Rhenium-188 Lipiodol for the Treatment of Hepatocellular Carcinoma (HCC)

Abstract

Hepatocellular carcinoma (HCC) is one of the world’s most common malignancies, causing almost one million deaths annually. About 550,000 new cases of HCC are reported every year. Worldwide, HCC accounts for approximately 5.4% of all cancers. This major health problem is the third cause of cancer-related deaths. It is the most frequent primary liver cancer and the most severe complication of chronic liver disease. Various forms of therapy such as surgical resection, orthotopic liver transplantation (OLT), percutaneous injection to induce coagulative necrosis of the tumour have been considered as radical treatment of HCC, aiming at curing the disease. However, these have been found to be of benefit only in patients with smaller and fewer tumours, good liver function and without vascular invasion or extrahepatic spread. Unfortunately, except in patients undergoing OLT, recurrence rate has remained extremely high. In most series the curative treatment options are represented mainly by surgery (resection or transplantation), but most patients are not candidates for a curative option and only palliative treatment could be given to such patients. Radionuclide therapy using radio-conjugates have been used in the palliative treatment of inoperable HCC. However, the costs of commercially available radiopharmaceuticals like I-131 Lipiodol, Y-90 SIR spheres and Y-90 Therasphere are prohibitively high. As a result, hundreds of thousands of needy and deserving patients of HCC are deprived of this treatment option. Development of Rhenium 188 Lipiodol and its use in an IAEA sponsored multicentre study for the treatment of HCC has been a big step forward in meeting the demands for making available a low cost and effective radio-conjugate for therapy of inoperable HCC. There are several advantages of the use of intra-arterial Re-188 Lipiodol injection as compared to other intraarterial treatments. It is easier to deliver compared to chemo-embolisation. In fact, in the IAEA study the technique was feasible in all the participating countries after a short learning period. Good tolerance of Re-188 Lipiodol therapy by the patients avoids a long hospitalisation period and expensive care. It is cheaper than I-131-Lipiodol, Y-90 glass-based or resin-based microspheres, which are now available commercially. Re-188 is available onsite from an in-house generator system, on demand. One generator system can be effectively used for over 6 months. The treatment procedure does not require patient isolation and finally the multimodality applications of Rhenium-188 ensures optimal utilisation of the radionuclide in a variety of other clinical conditions like rheumatoid arthritis, haemophilic bleeding joints (Radiosynovectomy), metastatic bone pain, intravascular radionuclide therapy to prevent restenosis of coronary artery following revascularisation, etc. This chapter provides a brief overview of the available radio-conjugates for the treatment of HCC, discusses their merits and demerits and comprehensively reviews the outcome of the phase-II study conducted by the IAEA on the treatment of HCC using Re-188 Lipiodol in the developing country setting.

Annexure-1

1.1 Protocol for Re-188 Lipiodol Therapy of HCC (Used in the IAEA’s Multi-Centre Study)

1.1.1 Eligibility Criteria

• 1. Histopathology diagnosis of HCC or association of hyper-vascularised liver Tumor(s) in cirrhotic/fibrotic liver.

• 2. Patients must have bi-dimensionally measurable disease by conventional imaging methods including radiography, ultrasound, computer tomography, or other anatomic imaging modalities. These modalities must demonstrate a solitary lesion > 5 cm in greatest diameter, OR < 3 lesions < 3 cm in greatest diameter, OR an inoperable solitary lesion > 5 cm in greatest diameter.

• 3. Alpha-feto-protein (αFP) above 400 μg/L.

• 4. Acceptable general condition defined by a Karnofsky Performance Status (KPS) ≥ 60 %; serum creatinine ≤2 mg/dL; ANC ≥ 1,500/μL and platelets ≥ 100 G/L; INR ≤ 1.5.

• 5. All patients must be off chemotherapy or immunotherapy for at least 4 weeks prior to receiving treatment.

• 6. Female patients of childbearing age are required to have a negative pregnancy test carried out the day of and prior to study entry, and must be asked to use effective contraception during the study.

• 7. All patients must be ambulatory with an ECOG of not more than 2.

• 8. All patients are required to provide written informed consent and the protocol must be approved by Institutional Medical Ethics Committee.

1.1.2 Contra-Indications/Exclusion Criteria

• 1. Patient with Child’s C status.

