Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 1, 2011, pp. 18-23

Indian Journal of Cancer, Vol. 48, No. 1, January-March, 2011, pp. 18-23

Symposium

Selective internal radiation therapy: ⁹⁰ Y (yttrium) labeled microspheres for liver malignancies (primary and metastatic)

MC Uthappa¹, R Ravikumar², A Gupta³

¹ Department of Radiology, Manipal Hospital, Old Airport Road, Bangalore-560 017, India
² Thambiran Hospital, Near K4 Police Station, Annanagar, Chennai, India
³ Sir Ganga Ram Hospital, Rajendra Nagar, New Delhi-110 060, India

Correspondence Address:
M C Uthappa
Department of Radiology, Manipal Hospital, Old Airport Road, Bangalore-560 017
India
uthappas@hotmail.com

Code Number: cn11003

Abstract

Keywords: Unresectable, quality-of-life, targeted therapy

Introduction

Involvement of liver by the disease is one of the most common features in cancer patients, with metastasis affecting this organ in more than one-third of all cancers. ^[1] This is particularly important for patients with colorectal cancer, where 50% develop liver metastasis (half of them showing evidence at the time of initial diagnosis). ^[2] For such patients, the ideal treatment would be liver resection (about 25% of patients are eligible), which represents the only potential cure available to patients. ^[3]

Besides cancer directed systemic chemotherapy/chemoimmunotherapy, such patients now have the option of alternative therapeutic methods like hepatic artery infusion chemotherapy, radiofrequency ablation, chemoembolization, stereotactic body radiation, and more recently, selective internal radiation therapy (SIRT) using radiolabeled beads/resins. ^[4] This last mode of therapy was developed in the 1980s in Perth, Western Australia. ^[5]

Selective Internal Radiation Therapy

The principle of SIRT is to provide radiation within the liver, using microscopic beads that are injected into the liver and preferentially are taken up at high concentration within the tumor site. Thus, it is essentially a flow-directed mode of treatment that is dependent on neoangiogenesis. This therapy, considered as a medical device, was approved by the US Food and Drug Administration (FDA) in March 2002 (also obtained TGA approval in Australia and BSI approval for Europe), and so far, more than 15,000 patients have undergone this form of therapy globally. ^[6],[7] Most commonly, it is used for patients having unresectable liver metastases from colorectal cancer, who do not have significant extrahepatic metastatic disease, and are refractory to/intolerant to/not fit for systemic chemotherapy.

It is interesting to know that there exists a fundamental difference in the source of blood supply of normal liver parenchyma (through the portal vein) and malignant tumors in the liver (through arterial perfusion). Also, the neo-vascularization of tumors results in 3-200 times greater microvascular density within the cancer as compared to the surrounding liver parenchyma - an ideal opportunity to "target" the malignant cells while sparing the normal ones. ⁹⁰ Yttrium labeled biocompatible resin microspheres (SIR-Spheres^® made by SirTex Medical, Sidney Australia) or glass beads (Theraspheres made by MDS Nordion, Ottawa, Canada), when infused into the hepatic artery, will therefore primarily concentrate within the tumor microvasculature. ^[8],[9] This treatment therefore offers a dual benefit - micro-embolization and high-dose interstitial radiotherapy.

⁹⁰ Yttrium ( ⁹⁰ Y) emits beta rays that have a half-life of about 64 hours and an average energy of just below 1 MeV. [One gigabecquerel (27 mCi) delivers a total absorbed radiation dose of 50 Gy/kg.]. Hence, the interstitial radiation penetrates to a mean distance of 2.5 mm (maximum 1.1 cm). ⁹⁰ Y decays to stable zirconium 90, during which 94% of the radiation is delivered in the first 11 days. ^[5],[10] SIRT is a technique that allows high average doses of radiation (200-300 Gy) to be given to liver tumors, with minimal serious effect on the nontumorous liver ^[10] (each vial has a dose of 3 GBq).

