Cryoablation

Number: 0100

Policy

  1. Aetna considers cryoablation of the prostate medically necessary for prostate cancer as a primary therapy alternative to surgery or irradiation in individuals with localized disease (T1 or T2 [organ confined] or T3 [locally advanced]) or as salvage therapy for recurrent cancer following failure of radiation therapy;

  2. Aetna considers cryoablation of the prostate experimental and investigational for members with benign prostatic hypertrophy (see CPB 0079 - Benign Prostatic Hypertrophy (BPH) Treatments);

  3. Aetna considers cryoablation for malignant endobronchial obstruction medically necessary.

  4. Aetna considers cryoablation of renal cell carcinoma, up to 4-cm in size, medically necessary when any of the following criteria is met:

    1. Persons who are considered high-risk surgical candidates; or
    2. Persons with renal insufficiency, as defined by a glomerular filtration rate of less than or equal to 60 ml/min/m2; or
    3. Persons with a solitary kidney.
  5. Aetna considers cryoablation (e.g., cryoballoon) medically necessary for the treatment of atrial fibrillation, with evidence of a localized site(s) of origin when the tachycardia is drug-resistant or the member is drug- intolerant or does not desire long-term drug therapy  (e.g., pulmonary vein isolation procedures); or

  6. Aetna considers cryoablation of breast carcinoma and fibroadenoma experimental and investigational.

  7. Aetna considers cryoablation medically necessary for the treatment of low-risk superficial basal cell carcinoma, and squamous cell carcinoma in situ (Bowen disease), where surgery or radiation is contraindicated or impractical.

  8. Aetna considers cryoablation medically necessary for soft tissue sarcoma of the extremities or the trunk in symptomatic persons with disseminated metastases.

  9. Aetna considers cryoablation experimental and investigational for the following (not an all-inclusive list) because its effectiveness for these indications has not been established.

    • Abdominal wall arterio-venous malformation
    • Abdominal wall endometriosis (endometrioma)
    • Allergic and non-allergic rhinitis (e.g., by means of the ClariFix device)
    • Barrett's esophagus
    • Benign prostatic hypertrophy
    • Bone and soft tissue tumors
    • Bony metastases from renal cell carcinoma
    • Breast carcinoma and fibroadenoma
    • Cancer pain
    • Chronic headache
    • Cutaneous sporotrichosis in pregnant women
    • Drooling
    • Esophageal cancer
    • Extra-abdominal desmoid tumors
    • Facet joint pain
    • Fibro-adipose vascular anomaly (FAVA) lesion
    • Hookworm-related cutaneous infection
    • Idiopathic ventricular tachycardia (VT)
    • Leiomyosarcoma
    • Lipoma
    • Metastatic hepatocellular carcinoma
    • Morton's neuroma
    • Neuroma
    • Non-small cell lung cancer (other than malignant endobronchial obstruction)
    • Osteoid osteoma
    • Pancreatic cancer
    • Peripheral nerve damage in the lower extremity
    • Plantar fibroma
    • Post-infarction VT
    • Premature ejaculation
    • Reduction of pain or opioid consumption after total knee arthroplasty
    • Residual facial arterio-venous malformations
    • Retinopathy of prematurity
    • Retroperitoneal soft-tissue sarcoma
    • Sacroiliac joint pain
    • Spinal giant cell tumors
    • Talc granuloma pain
    • Tuberous sclerosis-associated renal angiomyolipoma
  10. Aetna considers cryoablation medically necessary for cervical intraepithelial neoplasia.

  11. Aetna considers endoluminal cryoablation experimental and investigational for the treatment of symptomatic varicose veins because of insufficient evidence of its effectiveness. See CPB 50 - Varicose Veins.

  12. For cryoablation of hepatic lesions, see  CPB 0274 - Ablation of Hepatic Lesions.

  13. For cryoablation of the endometrium, see CPB 0091 - Endometrial Ablation.

  14. For cryosurgery of the skin, see CPB 0567 - Actinic Keratosis Treatments, and CPB 0633 - Benign Skin Lesion Removal.

  15. For cryosurgery of plantar fasciitis, see CPB 0235 - Plantar Fasciitis Treatments.

See also CPB 0016 - Back Pain - Invasive Procedures, and CPB 0728 - Barrett's Esophagus.

Background

Prostate Cancer

Cryosurgical ablation is an established method of treating localized prostate cancer.  In 1996, the American Urological Association revised their policy statement regarding cryosurgical ablation of the prostate to state that they believe that cryosurgical treatment of the prostate should be accepted as one of the methods of management of adenocarcinoma of the prostate.  They indicated that because the long-term curative efficacy of this treatment modality has not been established, when used, appropriate disclosure of facts regarding all other treatments for prostate cancer should be made to the patient.

Endobronchial Obstruction

Cryosurgical ablation has been shown to be an effective method for palliation of symptoms from malignant endobronchial obstruction.  The National Institute for Clinical Excellence (NICE, 2005) assessed cryotherapy for malignant endobronchial obstruction, and concluded that "[c]urrent evidence on the safety and efficacy of cryotherapy for malignant endobronchial obstruction appears adequate to support the use of the procedure provided that the normal arrangements are in place for consent, audit and clinical governance."  The assessment noted that the main aim of the procedure is palliation of symptoms such as cough, dyspnea and hemoptysis.  In 1 case series of 521 patients, 86 % had improvement in one or more symptoms and quality of life scores were significantly improved.  Dyspnea improved in 59 % of patients.  In 2 further studies, dyspnea improved in 71 % and 81 % of patients.  The assessment also noted that cryotherapy does not provide immediate relief of bronchial obstruction and is therefore not suitable for the emergency treatment of acute respiratory distress.

Renal Cancer

Cryotherapy may be used as an alternative to nephrectomy for renal carcinoma in persons who are not surgical candidates.  Incidental detection of solid renal masses during abdominal imaging is increasing in older patients.  Although these masses often are malignant histologically, many are indolent clinically.  A therapeutic option for patients who are poor surgical candidates is cryoablation, in which cryoprobes are inserted percutaneously into the mass, creating an "ice ball" that destroys the tumor.  According to the peer-reviewed medical literature, cryotherapy for ablation of renal cell carcinoma is a promising alternative for persons who are not candidates for total or partial nephrectomy.  Although it is potentially an attractive addition to available nephron-sparing surgical techniques, refinement of MR image guidance and percutaneous techniques for introducing cryogenic probes into the kidneys and other deep abdominal organs must be developed, and long-term data on the effectiveness of cryoablation of renal cell carcinoma are limited.

Cestari et al (2004) reported their experience with laparoscopic renal cryoablation in select cases of small renal neoplasms (n = 37).  They concluded that laparoscopic renal cryoablation for small renal masses appears to be a safe, reproducible, minimally invasive technique.  Medium term follow-up is encouraging, although further studies and prolonged follow-up are needed to access properly the role of this surgical technique.  This is in agreement with the findings of Johnson et al (2004) as well as Moon et al (2004).  Johnson and associates stated that ablation technologies (cryoablation and radiofrequency ablation) appear to have a low complication profile when used to treat small renal tumors.  The majority of complications are minor and require observation only.  Further study and follow-up are needed to determine their long-term effectiveness.  Moon and colleagues concluded that longer follow-up is required to fully define the role of laparoscopic cryoablation for the treatment of small renal tumors.

Desai et al (2005) compared peri-operative and short-term outcomes of laparoscopic partial nephrectomy versus laparoscopic cryoablation in patients with peripheral small renal tumors and concluded that, "[a]lthough the technical simplicity, decreased blood loss, and somewhat lower complication rate are attractive features of renal cryotherapy, this must be balanced against the current lack of long-term follow-up data that are needed to confirm the oncologic adequacy of this developmental procedure."  These findings are consistent with a review by Aron and Gill (2005) on renal tumor ablation methods that stated, "Although the initial outcomes of cryoablation and radiofrequency ablation are encouraging, long-term studies are necessary to confirm their lasting efficacy.  The optimal modality for tumor targeting, monitoring therapy, and follow-up remains to be determined."

Kaouk et al (2006) examined the experimental and clinical evolution of cryotherapy for small renal masses.  The authors stated that the major criticism of this and other ablative techniques is the associated lack of histological confirmation of complete tumor ablation.  They noted that long-term, diligently performed clinical trials that provide detailed, meticulous, sequential 5-year radiological and histological data are needed to confirm lasting effectiveness.  Furthermore, these data must be compared with those related to partial nephrectomy, which remains the reference standard.

