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Hepatic tumors can arise either as primary liver cancer or by metastasis to the liver from other tissues. Local therapy for hepatic metastasis is indicated only when there is no extrahepatic disease, which rarely occurs for patients with primary cancers other than colorectal carcinoma or certain neuroendocrine malignancies. At present, surgical resection with tumor-free margins or liver transplantation represents the only treatments with curative potential. For liver metastases from colorectal cancer, post-surgical adjuvant chemotherapy has been reported to decrease recurrence rates and prolong time to recurrence. However, most hepatic tumors are unresectable at diagnosis, due either to their anatomic location, size, number of lesions, or underlying liver reserve. Combined systemic and hepatic arterial chemotherapy may increase disease-free intervals for patients with hepatic metastases from colorectal cancer, but apparently is not beneficial for those with unresectable hepatocellular carcinoma.
Various loco-regional therapies for unresectable liver tumors are being studied, including cryosurgical ablation (cryosurgery), radiofrequency ablation (RFA), laser ablation, trans-hepatic artery embolization/chemoembolization, microwave coagulation, and percutaneous ethanol injection (PEI).
Radiofrequency Ablation (RFA)
In RFA, a probe is inserted into the center of a tumor and non-insulated electrodes, which are shaped like prongs, are projected into the tumor; heat is generated locally by a high frequency, alternating current that flows from the electrodes. The local heat treats the tissue adjacent to the probe resulting in a 3 cm to 5.5 cm sphere of dead tissue. The cells killed by RFA are not removed, but are gradually replaced by fibrosis and scar tissue. If there is local recurrence, it occurs at the edge, and in some cases may be retreated. RFA may be performed percutaneously, laparoscopically, or as an open procedure.
RFA has been investigated as a treatment for unresectable hepatic tumors, both as primary treatment and as a bridge to liver transplant. In the latter setting, it is hoped that RFA will reduce the incidence of tumor progression, and thus maintain a patient's candidacy for liver transplant during the wait time for a donor organ.
Cryosurgical Ablation
Cryosurgical ablation involves the freezing of target tissues, most often by inserting a probe into the tumor through which coolant is circulated. Cryosurgical ablation is typically performed as an open surgical technique but can be performed percutaneously or laparoscopically, all with ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT) guidance.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Radiofrequency ablation (RFA)
Radiofrequency ablation (RFA) of primary hepatocellular carcinoma (HCC) may be considered medically necessary:
Radiofrequency ablation (RFA) of hepatic metastatic tumors may be considered medically necessary when:
Radiofrequency ablation (RFA) is considered experimental, investigational and unproven for all tumors that do not meet the above criteria including, but not limited to, procedures performed to reduce tumor size so that a patient will meet eligibility criteria to become a transplant candidate.
Cryoablation of either primary or metastatic liver tumors is considered experimental, investigational and unproven.
Radiofrequency Ablation as a Primary Treatment of Unresectable Hepatocellular Liver Cancer
A 2003 TEC Assessment (1) addressed radiofrequency ablation (RFA) in the treatment of unresectable primary or metastatic liver tumors.
One of the first methods devised to ablate liver tumors involved percutaneous ethanol injection (PEI). Several nonrandomized trials in the 1990s confirmed that PEI could safely achieve complete necrosis in small hepatocellular cancers (HCCs), with 5-year survival rates of 32-38%. (2) However, the technique had several drawbacks, including the need for multiple treatment sessions and a high local progression rate of 17-38%. (2) Several randomized controlled trials (RCTs) have compared PEI and RFA in the treatment of small HCC. A systematic review of randomized trials for HCC treated with percutaneous ablation therapies was conducted by Cho and colleagues. (3) The authors identified 4 RCTs involving 652 patients that compared RFA with PEI. The review concluded that RFA demonstrated significantly improved 3-year survival in patients with HCC compared to ethanol injections. The majority of patients in these studies had one tumor, and more than 75% of the tumors were 3 cm or smaller in size. The 3-year survival with RFA ranged from 63 to 81%.
A review by McWilliams et al. reports that complete ablation rates for small to medium HCC exceed 80% in a single treatment session, and exceed 90% with 2 sessions. (2) Five-year survival rates in the largest studies are 40-58%, and local progression after complete ablation is uncommon (1-12%). (2)
Radiofrequency Ablation in the Transplant Setting for Unresectable Hepatocellular Cancer
In 2002, the United Network for Organ Sharing (UNOS) introduced a new liver allocation system—model for endstage liver disease (MELD)—for adult patients awaiting liver transplant. (4) The MELD score is a continuous disease severity scale incorporating bilirubin, prothrombin time (i.e., International Ratio for Prothrombin Activity [INR]), and creatinine into an equation, producing a number that ranges from 1 to 40. Aside from those in fulminant liver failure, donor livers are prioritized to those with the highest MELD number. This scale accurately predicts the risk of dying from liver disease except for those with HCC, who often have low MELD scores since bilirubin, INR, and creatinine levels are near normal. Therefore, patients with HCC are assigned additional allocation points according to the size and number (T stage) of tumor nodules, as follows:
In considering how to allocate the scarce donor organs, UNOS sought to balance risk of death on the waiting list against risk of recurrence after transplant. Patients with T1 lesions were considered at low risk of death on the waiting list, while those with T3 lesions are at high risk of post-transplant recurrence. Patients with T2 tumors have an increased risk of dying while on the waiting list compared with those having T1 lesions and an acceptable risk of post-transplant tumor recurrence. Therefore, UNOS criteria prioritize T2 HCC by allocating additional points equivalent to a MELD score predicting a 15% probability of death within 3 months. The definition of T2 lesions are often referred to as the "Milan criteria," in reference to a key 1996 study that examined the recurrence rate of HCC according to the size of the initial tumor. (5) Note that liver transplantation for those with T3 HCC is not prohibited, but these patients do not receive any priority on the waiting list. All patients with HCC awaiting transplantation are reassessed at 3-month intervals. Those whose tumors have progressed and are no longer T2 tumors will lose the additional allocation points.
Therefore, the UNOS allocation system provides incentives to use locoregional therapies in two different settings:
These two indications are discussed further here. It should be noted that the UNOS policy appears to implicitly recognize the role of locoregional therapy in the pretransplant setting. For example, section 22.214.171.124 ( i ) of the UNOS policy regarding the workup of patients with HCC states, as follows, "In addition, the patient must have at least one of the following: vascular blush corresponding to the area of suspicion seen on the above imaging studies, an alpha-fetoprotein level of >200 ng/mL, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of lesion, radiofrequency, cryo, or chemical ablation of lesion." (4)
Locoregional Therapy as a Technique to Prevent Tumor Progression While on the Waiting List
Several prior studies have reported drop-out rates of wait-listed patients treated with locoregional therapy. However, lacking controlled data, it is difficult to assess contributions of locoregional therapy to time on the waiting list. In addition, in 2002, as discussed above, UNOS revised its liver allocation policy, such that wait times for patients with HCC meeting the "Milan criteria" have now declined.
The majority of the literature has focused either on transcatheter arterial chemoembolization (TACE) or a variety of locoregional therapies. Given these limitations, the following case series have been reported. Fisher and colleagues reported on 33 patients who received multimodality ablation therapy, consisting primarily of RFA or TACE. Five patients (12%) were removed from the waiting list after waits of 5 to 14 months. (6) In this protocol, patients with tumors larger than 5 cm were not considered transplant candidates until the tumor was completely ablated using TACE, RFA, or another technique. Yamashiki and colleagues reported on 288 patients given various ablative therapies; the dropout rate due to tumor progression at 1 and 3 years was 6.2% and 23%, respectively. Tumors greater than 3 cm affected the dropout rate due to tumor progression. (7) Mazzaferro et al. reported on 50 patients with HCC who underwent RFA while awaiting transplantation; no patient had to be removed from the waiting list due to tumor progression over a mean wait time of 9.5 months. (8) The median tumor size was 3 cm, and 80% of patients met the Milan criteria. Similarly, Lu and colleagues reported on 52 patients who underwent RFA as a bridge to transplantation, 42 of whom met the Milan criteria. (9) After a mean of 12 months, 5.8% had dropped off the waiting list due to tumor progression.
In a 2008 paper, Belghiti and colleagues reviewed the literature reporting efficacy of local management approaches including resection, TACE, RFA, and no treatment. (10) They concluded that RFA can induce complete necrosis in the majority of small tumors (<2.5 cm), and that there is no data demonstrating that the treatment reduces the rate of drop out before transplantation or improves the survival after transplant. None of the studies included data from U.S. centers for patients listed after adoption of the Milan criteria. Porrett et al. retrospectively compared 31 patients treated with RFA with 33 untreated (U) controls. (11) Study endpoints included patient and disease-free survival, tumor recurrence, explant tumor viability, and the ability of magnetic resonance imaging (MRI) to detect viable tumor after therapy. Both cohorts had similar demographic, radiographic, and pathologic characteristics, although untreated patients waited longer for transplantation (119 [U] vs. 54 [RFA] days after MELD assignment) (p=0.05). Only 20% of treated tumors demonstrated complete ablation (necrosis) as defined by histologic examination of the entire lesion. Only 55% of lesions with histologic viable tumor were detected by MRI after pretransplant therapy. After 36 months of follow-up, there was no difference between the treated and untreated groups in overall survival (84 vs. 91%), disease-free survival (74% vs. 85%), cancer recurrence (23% vs. 12%), or mortality from cancer recurrence (57% vs. 25% —all respectively) (p>0.1). The authors concluded that viable tumor frequently persists after pretransplant locoregional therapy and neoadjuvant treatment does not appear to improve post-transplant outcomes in the current MELD era.