Indications

SIRT targets disease in the liver only. Hence, its current use is restricted to tumors that are limited to the liver, either as a primary or as the sole site of metastasis.^[5] Besides colorectal cancers, this therapy has shown benefit in patients with a variety of other tumors including carcinoid tumors, lung, breast, sarcoma, colon, hepatocellular, ocular melanoma [Table - 1]. ^[11]

Eligible patients are those with adequate liver functions (bilirubin < 2 mg/dl), Eastern Cooperative Oncology Group performance status of 0/1 and adequate renal function (GFR > 30 ml/min/m ² ) [Table - 2]. ^{[12],[13],[14],[15]} They have to undergo evaluation of tumor status [cancer (usually metastasis) largely confined to the liver by positron emission tomography/computed tomography (PET/CT) scan] as well as hepatic vascular status [good portal vein patency, hepatic artery and celiac axis by angiography; blood flow from hepatic artery to lungs and gastrointestinal tract by ^99m Tc-macro aggregated albumin (MAA) perfusion scintigraphy]. The gastroduodenal and right gastric arteries have to be coil-embolized to prevent reflux of the radioladen microspheres (usually done a day prior to the main procedure to allow for proper dosimetry and altered flow pattern assessment). ^[5] The SIRT procedure should be done only if less than 20% of the radioactivity reaches the lungs (hepatopulmonary shunting). ^[16] Beyond this, the risk of pulmonary complications (Adult respiratory distress syndrome (ARDS), radiation pneumonitis and interstitial lung disease) is unacceptable.

Dosimetry

Doses are calculated using basal surface area (BSA) or partition modeling, the latter being applicable only when the tumor is localized to discrete area within the liver. To ensure that liver parenchyma is protected, its dose should not exceed 70 Gy, whereas the tumor should receive 120 Gy. ^[17] These estimates are based on the experience of external beam irradiation. Actual calculations shall vary on a case to case basis [Table - 3]. For instance, hepatocellular carcinomas (HCCs) are highly vascular (compared to metastasis) and shall receive a significantly higher dose when calculations are based on BSA alone. HCCs shall also have a more uniform distribution within the entire tumor, in contrast to metastatic colorectal cancer (mCRC) where there is a selective concentration in the vascular peripheral rim of the metastasis. ^[18]

Procedure

SIRT should only be administered by centers that have the requisite facilities [Table - 4]. ^{[6],[12],[19]} For eligible patients, under local anesthesia and image guidance, a catheter is guided into the appropriate hepatic artery, placement and blood flow reconfirmed and Y-90 labeled spheres are infused from a microcatheter within the angiographic catheter to treat the entire liver.^[20] In some cases, if there are many small tumors scattered throughout the liver, two treatments can be given, with the right hepatic artery at one time and the left hepatic artery in a second treatment session. It is recommended that the microspheres are given in multiple brief infusions with contrast medium being injected in between. ^[5] Once the infusion is completed, the microcatheter is withdrawn into the angiographic catheter prior to its removal, to prevent unwanted deposition of radioactivity. The microspheres remain permanently embedded into the tumor and release the radiation over the next 14 days. ^[21]

After the procedure is completed (usually takes 1 hour including 15 minutes to infuse the ⁹⁰ Y labeled beads/resins), patients are required to lie flat for 2-6 hours. ^[4] Thereafter, the patients are scanned to check the level of radioactivity in the liver (vs. the rest of the body). Inpatient stay is usually for overnight observation (in some countries like Germany, regulations require patients receiving interstitial radiotherapy to be hospitalized for 48 hours). ^[4],[5] Precautions to prevent unnecessary exposure to radiation include avoiding close contact with pregnant women and children for a few days. This also means no close physical contact with any other persons for more than 2 hours at a time, sleeping alone at night and not allowing pets to sit on their laps. Normal contact can be resumed after a gap of 1 week. ^[5]

The first follow-up should be with the interventional radiologist within 6-8 weeks of the procedure. This must include complete imaging assessment, like PET/CT scan to identify early response. Thereafter, follow-up is commonly done at 3, 6, and 12 months, and annually thereafter. ^[5]

Clinical Results

Colorectal cancer

Clinical data from several phase II and a well-designed phase III studies show that even among heavily pretreated patients, the clinical benefit can be as much as 85% (study of 208 patients from Massachusetts General Hospital (MGH)). This translated into better survival (10.5 months vs. 4.5 months for non-responders). ^[22] In another study (100 patients with extensive colorectal metastases not amenable to resection or ablation), the estimated survival at 18 and 30 months was 32 ± 4.7% and 9 ± 2.9%, respectively, with the majority of deaths occurring due to progression at extrahepatic sites. ^[23]

