**5. Bridging therapies**

Due to the aggressive nature of HCC, liver transplantation is of paramount importance in the eradication of HCC and cirrhosis, as it results in a 5-year overall survival of 70% and a recurrence rate of less than 15% among patients whose HCC falls within established criteria (Decans, 2005; Wigg, 2010). However, fewer than 25% of all patients with HCC qualify for liver transplants. Due to an organ shortage, the average wait period for a liver transplant is 6-9 months. Increased waiting time for HCC patients increases the risk for tumor progression, even with priority listing, and waiting list drop-out, which is defined as withdrawal from the transplant waiting list due to death; tumor progression; or reasons such as becoming too ill for transplantation (Majno, 2010). The dropout rate for HCC patients on the waiting list is 8.7%, 16.9%, and 31.8% at 90, 180, and 365 days respectively. As the doubling time for HCC is approximately 6 months without treatment (Lee, 2007), increased waiting time for transplantation is problematic, and Model for End-Stage Liver Disease (MELD) exception points have been implemented to combat this issue. Since the institution of the MELD system in 2002, transplant candidates with HCC are applicable for listing prioritization via MELD exception points. Patients with HCC within Milan criteria (MC) and in some regions, San Francisco criteria, are granted a MELD exception of 22, followed by upgrades to 25 and 28 every 3 months provided that their tumor burden remains within range. MC is defined as 1 lesion ≤ 5 cm or up to 3 lesions ≤ 3 cm. Exception points result in shorter time to transplant – in 2007, approximately 62% of patients nationwide underwent transplantation within 3 months of receiving exception points for HCC (Yao, 2008). However, this system can be controversial, as some believe that tumors do not adequately degenerate between the time of ablative therapy and transplantation and that it is safer to wait 6 months after bridging before the patient is transplanted (Roberts, 2010). Others argue that tumor size limits are excessively exclusive and that Milan criteria should be expanded to include a larger tumor burden (Yao, 2008). While patients wait for transplant, loco regional ablative therapy, or bridging therapy, in the form of modalites such as Transarterial Chemoembolization (TACE) and Radiofrequency Ablation (RFA) is often employed with the goals of decreasing the waiting list dropout rate; decreasing the rate of tumor recurrence post transplant; and increasing long term survival after transplant (Lee, 2007). The BCLC staging and treatment strategy incorporates the different ablative therapies in patients with early stage (0); early stage (A); and intermittent stage (B) HCC.

#### **5.1 Goal of ablative therapies**

Bridging therapy for HCC serves the following roles: 1) to downstage HCC in patients whose tumor burden is outside MC to make the patient transplantable; 2) to prevent disease progression in patients within MC as they await transplant; and 3) to provide palliative and curative therapy in patients who are not OLTx candidates (Table 1). Bridging therapy can also improve the results of transplantation by excluding patients with recurrent disease or unfavorable tumor biology (Majno, 2010). An example of an integral management of HCC is shown in Graph 1.

> Downstaging to Milan/ UCSF criteria Prevent disease progression on the wait list Prevent dissemination during liver manipulation at transplant surgery Tumor therapy in non transplant/ non surgical candidates Palliative therapy

Table 1. Goal of bridging therapies

(Decans, 2005; Wigg, 2010). However, fewer than 25% of all patients with HCC qualify for liver transplants. Due to an organ shortage, the average wait period for a liver transplant is 6-9 months. Increased waiting time for HCC patients increases the risk for tumor progression, even with priority listing, and waiting list drop-out, which is defined as withdrawal from the transplant waiting list due to death; tumor progression; or reasons such as becoming too ill for transplantation (Majno, 2010). The dropout rate for HCC patients on the waiting list is 8.7%, 16.9%, and 31.8% at 90, 180, and 365 days respectively. As the doubling time for HCC is approximately 6 months without treatment (Lee, 2007), increased waiting time for transplantation is problematic, and Model for End-Stage Liver Disease (MELD) exception points have been implemented to combat this issue. Since the institution of the MELD system in 2002, transplant candidates with HCC are applicable for listing prioritization via MELD exception points. Patients with HCC within Milan criteria (MC) and in some regions, San Francisco criteria, are granted a MELD exception of 22, followed by upgrades to 25 and 28 every 3 months provided that their tumor burden remains within range. MC is defined as 1 lesion ≤ 5 cm or up to 3 lesions ≤ 3 cm. Exception points result in shorter time to transplant – in 2007, approximately 62% of patients nationwide underwent transplantation within 3 months of receiving exception points for HCC (Yao, 2008). However, this system can be controversial, as some believe that tumors do not adequately degenerate between the time of ablative therapy and transplantation and that it is safer to wait 6 months after bridging before the patient is transplanted (Roberts, 2010). Others argue that tumor size limits are excessively exclusive and that Milan criteria should be expanded to include a larger tumor burden (Yao, 2008). While patients wait for transplant, loco regional ablative therapy, or bridging therapy, in the form of modalites such as Transarterial Chemoembolization (TACE) and Radiofrequency Ablation (RFA) is often employed with the goals of decreasing the waiting list dropout rate; decreasing the rate of tumor recurrence post transplant; and increasing long term survival after transplant (Lee, 2007). The BCLC staging and treatment strategy incorporates the different ablative therapies

in patients with early stage (0); early stage (A); and intermittent stage (B) HCC.

Downstaging to Milan/ UCSF criteria Prevent disease progression on the wait list

Bridging therapy for HCC serves the following roles: 1) to downstage HCC in patients whose tumor burden is outside MC to make the patient transplantable; 2) to prevent disease progression in patients within MC as they await transplant; and 3) to provide palliative and curative therapy in patients who are not OLTx candidates (Table 1). Bridging therapy can also improve the results of transplantation by excluding patients with recurrent disease or unfavorable tumor biology (Majno, 2010). An example of an integral management of HCC is

Prevent dissemination during liver manipulation at transplant surgery

Tumor therapy in non transplant/ non surgical candidates

**5.1 Goal of ablative therapies** 

Palliative therapy

Table 1. Goal of bridging therapies

shown in Graph 1.