Current UNOS policy on allocation of livers indicates that candidates whose tumors have been ablated after meeting the criteria for additional MELD/PELD (PELD - calculator for persons under age 12 years) points will continue to receive additional points (equivalent to a 10% increase in mortality) every 3 months without review, even if the estimated size of residual viable tumor falls below stage T2 criteria. The policy also notes that candidates may be removed from the listing if they are determined to be unsuitable for transplantation based on progression of HCC.
Locoregional Therapies to Downgrade HCC Prior to Transplant
Radiofrequency Ablation to Downstage HCC Prior to Transplant
Yao et al. analyzed longer-term outcome data on HCC downstaging in a cohort of 61 patients with tumor stage exceeding T2 criteria enrolled between June 2002 and January 2007. (12) Eligibility criteria for downstaging included: 1) one lesion larger than 5 cm and up to 8 cm; 2) 2 to 3 lesions with at least 1 lesion larger than 3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or 3) 4 to 5 lesions with none larger than 3 cm, with total tumor diameter up to 8 cm. TACE and laparoscopic RFA (LRFA) either alone or in combination were the main methods used: 11 patients received LRFA alone, 14 received TACE and LRFA, and 9 received TACE and percutaneous RFA. A minimum observation period of 3 months after downstaging was required before liver transplant. Tumor downstaging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) received liver transplant, including 2 with live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent transplant, 13 had complete tumor necrosis, 17 met T2 criteria, and 5 exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after downstaging were 87.5% and 69.3%, respectively. The 1-year and 4-year post-transplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median post-transplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein greater than 1,000 ng/mL. From this small series, the authors conclude that successful downstaging can be achieved with excellent post-transplant outcomes.
A national conference involving transplant physicians was held to better characterize the long-term outcomes of liver transplantation for patients with HCC and to discuss the policy of assigning increased priority for candidates with stage T2 HCC on the transplant waiting list in the U.S. Goals of the conference were to standardize pathology reporting, develop specific imaging criteria, expand the Milan Criteria (the criteria used to measure tumor size to determine if a patient qualifies for transplant), discuss locoregional therapy, define criteria for downstaging transplantation, and review current liver allocation system for HCC patients. Pomfret and colleagues summarized the conference findings and recommendations. (13)
The workgroup on locoregional therapy found compelling evidence that pretransplant locoregional therapy decreases wait-list dropout, especially for patients who wait longer than 3-6 months for transplant. They note "there is a paucity of data comparing radiofrequency ablation (RFA) with transarterial therapies for the treatment of HCC prior to liver transplant and most single-center trials have a mixture of [locoregional therapies] included in the study population" and that, while early studies suggested a high rate of tumor seeding with percutaneous RFA, it is rare in larger series from experienced centers. The workgroup considering evidence to support expansion of MELD criteria for patients with HCC reported wide regional variation in the risk of death for patients without HCC. The "MELD score of the non-HCC patients was quite low in some regions. Post-transplant survival in HCC patients ranged from 25% in regions with few non-HCC patients with high MELD scores to greater than 70% in regions in which there was a greater need for liver transplant (higher MELD scores) in the non-HCC population." The workgroup observed that there is extreme variability of the time to transplantation of patients with HCC in the country suggesting that management of patients on the wait-list and outcomes may vary. In addition, "Concern has been raised that short times to liver transplant may lead to an increase in post-transplant recurrence because the tumor biology [aggressiveness] has not had enough time to be expressed. The lack of national data on recurrence rates limits one's ability to study this national experiment of nature based on the divergent waiting times for transplantation for HCC." There was agreement that the allocation policy should result in similar risks of removal from the waiting list and similar transplant rates for HCC and non-HCC candidates. In addition, the allocation policy should select HCC candidates so that there are similar post-transplant outcomes for HCC and non-HCC recipients. There was a general consensus for the development of a calculated continuous HCC priority score for ranking HCC candidates on the list that would incorporate the calculated MELD score, alpha-fetoprotein, tumor size, and rate of tumor growth. Only candidates with at least stage T2 tumors would receive additional HCC priority points. The paper discusses pretransplant local regional therapy to allow patients to maintain transplant candidacy, as well as to downstage to meet MELD criteria. The workgroup on the role of downstaging in transplant candidates with HCC noted inconsistent outcomes reported in the literature and proposed a definition of downstaging that would include TACE and various ablative techniques but not resection. The group noted that only 2 regions have adopted a downstaging protocol.
Yao and colleagues reported on a case series of 30 patients with HCC who underwent locoregional therapy specifically to downstage tumors to meet the University of California San Francisco (UCSF) criteria. (14) Eligibility for locoregional therapy seeking to downstage patients included either 1) 1 nodule between 5 and 8 cm in diameter; 2) 2 or 3 nodules with at least 1 between 3 and 5 cm in diameter, with a sum of diameters no greater than 8 cm; or 3) 4 or 5 nodules all less than or equal to 3 cm, with a sum of diameters less than 8 cm. Among the 30 patients, 21 (70%) met the criteria for locoregional therapy and 16 of these were successfully down-staged and underwent transplantation. No tumors recurred at a median follow-up of 16 months. The authors concluded that downstaging can be successfully achieved in most patients but that data regarding tumor recurrence requires longer follow-up.
Locoregional Therapies to Reduce Risk of Recurrence in Those with T3 tumors
An additional indication for locoregional therapies focuses on their use in patients with T3 tumors, specifically to reduce the incidence of recurrence post-transplant. If the incidence of recurrence can be reduced, then advocates have argued that the UNOS allocation criteria should not discriminate against patients with larger tumors. (15-19) Certainly some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in the seminal 1996 study, (5) the 4-year recurrence-free survival was 92% in those who met the "Milan criteria" compared to 59% in those who did not; additional studies confirm this difference in recurrence-free survival rate. (15) However, other institutions have reported similar outcomes with expanded criteria. For example, Yao and colleagues at University of California at San Francisco reported similar recurrence-free survival after transplant in patients with T2 and a subset of those with T3 tumors. This T3 subset was defined as a single lesion <6.5 cm or <3 lesions with none greater than 3 cm and with a sum of tumor diameters <8 cm. These expanded criteria are known as the UCSF criteria. (17)
The question is whether locoregional therapies (including both RFA and chemoembolization) may decrease the recurrence rate in patients meeting the UCSF criteria. Yao and colleagues published a detailed analysis of 121 patients with HCC who underwent transplantation. (20) Seventy-eight patients (64%) had T2 lesions, while an additional 27 patients (22.3%) met the expanded UCSF criteria, termed T3A lesions. The rest had T1, T3B, or T4 lesions. Individual patients received a variety of preoperative locoregional therapies, including TACE or ablative therapies, such as PEI, RFA, or combined therapies. A total of 38.7% of patients did not receive preoperative locoregional therapy. The 1- and 5-year recurrence-free survival was similar in those with T2 and T3A lesions, while the corresponding recurrence-free rates were significantly lower for those with T3B and T4 lesions.
The authors also compared recurrence-free survival of those who did and did not receive locoregional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the patient received locoregional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received locoregional therapy compared to 51.4% in those who did not. When the data for T2 and T3 lesions were grouped together, the 5-year recurrence-free survival was 93.8% for those who received locoregional therapy compared to 80.6% in those who did not. The authors concluded that preoperative locoregional therapy may confer a survival benefit in those with T2 or T3 lesions.
The authors note several limitations to the study, including the retrospective nature of the data and the marginal statistical significance of the improved survival given the small numbers of patients in each subgroup. For example, only 19 patients were in the T3A (i.e., UCSF expanded criteria) subgroup. In addition, no protocol specified which type of locoregional therapy to offer different patients. These therapies are only offered to those patients with adequate liver reserve; such patients may have an improved outcome regardless of the preoperative management.