Littrup and colleagues (2007) evaluated the results of initial and current techniques for percutaneous renal cryotherapy, including long-term imaging outcomes.  Computed tomography (CT)-guided percutaneous cryotherapy was performed on 49 masses in 48 out-patients and procedure comfort noted for each.  These 49 masses included 36 primary renal cell carcinomas (RCCs), 3 oncocytomas, 1 angiomyolipoma, 6 renal inflammatory lesions, 2 benign parenchymal changes, and 1 colon cancer metastasis.  All complications were graded according to standardized criteria.  Patients received only local anesthesia and moderate sedation during the procedure and were discharged with minimal discomfort within 4 to 6 hours.  All cryotherapy zones were well defined by CT during ablation as hypodense ice with an average diameter of 5.3 cm, covering an average tumor size of 3.3 cm.  Average ablation zone diameters showed significant reduction over time (p < 0.001), becoming significantly less than the original tumor size by 12 months (p < 0.05).  Major and minor complications were seen in 3 (6 %) and 11 (22 %) procedures, respectively.  At a mean follow-up of 1.6 years (range of 1 week to 3.8 years) for primary RCC patients, 4 failures (11.1 %) by imaging criteria were noted, but 1 proved to be inflammatory tissue at re-biopsy (estimated neoplastic failure rate = 3/36 [8.3 %]).  The authors concluded that percutaneous renal cryotherapy is a well-tolerated out-patient procedure that allows safe, CT monitoring of ice formation beyond visible tumor margins.  With appropriate cryoprobe placements, a low failure rate appears less dependent on tumor size or location.  Ablation volume involution was greater than 80 % after 6 months.

Atwell et al (2008) determined technical feasibility, safety and short-term outcomes following percutaneous renal cryoablation.  These investigators performed a retrospective review of 115 renal tumors in 110 elderly patients (mean age 72 years) treated with percutaneous cryoablation.  For most patients, cryoablation was recommended instead of surgery because of substantial medical co-morbidities or prior contralateral nephrectomy.  Mean tumor size was 3.3 cm (range of 1.5 to 7.3 cm), including 29 tumors 4.0 cm or larger and 21 tumors in the anterior kidney.  Of 90 renal mass biopsies performed, 52 (58 %) showed renal cell carcinoma.  All patients were admitted to the hospital following cryoablation and most (87 %) were discharged home the next day (range of 1 to 12 days).  There were 7 major complications associated with the 113 cryoablation procedures (6 %),  including pulmonary embolism, urosepsis, and large hematomas. Technical success (defined as extension of the ice ball beyond tumor margins and no post-ablation contrast enhancement of tumor parenchyma) was achieved in 112 of the 115 (97 %) treated tumors and 3 residual tumors were seen on 3-month follow-up imaging.  There has been no local progression in 80 tumors (100 % treatment success) followed 3 months or longer (mean of 13.3 months). Commenting on this study, Brett (2008) stated that cryoablation is a technically feasible approach for patients with incidentally discovered renal masses who are not good surgical candidates. Brett observed however, that follow-up was relatively brief, and the complication rate was not trivial. Brett noted that because many small renal tumors in older patients progress slowly or not at all, simple observation without intervention is another reasonable option.

Hinshaw and colleagues (2008) compared the outcome, complications, and charges of percutaneous renal cryoablation and laparoscopic cryoablation of solid renal masses.  A total of 30 percutaneous renal cryoablations (mean tumor size of 2.1 cm) in 30 patients (mean age of 67.0 years) and 60 laparoscopic renal cryoablations (mean tumor size of 2.5 cm) in 46 patients (mean age of 67.4 years) were compared.  The size of the tumor, procedural complications, hospital charges, length of hospital stay, and tumor follow-up parameters were recorded.  Monitoring after ablation was performed every 3 months using contrast-enhanced MRI or CT.  Both percutaneous cryoablation and laparoscopic cryoablation of solid renal masses had a high technical success rate (30/30 [100 %] and 59/60 [98.3 %]).  There was no significant difference in the rate of residual disease (3/30 [10 %] and 4/60 [6.7 %], p = 0.68), and the secondary effectiveness rate is 100 % for both groups to date.  One renal mass treated using laparoscopic cryoablation had a local recurrence, but none of the masses treated using percutaneous cryoablation had a recurrence.  The disease-specific survival is 100 % in both groups with no significant difference in the mean follow-up time (14.5 versus 14.6 months, p = 1.0) or major complication rate (0/30 [0 %] versus 3/60 [5.0 %], p = 0.55).  For the treatment of solid renal masses, percutaneous cryoablation was associated with 40 % lower hospital charges (mean of $14,175 versus $23,618, p < 0.00001) and a shorter hospital stay (mean +/- SD, 1.1 +/- 0.3 versus 2.4 +/- 2.1 days; p < 0.0001) than laparoscopic cryoablation.  The authors concluded that although certain tumors require laparoscopic intervention because of the location or size of the tumor, percutaneous renal cryoablation is safe and effective and is associated with lower charges when used for the treatment of small renal tumors.

Finley et al (2008) reviewed their 4-year experience with percutaneous cryoablation and laparoscopy for treating small renal masses.  An in-depth analysis was performed concerning demographics, hospital course and short-term outcome with respect to percutaneous versus laparoscopic cryoablation.  A total of 37 patients underwent treatment for 43 renal masses.  Of the 37 patients 19 underwent laparoscopic cryoablation (24 tumors) and 18 underwent percutaneous cryoablation (19 tumors) using computerized tomography fluoroscopy.  For percutaneous cryoablation a saline instillation was used in 58 % of cases to move non-renal vital structures away from the targeted renal mass.  There were 5 cases of hemorrhage requiring transfusion, all of which were associated with the use of multiple cryoprobes.  The transfusion rate in the percutaneous and laparoscopic cryoablation groups was 11.1 % and 27.8 %, respectively.  Operative time was significantly longer in the laparoscopic cryoablation group compared to the percutaneous cryoablation group at 147 minutes (range of 89 to 209) versus 250.2 (range of 151 to 360) minutes, respectively.  The overall complication rate (including transfusion) was lower in the percutaneous cryoablation group compared to the laparoscopic cryoablation group (4 of 18 [22.2 %] versus 8 of 20 [40 %], respectively).  Hospital stay was significantly shorter in the percutaneous versus laparoscopic cryoablation group at 1.3 versus 3.1 days, p < 0.0001, respectively.  Narcotic use in the percutaneous cryoablation group was more than half that used by the laparoscopic cryoablation group (5.1 versus 17.8 mg, p = 0.03, respectively).  Among patients with biopsy proven renal cell carcinoma during a median follow-up of 11.4 and 13.4 months in the percutaneous and laparoscopic cryoablation groups, cancer specific survival was 100 % and 100 %, respectively, and the treatment failure rate was 5.3 % and 4.2 %, respectively.  The authors concluded that percutaneous cryoablation is an efficient, minimally morbid method for the treatment of small renal masses and it appears to be superior to the laparoscopic approach.  Short-term follow-up has shown no difference in tumor recurrence or need for re-treatment.  Of note, hemorrhage was solely associated with the use of multiple probes.

Weight et al (2008) stated that follow-up after radiofrequency ablation and cryotherapy for small renal lesions lacks pathological analysis.  The definition of successful tumor ablation has been the absence of contrast enhancement on post-treatment magnetic resonance imaging or computerized tomography.  These researchers hypothesized that adding post-ablation kidney biopsy would help confirm treatment success.  From April 2002 to March 2006, a total of 109 renal lesions in 88 patients were ablated with percutaneous radiofrequency ablation and from September 1997 to January 2006 a total of 192 lesions in 176 patients were treated with laparoscopic cryoablation.  Patients were followed with radiographic imaging and post-ablation biopsy at 6 months.  Radiographic success at 6 months was 85 % (62 cases) and 90 % (125) for radiofrequency ablation and cryoablation, respectively.  At 6 months 134 lesions (45 %) were biopsied and success in the radiofrequency ablation cohort decreased to 64.8 % (24 cases), while cryoablation success remained high at 93.8 % (91).  Six of 13 patients (46.2 %) with a 6-month positive biopsy after radiofrequency ablation demonstrated no enhancement on post-treatment magnetic resonance imaging or computerized tomography.  In patients treated with cryoablation all positive biopsies revealed post-treatment enhancement on imaging just before biopsy.  The authors recommend post-radiofrequency ablation follow-up biopsy due to the significant risk of residual renal cell cancer without radiographic evidence, although to their knowledge the clinical significance of these viable cells remains to be determined.  In contrast, radiographic images of renal lesions treated with cryotherapy appeared to correlate adequately with corresponding histopathological findings in our series.

The National Comprehensive Cancer Network's clinical practice guideline for kidney cancer (2008) stated that patients in satisfactory medical condition should undergo surgical excision of stage I through III tumors.  However, a small set of elderly or infirm patients with small tumors may be offered surveillance alone or energy ablative techniques, such as radiofrequency ablation or cryoablation.

