Modelamiento del Negocio

4.2.2.1 Primary cancer of the liver

Therapy with curative intent can only be offered to approximately 30% of patients presenting with HCC⁵¹. Resection is usually offered to patients without cirrhosis, as long as there is no evidence of portal vein involvement or extra-hepatic spread. Liver failure following resection is a major concern in cirrhotic patients, and for the best results surgery should be restricted to patients with Child Pugh class A cirrhosis, who have a normal bilirubin and no evidence of portal hypertension (no varices, splenomegaly or

thrombocytopenia)⁵¹. In carefully selected patients, surgical resection can result in 5 year survival of approximately 70%⁵⁶. However, approximately 70% of patients will have a recurrence of HCC within 4 years of surgical resection⁵⁶. Initial experience with liver

transplantation was poor with high recurrence rates when liver transplantation was employed as a salvage procedure for patients with large tumours who were not candidates for surgical resection. The landmark study of Mazzaferro, et al. demonstrated that carefully selected HCC patients with small tumours could do as well as other liver transplant recipients

without HCC⁵⁷. Survival rates in excess of 70% at 5 years with recurrence rates of <20% are expected if the Milan criteria (1 tumour < 5cm or 3 tumours each <3 cm) are used to select patients for liver trnasplantation⁵⁸. Patients who are treated with resection or liver

transplantation often require several months to convalesce after the operation. Patients with HCC who are awaiting a liver transplant are often too ill to continue working and often do not return to work until at least 6-12 months after transplant. With median waiting times for liver transplantation being more than one year, a patient can be on long-term disability for a considerable period of time while they await and recover from liver transplantation surgery.

Percutaneous radiofrequency ablation (RFA) is an increasingly common technique used to treat patients with small tumours (<5 cm) where by the tumour is destroyed using thermal energy administered by a probe introduced under ultrasound guidance. RFA is a day procedure and is better tolerated then surgery. HCC 2cm can be successfully ablated in 97% of subjects and survival rates comparable to surgical resection have been reported for RFA of very early stage HCC⁵⁹. However, recurrence rates are higher for RFA compared to surgery, especially if tumours are larger than 3 cm. Recent meta-analysis have shown that RFA is superior to percutaneous ethanol injection (PEI) in ablating small tumours⁶⁰, but the later technique may still be employed if the HCC is near the liver capsule or blood vessels (where heat sink can occur with RFA).

For patients who are not candidates for resection, ablation or transplantation, treatment options currently employed include TACE, TARE and sorafenib. The proper selection of therapy depends on a variety of tumour and patient factors. TACE has been shown in meta-analysis to improve survival in patients with intermediate stage HCC (large or

multifocal HCC with no extrahepatic spread)⁶¹. There is no standard technique for performing TACE, and although generally well tolerated TACE can result in 2-3% peri-procedural mortality related to complications of the procedure⁶². TACE is best avoided in patients with portal vein thrombosis as there is an increased risk of liver failure due to ischemia. TACE performed with doxorubicin emitting beads (DC TACE) may be better tolerated and result in improved outcomes in a subgroup of patients (eg. Child Pugh class B cirrhosis or ECOG PS =1)⁶³. For patients with advanced HCC (malignant portal vein involvement or extrahepatic spread) sorafenib has been shown to result in a small but significant increase in life expectancy compared to placebo (10.7 vs. 7.9 months median survival)⁶⁴. Sorafenib therapy is generally well tolerated, but frequently causes hypertension, diarrhea and hand-foot reactions and it costs ~$5400 per month. Technological

advancements have allowed the delivery of tumouricidal doses of radiation to the liver while sparing normal liver tissues, although this technique is not widely available in Alberta.

TARE was developed as a new technique with the potential to deliver aggressive local radiation effects on the tumour with fewer systemic side-effects. Preliminary evidence would suggest that both TACE and TARE may also play a role in bridging patients to resection, ablation or transplantation.

4.1.2.2 Secondary cancer of the liver

Metastatic Colorectal Carcinoma

The history of care for mCRC patients was relatively stable until the late 1990s and early 2000s. With 5-Fluorouracil (5-FU) introduced in 1957 and the subsequent development of the biomodulator leucovorin (LV), the 5-FU/LV regimen of chemotherapy was the

standard of care until very recently⁶⁵. Median survival time for patients receiving 5-FU/LV was 12 months. The development of both irinotecan and oxaliplatin, which in clinical trials have shown to extend survival on average 8 months over the 5-FU/LV regimen, have shifted the standard of care to newer regimens that include one or both of these agents⁴². These agents are expensive, and account for the majority of increased treatment costs seen in mCRC. Regimens including FU/LV and either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) have consistently been shown to improve survival, albeit with increased toxicity.

