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.
Blue Cross and Blue Shield of Montana (BCBSMT) may consider cryosurgical ablation (cryoablation or cryosurgery) medically necessary for the treatment of breast fibroadenoma when ALL of the following criteria have been met:
- The lesion is sonographically visible; AND
- The diagnosis is histologically confirmed; AND
- The lesion is less than 2.5 cm in it largest diameter.
- Treatments of all other types of breast tumors (including localized breast lesions) except as noted above; or
- Pancreatic cancer; or
- Lung cancer; or
- Bone lesions; or
- Other solid tumors outside of the kidney, liver, prostate and skin.
This policy was originally created in 2013. A literature search was performed for the period of March 2010 through June 2012. The following is a summary of the key literature to date. The literature search identified publications discussing applications of cryosurgery for primary and metastatic tumors outside the kidneys, liver and prostate. All were uncontrolled case series with varied criteria to select patients for cryosurgery and reported limited data on long-term outcomes.
The following sections summarize those studies that adequately described baseline characteristics of the patient populations and the methods used for cryosurgery and also reported outcomes of treatment for 8 or more patients with the same diagnosis, or 8 or more procedures on the same malignancy. One article (1) discussed cryosurgery in 429 patients with a wide variety of primary and recurrent solid tumors (e.g., head and neck, lung, genital organs, sarcomas). Although the author reported survival for some patient subsets with certain of these malignancies, the article only reported baseline tumor and patient characteristics for those with breast cancer (see below).
In 2010, Zhao and Wu reported on a systematic review of minimally-invasive ablative techniques of early stage breast cancer. (2) The review noted that studies on cryoablation for breast cancer are primarily limited to pilot and feasibility studies in the research setting. Complete ablation of tumors was found to be reported within a wide range of 36-83%. Since there are many outstanding issues, including patient selection criteria and the ability to precisely determine the size of tumors and achieve 100% tumor cell death, the reviewers noted minimally-invasive thermal ablation techniques for breast cancer treatment, including cryoablation, should be limited until results from prospective, randomized clinical trials become available.
Three studies described the outcome of cryosurgery for advanced primary or recurrent breast cancer in 72 patients. (1, 3, 4) Cryosurgery was performed percutaneously with ultrasound guidance (n=15) or during an open surgical procedure (n=57). Patients were treated for advanced primary disease (44%) or recurrent tumors (56%). Tanaka reported the largest retrospective series: 9 patients with advanced primary tumors and 40 with recurrent disease. (1) The author reported 44% survival of primary breast cancer patients (n=9) at 3 and 5 years but did not report survival duration or other outcomes for those with recurrent or metastatic disease. The report also did not adequately describe selection criteria for those enrolled in the study, details of the procedure, and procedure-related adverse events. The other studies (3-5) were smaller series of patients and also were inadequate with respect to study design, analysis, and reporting of results. Furthermore, the study by Pfleiderer et al. (3) was a pilot trial to evaluate technical limitations of the procedure. Tumors were excised and evaluated by pathology days to weeks after cryosurgery, and the authors reported incomplete necrosis in tumors greater than 23 mm in diameter.
One case series by Sabel and colleagues explored the role of cryoablation as an alternative to surgical excision as a primary treatment of early stage breast cancer. (6) This Phase I study included 29 patients who underwent cryoablation of primary breast cancers measuring less than 2 cm in diameter, followed up 1 to 4 weeks later by standard surgical excision. Cryoablation was successful in patients with invasive ductal carcinoma less than 1.5 cm in diameter and with less than 25% ductal carcinoma in situ identified in a prior biopsy specimen. In a small series of 11 patients with breast cancer tumors less than 2 cm, Pusztaszeri et al. found residual tumor present in 6 cases when follow-up lumpectomy was performed approximately 4 weeks after cryoablation. (7) In a case series of 15 patients with breast cancer lesions that were 8 ± 4 mm in diameter, percutaneous cryoablation was performed 30-45 days prior to surgical resection. (8) Resection of the lesions confirmed complete necrosis occurred in 14 patients, but one lesion had residual disease considered to be probably due to incorrect probe placement.
Since available evidence did not include control groups or compare outcomes of cryosurgery to alternative strategies for managing similar patients, no conclusions can be made on the net health outcomes of cryosurgery for breast cancer. Therefore, cryosurgery for breast cancer is considered experimental, investigational and unproven.