An assessment by the National Institute for Health and Clinical Excellence (NICE, 2007) concluded: "Current evidence suggests that cryotherapy for renal cancer ablates tumour tissue and that its safety is adequate.  However, the evidence about its effect on long-term local control and survival is not yet adequate to support the use of this procedure without special arrangements for consent and for audit or research."  The NICE assessment noted that its specialist advisors commented that, because only a small number of patients have been treated with this procedure, long-term efficacy has yet to be established.  The specialist advisors to NICE also noted that the lack of histological data makes it difficult to determine whether total ablation of tumors has been achieved.

There is little evidence for use of cryoablation for large renal masses; larger tumors are more likely to be metastatic.  The NICE guidance on “Percutaneous cryotherapy for renal cancer” (2011) found that the maximum renal tumor size for which cryotherapy is recommended is approximately 4 cm (small, stage I tumors).

Breast Fibroadenomas

Cryoablation has been proposed as an alternative method for management of breast fibroadenomas.  A fibroadenoma is a benign solid lump of breast tissue, which is thought to result from an increased sensitivity to estrogen.  Fibroadenomas are very common and it is not unusual to have more than one.  They are mostly found in young women but can occur in women of any age.  Most fibroadenomas do not enlarge after diagnosis.  Some get smaller and some eventually disappear over time.  Fibroadenomas are usually managed conservatively, with periodic ultrasound evaluation.  Women who are very anxious about the presence of a tumor or who have enlarging masses are often referred for excisional biopsy.  The excised material can be submitted to pathology to confirm the benign diagnosis.

While the use of cryoablation for the treatment of breast fibroadenoma has gained in popularity, there is insufficient published literature to demonstrate the efficacy of this procedure.  Kaufman et al (2002, 2004) reported on the outcomes of cryoablation in 57 patients with breast fibroadenomas.  This study was limited to 12-month follow-up from a single investigator group, and did not include a direct comparison to surgical excision.  Kaufman et al (2005) reported outcomes for cryoablation in 37 treated fibroadenomas with a longer follow-up period of 2.6 years on average.  Of the original 84 % palpable fibroadenomas prior to treatment, 16 % remained palpable to the patient.  Of those fibroadenomas that were initially less than or equal to 2.0 cm in size, 6 % remained palpable.  A median volume reduction of 99 % was observed with ultrasound.  Although this procedure may offer a less invasive method of treating breast fibroadenomas, long-term data on the clinical effectiveness of this procedure versus surgical excision are needed.  Studies of cryoablation of breast carcinomas have been limited to preliminary evaluation studies.  There are no studies directly comparing the effectiveness of cryoablation to surgical incision in treatment of breast carcinomas.  Although cryoablation is less invasive than surgical incision, a key disadvantage of cryoablation is the lack of a tissue sample to examine histologically to ensure adequate surgical margins and complete removal of tumor.

Edwards et al (2004) provided a retrospective summary from a nationwide group of the early experience of cryoablation for the percutaneous treatment of breast fibroadenomas.  The authors concluded that an early community experience with office-based cryoablation of breast fibroadenomas is encouraging and comparable to the initial experience of high-volume tertiary centers.  More follow-up is necessary to determine long-term results and residual mammographic changes.

In a review of ablative approaches and breast cancer, Agnese and Burak (2005) stated that, "[a]blative therapies, including laser ablation, focused ultrasound, microwave ablation, radiofrequency ablation, and cryoablation, have been described.  All of these techniques have shown promise in the treatment of small cancers of the breast; however, additional research is needed to determine the efficacy of these techniques when they are used as the sole therapy and to determine the long-term local recurrence rates and survival associated with these treatment strategies."

An assessment on cryoablation for the treatment of breast fibroadenomas by the California Technology Assessment Forum (CTAF, 2006) concluded that this technology does not meet CTAF's criteria.  The assessment expressed concerns about the limitations in studies with long-term follow-up, and the lack of studies directly comparing cryoablation with other methods of management of breast fibroadenomas.  The CTAF assessment documents serious methodological problems with these studies.  The CTAF assessment states: "The largest series [Nurko et al, 2005] reported on 444 lesions, but follow-up was incomplete with fewer than 20 % of lesions evaluated at 12 months.  None of the case-series document the systematic use of any validated instrument to establish patient satisfaction, adverse events or to evaluate any other outcomes.  Follow-up was grossly inadequate to report intermediate length follow-up."

Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia, and is present in approximately 35 % of patients presenting for mitral valve surgery and in 1 to 6 % of adult patients undergoing other forms of cardiac surgery.  If left untreated, atrial fibrillation is associated with increased morbidity, and, in some subgroups, increased mortality.  Thus, concomitant management of the arrhythmia is indicated in most cardiac surgery patients with pre-existing AF.  Although the cut-and-sew Cox-maze III procedure is extremely effective, the advent of ablative energy sources such as radiofrequency and cryoablation has simplified the surgical treatment of atrial AF during concomitant cardiac procedures (Gillinov and Saltman, 2007).

A number of studies have examined the efficacy of cryoablation for atrial fibrillation. Doll and associates (2003) described their early experience in treatment of patients with chronic or paroxysmal AF with a tool for left atrial cryoablation.  A total of 28 patients underwent left atrial cryoablation with the Surgifrost CryoCath.  Patients underwent cryotherapy as an isolated procedure (n = 1), in combination with mitral valve surgery (n = 13), or with other surgical procedures (n = 14).  In all patients contiguous lesion lines to the orifices of the pulmonary veins (PVs) connected to the mitral annulus and the atriotomy were created.  Surgery was performed through a conventional sternotomy in 8 patients (29 %) and a right lateral mini-thoracotomy using video-assistance in 20 patients (71 %).  Post-operatively sinus rhythm (SR) was restored in 27 patients (96 %).  At discharge 82 % (23/28) of patients were in SR and 18 % (5/28) were in AF.  Four patients (14 %) required pace-maker implantation.  There was no in-hospital mortality.  At 6-month follow-up (19/28 patients) all were alive and 74 % were in stable SR, New York Heart Association functional class was 1.2 +/- 0.4.  The authors concluded that left atrial cryoablation with the Surgifrost argon cryocatheter is effective for the treatment of AF.  This new device is technically easy to handle, it can be applied through a median sternotomy or lateral mini-thoracotomy.  They stated that long-term follow-up is necessary to evaluate further rhythm outcome.

In a feasibility study, Hoyt and colleagues (2005) reported the findings of PV isolation (PVI) with cryoablation in 31 patients with paroxysmal AF.  Event monitors were used to measure the AF episode burden.  Serial spiral CT scans were obtained to monitor PV stenosis pre- and post-cryoablation.  Cryoablation was immediately successful for PVI in 29 of 31 patients (94 %), with 5.9 +/- 1.2 months of follow-up.  Additional RF ablation was performed for AF recurrences in 7 patients.  The remaining 22 patients with a single cryoablation procedure demonstrated a time-dependent, long-term reduction in the frequency of AF episodes.  At 6-month follow-up, 18 of 22 of cryo-treated only patients (82 %) were free of symptomatic AF episodes, and anti-arrhythmic drugs (AADs) were discontinued in 12 of 22 patients.  Serial spiral CT scans demonstrated no change in the cryo-treated PV ostial diameter.  The authors concluded that PV cryoablation was effective to control paroxysmal AF in most patients.  Early recurrences of AF post-cryoablation were common, though tended to resolve within 6 months post-ablation, consistent with a process of reverse atrial remodeling.  Cryoablation of the PVs did not cause PV stenosis or other serious adverse events.

Gaita and co-workers (2005) examined the role of PVI alone versus left atrial linear lesions in the treatment of permanent AF in patients with left atrial dilatation and valvular disease.  The primary end point was to assess the persistence of SR off AADs at 2-year follow-up and to correlate clinical outcome with surgical results validated with electro-anatomical mapping (EAM).  A total of 105 patients with permanent AF undergoing valve surgery were assigned to 3 different groups: in groups "U" and "7," left atrial linear cryoablation was performed, whereas in group "PV" patients, anatomical cryoisolation of pulmonary veins only was performed.  In groups U and 7, SR was achieved in 57 % of patients, whereas it was achieved in 20 % of PV patients during 2-year follow-up.  In the first 51 patients, the ablation schemes were validated with EAM.  The EAM showed that the U lesion was never obtained: in 59 % of these patients, a complete 7 lesion was achieved instead; in the 7 group, a complete 7 lesion was present in 65 % of patients, whereas a complete PVI was obtained in 71 % of patients.  Considering patients in whom a complete 7 lesion was demonstrated with the EAM, SR without AADs was achieved in 86 % of patients, whereas only 25 % of patients with complete PVI were in SR without AADs.  The authors concluded that in patients with permanent AF, left atrial dilatation and valvular heart disease linear lesions in the posterior region of the left atrium are more effective than PVI alone.  With cryoablation, the surgical intent is fulfilled in only approximately 65 % of the cases.