Radiofrequency Ablation as a Primary Treatment of Unresectable Liver Metastases from Colorectal Cancer
More than half of patients with colorectal cancer (CRC) will develop liver metastases, generally with a poor prognosis. (21) A median survival of 21 months has been observed in patients with a single CRC liver metastasis; those with several unilobar lesions have median survival of 15 months; and, those with disseminated metastases have median survival of less than 1 year. A number of first-line systemic chemotherapy regimens have been used to treat metastatic CRC, with a 2-year survival rate of 25% for those treated with 5-fluorouracil (5-FU) or 5-FU plus leucovorin. (21) With the introduction of newer agents, including irinotecan and oxaliplatin, and targeted drugs such as cetuximab and bevacizumab, 2-year survival rates have increased to 30-39%, with marked improvement in overall survival duration. As the liver is often the only site of metastases from CRC, however, locoregional therapies have been investigated. Surgical resection is considered the gold standard for treatment of CRC liver metastases, with 5-year actuarial survival rates that historically range from 28% to 38% but may reach 58% in appropriately selected, resectable patients without widely disseminated disease. (22,23) However, only 10-25% of patients with CRC metastases are eligible for surgical resection because of the extent and location of the lesions within the liver or because of the presence of comorbid conditions or disseminated disease. Unresectable cases or those for whom surgery is contraindicated typically are treated with systemic chemotherapy, with poor results and considerable adverse side effects.
Alternatively, RFA has been proposed as an approach to treat metastatic CRC in the liver. Early clinical experience with RFA comprised case series to establish feasibility, safety, tolerability, and local therapeutic efficacy in short-term follow-up. A 2006 literature review encompassing 6 case series (N=446) showed that RFA of unresectable CRC metastases was associated with 1-, 2-, and 3-year survival rates that ranged from 87-99%, 69-77%, and 37-58%, respectively. (22) While these results suggest RFA may have clinical benefit in this setting, a primary caveat is the definition of the term "unresectable" in the different series, and that different surgeons may have different opinions on this issue. Further, differences in lesion size, number, distribution, prior treatments, RFA technology, and physician experience may affect results, making it difficult to compare results of different studies.
Prospective studies in which RFA was compared with resection or systemic chemotherapy in well-defined consecutive cohorts of patients with localized CRC metastases and no evidence of additional metastatic disease have been conducted. In the first study, Abdalla and coworkers examined recurrence and survival rates for clinically similar patients treated with hepatic resection only (n=190), resection plus RFA (n=101), RFA only (n=57, open laparotomy by hepatobiliary surgeon), and systemic chemotherapy alone (n=70). (24) In the key relevant comparison, RFA versus chemotherapy in chemotherapy-naive patients with non-resectable CRC metastases (median 1 lesion per patient, range 1-8, median tumor size 2.5 cm), overall survival at 4 years was 22% in the RFA group compared with 10% in the chemotherapy group (p=0.005). Median survival was estimated at 25 months in the RFA group and 17 months in the chemotherapy group (p not reported). Recurrence anywhere in the liver at median follow-up of 21 months was 44% in the RFA group and 11% in the resection-only group (p<0.001), although the proportion of patients with distant recurrence as a component of failure was similar (41% resection, 40% RFA, p not significant).
In a second trial, a consecutive series of well-defined, previously untreated patients (n=201) without extrahepatic disease underwent laparotomy to determine therapeutic approach. (25) Three groups were identified: those amenable to hepatic resection (n=117); those for whom resection plus local ablation were indicated (RFA, n=27; cryoablation, n=18); and those deemed unresectable and unsuitable for local ablation (n=39) who received systemic chemotherapy. Median overall survival was 61 months (95% confidence interval [CI]: 41-81 months) in resected patients (median 1 tumor per patient, range 1-9, median diameter 3.8 cm), 31 months (95% CI: 20-42 months) in locally ablated patients (median 4 tumors per patient, range 1-19, median diameter 3 cm per lesion), and 26 months (95% CI: 17-35 months) in the chemotherapy patients (median 4 tumors per patient, range 1-17, median diameter 4 cm per lesion, p not significant, ablated vs. chemotherapy). Results from 2 validated quality-of-life instruments (EuroQol-5D and EORTC QLQ C-30) showed that patients treated by local ablation returned to baseline values within 3 months, whereas those treated with chemotherapy remained significantly lower (i.e., worse quality of life) than baseline over 12 months post-treatment (p<0.05).
In 2011, van Tilborg and colleagues reported long-term results in 100 patients with unresectable colorectal liver metastases who underwent a total of 126 RFA sessions (237 lesions). (26) Lesion size ranged from 0.2-8.3 cm (mean 2.4 cm). The mean follow-up time was 29 months (range 6-93 months). Major complications (including abscess, hemorrhage, grounding pad burns and diaphragm perforation) occurred in 8 patients. Factors that determined the success of the procedure included lesion size and the number and location of the lesions. Local tumor site recurrence was 5.6% for tumors less than 3 cm, 19.5% for tumors 3-5 cm, and 41.2% for those greater than 5 cm. Centrally located lesions recurred more often than peripheral ones, at 21.4% versus 6.5%, respectively, p=0.009. Mean survival time from the time of RFA was 56 months (95% CI: 45-67 months).
A review by Guenette and Dupuy in 2010 summarized the literature on the use of RFA for colorectal hepatic metastases. (27) Approximately 17 studies in the literature with greater than 50 patients treated with RFA for colorectal hepatic metastases reported survival. Average tumor size, reported in 15 studies ranged from 2.1 cm-4.2 cm. Five-year overall survival (OS), reported in 12 studies, ranged from 2% to 55.3% with a mean of 24.5%. The largest study series included in the review was by Lencioni et al. and consisted of 423 patients with average tumor size of 2.7 cm, 4 or fewer metastases, each 5 cm or less in greatest dimension, and no extrahepatic disease. (28) Overall survival in the Lencioni et al. study at 1, 3 and 5 years was 86%, 47% and 24%, respectively. The authors of the Guenette/Dupuy review concluded that 5-year survival rates following RFA appear to rival those following resection but that long-term data associated with RFA and colorectal hepatic metastases is sparse, randomized trials have failed recruitment, and patients with resectable disease should undergo resection if possible. However, given the efficacy of RFA as compared to chemotherapy alone, RFA should be considered as a primary treatment option in patients with unresectable disease.
Radiofrequency Ablation as a Treatment of Unresectable Liver Metastases from Neuroendocrine Tumors
Most reports of radiofrequency treatment of neuroendocrine liver metastases include small numbers of patients or subsets of patients in reports of more than one ablative method or very small subsets of larger case series of patients with various diagnoses.
Berber and Siperstein analyzed a large series of liver tumors treated with RFA. (29) Of 1,032 tumors in the study, 295 were neuroendocrine tumor metastases. The mean number of lesions treated was 5.6 (range: 1-16) and mean size was 2.3 cm (range: 0.5-10.0 cm). Local recurrence rates were lower in patients with neuroendocrine tumors than in patients with other tumor types; neuroendocrine tumors (19/295, 6%), colorectal metastases (161/480, 24%), noncolorectal, nonneuroendocrine metastases (28/126, 22%), and HCC (23/131, 18%). In patients with neuroendocrine tumors, 58% of the recurrences were evident at 1 year and 100% at 2 years versus 83% at 1 year and 97% at 2 years for colorectal metastases. Eight neuroendocrine tumors were eligible for repeat RFA; 7 were retreated and one was not. Symptom control and survival were not reported in this study.
Mazzaglia et al. report on a series gathered over 10 years of 63 patients with neuroendocrine metastases who were treated with 80 sessions of LRFA. (30) Tumor types were 36 carcinoid, 18 pancreatic islet cell, and 9 medullary thyroid cancer. Indications for enrollment in the study were liver metastases from neuroendocrine tumors, enlarging liver lesions, worsening of symptoms, and/or failure to respond to other treatment modalities, and predominance of disease in the liver; however, patients with additional minor extrahepatic disease were not excluded from the study. RFA was performed 1.6 years (range, 0.1-7.8 years) after diagnosis of liver metastases. Fourteen patients had repeat sessions for disease progression. The mean number of lesions treated at the first RFA session was 6 and the mean tumor size was 2.3 cm. One week after surgery, 92% of patients had at least partial symptom relief and 70% had complete relief. Symptom control lasted 11 +/- 2.3 months. Median survival times were 11 years post-diagnosis of primary tumor, 5.5 years postdiagnosis of neuroendocrine hepatic metastases, and 3.9 years after first RFA treatment.
Elias et al. report on 16 patients who underwent a one-step procedure comprising a combination of hepatectomy and RFA for treatment of gastroenteropancreatic endocrine tumors. (31) A mean of 15 +/- 9 liver tumors per patient were surgically removed, and a mean of 12 +/-8 were ablated using RFA. Three-year survival and disease-free survival rates were similar to those observed in the authors' preliminary series of 47 patients who had hepatectomy with a median of 7 liver tumors per patient. Venkatesan and colleagues report on 6 patients treated for pheochromocytoma metastases. (32) Complete ablation was achieved in 6 of 7 metastases. Mean follow-up was 12.3 months (range: 2.5-28 months).