A variety of case series have focused on the role of cryosurgery as an alternative to surgical excision of benign fibroadenomas. Kaufman and colleagues have published several case series reports on office-based ultrasound-guided cryoablation as a treatment of breast fibroadenomas. (9-13) These case series reported on a range of 29-68 patients followed for periods of 6 months to up to 2.6 years. It is likely that these case series include overlapping patients. At 1 year, patients reported 91% patient satisfaction and fibroadenomas became nonpalpable in 75% of cases. At follow-up averaging 2.6 years in 37 patients, the authors noted only 16% out of 84% of palpable fibroadenomas remained palpable after treatment and of the fibroadenomas that were initially 2 cm or less in size, only 6% remained palpable. (13) In this series of patients, the authors also noted that cryoablation did not produce artifact that might interfere with interpretation of mammograms. These small case series from the same group of investigators is inadequate to permit scientific conclusions. In addition, it is unclear whether “non palpability” is the most appropriate medical outcome. Fibroadenomas are benign lesions with only a very remote chance of malignant conversion, and thus complete surgical excision may be recommended primarily to allay patients’ concerns regarding harboring a palpable lesion.
Nurko and colleagues reported on outcomes at 6 and 12 months for 444 treated fibroadenomas reported to the FibroAdenoma Cryoablation Treatment (FACT) registry involving 55 different practice settings. (14) In these patients, before cryoablation, 75% of fibroadenomas were palpable by the patient. Follow-up at 6- and 12-month intervals showed palpable masses in 46% and 35%, respectively. When fibroadenomas were grouped by size, for lesions 2 cm or less, the treatment area was palpable in 28% at 12 months. For lesions more than 2 cm, the treatment area was palpable in 59% at 12 months. The authors noted they would continue to follow up these patients to better define resolution of the treatment-induced physical and radiographic findings. Comparative trials with adequate long-term follow-up are needed to assess this technology and determine how this approach compares with surgery, as well as with vacuum-assisted excision and with observation (approximately one-third regress over several years’ time).
Lee and colleagues conducted a systematic review of endoscopic cryoablation of lung and bronchial tumors. (15) Included in the review were 15 case studies and one comparative, observational study. Cryoablation was performed for inoperable, advanced lung and bronchial cancers in most studies. Some studies included patients with co-morbid conditions and poor general health that would not be considered surgical candidates. Complications occurred in 11.1% of patients from 10 studies and consisted of hemorrhage, mediastinal emphysema, atrial fibrillation, and dyspnea. Within 30 days of the procedure, death from hemoptysis and respiratory failure, considered to be most likely related to disease progression, occurred in 7.1% of patients. Improvements in pulmonary function and clinical symptoms occurred in studies reporting these outcomes. Because the studies in the review did not include control groups or compare outcomes of cryosurgery to alternative strategies for managing similar patients, no conclusions can be made on the net health outcomes of cryosurgery for lung cancer. Therefore, cryosurgery for lung cancer is considered experimental, investigational and unproven.
In 2012, Tao and colleagues reported on a systematic review of cryoablation for pancreatic cancer. (16) The authors identified 29 studies from the literature search and included 5 of these studies in the review. The 5 studies were all case series and considered to be of low quality. Adverse events, when mentioned in the studies, included delayed gastric emptying (0% to 40.9% in 3 studies), pancreatic leak (0% to 6.8% in 4 studies), biliary leak (0% to 6.8% in 3 studies), and one instance of upper gastrointestinal hemorrhage. Pain relief was reported in 3 studies and ranged from 66.7% to 100%. Median survival times reported in 3 studies ranged from 13.4 to 16 months. One-year total survival rates reported in 2 studies were 57.5% and 63.6%.
Kovach et al. (17) reported 10 cryosurgical ablations in 9 patients with unresectable pancreatic cancer using intraoperative ultrasound guidance during laparotomy. The authors report no intraoperative morbidity or mortality and adequate pain control in all patients postoperatively. At the time of publication, all patients were dead at an average of 5 months postoperatively (range: 1–11 months).
A pilot study on the combination of cryosurgery and (125) iodine seed implantation for treatment of locally advanced pancreatic cancer was reported by Xu et al. (18) Forty-nine patients were enrolled, 12 with liver metastases. Twenty patients received regional chemotherapy. At 3 months after therapy, most patients showed tumor necrosis with 20.4% of patients having complete response. Overall, the 6-, 12-, 24-, and 36-month survival rates were 94.9%, 63.1%, 22.8%, and 9.5%, respectively.
