Radioembolization

Fig. 9.1

Fifty-two-year-old male with recurrent CLM in the left lobe (liver resection was performed 4 years earlier) with liver progression despite three lines of chemotherapy. (a) Gadolinium-enhanced MRI. (b) PET-CT. (c) Hepatic angiogram at preparation phase shows tumor enhancement (dotted circle). Notice the right gastric (arrow), gastroduodenal (arrowhead) and falciform (double arrow) arteries. (d) Hepatic angiogram after gastroduodenal coil embolization (arrowhead). (e) Left hepatic angiogram clearly depicts the right gastric artery (arrow) supplying the lesser stomach curvature. (f) Left hepatic angiogram after right gastric artery coil embolization (arrow). Notice that the stomach is no longer supplied. (g) Selective angiogram of left hepatic artery (LHA) before Y90 infusion*. (h) Selective angiogram of middle hepatic artery (MHA) before Y90 infusion. (i) Follow-up PET-CT at 6 months after RE-Y90 showing complete response (no hyper metabolic activity) and calcification at the treatment site. *An ice pack was placed on the umbilical skin to induce flow arrest of distal falciform vessels (not shown)

Fig. 9.2

Seventy-eight-year-old male with recurrent isolated CLM in segment VIII despite previous surgery and two lines of chemotherapy. (a) T2-weighted MRI. (b) Gadolinium-enhanced MRI. (c) PET-CT. (d) Selective angiography of segment V and VIII shows tumor enhancement (circle). (e) Intra-arterial CBCT confirms tumor enhancement in segment VIII (dotted circle). (f) MAA tumor uptake at SPECT-CT confirming correct catheter position for treatment. (g) T2-weighted MRI. (h) Gadolinium enhanced MRI at 3-month follow-up after RE-Y90 shows treatment response by tumor lack of enhancement and shrinkage (arrows). (i, j) Follow-up contrast-enhanced CT at 15 months confirms complete tumor response

In the treatment phase, a new hepatic angiogram performed from the catheter is positioned in the exact position established during the simulation phase, and the liver vasculature is again verified in order to check the stability of the previous embolization of extrahepatic arteries and to rule out any new extrahepatic supply, preferentially using CBCT. Although uncommon, supplementary embolization may be performed if needed. In this session the Y90 microspheres are then slowly injected, mimicking the injection of Tc99-MAA at the simulation phase. The same day, before leaving hospital, a positron emission tomography (PET) or bremsstrahlung nuclear imaging is performed to check the intra arterial injected Y90 distribution.

Indications, Contraindications, and Patient Selection

RE-Y90 in CLM is reserved for patients that are not candidates for surgical resection. A Consensus Panel Report by the Radioembolization Brachytherapy Oncology Consortium provides detailed guidelines for RE-Y90 eligibility and patient selection [3]. Main indications of RE-Y90 are suited in different clinical settings such as failed first- or second-line systemic chemotherapeutic regimens, salvage or palliative treatment and neoadjuvant therapy prior to surgical resection [2, 3, 6, 8]. Recent publications showed promising results of RE-Y90 in earlier metastatic disease associated with induction and maintenance chemotherapy, including level 1 evidence of better liver progression-free survival (PFS) when FOLFOX was associated to RE as first-line treatment [9, 10].

The best candidates for RE are patients with unresectable liver-only or liver-dominant tumor burden, preserved liver function, and good general clinical status [6]. Therefore, pre-treatment evaluation includes not only a clinical and laboratory check-up but also imaging studies, including a chest CT together with a three-phase MDCT and/or gadolinium-enhanced MRI of the liver, not only for assessment of liver tumor burden but to rule out or measure extrahepatic disease. A whole-body FDG-PET/CT may contribute to decision-making due to its high sensitivity for intrahepatic and extrahepatic tumor. Furthermore, therapy–response assessment is more accurate if a metabolic imaging has been performed before the RE-Y90, as well as MDCT or MRI.

In patients with excessive tumor burden and/or limited hepatic reserve, demonstrated by elevated levels of bilirubin (>3 mg/dl), elevated liver enzymes (AST/ALT 5 × upper normal limit), altered INR (>1.6), or reduced serum albumin (<3 g/dl), RE is contraindicated because of the risk of developing radiation-induced liver failure [3–8]. Patients with poor clinical condition (Eastern Cooperative Oncology Group: ECOG >2) are also at a higher risk of developing severe side–effects, and treatment outcome is usually worse; therefore, the indication of RE is questionable in this clinical situation [3–8].

As in any other intra-arterial liver-directed therapy, the renal function and the biliary integrity should be monitored before treatment. Renal function impairment is a relative contraindication because of the use of iodine contrast media necessary to perform the diagnostic and therapeutic angiogram previous to RE-Y90. Patients with impaired biliary sphincter at the duodenum junction (biloenteric anastomoses, papillotomy, biliary stenting) may be at a higher risk of cholangitis and liver abscess formation in the follow-up weeks after RE, but this does not constitute an absolute contraindication [5, 7]. In a specific patient, these potential hazards have to be weighed against the potential benefit of the RE treatment.