Radiofrequency Ablation as a Primary Treatment of Unresectable Liver Metastases from Tumors other than Colorectal Cancer and Neuroendocrine Tumors
Breast Cancer
A number of case series report RFA of breast cancer liver metastases. In a retrospective review, Meloni et al. assessed local control and intermediate- and long-term survival in 52 patients. (33) Inclusion criteria were fewer than 5 tumors, maximum tumor diameter of 5 cm or smaller, and disease confined to the liver or stable with medical therapy. Complete tumor necrosis was achieved in 97% of tumors. Median time to follow-up from diagnosis of liver metastasis and from RFA was 37.2 and 19.1 months, respectively. Local tumor progression occurred in 25% of patients, and new intrahepatic metastases developed in 53%. Overall median survival time, from the time the first liver metastasis was diagnosed, was 42 months, and 5-year survival was 32%.
Patients with tumors 2.5 cm in diameter or larger had a worse prognosis than those with smaller tumors. The authors conclude that these survival rates are comparable to those reported in the literature for surgery or laser ablation. In another series of 43 breast cancer patients with 111 liver metastases, technical success was achieved in 107 metastases (96%). (34) During follow-up, local tumor progression was observed in 15 metastases. The estimated overall median survival was 58.6 months. Survival was significantly lower among patients with extrahepatic disease, with the exception of skeletal metastases.
A series of 19 patients was reported by Lawes et al. (35) Eight patients had disease confined to the liver, with 11 also having stable extrahepatic disease. At the time of the report, 7 patients, with disease confined to the liver at presentation, were alive, as were 6 with extra-hepatic disease; median follow-up after RFA was 15 months (range: 0-77 months). Survival at 30 months was 41.6%. RFA failed to control hepatic disease in 3 patients.
Other reports include 16 or fewer subjects. All of the authors report that RFA of breast cancer liver metastases is technically feasible and may provide a survival benefit in women without extra-hepatic or stable extrahepatic disease (excluding bone metastases).
Jones et al. evaluated RFA in a series of patients with sarcoma. (36) Thirteen gastrointestinal stromal tumor (GIST) patients and 12 with other histological subtypes received RFA for metastatic disease in the liver: 12 of these responded to the first RFA procedure and 1 achieved stable disease. Two GIST patients received RFA on 2 occasions to separate lesions within the liver, and both responded to the second RFA procedure. Of the other subtypes: 7 underwent RFA to liver lesions, 5 of these responded to RFA, 1 progressed and 1 was not assessable for response at the time of analysis. RFA was well-tolerated in this series of sarcoma patients. RFA may have a role in patients with GIST who have progression in a single metastasis but stable disease elsewhere. The authors advise that further larger studies are required to better define the role of this technique in this patient population.
A case series of 66 patients who underwent hepatic resection (n=35), resection and RFA (n=18), or RFA alone (n=13) was reported by Pawlik et al. (37) After a median follow-up of 35.8 months, 44 patients had recurrence (intrahepatic only, n=16; extrahepatic only, n=11; both, n=17). The 1-, 3-, and 5-year overall survival rates were 91.5%, 65.4%, and 27.1%, respectively. The authors recommend that patients with metastatic disease who can be rendered surgically free of disease be considered for potential hepatic resection.
Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) indicates that ablative techniques may be used in the treatment of certain hepatic tumors. The guideline on hepatobiliary cancer includes cryoablation in a list of ablative techniques; however the literature cited in the guideline reports on only radiofrequency ablation and ethanol ablation. (73) The NCCN neuroendocrine guidelines indicate cryotherapy is an option for unresectable liver metastases. (74) The guideline on treatment of metastatic hepatic lesions for colon cancer indicates that ablative techniques may be considered alone or in conjunction with resection. (72, 74) However, cryoablation is not listed anywhere in the guideline. The potential role of chemotherapy in converting unresectable to resectable hepatic lesions is also discussed.
For treating patients with unresectable HCC, numerous studies including randomized trials demonstrate that in patients with small foci of HCC (no more than 3 lesions), RFA appears to be better than ethanol injection in achieving complete ablation and preventing local recurrence. Three-year survival rates of 80% have been reported. Thus RFA in patients with HCC who are not candidates for resection or transplant may be considered medically necessary.
A substantial body of literature has been published on the use of RFA to treat colorectal cancer metastases in the liver. Two prospective studies comprise good evidence that overall survival following RFA is at least equivalent and likely better than that obtained with currently accepted systemic chemotherapy in well-matched patients with unresectable hepatic metastatic colorectal cancer who do not have extrahepatic disease. Additional evidence from 1 comparative study suggests RFA has a lesser deleterious effect on quality of life than chemotherapy and that RFA patients recover quality of life significantly faster than chemotherapy recipients. Quicker recovery of quality of life may be viewed as a net health benefit when viewed in the context of expected survival durations of patients with metastatic cancer. In addition, results from a number of uncontrolled case series also suggest RFA of hepatic colorectal cancer metastases produces long-term survival that is at minimal equivalent and likely superior to historical outcomes achieved with systemic chemotherapy. Although indirect comparisons of series results are difficult, the body of data shows consistent change in direction and magnitude of effect that suggests an RFA benefit. It should be recognized, however, that patients treated with RFA in different series may have better prognosis than those who undergo chemotherapy, suggesting patient selection bias may at least partially explain the apparent better outcomes observed following RFA. Given the caveats outlined above, the available body of clinical evidence is sufficient to conclude that RFA of unresectable colorectal cancer metastases to the liver, absent extrahepatic metastatic disease, may be considered medically necessary.
Evidence shows that durable tumor and symptom control of neuroendocrine liver metastases can be achieved by radiofrequency ablation. This evidence is based on case series; neuroendocrine tumors are uncommon. Therefore, RFA of hepatic metastases of neuroendocrine tumors may be considered medically necessary in patients whose symptoms are not controlled by systemic therapy.
Transplant clinicians find the evidence compelling that use of locoregional therapy reduces the dropout rate of patients with HCC awaiting a liver transplant. After listing for transplant, UNOS does not reassign status based on tumor shrinkage from locoregional therapy. A number of approaches are accepted for use in this situation, including TACE and RFA. Small case series conclude that patients managed on the transplant list with locoregional therapy have outcomes comparable to patients who do not receive pretransplant treatment. However, earlier liver transplant for HCC patients may reduce the need for RFA in this situation. Thus, given the strong clinical support, UNOS position, and clinical studies, RFA may be considered medically necessary as a bridge to liver transplant.
Currently, there is less evidence available for patients treated with RFA to specifically downsize (downstage) tumors (tumors of stage greater than T2) to meet priority transplant criteria, and its use for this application is considered experimental, investigational and unproven.
The published evidence for demonstrating improved health outcomes with RFA of other hepatic metastatic tumors (e.g., breast cancer and sarcoma) is lacking. Comparative trials are needed for these malignancies that may have associated systemic disease. Because the data are insufficient, use of RFA in these tumors is considered experimental, investigational and unproven.
Practice Guidelines and Position Statements
The Society of Interventional Radiology published a position statement on percutaneous radiofrequency ablation for the treatment of liver tumors in 2009. (38) It is the position of the Society that "percutaneous RF ablation of hepatic tumors is a safe and effective treatment for selected patients with HCC and colorectal carcinoma metastases" and that the current literature is insufficient to support any recommendations supporting or refuting the use of RFA in other diseases.
The National Comprehensive Cancer Network (NCCN) guidelines recommend (39-41):
The National Institute for Health and Clinical Excellence (NICE) published guidance on RFA for colorectal liver metastases in 2009 stating that current evidence on safety and effectiveness is sufficient to support use of the procedure in patients unfit or otherwise unsuitable for hepatic resection, or in those who have previously had hepatic resection, (42) and published guidance in 2003 stating that current evidence of the safety and efficacy of RFA for hepatocellular carcinoma appears adequate to support use of the procedure. (43)
A 2000 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (45) that found insufficient data to permit conclusions regarding the effect of cryosurgery on health outcomes of patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma, or liver metastases.
Four patient groups have been treated with hepatic cryosurgery—those with: primary HCC, liver metastases from colorectal cancer, neuroendocrine tumors metastatic to the liver, or liver metastases from other non-colorectal cancers.
Hepatocellular carcinoma (HCC)
Authors of a 2009 Cochrane review of cryotherapy for HCC reported finding 2 prospective cohort studies and 2 retrospective studies in their literature search but no randomized controlled trials (RCTs) or quasi-randomized, controlled trials. (46) Only one study could be considered for the assessment of benefit. In that study (47), results were stratified according to both the type of hepatic malignancy (primary or secondary) and the intervention group (percutaneous cryotherapy or percutaneous radiofrequency ablation [RFA]). Sixty-four patients were treated based on random availability of probes; 31 patients received cryotherapy and 33 received RFA. Of all patients treated, 26 (84%) of 31 who had cryotherapy and 24 (73%) of 33 who had RF developed a local recurrence, all within 1 year. The distribution of primary cancers was not specified. Among the HCC patients, rates of initial tumor ablation were similar after cryosurgery or RFA (65% and 76%, respectively), but local recurrences were more frequent after cryosurgery (38%) than after RFA (17%). Survival at 1 year did not differ by ablative technique (cryosurgery, 66%; RFA, 61%). The study did not include controls managed with an established alternative. Authors of the Cochrane review concluded that there is no evidence to recommend or refute cryotherapy in the treatment of patients with HCC and that randomized, clinical trials may be useful.
