chemotherapy superior response rates and time to progression over treatment with chemotherapy alone were seen in patients with colorectal cancer . With the exception of hepatocellular carcinoma results in other tumour types have not been so encouraging .
We report here the first prospective series conducted to better define the efficacy and safety of SIR-spheres(Yttrium90) in patients with colorectal cancer and liver metastases that have previously received 5-FU based chemotherapy. No financial support was received from SIRTex for the purposes of this study.
Data for consecutive patients with metastatic colorectal cancer treated with Sirtex microspheres were collected prospectively across 3 Australian centres from Jan 2002 and March 2004. During this period of the time both oxaliplatin and irinotecan were not reimbursable in Australia as part of first-line therapy for patients with metastatic colorectal cancer outside of a clinical trial. These agents were available for patients that had progressed following initial 5-FU based treatment.
Patients were informed of the available evidence regarding SIR-spheres treatment. Patients that elected to proceed with treatment were informed that data would be collected prospectively as part of a research project. Toxicities and protocols were outlined in accordance with the manufacturer's guidelines and were common across all participating centres. Patients were considered eligible if they had liver metastases from colorectal cancer with histological confirmation of their primary tumour. All patients were required to have measurable disease within the liver. Extra-hepatic disease was allowed if the liver was the dominant site of disease.
Patients with an expected survival of less than 3 months, documented brain metastases, or a poor performance status (ECOG >2) were excluded. Adequate hepatic, renal and liver function was required including a normal clotting profile, an albumin >30 g/L, bilirubin <20 umol/L and no evidence of liver decompensation such as ascites or portal hypertension was permitted. Patients with portal vein thrombosis were also excluded from this study.
Previous treatment with chemotherapy was allowed provided this had been more than 2 months prior to planned treatment with SIR-spheres. Patients received bolus 5FU chemotherapy concurrent with the SIR-spheres, as a radiosensitiser, and subsequently in responding patients at the investigator's discretion.
Pre treatment workup and disease evaluation
All patients underwent a standard pre-treatment evaluation as per manufacturers guidelines. An hepatic angiogram was performed to define arterial anatomy prior to treatment and to permit a nuclear medicine scan with radio labeled Tc 99 m-MAA (macro-aggregated albumin) in order to exclude patients at high risk of lung (radiation pneumonitis) or GI toxicity (gastric/duodenal ulceration) due to hepato-systemic shunting or aberrant vasculature. The fraction of extra-hepatic shunting was determined for each patient as a percentage. Patients who had shunting of greater than 20% were excluded from the study. Shunting of between 12 and 20% resulted in a reduction in the dosage of spheres delivered. The final dose of SIR-spheres administered in units of GBq was calculated according to each patient's body surface area and percentage of tumour involvement of liver (an assessment made by the radiologist after viewing the baseline CT scan). Across the three participating centres, the workup and delivery of SIR spheres was performed by a total of four experienced interventional radiologists with two centres having all treatment administered by a single interventional radiologist.
Following a single treatment of SIR-spheres, two weeks after the MAA scan, patients were routinely followed and assessed at monthly intervals. Acute toxicity was assessed initially and at subsequent clinical visits. All toxicities were graded according to National Cancer Institute (NCI) Common Toxicity Criteria, and performance status according to Eastern Cooperative Oncology Group (ECOG) criteria. Disease evaluation was performed by CT imaging at 2 months and bi-monthly thereafter until disease progression. A complete response (CR) was defined as the disappearance of all target lesions. A partial response (PR) was defined as >30 percent decrease in the sum of the longest dimension of the target lesions at 2 months. All responses were confirmed on repeat imaging. Progressive disease (PD) was defined as a >20 percent increase in the sum of the longest recorded target lesion(s) within the liver or the development of new or progressive extrahepatic disease. Stable disease (SD) was defined as a decrease not sufficient to qualify for a PR nor an increase not sufficient to qualify for PD. The results of all staging investigations and toxicity assessments were collected and analysed prospectively. The duration of response was determined from the date of the first response evaluation at 2 months until progressive disease.
Failed 5FU alone
Failed 5FU + CPT-11 and Oxaliplatin
Failed 5FU + either CPT-11 or Oxaliplatin
Results At 2 months by patient group (*1 patient died prior to the first evaluation and has been classified as progressive disease).