Mack et al (2005) reported their findings of using argon-based endocardial cryoablation for the treatment of AF in patients undergoing concomitant cardiac procedures.  A total of 63 patients with AF who were undergoing concomitant cardiac procedures had the same left atrial endocardial lesion set using a flexible argon-based cryoablative device.  Mean age was 65.1 +/- 1.3 years.  Sixty-two percent had permanent AF, whereas 38 % had paroxysmal AF.  Mean duration of AF was 30.5 +/- 4.8 months.  Mean left atrial diameter was 5.5 +/- 0.1 cm.  Mean ejection fraction was 45 +/- 1.4 %.  All endocardial lesions were performed for 1 minute once tissue temperature reached -40 degrees C.  Follow-up echocardiograms were obtained to determine freedom from AF. Kaplan-Meier analysis demonstrated an 88.5 % freedom from AF rate at 12 months.  Ablation time was 16.8 +/- 0.6 minutes.  There were no in-hospital deaths and no strokes.  Twelve patients (19 %) required post-operative permanent pace-maker placement.  The authors concluded that cryoablation using this flexible argon-based device for the treatment of AF during concomitant cardiac procedures was safe and effective, with 88.5 % of patients free from AF at 12 months.

Neuwirth et al (2007) evaluated effectiveness of surgical cryoMAZE ablation for chronic AF in patients undergoing mitral valve surgical intervention.  A total of 47 patients (31 females), aged 67.3 +/- 7.3 years who underwent surgical intervention for severe mitral regurgitation were studied.  Mitral valvuloplasty was performed in 21 patients, and mitral valve replacement in 26 patients.  Combined procedure was employed in 35 patients; simultaneous aorto-coronary bypass was performed in 16 patients, tricuspid valvuloplasty (TVP) in 5 patients, and aortic valve replacement (AVR) in 5 patients.  The mean follow-up time was 19 +/- 10 months.  After 6 or 12 months, 36 or 32 patients were seen and 23 (64 %) or 22 (69 %) of them were in stable SR, respectively.  In the subset of 24 patients with simultaneous intervention on a different valve (TVP or AVR), after 6 or 12 months, 14 (74 %) or 15 (83 %) patients had stable SR, respectively.  In the follow-up period, 2 patients underwent successful catheter ablation for type I atrial flutter or for a residual left atrial atypical flutter.  The authors concluded that cryoMAZE ablation for chronic AF performed during the mitral valve surgical intervention resulted in a long-term stable SR in a high proportion of patients, particularly in patients with simultaneous intervention on two or three different valves.

Blomström-Lundqvist et al (2007) examined the effectiveness of epicardial left atrial (LA) cryoablation in eliminating AF in patients undergoing mitral valve surgery (MVS).  These researchers hypothesized that MVS combined with LA cryoablation is superior to MVS alone.  A total of 69 patients with permanent AF, included at four centers, underwent MVS with or without epicardial LA cryoablation.  The primary endpoint was regained SR.  Risk factors for failed AF cryoablation were elucidated.  Sixty-five out of 69 patients reached the primary endpoint.  At 6- and 12-month follow-up, 73.3 % of patients who underwent cryoablation had regained SR at both follow-ups, compared with 45.7 % and 42.9 % of patients, respectively, who underwent MVS alone (group differences, at 6-month p = 0.024, at 12-month p = 0.013).  The in-hospital complication rate was 11.4 % in the MVS group and 26.5 % in the cryoablation group (p = 0.110).  Risk factors for failed elimination of AF by cryoablation were duration of permanent AF (p = 0.012) and presence of coronary artery disease (p = 0.047), according to multiple logistic regression analysis.  The authors concluded that this prospective randomized study showed that combining MVS with epicardial LA cryoablation is significantly better in eliminating pre-operative permanent AF than MVS alone.

The National Institute for Clinical Excellence (2005) concluded that current evidence on the safety and effectiveness of cryoablation for AF in association with other cardiac surgery appears adequate.

The American College of Cardiology and the American Heart Association clinical guidelines addressing management of AF (Wann 2011) offered a Class I recommendation based on Level A data for catheter ablation in patients with symptomatic paroxysmal AF who have failed treatment with an anti-arrhythmic drug. This recommendation does not distinguish between radiofrequency or cryoballoon ablation. A Heart Rhythm Society consensus statement on the management of AF similarly gave a class I recommendation for catheter-based ablation for the treatment of drug refractory recurrent symptomatic paroxysmal AF based on studies comparing ablation to standard drug therapy that consistently reported that ablation resulted in a significant improvement in rhythm control. The consensus statement included a review of the randomized STOP-AF trial comparing cryoballoon ablation with the standard of drug therapy. Similar to studies of radiofrequency ablation, the results of the STOP-AF trial indicate that cryoballoon ablation results in a significant improvement in rhythm control. 

Skin Cancer

Guidelines on basal cell skin cancer from the National Comprehensive Cancer Network (NCCN, 2009) provide a limited role of cryotherapy in the treatment of skin cancers.  The NCCN guidelines state that, in patients with low-risk, superficial basal cell skin cancer or low-risk squamous cell carcinoma in situ (Bowen's disease), vigorous cryotherapy may be considered where surgery or radiation is contraindicated or impractical, even though the cure rate may be lower.  The British Association of Dermatologists' guidelines for the management of basal cell carcinoma (Telfer et al, 2008) stated that cryosurgery is a good treatment for low-risk basal cell carcinoma.

Other indications

Guidelines from the National Comprehensive Cancer Network (NCCN, 2009) on soft tissue sarcoma have included cryoablation as an option for symptomatic persons with disseminated metastatic soft tissue sarcoma of the trunk and extremities.

There is a lack of evidence regarding the use of cryoablation for the treatment of plantar fibroma.  In the absence of peer-reviewed data, the use of cryoablation is not recommended for this condition.

Birkenmaier and colleagues (2007) stated that facet joint pain is an important aspect of degenerative lumbar spine disease, and radiofrequency medial branch neurotomy remains an established therapy, while cryodenervation has still been poorly examined.  In a prospective clinical case series, these researchers examined the effects of medial branch cryodenervation in the treatment of lumbar facet joint pain.  Patient selection was based on medical history, physical examination and positive medial branch blocks.  Percutaneous medial branch cryodenervation was performed using a Lloyd Neurostat 2000.  Target parameters were LBP (by means of visual analog scale [VAS], limitation of activity (McNab) and overall satisfaction.  A total fo 50 patients were recruited, and 46 completed the study.  The follow-up time was 1 year.  At 6 weeks, 33 patients (72 %) were pain-free or had major improvement of LBP; 13 (28 %) had no or little improvement.  Including failures, mean LBP decreased significantly from 7.7 pre-operatively to 3.2 at 6 weeks, 3.3 at 3 months, 3.0 at 6 months and 4.2 at 12 months (p < 0.0001).  Limitation of the activities of daily living improved parallel to reduced pain.  The authors cited
  1. other sources of LBP,
  2. false-positive diagnostic blocks, and
  3. inadequate technique as possible explanations for cryodenervation failure in some of the study subjects.

Kujak and colleagues (2010) described their early experiences with using percutaneous cryoablation for local control of extra-abdominal desmoid (EAD) tumors in patients whose tumors had failed to respond to standard therapy.  A total of 5 patients (2 males and 3 females) were included in this study.  Three of these patients had been referred for cryoablation for local tumor control, and 2 had been referred for palliation of inoperable tumors.  The age range of the patients at the time of cryoablation was 9 to 41 years.  Treated EAD tumors were located in the neck, shoulders and trunk and ranged in size from 3.0 cm to 10.0 cm.  Medical records were reviewed for short-term and long-term follow-up, and patients were contacted for additional follow-up.  Patients were asked to rate their pain as absent, mild, moderate or severe, and to compare it with their levels before cryoablation, describing it as improved, unchanged or worsened.  Radiology records were reviewed to follow the size of the EAD tumors before and after cryotherapy.  For the 3 patients referred for local control of EAD tumors, complete tumor coverage with the ablation zones was achieved.  Two of these patients, with masses 3.0 cm and 4.9 cm in diameter, reported complete absence of pain at both short-term and long-term follow-up at 13 months and 49 months.  Their tumors had completely resolved on long-term imaging follow-up at 19 months and 43 months.  The third patient, with a 6.1 cm mass, reported improved mild pain at 6 months, and imaging showed a moderate decrease of tumor size.  For the 2 patients referred for palliative therapy, initial partial pain relief was felt 2 weeks after the procedure.  At long-term (58 months) follow-up of 1 patient with a 9.1 cm mass, the tumor was still present although reduced in size, and local pain had returned to its former moderate level.  In the other patient who underwent only partial treatment of a 10.0 cm mass, at long-term follow-up (36 months) the mass had enlarged and pain had returned to the pre-treatment, moderate level.  The authors concluded that cryoablation appears to be an effective alternative treatment for local control of small and moderately sized EAD tumors, but it is likely of limited use in patients with larger tumors that have untreatable regions due to involvement of vital structures.  They stated that continued research evaluating cryoablation for the treatment of EAD tumors is needed.