Clavien et al. (48) treated 15 patients with cirrhosis and a single liver lesion (biopsy-proved HCC or suspicious mass on imaging) using open cryosurgery after transhepatic arterial chemoembolization. In all patients, cryosurgery was offered because the tumor was "unresectable or surgical resection was not thought to be feasible because of tumor location or size, or patient comorbidity." Actuarial survival rate of these patients after cryosurgery was 79% at 5 years. The study did not include a control group.
In a 2009 study, Zhou and colleagues divided 124 patients with primary nonresectable HCC into early, middle, and advanced stage groups by Barcelona Clinic Liver Cancer staging classification. (49) After argon-helium cryoablation, serum level of alpha-fetoprotein was reduced in 76 (82.6%), and 205 (92.3%) of 222 tumor lesions were diminished or unchanged. Median survival time was 31.35 months in the early stage, 17.4 months in the middle stage, and 6.8 months in the late stage groups. As of April 2008, 14 patients survived and 110 had died. To determine risk factors that predict metastasis and recurrence Wang et al. studied a series of 156 patients with hepatitis B (HBV)-related HCC and tumors smaller than 5 cm in diameter who underwent curative cryoablation. (50) One-, 2-, and 3-year overall survival rates were 92%, 82%, and 64%, respectively, and 1-, 2-, and 3-year recurrence-free survival rates were 72%, 56%, and 43%, respectively. The multivariate analysis showed that Child-Pugh class and expression of vascular endothelial growth factor (VEGF) in HCC tissues could be used as independent prognostic factors for overall survival. The expression of VEGF in HCC tissues and HBV basal core promoter mutations were independent prognostic factors for recurrence-free survival (RFS).
In a nonrandomized comparative study, Xu and colleagues evaluated outcomes of cryosurgery alone and transcatheter arterial chemoembolization (TACE) followed by cryosurgery in 420 patients with nonresectable HCC. (51) Patients in the sequential TACE-cryosurgery group tended to have larger tumors and a greater number of tumors than patients in the cryoablation alone group. Tumors larger than 10 cm were seen only in the sequential group. During mean follow-up of 42 months (range: 24–70), the local recurrence rate at the ablated area was 17% for all patients, 11% in the sequential group, and 23% in the cryosurgery alone group (p=0.001). One- and 2-year survival rates were similar in both treatment groups (p=0.69); however, 5-year survival rates were 39% in the sequential group and 23% in the cryosurgery alone group (p=0.001). Eighteen patients with large HCC (i.e., larger than 5 cm) survived for more than 5 years after sequential TACE-cryosurgery, while no patient with large HCC and cryosurgery alone survived more than 5 years. The incidence of hepatic bleeding was higher in the cryosurgery alone group. The authors conclude that pre-cryosurgical TACE may increase the efficacy of cryoablation and reduce adverse effects.
Neuroendocrine cancer liver metastases
Neuroendocrine tumors are relatively slow-growing malignancies (mean survival times of 5–10 years) that commonly metastasize to the liver. As with other cancers, the most successful treatment of hepatic metastasis is resection with tumor-free margins, but treatment benefits for a slow-growing tumor must be weighed against the morbidity and mortality of major surgery. (52) The intent of cryosurgery in these cases is to minimize or eliminate symptoms caused by liver metastases while avoiding the complications of open surgery.
A 2009 Cochrane review evaluated the benefits and harms of liver resection versus other treatments in patients with resectable liver metastases from gastro-entero-pancreatic neuroendocrine tumors. (53) Trials comparing liver resection (alone or in combination with RFA or cryoablation) versus other interventions (chemotherapy, hormonotherapy, or immunotherapy) and studies comparing liver resection and thermal ablation (RFA or cryoablation) were sought. Authors of the Cochrane review reported finding neither an RCT suitable for review nor any quasi-randomized, cohort, or case-control studies "that could inform meaningfully." No analysis was performed, and the authors refer to only RFA in their discussion, noting that RF is not suitable for large tumors (i.e., larger than 5-6 cm) and that neuroendocrine liver metastases are frequently larger than that. The authors conclude that further randomized trials comparing surgical resection and RFA in selected patients may be appropriate.
Only one study (54) reported outcomes of cryosurgery in a substantial number of patients with hepatic metastases from neuroendocrine cancer. This study used cytoreduction (resection, cryosurgery, RFA, or a combination) and adjuvant therapy (octreotide, chemotherapy, radiation, interferon alfa) in 31 patients with neuroendocrine metastases to the liver and "progressive symptoms refractory to conventional therapy." Following treatment, symptoms were eliminated in 87% of patients; median symptom-free interval was 60 months with octreotide and 16 months with alternatives. Since outcomes were not reported separately for different cytoreductive techniques, it was not possible to compare the benefits of cryosurgery with those of other cytoreductive approaches or octreotide alone.
Liver metastases from other cancers including colorectal cancer
A 2008 Cochrane review was undertaken to compare outcomes of resection of colorectal cancer liver metastases to no intervention or other modalities of intervention, including RFA and cryosurgery. (55) Only RCTs reporting on patients who had curative surgery for adenocarcinoma of the colon or rectum and who had been diagnosed with liver metastases and who were eligible for liver resection were considered. Only one randomized trial was identified, a 1997 study from the Ukraine comparing surgical resection and cryosurgery in 123 subjects, 82 of whom had liver metastases from primary colorectal cancers and the remainder who had metastases from other primary tumors. (56) Survival outcomes were not provided by type of cryogenic procedure or primary tumor site. The authors of the Cochrane review conclude that local ablative therapies are probably useful but that they need to be further evaluated in a RCT.
They also observe that "of the non-colorectal gastrointestinal primaries, at present only hepatectomy for gastric metastases can be cautiously recommended. For non-gastrointestinal primaries, hepatic metastases probably represent widespread dissemination even if occult, and therefore, hepatectomy may only be of value when effective adjuvant treatments are available."
In a 2002 review of the literature, Sotsky and Ravikumar (57) summarized the results of 27 studies reporting outcomes of cryosurgery in more than 1,000 patients. In studies with only patients with colorectal cancer, outcomes diverged markedly (median survival ranged from 18 to greater than 33 months), liver recurrences were frequent (20–50%), and significant procedure-related complications were common. (58) While the review's authors asserted that cryosurgery is an established procedure, the data reported in the studies cited in the review appear inconclusive, since baseline characteristics of study populations were heterogeneous, and published outcomes were variable and inconsistently reported.
A Phase I comparison of single versus dual cryoprobe configurations in 15 patients given multiple treatments (25 single-probe and 14 dual-probe) did not report long-term outcomes or health benefits. (59) Three studies administered cryosurgery as a planned or incidental adjunct to surgery in patients with hepatic tumors. (60-62) Two of these were retrospective studies (60, 62), and all 3 pooled results across patients with heterogeneous disease characteristics (e.g., tumors of varied numbers and location). A prospective study (61) did not adequately describe criteria used to select patients for cryosurgery. Another report was a "retrospective review of prospectively collected data" on 172 patients treated with cryosurgery with (n=157) or without (n=25) post-procedure 5-fluorouracil or 5-fluorodeoxyuridine as hepatic arterial chemotherapy (HAC), and with (n=80) or without (n=92) resection (63). The authors concluded that the results of cryosurgery in their study (25% survival at 5 years) are encouraging but may partly reflect the effects of HAC, completeness (or, rather, incompleteness) of cryosurgery in some patient groups, and patient selection.
Niu and colleagues reported on an analysis of data collected prospectively for patients who underwent hepatic resection for metastatic colorectal cancer with or without cryoablation from 1990 to 2006. (64) A decision about resectability was determined at the time of surgery. Patients who had resections and cryoablation were more likely to have bilobar disease (85% vs. 27%, respectively) and to have 6 or more lesions (35% vs. 3%, respectively). In addition, 73% of this combined treatment group received HAC compared to 32% in the resection-only group. Median follow-up was 25 months (range: 1–124 months). The 30-day perioperative mortality was 3.1%. For the resection group, the median survival was 34 months, with 1-, 3- and 5-year survival values of 88%, 47%, and 32%, respectively. The median survival for the resection/cryotherapy group was 29 months, with 1-, 3- and 5-year survival values of 84%, 43%, and 24%, respectively (p=0.206). The overall recurrence rates were 66% for resection only, but 78% for resection/cryotherapy. Five factors were independently associated with an improved survival: absence of extrahepatic disease at diagnosis, well- or moderately differentiated colorectal cancer, largest lesion size being 4 cm or less, a postoperative carcinoembryonic antigen (CEA) of 5 ng/mL or less, and absence of liver recurrence. While the recurrence rates between groups were not different in this study, it is not clear how representative the patients who had resection/cryotherapy are of the total potential patients. The comparability of the 2 groups is uncertain, especially given the differential use of HAC. In this study, a direct comparison was not made to chemotherapy. Finally, the 16-year duration of the study raises concerns about inter-current changes that could have had an impact on the results.