Different iterations of the FOLFOX regimen exist, with the method and time frame of drug delivery and the dose of oxaliplatin varying, numbers are used to differentiate the regimens with FOLOFX6 being the most current. In a pivotal randomized phase III study by

Tournigand et al. (2004)⁶⁶, patients either received FOLFIRI or FOLFOX6 regimens as first line therapy and then crossed over to the other arm, to receive second line therapy with the other chemotherapy regimen, once unacceptable toxicity or disease progression was

observed. Hence, patients received both FOLFIRI and FOLFOX6 regimens. Overall survival was 21.5 months for the patients who received FOLFIRI first and 20.6 months for patients receiving FOLFOX6 first. This study was the first to demonstrate an overall

survival in excess of 20 months. It is important to note that in this study 84% of patients had liver metastases. Subsequent studies demonstrated that the greatest survival benefits are observed when patients are exposed to all three chemotherapy agents currently considered for standard of care (i.e. FU/LV, oxaliplatin and irinotecan)⁶⁵. In general, toxicities and SAE are higher with these new regimens than with 5-FU/LV, but the survival benefit seems to outweigh the potential risks of therapy. Additionally, the safety profiles of FOLFIRI and

FOLFOX differ with FOLFIRI having significantly more SAE (i.e. mucositis, nausea/vomiting, alopecia) but FOLFOX having more grade 3 and 4 toxicities (i.e.

neutropenia and neurosensory)⁶⁵. Choice on which regimen to use is governed by patient and physician preference. Newer biologic agents have also been shown to increase survival times when combined with chemotherapy regimens. Bevacizumab, a monoclonal antibody, when combined with chemotherapy regimens has been shown to increase median survival times by approximately three to four months, when added to FOLFIRI/FOLFOX regimens it is approximated that a median survival time of 23 months could be reached⁶⁷.

Metastatic Neuroendocrine Tumours

The frequency and severity of hepatic metastases from mNET and the associated hormone production and protracted clinical course make a large number of treatment options possible⁴⁵. As with HCC, surgical resection or transplantation are the treatments of choice for eligible patients. Typically, only 10% of patients will be candidates for surgical resection due to the extent of disease. Unfortunately, even for those who are candidates, frequent recurrence of disease after resection occurs and is evidence of the persistent nature of these tumours⁴⁵. For patients not candidates for surgery, RFA, transarterial embolization (TAE), TACE and systemic chemotherapy are all possible treatment options. Treatment with any of these therapies is based on the extent of disease progression, and like with HCC and CRCLM, patients that have large tumours (>3cm) and poor underlying liver function face a poor prognosis. If TACE or TAE are selected they are performed according to the same protocol used for HCC.

4.2.2. Procedures Overview and Trends

4.2.2.1. Standard Care

HCC is usually diagnosed in cirrhotic individuals as a suspicious nodule on

ultrasound. Dynamic contrast imaging with CT, MRI or contrast enhanced ultrasound (along with AFP) is used to establish the diagnosis. Liver biopsy is rarely required to make the diagnosis. These tests are also used to determine the extent of disease in the liver and if there is extra-hepatic dissemination. A standard battery of tests are done to measure the patient’s liver and renal function. In Alberta, the standard staging criteria followed is the BCLC staging criteria (see Appendix I). A guideline for the treatment of HCC has been developed for Alberta Health Services by the Provincial Gastrointestinal Tumour Team⁶⁸. A

multidisciplinary team should decide on resectability, transplantation or RFA.

Non-resectable, intermediate stage, patients without extra-hepatic disease and no main portal vein thrombosis are potential candidates for treatment with TACE. The typical BCLC

intermediate stage patient, that would be a candidate for TACE, should have good underlying liver function (Child-Pugh A or B) and performance status (ECOG = 0 or 1).

The tumour characteristics for this stage would include multinodular disease, absence of extra-hepatic metastases, patency of the portal vein and adequate liver and kidney function.

The goal of therapy is to maintain or to improve the patient’s quality of life, and to prolong life if possible.