Li and colleagues reported on a retrospective study of 142 patients with unresectable pancreatic cancer treated with palliative bypass with (n=68) or without cryoablation (n=74) from 1995 to 2002. (19) Median dominant tumor sizes decreased from 4.3 cm to 2.4 cm in 36 of 55 patients (65%) 3 months after cryoablation. Survival rates were not significantly different between groups, with the cryoablation group surviving a median of 350 days versus 257 days in the group that did not receive cryoablation. Complications overall were not significantly different between the 2 groups. However, a higher percentage of delayed gastric emptying occurred in the cryoablation group compared to the group that did not receive cryoablation (36.8% vs. 16.2%, respectively).
Because these studies did not include control groups or compare outcomes of cryosurgery to alternative strategies for managing similar patients, no conclusions can be made on the net health outcomes of cryosurgery for pancreatic cancer. Therefore, cryosurgery for pancreatic cancer is considered experimental, investigational and unproven.
Other Conditions (including bone lesions)
Meller et al. (20) report a retrospective analysis of a single center experience of 440 bone tumor cryosurgery procedures performed between 1988 and 2002, two-thirds of them for primary benign-aggressive and low-grade malignant lesions, and one-third for primary high-grade and metastatic bone tumors. At median follow-up of 7 years (range 3–18 years), overall recurrence rate was 8%. Based on their experience, the authors suggest that the ideal case for cryosurgery is a young adult with involvement of long bone, a benign-aggressive or low-grade malignant bone tumor, a good cavity with greater than 75% thick surrounding walls, none or minimal soft tissue component, and at least +/-1 cm of subchondral bone left near a joint surface after curettage and burr drilling.
Other articles identified in the literature search related to use of cryoablation in other cancers either involved small numbers of patients or limited follow-up. Therefore, cryosurgery use for other conditions, outside of the kidneys, liver and prostate, including bone and soft tissue, is considered experimental, investigational and unproven.
Ongoing Clinical Trials
A search of online site www.clinicaltrials.gov in June 2012 found no randomized controlled trials. Over 186 trials were listed for numerous conditions that cryosurgical ablation may be utilized. Several ongoing non-randomized clinical trials addressing cryoablation in breast, bone, lung, and pancreatic were identified and are listed as follows:
- Safety and Efficacy of Cryoablation for Abdominal Pain Associated with Pancreatic Cancer (NCT01335945) is listed as recruiting participants. This interventional study is sponsored by Galil Medical to measure abdominal pain reduction following cryoablation of the celiac plexus and the duration of pain relief. The posting lists an estimated enrollment of 20 subjects, with August 2012 as the estimated primary completion date. (21)
- Safety and Efficacy of Cryoablation for the Palliation of Painful Bone Metastases (NCT01461265) is listed as recruiting participants with the goal of enrolling an estimated 40 subjects beginning in mid-2012 for an estimated completion date of June 2013. This interventional study is sponsored by Galil Medical to measure the difference of pre- and post-treatment of worst pain from baseline to 24 hours, interval follow-ups to 24 weeks. (22) A similar study, also sponsored by Galil Medical, utilizing radiation therapy in combination with cryoablation, Safety and Efficacy of Cryoablation Combined with Radiation Therapy for the Palliation of Painful Bone Metastases (NCT01461252), has not reported starting to enroll participants as of July 31, 2012. (23)
- Safety and Efficacy of Cryoablation for Metastatic Lung Tumors (ECLIPSE) (NCT01307501) is listed as recruiting participants. This interventional study is sponsored by Galil Medical to measure local tumor control and increase overall survival. The posting lists an estimated enrollment of 40 subjects, with August 2017 as the estimated primary completion date. (24)
- Cryoablation or External-Beam Radiation Therapy in Treating Patients with Painful Bone Metastases (NCT00540969), sponsored by the North Central Cancer Treatment Group and the National Cancer Institute (NCI), is listed as having completed the study. This interventional randomized phase III clinical trial studied cryoablation to see how well it works compared with external-beam radiation therapy in treating patients with painful bone metastases. The enrollment was set for 140 participants. The results have been posted on the NCI web site. (25)
- Cryoablation for Invasive Breast Carcinoma Following Neoadjuvant Therapy (NCT01388777) is listed as recruiting participants. This interventional study is sponsored by M.D. Anderson Cancer Center to learn about the level of effectiveness of using ultrasound-guided cryoablation in patients with invasive breast cancer. The safety of this procedure will also be studied. The posting lists an estimated 10 subjects, with January 2014 as the estimated primary completion date. (26)