In a small number of patients, RE could be contraindicated due to vascular abnormalities or the extent of lung shunting (lung exposure >30 Gy). These criteria are established at the work-up procedure performed by the interventional radiologist (preparation/simulation phase) before the RE-Y90 is confirmed, thereby preventing inappropriate treatment of the patient. The interventional radiologist may correct some cases of excessive shunting to the lung or gastrointestinal tract by proper vessel embolization, as described in previous paragraphs [6, 7]. Thus, an appropriate previous preparation/simulation test (low LSF, no extrahepatic deposits of Tc 99-MAA, acceptable dosimetry) is mandatory to perform the RE treatment safely.

Efficacy and Clinical Results

Multiple studies suggest that RE-Y90 is effective in slowing disease progression and improving survival. Localized high-dose tumor-directed radiation is an effective treatment for reducing the burden of CLM [4, 6, 8, 11–14]. A single treatment with RE induces profound cytoreduction of CLM in the liver, and significantly prolongs time to progression (TTP), PFS, and overall survival (OS), even among patients with highly chemo-refractory disease [3, 4]. The recruitment of a large proportion of these patients for RE has been among those with advanced, chemo-refractory disease [3–6, 15–17]. However, RE-Y90 has recently been shown to downsize tumors for potentially curative surgical resection in patients with earlier unresectable CLM that have received chemotherapy before or are chemo-refractory[18]. In clinical practice, RE-Y90 is integrated in the paradigm of management of CLM in three different settings: as first-line treatment, second-line treatment or as salvage therapy [4, 6, 9].

Radioembolization as First-Line Treatment

The current clinical data support the potential of RE-Y90 in downstaging and delaying liver disease progression in patients with CLM. Such findings provide opportunities to develop RE-Y90 treatment in patients with predominant liver disease to prolong first-line DFS and OS, and to impact positively on tumor downstaging for the potential of conversion to allow hepatic metastases resection [6, 9].

Two pioneering randomized clinical trials performed in the last decade showed the utility of RE-Y90 in the first-line treatment of patients with CLM, with encouraging results in terms of overall response rates (ORR), PFS, and OS [11, 12]. These studies compared the use of intra-arterial FUDR with and without RE and intravenous FU/LV with and without RE respectively, and clearly showed the benefits of RE-Y90. These studies have some limitations, such as the small size and the use of cytotoxic drugs that are not currently used as first-line treatments. To study the utility of RE-Y90 in the current paradigm of CLM chemotherapy regimens, three international randomized Phase III trials (the SIRFLOX, FOXFIRE and Global FOXFIRE) were conducted to report on the PFS and OS [10, 19, 20]. The SIRFLOX study showed improvement in liver PFS, with 31% reduction in risk of liver progression when combining RE-Y90 with FOLFOX, while not increasing toxicity [10]. The FOXFIRE and Global FOXFIRE are still on-going, and will be powered to test the impact of RE-Y90 on OS [20].

Some authors suggest the incorporation of RE-Y90 in the first-line treatment, for the purpose of extending clinical benefits from maintenance therapy [9]. Indeed, the most common approach toward unresectable CLM involves the use of induction chemotherapy combined with bevacizumab. However, chemotherapy-induced toxicities encountered with combination regimens may lead in some patients to a milder maintenance form of treatment after few weeks of induction therapy. Maintenance therapy, usually fluoropyrimidine with bevacizumab, has limited efficacy and progression occurs in few months in the majority of patients. The combination of RE-Y90 during induction therapy or during maintenance therapy has the potential to prolong liver PFS, therefore improving patient outcome and delaying the need for more toxic second-line combination treatments [9]. Interestingly enough, the European Society of Medical Oncology (ESMO) consensus guidelines suggest that RE-Y90 of CLM in earlier treatment lines may be interesting as consolidation treatment [20].

Another beneficial possibility to combine RE-Y90 in the first-line setting is in those patients who cannot tolerate intensive chemotherapy. Aged patients with CLM and vascular comorbidities may be frail enough to be considered for combination chemotherapy or antiangiogenic agents. For such patients, first-line treatment is often limited to single agent 5-FU/LV or capecitabine monotherapy, a strategy associated with a median PFS of 4–5 months [9]. The integration of RE-Y90 with fluoropyrimidine in the first-line treatment of liver-predominant CLM has the potential of delaying progression without significantly impacting patients’ performance status [9]. An advantage of RE-Y90 which should always be considered is its favorable toxicity profile when combined with fluoropyrimidine or FOLFOX, and yet it results in major clinical responses in the majority of the treated population [13].

The high efficacy of conversion therapy with aggressive chemotherapy such as FOLFOXFIRI discourages the initial use of RE-Y90 in CLM in the neoadjuvant setting, except for specific situations such as intolerance or inadequate initial response to induction chemotherapy [9]. However some authors suggest that RE-Y90 may be a good alternative in potential candidates for resection, but with small future liver remnant volume [8, 21, 22]. A matched-pair analysis comparing RE-Y90 with portal vein embolisation showed a lesser, but still pronounced benefit of RE-Y90 with regard to contralateral liver hypertrophy, following simultaneous treatment of the ipsilateral tumor load with Y90 [22].

Only gold members can continue reading. Log In or Register to continue