In a multi-center, retrospective, cohort study, Greenwald et al (2010) evaluated the safety and effectiveness of cryotherapy in esophageal carcinoma.  Subjects with esophageal carcinoma in whom conventional therapy failed and those who refused or were ineligible for conventional therapy were included in this study; and they received cryotherapy with follow-up biopsies.  Treatment was complete when tumor eradication was confirmed by biopsy or when treatment was halted because of tumor progression, patient preference, or co-morbid condition.  Main outcome measures were complete eradication of luminal cancer and adverse events.  A total of 79 subjects (median age of 76 years, 81 % male, 94 % with adenocarcinoma) were treated.  Tumor stage included T1-60, T2-16, and T3/4-3.  Mean tumor length was 4.0 cm (range of 1 to 15 cm).  Previous treatment including endoscopic resection, photodynamic therapy, esophagectomy, chemotherapy, and radiation therapy failed in 53 subjects (67 %).  Only 49 patients completed treatment.  Complete response of intraluminal disease was seen in 31 of 49 subjects (61.2 %), including 18 of 24 (75 %) with mucosal cancer.  Mean (standard deviation) length of follow-up after treatment was 10.6 (8.4) months overall and 11.5 (2.8) months for T1 disease.  No serious adverse events were reported.  Benign stricture developed in 10 (13 %), with esophageal narrowing from previous endoscopic resection, radiotherapy, or photodynamic therapy noted in 9 of 10 subjects.  The authors concluded that spray cryotherapy is safe and well-tolerated for esophageal cancer.  They noted that short-term results suggested that it is effective in those who could not receive conventional treatment, especially for those with mucosal cancer.  Limitations of this study included its retrospective study design, short-term follow-up, and that only 49 of the 79 subjects (62 %) completed treatment, which could have skewed the findings of this study.

Timmermans et al (2010) reported the feasibility and safety of catheter-based cryoablation for the treatment of post-infarction and idiopathic ventricular tachycardia (VT).  Catheter-based cryoablation was performed in 17 patients (15 men, 58 +/- 18 years).  Ventricular tachycardia occurred after a prior myocardial infarction in 10 and was idiopathic in 7 patients.  Cryoablation was performed with a 10-F, 6.5-mm tipped catheter.  The ablation site was selected using entrainment mapping techniques for post-infarction VT.  The site of the earliest activation time with optimal pace mapping was used for ablation of idiopathic VT.  All targeted VTs (12 post-infarction and 7 idiopathic) were acute successfully ablated after a median number of 2 applications of 5 mins with an average temperature of -82 +/- 4 degrees C.  Mean procedure and fluoroscopy times were 204 +/- 52 and 52 +/- 20 mins for post-infarction VT and 203 +/- 24 and 38 +/- 15 mins for idiopathic VT.  No cryocatheter or cryoenergy complications were observed.  After a follow-up of 6 months, 4 of the 10 patients with post-infarction VT had a recurrence.  In 1 of the 7 patients with idiopathic VT the index arrhythmia recurred.  The authors concluded that in this small patient population, catheter-based cryoablation of VT was safe and effective.  They stated that future studies are needed to evaluate the effect of cryothermy in a larger group of patients, especially those with post-infarction VT.

Yamauchi and colleagues (2012) evaluated the mid-term results of percutaneous cryoablation for medically inoperable stage I non-small cell lung cancer.  Between January 2004 and June 2010, a total of 160 patients underwent computer tomography-guided percutaneous cryoablation for lung tumors at the authors’ institution.  Of these patients, histologically proven stage I lung cancer patients with more than 1 year of follow-up, were retrospectively reviewed.  All of these patients were considered to be medically inoperable with Charlson co-morbidity index of 3 or greater.  Follow-up was based primarily on computed tomography.  There were 22 patients with 34 tumors who underwent 25 sessions of cryoablation treatment.  Complications were pneumothoraces in 7 treatments (28 %, chest tube required in 1 treatment), and pleural effusions in 8 treatments (31 %).  The observation period ranged from 12 to 68 months, average 29 +/- 19 months, median 23 months.  Local tumor progression was observed in 1 tumor (3 %).  Mean local tumor progression-free interval was 69 +/- 2 months.  One patient died of lung cancer progression at 68 months.  Two patients died of acute exacerbations of idiopathic pulmonary fibrosis which were not considered to be directly associated with cryoablation, at 12 and 18 months, respectively.  The overall 2- and 3-year survivals were 88 % and 88 %, respectively.  Mean overall survival was 62 +/- 4 months.  Median overall survival was 68 months.  The disease-free 2- and 3-year survivals were 78 % and 67 %, respectively.  Mean disease-free survival was 46 +/- 6 months.  Pulmonary function tests were done in 16 patients (18 treatments) before and after cryoablation.  Percentage of predicted vital capacity, and percentage of predicted forced expiratory volume in 1 second, did not differ significantly before and after cryoablation (93 +/- 23 versus 90 +/- 21, and 70 +/- 11 versus 70 +/- 12, respectively).  The authors concluded that although further accumulation of data is necessary regarding efficacy, cryoablation may be a feasible option in medically inoperable stage I lung cancer patients.

In a report by the American Academy of Ophthalmology, Simpson and associates (2012) evaluated the role of cryotherapy in the current treatment of retinopathy of prematurity (ROP).  Literature searches of PubMed and the Cochrane Library were conducted on December 2, 2009, for articles published after 1984.  The searches included all languages and retrieved 187 relevant citations; 13 articles were deemed relevant to the assessment question and were rated according to the strength of evidence.  Four articles reported results from 2 large multi-center randomized clinical trials, and the remaining 9 articles reported results of 3 small randomized trials that directly compared cryotherapy and laser.  Neither of the multi-center randomized clinical trials was a direct comparison of cryotherapy with laser.  These studies were used to evaluate the comparative trials based on treatment criteria, study populations, and clinical results.  Higher percentages of poor structural and functional outcomes generally were seen in eyes treated with cryotherapy compared with eyes undergoing laser treatment.  Higher rates of systemic complications and myopia also were identified after treatment with cryotherapy.  No clinical studies are available to support treatment with cryotherapy for type 1 ROP as defined by the Early Treatment for ROP [ETROP] Study, especially given practical factors such as the need to treat posteriorly in younger patients who may be more susceptible to systemic complications from treatment The authors concluded that despite a relative paucity of level I evidence directly comparing cryotherapy and laser treatment for threshold ROP, the literature suggests that neonatal facilities should gain access to laser technology and laser-trained ophthalmic staff to achieve better outcomes for treatment of the disease.  Advantages of laser photocoagulation, including easier administration, lower rates of complications, and efficacy that is at least equivalent to cryotherapy, reduce the necessity for further study and make further randomized clinical trials comparing these 2 treatment methods unlikely.  Any future trials are likely to sue a pharmacologic approach such as bevacizumab alone or bevacizumab either in combination with or in comparison with laser as the preferred method for ablative therapy.

Martin-Hirsch et al (2010) stated that cervical intraepithelial neoplasia (CIN) is the most common pre-malignant lesion.  Atypical squamous changes occur in the transformation zone of the cervix with mild, moderate or severe changes described by their depth (CIN 1, 2 or 3).  Cervical intraepithelial neoplasia is treated by local ablation or lower morbidity excision techniques.  Choice of treatment depends on the grade and extent of the disease.  Ina Cochrane review, these investigators evaluated the effectiveness and safety of alternative surgical treatments for CIN.  They searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE and EMBASE (up to April 2009).  They also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.  Randomized controlled trials (RCTs) of alternative surgical treatments in women with CIN were selected for analysis.  Two review authors independently abstracted data and assessed risks of bias.  Risk ratios that compared residual disease after the follow-up examination and adverse events in women who received laser ablation, laser conisation, large loop excision of the transformation zone (LLETZ), knife conisation, or cryotherapy were pooled in random-effects model meta-analyses.  A total of 29 trials were included; 7 surgical techniques were tested in various comparisons.  No significant differences in treatment failures were demonstrated in terms of persistent disease after treatment. L arge loop excision of the transformation zone appeared to provide the most reliable specimens for histology with the least morbidity.  Morbidity was lower than with laser conisation, although the trials did not provide data for every outcome measure.  There were not enough data to assess the effect on morbidity when compared with laser ablation.  The authors concluded that the evidence suggested that there is no obvious superior surgical technique for treating CIN in terms of treatment failures or operative morbidity.