• 2. Clinically significant cardiac disease (New York Heart Association Class (III/IV).

• 3. Serious infection requiring treatment with antibiotics, or other serious illness.

• 4. Pregnancy or lactation.

• 5. Survival expectancy of less than 3 months.

• 6. Evidence of extra-hepatic spread.

1.1.3 Pre-Therapy Procedures

• 1. Informed consent and education of the patients: In all patients informed consents should be taken in accordance with the local and national regulations and protocols. It is the responsibility of the hospital or the institution which provides this service to prepare easy to understand leaflets and other informative brochures to enhance patient awareness, assurance, cooperation and compliance.

• 2. Pretreatment clinical assessment, imaging, blood tests, and other investigations:

  • History and physical examination.

  • CT Scan.

  • Alpha-feto-protein (αFP).

  • Complete blood count, prothrombin time, adjusted partial thromboplastin time, international normalised ratio.

  • Liver function tests (bilirubin, ALT, serum albumin), serum creatinine.

  • 12-Lead electrocardiogram.

  • Chest X-ray; additional X-rays and scan as required for determining extent of disease.

• 3. Medications to start or stop:

  • To stop chemotherapy 4 weeks before Re-188 Lipiodol Therapy.

• 4. Diet Instructions: None.

1.2 Therapy Procedure

1.2.1 Co-management with Other Clinicians—Responsibilities and Obligations

• 1. Interventionist Radiologists: Angiography, Care of catheterisation (haemorrhage/infection).

• 2. Hepatologists/oncologists: Patient selection, pre and post therapy evaluation, follow up of the patient, management of clinical complications.

• 3. Nuclear Medicine Physician: Procurement of radio-activity, patient evaluation, radiopharmaceutical preparation, quality control of radio-conjugate, dosimetry calculation, evaluation of bio-distribution of radio-conjugate, radiation protection, administration of radioactivity, follow-up assessment, record keeping.

1.2.2 Care for Co-Morbidities

Management of liver cancer requires team efforts from a group of professionals consisting of hepatologist, surgeon, medical oncologist, interventional radiologist, nuclear medicine physician, physicist, radiopharmacist, etc. Depending on the expertise and skills required, the respective experts should assume responsibilities and manage the complications/morbidities associated with this therapy as and when required.

1.3 Dose Administration

A dosimetry protocol may be followed to determine the MTD which would not deliver more than 1.5 Gy to marrow, 30 Gy to liver or 12 Gy to Lungs. An outline of the dosimetry protocol has been provided earlier in this chapter. However it has been shown in a study conducted by the IAEA that administration of a fixed dose of 100 mCi of Re-188 Lipiodol would in general not cross the MTD and at the same time provide adequate dose to the tumour to be effective. Hence, in the absence of a patient specific dosimetry, a dose of 100 mCi of Re-188 Lipiodol is recommended. Dose is administered trans-arterially into the hepatic artery (selective or ultra-selective) through a catheter.

1.3.1 For Inpatient Therapy

All patients treated with high doses of Re-188 Lipiodol require hospitalisation. All recommendations with regard to radiation protection, waste disposal and safety should be strictly followed.

1.3.2 Post-Therapy Management

1.3.2.1 Post Therapy Imaging

Anterior and posterior whole body scans at 20 cm/min or 5 min spot chest and abdomen images should be obtained at 24 h after therapy.

1.3.3 Monitoring Tests (and Schedule)

• 1. Vital signs to be monitored and recorded before each fraction, 30 min and 1 h after end of infusion; and hourly thereafter until 3 h after the end of infusion. Patients will also be monitored for adverse events notably right upper quadrant pain, nausea and vomiting.

• 2. Serum bilirubin, ALT, albumin; and coagulation profile (PT, APTT, INR) to be obtained immediately prior to therapy, and then weekly until 4 weeks after the last treatment or until recovery from any toxicity. Subsequently, these studies will be obtained every 4 weeks.

• 3. Clinical examination and assessment every month.

• 4. AFP every month and CT scan at 2, 6 and 12 months after therapy.

1.3.4 Retreatment

Patients may receive more than one treatment. The second treatment may be considered after a period of 3–6 months. The decision to retreat the patient should be undertaken on a case by case basis after taking into consideration several factors including patient’s general condition, response to first therapy and inclusion criteria as described before.