TACE, like TARE, relies on the fact that most of the blood supply to the tumour is preferentially derived from the hepatic artery. It involves the placement of an intravascular catheter into the hepatic artery, using a femoral approach, then injecting chemotherapeutics

and embolic agents, which occlude the relevant branches of the hepatic artery. TACE targets tumours in two fashions. There is an ischemic effect on the tumour, which results from the embolization of feeding arteries, and there is a chemotherapeutic effect from the drug regimen. There is no consensus on how to perform TACE or on which chemotherapy agent is best⁶². If doxorubicin is considered, assessment of left ventricular ejection function by a multi gated acquisition scan (MUGA) or cardiac ultrasound is suggested prior to the procedure. TACE is performed as an inpatient procedure with a median hospital stay of 4 days (IQR 3-5 days, range 2-25 days) at the Foothills Medical Centre in Calgary. The length of inpatient stay is dependant on extent of post-embolization syndrome and side effects of chemotherapy.

Sorafenib is the standard of care for patients with advanced HCC. Sorafenib is an orally active inhibitor of multiple cell surface tyrosine kinases. In two placebo controlled trials involving over 800 patients demonstrated an increased overall survival of 2-3 months^{64, 69}.

The Provincial Gastrointestinal Tumour Team felt that the role of TARE was yet to be determined and it was not included in the clinical practice guidelines. Some members of the team believed TARE however may have a role in patients who are not candidates for TACE (i.e. those with portal vein thrombosis (PVT) etc), in patients with very large tumours or in patients who have failed TACE.

The Provincial Gastrointestinal Tumour Team has also developed clinical practice guidelines for the treatment of mCRC in Alberta¹⁴. Metastatic colorectal cancer describes the situation where a cancer that originated within the colon or rectum (and, often, regional

lymph nodes) has spread to other organs (typically, the liver and/or lungs). “Generally, this represents an incurable situation for which palliative options (e.g. best supportive care, palliative chemotherapy) may be considered”¹⁴. “In the situation where the liver represents the major site of spread (CRCLM), and resection of metastases would be facilitated by a reduction in the size of the liver metastasis, patients should be treated with chemotherapy to optimal resectability rather than to maximal response or progression”¹⁴. “Only a limited number of chemotherapy cycles should be delivered to minimize the consequences to normal liver tissue and their resultant adverse effects post-liver metastastectomy”¹⁴. The goals of therapy in this case include maximizing the patients’ quality of life, and prolonging survival.

As mentioned in section 4.1.2.2., standard palliative chemotherapy for treatment of CRCLM, has shifted from the exclusive 5-FU/LV regimen to the newer FOLFIRI and FOLFOX6 regimens which include agent’s irinotecan and oxaliplatin respectively. As outlined in the provincial clinical guidelines, sequences of therapy may include FOLFIRI followed by FOLFOX6, FOLFOX6 followed by FOLFIRI, FOLFOX6 followed by irinotecan or a combination of other drug administrations and sequences. For the purposes of this report, standard of care for CRCLM patients will be restricted to FOLFIRI and FOLFOX6 regimens. The FOLFIRI regimen includes the concurrent administration of 180mg/m² of irinotecan over 90 minutes, with 200mg/m² leucovorin over two hours followed by a bolus of 400mg/m² of 5-Fluorouracil, all given intravenously. A continuous administration, over forty-six hours, of 2,400mg/m² 5-Fluorouracil is then given every two weeks intravenously¹⁴. If a patient progresses on FOLFIRI they are typically switched to a

FOLFOX6 regimen. The FOLFOX6 regimen is identical to the FOLFIRI regimen with the exception that 100mg/m² of oxaliplatin, over two hours, is administered instead of

irinotecan¹⁴. Again, progression on this regimen usually constitutes a switch to FOLFIRI or irinotecan. It is noted in the guidelines, that due to oxaliplatins propensity to cause sensory neuropathy, the preferential sequence involves non-oxaliplatin regimens first (i.e. FOLFIRI) and then at disease progression a switch to an oxaliplatin containing regimen¹⁴. The sequence of FOLFIRI then FOLFOX6 or vice versa has been shown to be equivalent in terms of survival benefit⁶⁶.

Provincial guidelines for the treatment of mNET have not been developed. As mentioned in 4.1.2.2. many treatment options exist for mNET with TAE and TACE being the standard care for non-resectable or ablatable patients. For patients with rapidly

advancing disease, or TACE failures, palliative chemotherapy is also offered.