Seifert et al. reported on a series of patients with colorectal liver metastases that were treated from 1996–2002. (65) In this series, 168 patients underwent resection and 55 had cryosurgical ablation (CSA) (in 25 of these patients, it was combined with resection.) Twenty-nine percent (16 of 55) of the ablation group had prior liver resection compared with only 5% in the resection group. Twenty percent of both groups had extrahepatic disease at the time of surgery. With a median follow-up of 23 months, median and 5-year survival rates following resection and cryotherapy were comparable, with 29 months and 29 months and 23% and 26%, respectively. However, the median disease-free survival (DFS) times and 5-year DFS rates following resection were superior at 10 months and 19%, respectively for resection compared with 6 months and 12%, respectively for cryotherapy. Overall recurrence was 61% in the resection group and 76% in the cryotherapy group, and liver recurrence was 45% and 71%, respectively. Limitations of this study include the small sample size, limited follow-up, and noncomparability of the groups.
Ruers and colleagues reported on a consecutive series of 201 colorectal cancer patients, without extrahepatic disease, treated between 1995 and 2004 and who underwent laparotomy for surgical treatment of liver metastases. (66) These patients were prospectively followed up for survival and quality of life. At laparotomy, 3 groups were identified: patients in whom radical resection of metastases proved feasible, patients in whom resection was not feasible and received local ablative therapy (with or without resection), and patients in whom resection or local ablation was not feasible for technical reasons and who received systemic chemotherapy. The study reported that patients in the chemotherapy and local ablation groups were comparable for all prognostic variables tested. For the local ablation group, overall survival (OS) at 2 and 5 years was 56% and 27%, respectively (median: 31 months; n=45), for the chemotherapy group 51% and 15%, respectively (median: 26 months; n=39; p=0.252). After resection, these figures were 83% and 51%, respectively (median: 61 months; n=117; p<0.001). The median DFS after local ablation was 9 months. The authors concluded that although OS of local ablation versus chemotherapy did not reach statistical significance, the median DFS of 9 months suggested a beneficial effect of local tumor ablation. However, given the heterogeneity of the groups in this study, it is very difficult to compare outcomes among the groups. In addition, this study used both cryotherapy and RF for local ablation, and results are reported for the combined group.
In a relatively small study, Joosten et al. reported on 58 patients with unresectable colorectal liver metastases where CSA or RFAs were performed in patients not eligible for resection. (67) Median follow-up was 26 and 25 months for CSA and RFA, respectively. One- and 2-year survival rates were 76% and 61% for CSA and 93% and 75% for RFA, respectively. In a lesion-based analysis, the local recurrence rate was 9% after CSA and 6% after RFA. Complication rates were 30% and 11% after CSA and RFA, respectively (p=0.052). While the small size of this study makes drawing conclusions difficult, it does raise questions about the relative efficacy of both techniques.
Kornprat and colleagues reported on thermoablation combined with resection in the treatment of hepatic metastasis from colorectal cancer. (68) In this series, from January 1, 1998, to December 31, 2003, 665 patients with colorectal metastases underwent hepatic resection. Of these, 39 (5.9%) had additional intraoperative thermoablative procedures (19 RFA, 20 CSA). The total morbidity rate was 41% (16 of 39). No RFA-related complications occurred; however, 3 patients developed an abscess at cryoablation sites. The median DFS was 12.3 months (range: 8.4–16.2 months). Overall, the local in situ recurrence rate according to number of ablated tumors was 14% for RFA and 12% for CSA. Tumor size correlated directly with recurrence (p=0.02) in RFA-treated lesions. In the comment section of this paper, the authors indicate that an ongoing controversy is whether resection of extensive disease combined with chemotherapy is better than either treatment alone.
Xu et al. reported on a series of 326 patients with nonresectable hepatic colorectal metastases treated with 526 percutaneous cryosurgery procedures. (69) At 3 months' post-treatment, CEA levels decreased to normal range in 197 (77.5%) of patients who had elevated markers before cryosurgery. Among 280 patients who had computed tomography (CT) follow-up, cryotreated lesions showed complete response in 41 patients (14.6%), partial response in 115 (41.1%), stable disease in 68 (24.3%), and progressive disease in 56 (20%). During median follow-up of 32 months (range: 7–61 months), the recurrence rate was 47.2%. The recurrence rate at the cryotreated site was 6.4% for all cases. During median follow-up of 36 months, the median survival of all patients was 29 months (3–62 months). OS was 78%, 62%, 41%, 34%, and 23% at 1, 2, 3, 4, and 5 years, respectively, after treatment. Patients with tumor size smaller than 3 cm, tumor in right lobe of liver, CEA levels less than 100 ng/dL and post-cryosurgery TACE had higher survival rates.
Procedure-related complications
Cryosurgery is not a benign procedure. Treatment-related deaths occur in approximately 2% of study populations and are most often caused by cryoshock, liver failure, hemorrhage, pneumonia/sepsis, and acute myocardial infarction. (70) Clinically significant nonfatal complication rates in the reviewed studies ranged from zero to 83% and were generally due to the same causes as treatment-related deaths. The likelihood of complications arising from cryosurgery may be predicted, in part, by the extent of the procedure, (71) but much of the treatment-related morbidity and mortality reflect the generally poor health status of patients with advanced hepatic disease.
Most patients in published series were candidates for cryosurgery because of unresectable disease, due either to large number of metastases, inaccessible location (e.g., near large vessels), or insufficient hepatic reserve to support resection. However, some of the studies included patients with resectable tumors, as well as patients with unresectable tumors. Furthermore some studies pooled results for mixed series of patients with liver metastases from various non-colorectal cancers (e.g., breast, sarcoma, ovarian, testicular, pancreatic, esophageal, head and neck) despite the differing characteristics and prognoses of these malignancies. Few controlled studies were found and those had methodological weaknesses including lack of randomization, noncomparable groups. Therefore, published outcomes of cryosurgery are inconclusive. The recent literature provides little new information on cryosurgical techniques, and interest appears to be concentrated on radiofrequency ablation.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member's benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
50.23, 50.24, 50.25, 50.29, 155.0, 155.2, 197.7, 209.72, 259.2
C22.0-C22.9, C78.7, C7b.02, 0F500ZZ, 0F510ZZ, 0F520ZZ, 0F503ZZ, 0F513ZZ, 0F523ZZ, 0F504ZZ, 0F514ZZ, 0F524ZZ


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As a reward for sticking with PvP, I would like one new mission type. Just one. Two would be tremendous. Three would probably kill me with delight.
Basically, the OP is advocating the cutting of rewards in half. At least, I'm on the losing side about half the time, so my rewards would be cut in half. Let's see ..... does that motivate me to play PvP?
No wait maybe I was unclear. I don't want to change the existing reward for the looser at all. If you lose you will still get the same reward as now. Nothing will change for you. BUT if you win you will get an additional item box like you get from Aid the Planet missions or the Foundry daily.
I don't want to take away anything (taking something away is never a good idea as we have experienced some time now). I only want to give the winner a little bit more. Nothing game breaking because as those who get such boxes from time to time know it is pure luck to get something really good. Most of the time it's some green chunk anyway.


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Reaching Hard-to-Reach Populations with Health Information: mHealth in Viet Nam
With a grant from the Rockefeller Foundation, Pathfinder implemented a one-year pilot project to target ethnic minority populations in the Central Highlands and Northern Mountains regions of Viet Nam with health messages. The education messages were delivered to beneficiaries through text messages and interactive voice response systems. The project was able to reach a large number of targeted individuals with culturally sensitive messages in three local languages. The project, the first of its kind in Viet Nam, attracted great attention from several local partners, including the MOH. As proof of its success, PEPFAR/USAID has granted Pathfinder a small grant to expand the project approach to reach two most-at-risk populations: intravenous drug users and men who have sex with men.
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eHealth in Viet Nam
Pathfinder is enhancing the health management information system in Viet Nam in order to strengthen the health sector's planning and management and to reduce inequities among poor and vulnerable populations.
Improving Health Care for Ethnic Minority Populations through Pre-Service Training in Viet Nam: A Systems-Based Approach
This project improved access to high quality, culturally appropriate health care in mountainous and underserved areas where many ethnic minorities live by partnering with medical schools in Viet Nam.
Improving HIV Prevention for Youth through Youth Education at Schools and in the Community
In Viet Nam, Pathfinder taught young people about HIV prevention and provided other life skills-based training to improve sexual and reproductive health among 15-24-year-olds.
Pathfinder Chosen by USAID to Lead New Services de Santé de Qualité pour Haiti Central and South Project
Pathfinder International is pleased to announce that we have been chosen by USAID to lead a new five-year, $56.7 million project in Haiti – Services de Santé de Qualité pour Haiti (SSQH) Central and South.