Lewis et al (2011) noted that in low-resource settings, cryotherapy can be cost-effective, affordable, and a first-line treatment for CIN of any grade.  These investigators reported the acceptability, safety and effectiveness of cryotherapy for women with CIN in Western Kenya.  Visual inspection with acetic acid (VIA)-positive women and those suspected of having cervical cancer based on an initial evaluation at a primary health facility were referred to the district hospital for colposcopy and additional evaluation using visual inspection with Lugol's iodine (VILI) and/or visual inspection with acetic acid and magnification (VIAM).  Cryotherapy was offered immediately to women diagnosed with appropriate CIN lesions based on colposcopy or after waiting for a confirmatory cervical biopsy and a follow-up visit occurred 1 year later.  A total of 91 women (aged 30 to 39 years) had CIN appropriate for cryotherapy.  Approximately 36 % (24/67) were due for their 1 year follow-up visit and 20 of 24 (83.3 %) attended.  Complete data were available for 18 of 20 (90 %) and 13 (72.2 %) had no sign of CIN.  No serious adverse events were reported 1 to 3 months after cryotherapy.  All respondents reported that the treatment experience was acceptable.  The authors concluded that cryotherapy was acceptable, safe and effective.

Sauvaget et al (2013) provided an updated and comprehensive estimate of the efficacy of cryotherapy for CIN.  A literature search identified original studies (RCTs and clinical reports).  Studies reporting cure rates, acceptability, and safety of cryotherapy were included in the analysis.  Number of persistent or recurrent lesions at follow-up, adverse events, and complications were recorded.  Quality of the methodology was also assessed.  Meta-analyses were performed according to CIN thresholds, geographic region, study year, setting, study design, presence of endocervical involvement, freezing method, duration of follow-up, and status of the cryotherapy provider.  A total of 146 articles were retrieved; 77 papers -- equivalent to 28,827 cases of treated CIN -- were included in the meta-analysis.  Cryotherapy achieved cure rates of 94.0 % (CIN1), 92.0 % (CIN2), and 85.0 % (CIN3).  Use of the double-freeze method and absence of endocervical involvement significantly increased cure rates.  Minimal complications were reported as adverse effects.  The authors concluded that cryotherapy is an effective, safe, and acceptable treatment for CIN.  It has been shown to be successful in low-resource settings, enabling availability and accessibility of early detection services.

In a multi-center RCT, Klem et al (2009) compared cryo-stripping of the great saphenous vein (GSV) with conventional stripping.  The study randomized 494 patients with symptomatic (CEAP) clinical severity class 2 to 4 to cryo-stripping (n = 249) or conventional stripping (n = 245).  The primary outcome was residual GSV 6 months after surgery measured by venous duplex ultrasound imaging.  Secondary outcomes were quality of life, operation time, and post-operative neural damage.  Duration of follow-up was 6 months.  Quality of life was measured at 6 and 26 weeks post-operatively with the Aberdeen Varicose Vein Questionnaire (AVVQ) and Medical Outcomes Study Short-Form 36 (SF-36) Health Survey.  The 2 groups were well-matched at baseline.  The percentage of patients with residual GSV at 6 months (primary outcome) was 44 % (102 of 230) in the cryo-stripping group and 15 % (33 of 215) in the conventional group (difference 29 %; 95 % confidence interval [CI]: 21 % to 37 %, p < 0.001).  Median operation time was significantly shorter in the cryo-stripping group (30 minutes) compared with the conventional group (39 minutes).  Neural damage was 12 % in both groups, and thus not significantly different.  Scores on the subdomains of the SF-36 showed no significant change between the groups.  The AVVQ after conventional stripping was 8.0, which was a better result than the 11.7 result after cryo-stripping (difference of 2.6 points; 95 % CI: 1.0 to 4.2; p = 0.001, repeated measurements analysis of variance with adjustment for baseline scores).  The authors concluded that cryo-stripping accounts for numerous procedural failures and hence residual GSV in patients.  The AVVQ showed small but significantly better results for patients after a conventional stripping.  Thus, cryo-stripping has no benefits over conventional stripping.

Krummel et al (2014) stated that renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs.  These researchers described the case of a 19-year old female with multiple bilateral renal AMLs.  The renal AMLs measured up to 6-cm in size.  She was first treated with a low-dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed.  No side-effects of either treatment were reported.  At 12 months post-cryoablation, no recurrence of the AML was noted.  The authors concluded that this was the first report of this treatment strategy and the case study revealed that combining a low-dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome.  They stated that this therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.

Song et al (2014) examined the safety and effectiveness of palliative bypass surgery combined with cryoablation to treat patients with advanced pancreatic cancer and compared them with those of palliative bypass surgery alone.  Medical records of 118 patients with advanced pancreatic cancer who received palliative bypass surgery combined with cryoablation (the combination treatment group) or bypass surgery alone (the bypass surgery group) from June 30, 2008 to December 31, 2010 were retrospectively reviewed.  Their baseline and post-operative parameters were collected and compared.  In both groups, abdominal distension and pain was significantly improved after treatment.  Pre-operative jaundice was more common in the bypass surgery group.  Backache was more frequent in the combination treatment group, which were both relieved.  Pre-operative serum bilirubin level was higher in the bypass surgery group that was decreased significantly after treatment.  However, significant reductions in tumor size as well as serum carbohydrate antigen 19-9 (CA19-9) level were only found in the combination treatment group.  There was no significant difference in the incidence of post-operative complications and prognosis between the 2 groups.  The authors concluded that cryoablation can reduce the tumor size and relieve the patients' symptoms and signs such as abdominal discomfort and backache, although it could not improve the patients' prognosis significantly.

In a preliminary study, Cornelis et al (2014) reported the short-term local control of percutaneous image-guided cryoablation of localized symptomatic abdominal scar endometrioma.  A total of 4 consecutive patients (mean age of 34.5 years) with a total of 10 lesions were included, with mean pre-operative pain of 7 (range of 5 to 9) on the VAS.  Cryoablation was performed in a single session under general anesthesia.  Post-operative superficial edema disappeared within 2 weeks for all patients.  No severe complications (greater than grade 2 according to the common terminology criteria for adverse events [CTCAE] classification) were reported.  Mean post-operative pain was 1.7 at 6 months (range of 0 to 5) and magnetic resonance imaging demonstrated a significant volume decrease for all patients (range of 72.2 to 100 %; p = 0.028).  The authors concluded that percutaneous cryoablation showed promising local control in patients with symptomatic abdominal wall endometriosis.  These preliminary findings need to be validated by well-designed studies.

Bone and Soft Tissue Tumors

Iguchi et al (2016) noted that a single-center, prospective study is being conducted to evaluate the safety of the cryoablation for patients with pathologically diagnosed painful bone and soft tissue tumors.  Enrollment of 10 patients is planned over the 3-year recruitment period.  Patients have related local pain after receiving medications or external radiation therapies will be included in this study.  Percutaneous cryoablation will be performed under imaging guidance, and a temperature sensor will be used during treatment as necessary.  The primary end-point is prevalence of severe adverse events (AEs) within 4 weeks after therapy.  The secondary end-point is effectiveness 4 weeks after the procedure.

Drooling

Buethe and colleagues (2016) evaluated the imaging, histologic changes and safety of CT-guided cryoablation of the parotid glands in a porcine model.  Unilateral CT-guided parotid gland cryoablation was performed in 5 juvenile miniature pigs.  The ablated parotid glands underwent 2 cycles of 10-minute freeze and 5-minute thaw using three 17-G cryoprobes.  The animals were monitored daily for complications including pain, frost-bite, infection, and sialocele or fistula formation.  Follow-up CT was performed at 6 weeks post-cryoablation.  Pathologic evaluation was performed on 2 of the ablated parotid glands.  All cryoablations in 5 right parotid glands, with 3 sites in each gland, were technically successful.  No symptoms suggestive of facial nerve damage were observed during 6-week follow-up.  One pig developed an infected sialocele, which was treated with percutaneous drainage and oral antibiotic therapy.  No CT evidence of sialocele or other abnormality was identified at the 6-week follow-up in all pigs.  Histologic evaluation was performed on 2 of the parotid gland specimens, 1 with the treated sialocele, and 1 of the remaining pigs without sialocele.  Both glands demonstrated post-procedural intra-glandular lymph nodes and reactive changes without evidence of sialocele or abscess on histopathology.  The authors concluded that cryoablation of parotid glands was technically feasible in a porcine model.  Only 1 pig developed sialocele, which was successfully treated.  They stated that further research is needed to determine the potential use of salivary gland cryoablation to treat patients with drooling.