4.2.2.2. TARE

As mentioned previously, patients with non-resectable tumours that have limited extra-hepatic disease and good underlying liver function are potential candidates for treatment with TARE. Additionally, patients are evaluated for hepatic vascular anatomy, arteriovenous shunting, renal function and the general ability to tolerate the implanted radiation. The careful selection of patients is crucial for treatment safety, as adverse events are directly related to patient suitability. As many of the pre-treatment assessments require radiological evaluation, a radiological work up is highly recommended for all patients considered for treatment. The pre-treatment work up should include the following tests:

 hepatic angiogram

 combined angiogram/CT scan

 possible embolization of the gastro-duodenal or other artery that might result in inadvertent delivery of microspheres

 MAA nuclear medicine SPECT scan to calculate a shunt fraction

 Tests of liver function

If a patient is considered suitable after all pre-treatment evaluation, the procedure is scheduled and the microspheres are ordered. The specific dosing information and ordering process for obtaining the spheres is discussed in section 5.1.1. The TARE procedure is an outpatient procedure, albeit a long one. At Stanford Medical Center, the patient is told that the first angiographic/radiological workup will take 12 hours and the second (injection of microspheres) will consume 6 hours of time. This time is spread over a two day period. On the day of treatment, the patient is asked to arrive approximately two hours before the procedure is scheduled. Typically paperwork, medical history and allergy information is taken and an IV containing anti-nausea medication and a mild steroid to reduce possible side effects is administered. Routine lab work is performed prior to moving the patient to the appropriate angiography suite. The patient is also required to not eat or drink for a specified time the night before the procedure⁷⁰.

In the angiography suite, the interventional radiologist inserts a catheter into the femoral artery and to the liver. An angiogram is taken to ensure the catheter is properly placed in the hepatic artery. Once the catheter is in place, the microsphere dose and delivery set is brought into the suite and attached to the catheter (see Appendix IX). The

microspheres are then infused under fluoroscopy. The infusion takes approximately 20 minutes.

After infusion of the microspheres, the catheter is removed and the artery sealed.

The incision leaves a small mark in the groin area, which is cleaned and bandaged prior to relocation to the recovery room. The patient needs to lie flat for two to four hours while staff monitor and provide post-procedure instructions including radiation safety guidelines.

If all goes according to plan, the patient is allowed to return home the same day. Many patients experience nausea or flu-like symptoms which generally subside in three to four days.

4.2.2.3 Comparators

The two comparators for TARE with respect to standard of care for HCC patients in Alberta are TACE (intermediate stage patients), and sorafenib (advanced staged

patients)⁶⁸. TACE and TARE are very similar procedures and involve many of the same pre-treatment evaluations, equipment, techniques, staff and support. The main differences between TACE and TARE, with respect to procedure protocol, is the additional angiogram required for TARE, the actual infusion of microspheres and the precautions that must be taken to assure that the radioactive material is set up, handled and stored properly. Of importance is the fact that TACE is performed as an inpatient procedure, while TARE is typically an outpatient procedure.

The two most appropriate comparators for TARE with respect to standard of care for CRCLM patients in Alberta are systemic and regional chemotherapy. A variety of

chemotherapy drug regimens exist, the most commonly employed regimens being FOLFIRI and FOLFOX6.

No comparator was selected for mNET, as no clinical guidelines exist for standard of care in Alberta, and due to the relatively diverse array of treatment options (including systemic and regional chemotherapy regimens). For patients that do not respond to chemotherapy, RFA, TACE and TARE have all been used as standard of care. These procedures are performed in a fashion consistent with what is described for HCC.

4.2.3. Access to Technology in Alberta

Access to TARE in Alberta is assumed to parallel access to TACE, although

currently TARE is only performed in Edmonton. As the protocol for these two procedures is almost identical, it is assumed that access to the technology would be similar as well. As such, it is anticipated that there will be no barriers to care in terms of waitlists or utilization.

The main consideration relevant to access is the fact that TARE will likely only be

performed in Calgary or Edmonton requiring patients to travel to these centers if they live in other jurisdictions.

4.2.4. Demand for Technology

Demand for TARE is anticipated to be limited, at least initially, to the cancer types identified in the report (i.e. HCC, CRCLM and mNET), although TARE has and is used in other cases of metastatic disease (i.e. breast, lung, eye etc). Using AHW data, in 2008, it was estimated that 1,422 patients had hepatic neoplasia in Alberta^a (i.e. HCC, secondary

malignant neoplasm of the liver, carcinoid syndrome). Another 1,266 Albertans were

a Both physician and inpatient claims data were used for all prevalence, incidence and demand estimates and

diagnosed with CRC, many of which will develop CRCLM at some point. These numbers represent the largest demand possible for TARE (in 2008) and obviously are not realistic, given the curative therapies available for those patients in early disease stages. However, as TARE may play a role in maintaining patients on transplant waitlists or prior to resection or

diagnosed with CRC, many of which will develop CRCLM at some point. These numbers represent the largest demand possible for TARE (in 2008) and obviously are not realistic, given the curative therapies available for those patients in early disease stages. However, as TARE may play a role in maintaining patients on transplant waitlists or prior to resection or