Partial Response (%)
Stable Disease (%)
Progressive Disease (%)
Overall (n = 30)
Failed 5FU alone (n = 8)
Failed 5FU and CPT-11 and Oxal (n = 14) containing regimens
Failed 5FU and either CPT-11 or Oxaliplatin (n = 8) containing regimens
Extra-Hepatic disease (n = 7)
ECOG 2 (n = 3)
All responses occurred in patients with disease confined to the liver (n = 24) and no responses were seen in patients with a performance status of 2 (n = 3). In the 8 patients that had received only prior 5-FU there were 6 responses (75%). In the patients that had received oxaliplatin and/or irinotecan (n = 22) there were 5 responses (23%). This included responses in 3 of 14 (21%) patients that had previously received all standard chemotherapy options. No other factors were apparently predictive of response, including the bulk of disease, in this study.
Overall toxicity assessments were carried out according to NCI common toxicity criteria at all three centres. The findings were consistent across all study sites with between 2–8 weeks of lethargy, anorexia, nausea and RUQ pain being observed to a variable extent in most patients. However, in most cases, these side effects were mild and self-limiting following treatment with standard anti-emetics and analgesics medication. Three patients reported severe nausea and lethargy for 2 weeks following treatment and moderate symptoms were reported in several patients up to 1 month following treatment.
Other serious toxicity potentially related to SIR-spheres included a single patient who was admitted to hospital with acute right upper quadrant pain and marked deterioration in her liver function tests one month following treatment with SIR-spheres. The clinical assessment was that the patient likely had radiation hepatitis. Her symptoms settled with conservative management.
This prospective evaluation documents the experience in our three institutions of using Selective Internal Radiation spheres to treat liver metastases from colorectal cancer in patients that had previously received 5-FU chemotherapy. Our series adds to the published experience documenting the activity of this treatment in selected patients, along with the potential for significant toxicity. For the period of this study oxaliplatin and irinotecan were available in Australia only for patients that had progressed following initial 5-FU based treatment and this is reflected in the study design.
Overall in our experience, treatment with SIR-spheres demonstrated promising activity in pre-treated patients with liver metastases from colorectal cancer. Partial responses were seen in six of the eight patients that had failed 5FU alone. This includes one patient that was able to undergo potentially curative resection of residual liver disease after further response to systemic chemotherapy and she remains disease free 22 months later. The response rate in our series is similar to that reported in the previous small randomized study where this combination was used first-line . The progression free and overall survival data for our study are shown in Figure 3. Due to the small patients numbers this activity may partly reflect chance or patient selection. However, this is encouraging efficacy as the alternative treatment for these patients would have been irinotecan alone or oxaliplatin plus 5-FU where responses are typically seen in less than 20% of patients [10, 11].
Significant response rates were also seen in patients that had progressed through several lines of chemotherapy. Notably, fourteen of these patients had previously received both irinotecan and oxaliplatin, and the response rate was maintained in this group. The only treatment other option open to these patients would be cetuximab, a monoclonal antibody directed at the epidermal growth factor receptor (EGFR). As a single agent responses are seen in about 10% of patients  and response rates are higher when concurrent irinotecan is administered . However, not all patients are suitable for cetuximab as approximately 25% of patients do not express the EGFR. Based on our results SIR-spheres appear to be a good option for patients with colorectal cancer who have liver only disease and maintain a good performance status following progression on all standard chemotherapy drugs. The suggestion from our results is that benefit from the addition of SIR-spheres will be greater if used earlier, but this will need to be confirmed in larger studies.
The toxicity data from our experience was consistent with findings from earlier trials involving SIR-spheres. The 13% severe gastric/duodenal ulceration rate is significant and is consistent with a recent larger study reporting a 12% GI ulceration rate . Gastrointestinal ulceration occurred despite strictly adhered to protocols of pre-treatment workup and treatment only by experienced interventional radiologists. The product information recommends routine use of a H-2 antagonist prophylactically the day before the procedure and for a month afterwards in view of the known association of peptic ulceration with SIR-spheres treatment . Although this was not part of our treatment protocol, the prophylactic use of proton-pump inhibitors or H-2 antagonists should be considered in patients treated with SIR-spheres. In our analysis there were no apparent indicators of which patients were likely to experience toxicity. In particular this did not appear related to disease bulk or patient performance status.