Pathfinder stands by health care needs of ethnic minorities in Vietnam
Pathfinder, in collaboration with Vietnam's Committee for Ethnic and Minority Affairs and the Health Strategy & Policy Institutes of Vietnam's Ministry of Health, disseminated the results of an assessment on the health care services for ethnic minorities of small population in Vietnam.


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Find out more http://twittercounter.com/pages/you via @TheCounter #paidwithatweet"


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PwC's VAT Online Helpful to Tax Professionals
A new service from PricewaterhouseCoopers offers detailed information on the VAT, or Value Added Tax, along with news feeds on the latest developments in the VAT arena.
This site is helpful to finance directors and tax preparers/professionals who are seeking more information on how the VAT is affected on a day-to-day basis across the world. Known as GlobalVatOnline has information on VAT rules and rates in more than 70 countries.
"GlobalVatOnLine is an on-line repository of information and news about VAT and how to manage it. Our aim was to collect key VAT data from around the world and present it in one place in an easily accessible manner," says Mark Friedlich, COO of the service. "We believe it will become an essential tool for companies trading overseas who have to contend with increasingly complex VAT regimes."
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yeah and this one is done :wave:
Type: Posts; User: jebglx
yeah and this one is done :wave:
I'll vouch for John...good guy 😃
:thumbup: I searched :p
I love reading build threads and all the work that goes into either restoring a vehicle or modding a mad vehicle :laugh:
post up your favorites. here are a couple of mine:
Ocean Blue Rabbit
you should see if you can hide a gopro under the underpass facing the intersection :laugh:
I'm pretty sure you can't tech your own car or else everyone would do that
I love the B-26 and feel like it gets no love :p
this is very cool
9 disappointing facts about Chipotle
that being said, I love me some Chipotle when I'm out of town.
But when I'm home, I go to CaliBurrito- a local joint owned by surfer hippies and they employ...
Caught on camera: Onlookers injured in demolition derby mishap
best quote of the article from the track owner:
"Maybe for the youth classes we will have to start blocking that off, but I...
yup...still original tires :eek:
but he's got that covered ;)
bwahahahahahaha :laugh:
I just spit water on my screen :D
I believe that 356 won best of show
Oley, PA
love this show and the swap meet...oh man, one of the best
but guess who's car was at his shop this afternoon :facepalm::banghead:?
holy crap :eek:
me too. I saw this car the day he bought it. it's a lot bigger than I imagined a Esprit would be :eek:
this car is pretty flawless ad packed full of 80s goodness.
great buy, Josh
this a thousand times.


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Quote of the Day: D'Antoni says Lakers have All-Star team, but not in a good way
Jan 24, 2013, 3:18 PM EDT
"We've got an All-Star team. Have you ever watched an All-Star Game? It's God-awful because everybody gets the ball, they go one-on-one and then they play no defense. That's our team."
—Lakers coach Mike D'Antoni after another embarrassing Lakers loss, this one to Memphis on Wednesday night. The quote comes from Adrian Wojnarowski of Yahoo Sports.
Clever quote. The question of course really is what is D'Antoni going to do about it? What about the players? Because right now the answer looks like point fingers and sulk. Which doesn't win a lot of games.
- readysethike - Jan 24, 2013 at 3:37 PM
if they were going to be this bad they couldve kept mike brown
- loungefly74 - Jan 24, 2013 at 3:49 PM
exactly! what is D'Antoni going to do about it? If the Lakers decide to revamp the roster to MD's preference, fine…then do it…because in most sports (especially the big 4), if the coach loses the team, he is gone. So Buss family, you telling me you are committed to MD for the next few years?
on a side note:
(…loungefly is now seeking his pleasure from PFT where his 49ers are finally in back the big show…and still reminiscing about his SF Giants' WS victory. damn…this could have been the year for a "trifecta/triple crown" IF the Lakers were good. came closest in 1989…Lakers, 49ers win but Giants lose in WS)
- bougin89 - Jan 24, 2013 at 3:59 PM
This is the first time I've read a quote from Mr. D'Antoni and have to say good job. I don't have a crummy made up quote making fun of him for this one.
Coach actually gives a direct, correct answer. Check that off the list of goals this season for Mr. D'Antoni.
- fotydaze - Jan 24, 2013 at 4:19 PM
BICKERSTAFF!!!! 4-1 this year as head coach, his only loss to the spurs on a last second lucky shot. the only coach that didn't try to implement a system he let them play
- dacapt704 - Jan 24, 2013 at 4:38 PM
So….isn't that the fault of um….THE COACH??
Dude is terrible…
- dalucks - Jan 24, 2013 at 4:51 PM
When will people realize that Mike Antioni is a highly overrated head coach?
There is no D in his gameplan.
- rodyaugu - Jan 24, 2013 at 6:00 PM
That was a subtle shot at Kobe Bryant, because he's the only player on the lakers that goes one on one and play no defense.
- abchome - Jan 24, 2013 at 6:00 PM
If you want your team to play good defense, you have to install defensive scheme, practice and make players accountable. Screaming defense on sideline doesn't help.
- rickysports - Jan 24, 2013 at 9:50 PM
If you want the Lakers to win you have to bench or trade Kobe because no superstar player shoots under 50% and expects to win. AND/OR get rid of D'Antoni
- badintent - Jan 25, 2013 at 1:43 AM
Mike Brown has 3 million reasons to keep laughing.With the rest of us on the East Coast.
- fanofevilempire - Jan 25, 2013 at 7:30 AM
the truth is the Lakers are an injured team.
they have no bench, no rotation to speak about.
the players do not fit the coaches system.
- ph53knowsall - Jan 25, 2013 at 8:30 AM
The truth is, its a collection of players that don't fit together well. Buss Jr. went and tried to play fantasy basketball with real players.
D'antoni made a correct statement. He's seems to be the only person asscociated with lakers, including the fans, that has a firm grasp on the situation.
- patrick800series - Jan 25, 2013 at 10:51 AM
seems like they might miss A.Bynum more than anybody thinks, they were a playoff team yntil he left
- patrick800series - Jan 25, 2013 at 10:51 AM
Top Posts
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- Bulls front office on Tom Thibodeau firing: "We probably wouldn't be sitting here if we won a championship" 11
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A man risked his life Wednesday to save two dogs after they fell through the ice on the Portage River.
Scott Cline used his canoe to slide across the ice to rescue the dogs, but could not make it back to shore, according to the Ottawa County Sheriff's office.
Sheriff's deputies couldn't reach him because he was too far out. They called the U.S. Coast Guard, which sent an airboat.
Cline was up to his knees in the frigid water, but was not treated for any injuries or hypothermia, Deputy James Hanney said. The two black Labrador retrievers were also OK.
"When they reached the shore, they started running around," he said.
Joe Andrews of Port Clinton also tried to rescue his dogs with the help of Don Shartell, but the bow of their rowboat broke through the ice before they could reach the animals.
Andrews and Shartell were taken to shore when deputies arrived.
Cline and Shartell were remodeling a home nearby when they heard the dogs go through the ice.


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Live updates
Police tweet picture of Yeadon car crash
Yeadon pensioner found
Leeds Pensioner Maureen Atkinson, from Yeadon, who was reported missing yesterday has been found safe and well in Rodley this morning.
Missing Yeadon woman
Police are appealing for information to trace an elderly Yeadon woman who has gone missing from home.
Maureen Atkinson, aged 79, has Alzheimer's and heart trouble and her family are extremely concerned for her welfare.
She was reported missing on Monday and was last seen at Otley bus station at about 1.20pm having been in Yeadon shortly before that. She had caught a bus from Pontefract to Leeds earlier that morning.
She is described as white, with short grey hair, and was wearing a red three-quarter length coat and hat that is possibly grey and was pulling a dark blue shopping bag on wheels.
Firm fined £377,500 after worker's death
A specialist engineering company in Leeds has been ordered to pay £377,500 in fines and costs after protracted safety failings led to the death of a worker from fatal head injuries caused by a powered valve.
Graham Britten, 46, of Kippax, Leeds, was carrying out maintenance in a vacuum casting furnace at AETC Ltd in Yeadon when the main isolation valve closed suddenly, trapping his head. He was pronounced dead at the scene. The incident, in 2009, was investigated by the Health and Safety Executive.
Leeds Crown Court was told today that HSE uncovered repeated failings by AETC Ltd ,The firm was fined £300,000 and ordered to pay £77,500 in costs after pleading guilty to breaching Section 2(1) of the Health and Safety at Work etc Act 1974.
Body pulled from river in West Yorkshire
A missing woman pulled from a river at Nunroyd Park has died in hospital. Officers searching for the 66-year-old found her in the water at the park in Yeadon last night. West Yorkshire police are investigating the circumstances.
Village Green status for Yeadon Banks
An area of Leeds has had its Village Green status confirmed by the Court of Appeal.
After a long battle between residents and Leeds Group plc, the 12 acre Yeadon Banks site has been confirmed as a Village Green, meaning development work cannot take place.
Greg Mulholland MP has been supporting the residents.