Premature Ejaculation

David Prologo et al (2013) evaluated the feasibility, safety, and effectiveness of image-guided cryoablation for the of premature ejaculation (PE).  Prospective institutional review board approval was obtained, and 24 subjects with PE were enrolled.  All patients underwent unilateral percutaneous CT-guided cryoablation of the dorsal penile nerve (DPN).  Post-procedural intravaginal ejaculatory latency times (IELTs) and PE Profile (PEP) results served as outcome variables.  In addition, subjects were asked whether they would have the procedure done again based on their experience at the 180- and 360-day marks.  The technical success rate was 100 %.  Baseline average IELT was 54.7 seconds ± 7.8 (n = 24), which increased to a maximum of 256 seconds ± 104 (n = 11; p = 0.241) by day 7 and decreased to 182.5 seconds ± 87.8 (n = 6; p = 0.0342) by day 90.  The mean IELT remained at 182.5 seconds ± 27.6 at day 180 (n = 23; p < 0.0001) and decreased to 140.9 seconds ± 83.6 by 1 year (n = 22; p < 0.001); PEP scores improved overall, IELTs significantly improved at 180 and 360 days, and 83 % of subjects reported that they would undergo the procedure again if given the same opportunity.  There were no procedure-related complications.  The authors concluded that CT-guided percutaneous unilateral cryoablation of the DPN is a feasible, safe, single-day out-patient procedure for the treatment of symptomatic PE.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Treatment of male sexual dysfunction” (Cunningham and Khera, 2016) does not mention cryoablation as a therapeutic option.

Residual Facial Arterio-Venous Malformations

Woolen and Gemmete (2016) reported the findings of 4 patients (mean age of 22 years; range of 17 to 26) with facial arterio-venous malformations (AVMs) who underwent arterial ethanol and N-butyl cyanoacrylate embolization followed by percutaneous cryoablation of residual inaccessible AVMs.  After the procedure, minor complications classified as type B according to the Society of Interventional Radiology (SIR) classification system occurred in 75 % (3/4) of patients; 1 patient achieved 90 % obliteration of AVM, and 3 patients had complete obliteration of AVM at 1-year follow-up.  The authors concluded that the findings of this study showed that percutaneous cryoablation may be a viable therapeutic option for residual facial AVMs after ethanol and glue embolization.  These preliminary findings need to be validated by well-designed studies.

Retroperitoneal Soft-Tissue Sarcoma

Fan and colleagues (2016) evaluated the pain-alleviating effect of CT-guided percutaneous cryoablation for recurrent retroperitoneal soft-tissue sarcomas (RPSs).  Data from 19 men and 20 women (median age of 50.3 years) with recurrent malignant RPS who underwent percutaneous cryoablation were reviewed retrospectively.  A total of 50 tumors were treated by cryoablation, including a single tumor in 29 patients, 2 tumors in 9, and 3 tumors in 1; AEs and analgesic outcomes were compared as a function of tumor size (less than 10 cm and greater than or equal to 10 cm).  Efficacy was assessed based on modified Response Evaluation Criteria In Solid Tumors and progression-free survival (PFS).  Grade 1/2 AEs included fever (n = 17), emesis (n = 7), frost-bite (n = 5), and local pain (n = 4).  The median follow-up period and PFS were 18.5 months (range of 12 to 42) and 13.4 months ± 6.2, respectively.  At the end of follow-up, 13 patients had died and 26 were living.  The mean severe local pain scores on pre-treatment day 1 and post-treatment days 1, 5, 10, 15, 20, and 25 were 7.49, 7.40, 6.51, 5.81, 5.35, 5.04, and 5.44, respectively, and significant differences versus pre-treatment (p < 0.001) were reported for post-treatment days 5 to 25.  Immediate relief occurred more frequently in the small-tumor group (4 of 7; 57.1 %; p = 0.018), whereas delayed relief occurred more frequently in the large-tumor group (17 of 22; 77.3 %; p = 0.030).  The authors concluded that minimally invasive percutaneous cryoablation improved local pain and is a feasible treatment for recurrent RPSs.  These preliminary findings need to be validated by well-designed studies.

Spinal Giant Cell Tumors

Schwimer and co-workers (1981) reported 4 cases of giant cell tumor (GCT) of the cervico-thoracic spine.  Patients were women aged 17 to 20 years.  These investigators noted that treatment consisted of surgical extirpation and radiation therapy; however, carefully monitored cryotherapy of this lesion may be a feasible new therapeutic method.  The author stated that due to their relatively inaccessible location, spinal GCT (SGCT) will be difficult to treat adequately, and can be expected to recur and cause neurologic compromise in a significant proportion of cases.

Althausen and colleagues (2002) stated that sacral GCTs are rare primary bone tumors.  Recent reports have demonstrated diminished GCT recurrence with cryosurgery by using a "direct pour" technique with liquid nitrogen.  Although successful in decreasing tumor recurrence, this technique was accompanied by a 4 to 8 % rate of skin necrosis and high rates of pathologic fracture.  These researchers described resection and a novel, controlled method of argon-based cryotherapy (followed by a unique pelvic reconstruction) for a large, sacral GCT.  A 29-year old woman presented with complaints of right foot-drop and decreased sensation of the right buttock, posterior thigh, posterior calf, and lateral aspect of the right foot.  Radiographic evaluation revealed a mass in the right sacrum; histologic examination of CT-guided biopsy revealed a GCT.  A combined anterior abdominal and posterior sacral approach was performed, the tumor was resected, and the margin of the cavity was treated with controlled argon-based cryotherapy.  The combination of thermocouples, electromyographic monitoring, and rapid freeze-thaw cycles allowed a controlled ablation of the tumor margin while ensuring that surrounding structures, such as the rectal wall, sacral nerves, and gluteal muscles, were not damaged.  Posterior spinal fusion L4 to sacrum, posterior spinal instrumentation L4 to pelvis, and allograft reconstruction of the right sacrum were performed.  The patient recovered well without skin necrosis or pathologic fracture.  Urinary and fecal continence were preserved.  At the 20-month follow-up the patient had no evidence of local tumor recurrence and was fully ambulatory without a brace or narcotic medication.  The  authors concluded that a novel multi-modality approach, consisting of resection, controlled cryosurgery, and a unique lumbo-pelvic reconstruction, was safe and successful in managing a challenging proximal sacral GCT; 20 months after surgery the patient had excellent bowel and bladder control, no tumor recurrence, and functional ambulation without a brace or pain.  This was a single-case study with a multi-modality approach.

Luksanapruksa and associates (2016) noted that SGCT remain challenging tumors to treat.  Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking.  These investigators reviewed the peer-reviewed literature that addresses current therapeutic options and management of SGCT to produce an evidence-based treatment algorithm.  They performed a systematic review.  Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and Embase searches using keywords "giant cell tumor" and "spine" and "treatment".  Relevant articles were selected by the authors and reviewed.  A total of 515 studies were identified, of which 81 studies were included.  Complete surgical resections of SCGT resulted in the lowest recurrence rates.  However, morbidity of en bloc resections is high and in some cases, surgery is not possible.  Intralesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive.  Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon.  The authors concluded that complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present; denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT.  According to these researchers, the best level of evidence regarding the use of cryotherapy as an intra-operative adjuvant modality for intralesional resections was III.

Domovitov and colleagues (2016) stated that there is no consensus regarding the appropriate treatment of sacral GCT.  There are 3 main management problems:
  1. tumor control,
  2. neurological loss, and
  3. pelvic instability. 

These researchers examined oncological, neurological, and structural outcomes of sacral GCT after intralesional excision and local intra-operative adjunctive treatment. They retrospectively reviewed the records of 24 patients with sacral GCT who underwent conservative surgery (intralesional resection/curettage) at Memorial Sloan Kettering Cancer Center from 1973 through 2012.  They analyzed patient demographic data, tumor characteristics, and operative techniques, and examined possible correlations with post-operative functional outcomes, complications, recurrence, and mortality.  There were 7 local recurrences (30 %) and 3 distant recurrences (13 %); 3 of 24 patients (12.5 %) had significant neurological loss after treatment -- specifically, severe bowel and/or bladder dysfunction, but all regained function within 1 to 4 years.  Larger tumor size (greater than 320 cm3) was associated with greater post-operative neurological loss.  Radiation therapy and pre-operative embolization were associated with prolonged disease-free survival (DFS).  There were no local recurrences among the 11 patients who were treated with both modalities.  Based on radiographic and clinical assessment, spino-pelvic stability was present in 23 of 24 patients at final follow-up.  The authors concluded that high local and distant recurrence rates associated with sacral GCT suggested the need for careful local and systemic follow-up in managing these patients.  Intra-operative preservation of sacral roots was associated with better pain relief, improvement in ambulatory function, and retention of bowel/bladder function in most patients.  Fusion and instrumentation of the sacroiliac joint successfully achieved spino-pelvic stability in cases deemed clinically unstable.  They stated that despite improvement in the management of sacral GCT over 35 years, a need for novel therapies remains.  The strategy of combining radiotherapy and embolization merits further study.  Cryosurgery is one of the keywords described in this study.