- Cryotherapy in Treating Patients with Primary Stage I Non-Small Cell Lung Cancer or Lung Metastasis (NCT00890617) is listed as recruiting participants with the goal of enrolling an estimated 10 subjects for an expected completed date of April 2012. This interventional pilot study is sponsored by the Barbara Ann Karmanos Cancer Institute and the NCI, to evaluate how well cryotherapy works in treating patients with primary stage I non-small cell lung cancer or lung metastasis. (27)
- Cryoablation Therapy in Treating Patients with Invasive Ductal Breast Cancer (NCT00723294) is listed as recruiting participants. This interventional phase II study is sponsored by the American College of Surgeons and the NCI, to measure how well cryoablation therapy works in treating patients with invasive ductal breast cancer. The posting lists an estimated enrollment of 99 subjects, with March 2013 as the estimated primary completion date. (28)
- Analysis of Percutaneous Ablations for Cancer Treatment (NCT01563679) is listed as recruiting participants with the goal of enrolling an estimated 500 subjects for an expected completed date of August 2013. This observational pilot study is sponsored by Emory University to evaluate the patient's clinical and radiology findings, pathology findings, survival, treatment responses, and complications after their locoregional therapy. (29)
- ICE-SENSE™ Cryotherapy for Breast Fibroadenoma Trial (ICE-CRYSTAL) (NCT00910312) is a cryotherapy device for office-based ultrasound-guided treatment of breast fibroadenoma. This interventional study is sponsored IceCure Medical Ltd., to determine whether the Ice-Sense, a novel cryotherapy system (a system that freezes tissues), is safe and effective in the treatment of benign breast tumors such as fibroadenoma. The enrollment to date is 54 subjects, but no longer recruiting participants. The expected completed is listed as December 2012. Published outcomes have not been posted. (30)
- Cryotherapy in Treating Patients With Lung Cancer That Has Spread to the Other Lung or Parts of the Body (NCT01325753), an interventional pilot study of cryoablation of metastatic lung or pleura tumors in patients, for safety and efficacy in treating tumors less than or equal to 3.5 cm in patients with pulmonary metastatic disease. The study, sponsored by Comprehensive Cancer Center of Wake Forrest University, has been withdrawn prior to recruitment. (31)
Practice Guidelines and Position Statements
The American Society of Breast Surgeons 2008 Consensus Statement on Management of Fibroadenomas of the Breast indicates cryoablation is appropriate for histologically confirmed fibroadenoma lesions that are less than 4 cm in largest diameter and sonographically visible. (32) Cryoablation of fibroadenoma of the breast is contraindicated when ultrasound visualization is poor or core biopsy suggests a diagnosis of cystosarcoma phyllodes tumor or other malignancy or if physical examination or imaging is discordant with a biopsy diagnosis of fibroadenoma.
The National Comprehensive Cancer Network (NCCN) Practice Guidelines for Non-Small Cell Lung Cancer (33) indicate surgical resection is the preferred local treatment but cryotherapy and other approaches are listed as treatment options. The NCCN discussed the use of cryotherapy in treatment of bone cancer, “low recurrence rates in patients with grade I intracompartmental chondrosarcomas”; however, the NCCN did not include the use of cryotherapy in their recommendations. (34) Cryotherapy was not included in the current NCCN guidelines for treatment of breast, lung, or pancreatic cancers.
The American College of Surgeons has not or released or posted on their web site an official guideline or consensus statement in the use of cryoablative or cryotherapy procedures.
The current evidence on cryoablation for indications identified in this policy consists largely of non-comparative, case series and is insufficient to permit conclusions concerning the effect of cryoablation on health outcomes. Therefore, cryoablation is considered experimental, investigational and unproven for solid tumors other than those of the kidney, liver and prostate. Comparative studies with larger numbers of subjects and longer follow-up are needed.
Additional literature review was completed through March 2013.
In a 2004 multi-institutional investigation that Kaufman was one of the investigators, 124 lesions in 102 patients were monitored for 12 months. (35) Two different techniques were used: Double HI FREEZE and Tailored Freeze. The results from the Tailored Freeze had better results recorded at 12 months. The median reduction of tumor volume was 91%, of those 84% were less than 2.5 cm in the maximum diameter and were non-palpable. For the entire study, 73% of the treated lesions were nonpalpable. The study authors concluded cryoablation freezing techniques improved with the evolution in the cryoprobe design, resulting in safety and effectiveness of the procedure. Therefore, cryosurgical ablation will be considered medically necessary for benign fibroadenoma breast lesions when the lesion is confirmed by sonogram, histology, and less than 2.5 cm in the largest diameter.
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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.
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