Vera Marland recalls the early days of Leeds Bradford Airport
- ITV Report
80 Years On: Still Flying High
80 Years On: Still Flying High
An exhibition of archive footage and stills will go on display at Leeds Central Library, they are also available online at The Yorkshire Film Archive.


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Design: PD2247
Fancy Monogram Personalized Playing Card Case
Personalized Playing Card Case
Made to Order - 1 business day processing+shipping
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Celebrate your big day with a useful favor!
This Fancy Monogram Personalized Playing Card Case is a fun favor to hand out to your guests. Each Fancy Monogram Card Case measures 2 1/2 inches wide x 3 3/4 inches high x 7/8 inch deep and is made of white metal. You'll get a standard poker deck in each one so you're friends can start playing immediately.
Please allow ample time for delivery. Our ship date for this product is noted in your shopping cart. Many items are shipped separately, so please allow extra time for these items to arrive. Shipping charges are based on the value of the merchandise and not the number of shipments. For additional shipping information, contact our Customer Service Department at (firstname.lastname@example.com or 1-800-314-8794).
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I love them... They were a perfect addition to my bar area.. the cards were a little to small but they work and looked great. My friends loved my personalized case so much... 4 of them are missing...lol
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It was New York City in the summer of 2012 when filmmaker/poet Adam Nichols Russell was hospitalized after an unexpected traumatic manic episode, later diagnosed as Bi Polar Disorder. This two part book featuring poetry and photography is part first hand account via poetic documentation during hospitalization, and partly composed of pieces created throughout recovery in Connecticut. The contrast of an artist in a manic state, enveloped by the frenetic city, with the quiet, reflective, nature of suburban/rural existence after diagnosis is stark. Ultimately, this book serves as a reminder of the complexity and power of the mind while taking on the misconceived benefits of altered states.
ADAM NICHOLS RUSSELL Was born and raised in Connecticut, spent time at college in Boston, lived abroad in Mexico City, then ultimately graduated from the Film and Media Arts program at Temple University in Philadelphia. He spent six years immersed in all aspects of the film and television industry in Los Angeles and NYC. These experiences have shaped how he views the world and directly influences his filmmaking and storytelling. Russell continued exploring his longtime love of poetry by releasing an evocative chapbook of select poems: "Lost Angles" (2012), an examination of his time in LA and rumination on the city itself. This combination of poetic verse, and an eye for visual composition is an essential component found in virtually all of his creative endeavors.
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42 CFR 401.705 - Eligibility criteria for qualified entities.
(a) Eligibility criteria: To be eligible to apply to receive data as a qualified entity under this subpart, an applicant generally must demonstrate expertise and sustained experience, defined as 3 or more years, in the following three areas, as applicable and appropriate to the proposed use:
(i) Expertise in the areas of measurement that they propose to use in accurately calculating quality, and efficiency, effectiveness, or resource use measures from claims data, including the following:
(A) Identifying an appropriate method to attribute a particular patient's services to specific providers and suppliers.
(B) Ensuring the use of approaches to ensure statistical validity such as a minimum number of observations or minimum denominator for each measure.
(C) Using methods for risk-adjustment to account for variations in both case-mix and severity among providers and suppliers.
(ii) A plan for a business model that is projected to cover the costs of performing the required functions, including the fee for the data.
(iv) Designing, and continuously improving the format of performance reports on providers and suppliers.
(v) Preparing an understandable description of the measures used to evaluate the performance of providers and suppliers so that consumers, providers and suppliers, health plans, researchers, and other stakeholders can assess performance reports.
(vi) Implementing and maintaining a process for providers and suppliers identified in a report to review the report prior to publication and providing a timely response to provider and supplier inquiries regarding requests for data, error correction, and appeals.
(vii) Establishing, maintaining, and monitoring a rigorous data privacy and security program, including disclosing to CMS any inappropriate disclosures of beneficiary identifiable information, violations of applicable federal and State privacy and security laws and regulations for the preceding 10-year period (or, if the applicant has not been in existence for 10 years, the length of time the applicant has been an organization), and any corrective actions taken to address the issues.
(viii) Accurately preparing performance reports on providers and suppliers and making performance report information available to the public in aggregate form, that is, at the provider or supplier level.
(2) Expertise in combining Medicare claims data with claims data from other sources, including demonstrating to the Secretary's satisfaction that the claims data from other sources that it intends to combine with the Medicare data received under this subpart address the methodological concerns regarding sample size and reliability that have been expressed by stakeholders regarding the calculation of performance measures from a single payer source.
(3) Expertise in establishing, documenting and implementing rigorous data privacy and security policies including enforcement mechanisms.
(b) Source of expertise and experience: An applicant may demonstrate expertise and experience in any or all of the areas described in paragraph (a) of this section through one of the following:
Title 42 published on 2014-10-01
The following are only the Rules published in the Federal Register after the published date of Title 42.
For a complete list of all Rules, Proposed Rules, and Notices view the Rulemaking tab.
Title 42 published on 2014-10-01
The following are ALL rules, proposed rules, and notices (chronologically) published in the Federal Register relating to 42 CFR 401 after this date.


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60-year-old single malt Scotch whisky priced at $350,000 at recent wine exhibition
Published on Nov 18, 2013 2:38 PM
Imagine a bottle of wine that costs as much as a Housing Board flat.
The most expensive item at the third annual Masters of Wines and Spirits showcase over the weekend was a bottle of 60-year-old single malt Scotch whisky that cost $350,000. Part of The Dalmore Constellation Collection, it is of 1951 vintage and the oldest whisky available from the Scottish distillery.
It was one of 79 individual bottles and collections of high-end spirits and wines at the one-day exhibition at the National Museum of Singapore last Saturday. The event was organised by luxury retailer DFS Group.
The entire collection is on sale at DFS concessions in Changi Airport Terminals 1 to 3. It is displayed as part of the Masters of Wines and Spirits World Traveller Showcase until the end of February.
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Companionship comes in all shapes, sizes, and species. Add this cuddly, offbeat pair to your friendship circle. A hang tag reads, "What Would I Do Without You?" which makes it a great gift for that very special someone.
There are teddy bears, and then there are Gund teddy bears. Founded by German immigrant Adolph Gund in 1898, the company has gained worldwide recognition for its wonderfully soft, delightfully designed plush toys. Each of its creations is a tangible manifestation of a hug and a cuddle. It's little wonder, then, that while a child will keep his first Gund for life, it's most likely not going to be his last Gund.


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The Vintage Collection
Purely Diamonds offers a beautiful selection of Vintage inspired diamond rings that are guaranteed to give your fine jewellery collection a sophisticated and stylish touch. Inspired by the elegance and opulence of the 1920's and 30's, these stunning diamond rings feature the geometric patterns and classic motifs the period was known for with an attention to detail that makes this jewellery style one of the most beloved of all time. The perfect diamond accessory for that little black dress, our Art Deco inspired diamond rings are sure to be a showstopper.


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To document the built heritage of the tea gardens of Assam and preserve them for the future generations, the Indian National Trust for Art and Cultural Heritage on Friday released a book, "Burra Bungalows And All That", at its Lodhi Road office here.
The coffee-table book, which gives a glimpse into the heritage of the tea industry of Assam through interesting historical facts and colourful pictures, has been produced by the Calcutta Regional Chapter of INTACH over a period of three years.
According to Calcutta Chapter of INTACH convenor G. M. Kapur, who has edited this book, the objective behind producing the book was to preserve some of the built heritage of the tea gardens for posterity.
Records for posterity
"This is not a photo-journalistic effort. The idea behind documenting the built heritage of the tea gardens was to list all tangible and intangible records for posterity. Today in Assam there is only one tea garden bungalow with a thatched roof. Thatched roofs had to be removed from all bungalows because of cost of insurance and fire hazard. If anyone asks how a thatched roof bungalow looks like no one will have the answer."
Pointing out that the book has also been produced to give fillip to tourism, Mr. Kapur said the book will hopefully induce Indian as well as overseas travellers to experience and explore the heritage of tea industry in the North-eastern State.
"Travellers can explore places of historical and green natural beauty, besides getting a first-hand experience of the culture and life the local population leads," added Mr. Kapur, who plans to produce another book on the tea garden heritage of North Bengal.
Releasing "Burra Bungalows And All That", Tourism Ministry Joint Secretary Usha Sharma said her Ministry would be a major beneficiary of the book. "The book focuses on a subject which is close to my heart and those who work in the Ministry."
She said the Tourism Ministry was toying with the idea of conserving the tea garden bungalows built by British and transforming them in order to lure travellers. "We can have interesting packages whether travellers can pluck cherries. Living in such places can be a really romantic experience."
Dispelling the myth that Indian tea industry owed its existence to China, a tea industry expert Praful Goradia said: "When we come to generalities, some people say that we owe our tea to China. This is a great myth. While it is true that the East India Company smuggled seeds from China, the fact of the matter is that 95 per cent of Indian tea from the North to the South comes from Assam where bushes have been growing for centuries. In fact, it was Governor General William Bentinck who decided that India must become self-reliant in tea."