In summary, this series has demonstrated that treatment with SIR-spheres produces encouraging responses in pretreated patients with colorectal cancer. Further studies in this group of patients should be pursued. On the basis of our results, thought should be given to stratifying patients according to the presence or absence of extrahepatic disease and according to performance status. We have also demonstrated the potential for significant toxicity, and such treatment should only be conducted in centres with experienced interventional radiologists.
- Australian Institute of Health and Welfare (AIHW), Australasian Association of Cancer Registries (AACR): Cancer in Australia 2000. 2003, Canberra: AIHWGoogle Scholar
- Pisani P, Parkin DM, Bray F, Ferlay J: Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999, 83: 18-29. 10.1002/(SICI)1097-0215(19990924)83:1<18::AID-IJC5>3.0.CO;2-M.View ArticlePubMedGoogle Scholar
- Weiss L, Grundmann E, Torhorst J, Harveit F, Moberg I, Eder M, Fenoglio-Preiser C, Napier J, et al: Haematogenous Metastasis patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol. 1986, 150: 195-203. 10.1002/path.1711500308.View ArticlePubMedGoogle Scholar
- Ingold JA, Reed GB, Kaplan HS, Bagshaw MA: Radiation hepatitis. AM J Roentgenol Radium Ther Nucl Med. 1965, 03: 200-208.Google Scholar
- Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF: Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys. 1995, 31: 1237-48. 10.1016/0360-3016(94)00418-K.View ArticlePubMedGoogle Scholar
- Gray BN, Anderson JE, Burton MA, van Hazel G, Codde J, Morgan C, et al: Regression of liver metastases following treatment with yttrium-90 microspheres. Aust N Z J Surg. 1992, 62: 105-10.View ArticlePubMedGoogle Scholar
- Gray B, Van Hazel G, Hope M, Burton M, Moroz P, Anderson J, Gebski V: Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001, 12: 1711-20. 10.1023/A:1013569329846.View ArticlePubMedGoogle Scholar
- Lau WY, Ho S, Leung TW, Chan M, Ho R, Johnson PJ, Li AK: Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys. 1998, 40: 583-92. 10.1016/S0360-3016(97)00818-3.View ArticlePubMedGoogle Scholar
- Lim L, Gibbs P, Yip D, Shapiro JD, Dowling R, Smith D, Little A, Bailey W, Liechtenstein M: A prospective study of treatment with Selective Internal Radiation Therapy (SIR spheres) in patients with unresectable primary or secondary hepatic malignancies. Internal Medicine Journal. (in press-to be published in April 2005 edition of Internal Medicine Journal)
- Rougier P, Van Custem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998, 352: 1407-1412. 10.1016/S0140-6736(98)03085-2.View ArticlePubMedGoogle Scholar
- Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol. 2003, 21: 2059-2069. 10.1200/JCO.2003.11.126.View ArticlePubMedGoogle Scholar
- Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004, 351: 337-45. 10.1056/NEJMoa033025.View ArticlePubMedGoogle Scholar
- Saltz L, Meropol NJ, Loehrer PJ, Needle M, Kopit J, Mayer RJ: Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor. J Clin Oncol. 2004, 22: 1201-1208. 10.1200/JCO.2004.10.182.View ArticlePubMedGoogle Scholar
- Stubbs RS, Cannan RJ, Mitchell AW: Selective internal radiation therapy with 90yttrium microspheres for extensive colorectal liver metastases. J Gastrointest Surg. 2001, 5: 294-302. 10.1016/S1091-255X(01)80051-2.View ArticlePubMedGoogle Scholar
- Sirtex Medical Limited: SIR-Spheres Product Monograph, Sydney. 2002, [http://www.sirtex.com.au/p=77]Google Scholar
- Scrag D: The price tag on progress chemotherapy for colorectal cancer. N Engl J Med. 2004, 351 (4): 317-9. 10.1056/NEJMp048143.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/5/132/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.