Initial US FDA approval was given on the basis of a phase III trial in colorectal cancer patients with unresectable metastatic disease involving both the lobes of the liver, who had undergone complete resection of the primary. Patients were randomized to intra-arterial Floxuridine (FUDR) with or without a single dose of the resin microspheres. ^[24] The study arm showed a significantly better time to tumor progression (15.9 vs. 9.7 months; P < 0.01). The overall response rate (ORR) was also better (44% vs. 17.6%; P = 0.01). In this study, 1, 3 and 5 year overall survival (OS) was better for the study arm (72%, 17% and 3.5% for the study arm vs. 68%, 6.5% and 0% for the control arm). In fact, survival of the majority of patients was influenced by the development of extrahepatic disease, an area not addressed by the treatment given.^[24] Interestingly, there was no increase in grade 3 or 4 toxicity or loss of quality of life, by addition of SIRT.

Subsequently, phase I and II studies used systemic 5 FU/LV with or without oxaliplatin or irinotecan. The randomized phase II trials once again showed the benefit of adding ⁹⁰ Y best confirmed responses (8 partial response (PR) versus 0 PR; P < 0.001; N = 21). ^[25] The time to tumor progression (TTP) was 18.6 months versus 3.6 months (P < 0.0005) and median OS was 29.4 months versus 12.8 months (P = 0.002).

In 25 irinotecan naïve patients, this drug was combined with ⁹⁰ Y radioembolization. A total of 11 out of 23 evaluable patients (48%) showed PR, and the median OS was 12.2 months [Table - 5]. ^[16] The dose of irinotecan that could be given safely in combination with SIRT was 100 mg/m ² on days 1 and 8 of the three weekly cycle.

In one interesting study, the role of chemoembolization was compared to that of STIR. ^[26] The main objective was to compare the ability to downstage from T3 to T2 status, thus making the patients eligible for liver transplantation. In this group of 86 cases, the ORR in the ⁹⁰ Y arm was 61% as compared to 37% with chemoembolization. Downstaging was also higher in the study arm (58% vs. 31% with chemoembolization alone). The event free survival (EFS) and OS also showed better (17.7 and 35.7 months, respectively) results with ⁹⁰ Y as compared to chemoembolization (7.1 and 18.7 months, respectively).

Currently, SIRT has become an attractive option even as a first-line therapy for mCRC, in combination with standard multiagent chemotherapy. ^[27],[28]

Hepatocellular carcinoma

Initial studies in primary inoperable HCC showed that the outcome was dose dependent; patients receiving >120 Gy survived 55.9 weeks compared with 26.2 weeks for those patients who received <120 Gy, with repeat treatments adding to the survival benefits. ^[29],[30] Another study using ⁹⁰ Y microsphere showed it was possible to downstage non-resectable disease, making the patients eligible for transplantation, resection or radio frequency ablation (RFA). ^[31],[32]

Data from five studies that evaluated ⁹⁰ Y microsphere therapy in unresectable HCC included 514 patients (from 35 to 291 patients in individual studies), giving an ORR of 20-57% and a median OS of 17.2-26.6 months. ^[33]

Currently, this modality of therapy is applicable in as many as 26 different types of tumors [Table - 1].

Complications

Pain (at the time of infusion and for a few hours thereafter), fever (for up to 7 days), loss of appetite, lethargy and fatigue (for several weeks) are the common side effects. Acute pain in upper abdomen and nausea are seen in up to 30% of cases and gastric ulcers in 5% of patients. Such symptoms come under the label of "post embolization syndrome" that typically occur 1-14 days after the procedure. Radiation induced ulcers are resistant to healing and therefore should be prevented as far as possible (by taking proton pump inhibitors and antacids for the first month to prevent gastritis and peptic ulceration). ^[34] Rarely, the patient may also develop radiation induced hepatitis, pancreatitis or lung damage (which can be severe and rarely fatal). Radiation pneumonitis occurs if the dose to the lung exceeds 30 Gy. ^[35] Pancytopenia used to occur with the earlier version of ⁹⁰ Y microspheres and has not been reported with the improved version currently available. ^[36]

Conclusions

We conclude that we now have an exciting new modality in the treatment of liver malignancies. This provides improved response, time to tumor progression and overall survival in selected patients. It has an important role in HCC, colorectal cancer and other malignancies that commonly metastasize to the liver. Future studies will refine our understanding of optimizing patient eligibility, dose (fractionated or not), frequency (second treatment at progression) as well as novel applications [Table - 6].

References

Copyright 2011 - Indian Journal of Cancer

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