Furthermore, an UpToDate review on “Giant cell tumor of bone” (Thomas and Desai, 2016) stated that “Local adjuvants -- In an attempt to decrease local recurrence rates after intralesional curettage, various surgical adjuvant therapies have been tried.  Examples include the use of bone cement (polymethylmethacrylate, PMMA), aqueous zinc chloride, phenol, cryotherapy with or without cement, argon beam coagulation, and the use of a high-speed burr to remove peritumoral bone.  There are no randomized trials to support benefit of a local adjuvant over curettage alone.  In contemporary retrospective series of patients treated with intralesional curettage with a local adjuvant, local recurrence rates are 13 to 22 %, which compare favorably with those seen following wide local excision.  However, a large series suggested no benefit from the use of local adjuvants, provided there is adequate surgical tumor removal.  There are also no trials comparing outcomes with different adjuvant approaches.  However, bone cement has emerged as the preferred adjuvant agent.  Filling the cavity with bone cement allows immediate weight bearing, and the heat induced during the setting of the cement is thought to kill any remaining tumor cells, thus decreasing the risk of a local recurrence.  Furthermore, the radiologic features of a cement-filled cavity are ideal to permit early identification of local recurrences”.

Bony Metastases from Renal Cell Carcinoma

European Society for Medical Oncology (ESMO)’s clinical practice guidelines on “Renal cell carcinoma” (Escudier et al, 2016) recommended radiotherapy for the management of symptomatic bone lesions.

Coupal and colleagues (2017) stated that metastases to the bone are common in cancer patients, and it has been estimated that up to 50 % of patients with pelvic bone metastases will not achieve adequate pain control with medications alone.  This has resulted in a paradigm shift over recent years towards the development of minimally invasive image-guided therapeutic options for palliation of bony metastases.  Despite these advents, large metastatic lesions are still often considered to be "hopeless cases" that would garner little to no benefit from image-guided intervention.  In a retrospective analysis, these investigators evaluated the safety and effectiveness of a novel approach -- combined percutaneous cryoablation and cementoplasty -- for palliation of such large metastases to the pelvis.  This study was conducted from January 2013 to December 2016, where consecutive patients referred for pain management of large pelvic bone metastases underwent combination percutaneous cryoablation and cementoplasty.  This study took place at a tertiary care center after patients were referred following formal review from a multi-disciplinary conference, which was comprised of interventional radiologists, pain management and palliative care physicians, radiation and medical oncologists, and when available, anesthesiologists.  A total of 48 patients (36 men and 12 women) with a mean cohort age of 77.5 years (range of 52 to 89 years) were referred from the multi-disciplinary conference for palliation of pelvic bone metastases.  The inclusion criteria included patients with metastases greater or equal to 5.0 cm and significant pain refractory to conventional pain management regimens.  All of the patients were deemed not to be surgical candidates.  Mean pain scores were collected at numerous time-points along with procedural technical success rates and complication rates.  Combination cryoablation and cementoplasty was performed on 48 consecutively referred patients with a 100 % technical success rate and no immediate complications.  The pain levels demonstrated a significant decrease (p < 0.001) following intervention, with mean pain scores of 7.9 (range of 5 to 10) and 1.2 (range of 0 to 7) throughout the week prior to intervention and at 24 hours post-intervention, respectively.  The post-intervention pain scores remained stable at 1 to 9 weeks follow-up (mean of 4.1 weeks); 3 patents (6.3 %) reported no change in pain following the intervention; however, no patients reported worsened pain.  The authors concluded that combination cryoablation and cementoplasty is a novel and effective treatment option for palliation of large pelvic bone metastases.  Marked improvements in pain, as well as mobility and quality of life (QOL), were often attainable.

The drawbacks of this study included its retrospective nature, which limited the acquisition of ancillary data for all of the patients, such as: pre- and post-procedural opiate requirements, improvement in mobility, and formal QOL measures.  These investigators noted that while they had numerous qualitative measures demonstrating profound improvements in mobility and QOL, prospective studies are needed in the future literature.  Another drawback of this study was the length of follow-up (mean of 4.1 weeks), which was restricted in many cases given the life expectancy of the study cohort.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Kidney cancer” (Version 1.2018) has no recommendation for cryoablation of metastases.  The guidelines recommends cryosurgery for localized renal lesions.

Chronic Headache

UpToDate reviews on “Overview of chronic daily headache” (Garza and Schwedt, 2017a), “Headache in children: Approach to evaluation and general management strategies” (Bonthius et al, 2017), and “New daily persistent headache” (Garza and Schwedt, 2017b) do not mention cryoablation as a therapeutic option

Hookworm-Related Cutaneous Infection

UpToDate reviews on “Hookworm infection” (Weller and Leder, 2017a) and “Hookworm-related cutaneous larva migrans” (Weller and Leder, 2017b) do not mention cryotherapy as a therapeutic option.

Peripheral Nerve Damage in the Lower Extremity

Chen et al (2004) evaluated the effectiveness of axonal repair technique for treatment of peripheral nerve injury clinically.  In 1998, the authors applied axonal repair technique to treat peripheral nerve injuries in 12 patients with 13 nerves.  It consisted of 4 steps, i.e.,
  1. stumps of the nerve being soaked in a modified Collins fluid,
  2. frozen,
  3. trimmed, and
  4. coated with glue, making the injured nerve repaired at the axonal level. 

Patients were followed-up for an average of 13 months.  Results showed that in 4 cases of 1st-stage contralateral C7 transfer, regenerating axons reached to the sternoclavicular joint or axilla at 4 to 7 months, offering the timing for performing the 2nd-stage contralateral C7 transfer.  In 5 cases of accessory nerve transferred to the suprascapular nerve, the abduction of the shoulder was 40 degree on average.  In the other 3 patients with 4 different nerves repaired, results were also satisfactory.  The authors concluded that this technique was promising in the treatment of peripheral nerve injury.

Allergic and Non-Allergic Rhinitis (e.g., by Means of the ClariFix Device)

Hwang et al (2017) reported the first series of patients treated for chronic rhinitis using a novel device designed for office-based cryosurgical ablation of the posterior nasal nerve (PNN).  A total of 27 patients with chronic rhinorrhea and/or nasal congestion for greater than 3 months were recruited (allergic or non-allergic rhinitis), with minimum rhinorrhea and/or congestion sub-scores of 2 as part of the Total Nasal Symptom Score [TNSS]).  Under local anesthesia, a hand-held cryotherapy device (the ClariFix device) was applied endoscopically to the posterior middle meatus and was used to freeze the PNN region bilaterally.  Patients were followed-up after 7, 30, 90, 180, and 365 days to assess TNSS.  The procedure was successfully completed in 100 % of patients, with no complications; 74 % reported no or mild discomfort by the 1st post-procedure day.  TNSS was reduced significantly at 30 days (mean ± standard deviation: 6.2 ± 0.5 at baseline, 2.6 ± 0.3 at 30 days, n = 27, p < 0.001), with continued reduction at 90 (2.7 ± 0.4, n = 24, p < 0.001), 180 (2.3 ± 0.5, n = 21, p < 0.001), and 365 days (1.9 ± 0.3, n = 15, p < 0.001).  Both rhinorrhea and congestion sub-scores decreased significantly at 30, 90, 180, and 365 days compared to baseline (p < 0.001).  Allergic and non-allergic sub-cohorts both appeared to benefit from treatment.  The authors concluded that office-based cryotherapy of the PNN region was safe and well-tolerated; symptom scores were significantly decreased by 7 days post-procedure and remained lower at 30, 90, 180, and 365 days.  Moreover, these researchers stated that in addition to following the current cohort for an extended period of time, larger cohort studies for both allergic rhinitis and non-allergic rhinitis will be conducted, to fully evaluate the ClariFix device and procedure for these patient subsets.

The authors stated that the drawbacks of this study included the small sample size (n = 27) and loss to follow‐up during the extended period (6patients were lost to follow‐up at 180 days, and 12 patients could not be reached at 365 days).  Medication use was not systematically tracked in this study but will be tracked in future studies.

Paprocka-Zjawiona and colleagues (2018) noted that pharmacotherapy of both allergic and non-allergic rhinitis is not always effective.  These investigators examined the effectiveness of treatment of patients with allergic and non-allergic vasomotor rhinitis using cryoablation.  The study involved 60 patients, including 28 women and 32 men, aged 17 to 76 years (average of 39) with rhinitis.  All participants were assigned into 2 groups: Group I -- 18 patients with chronic allergic rhinitis; and Group II -- 42 patients with chronic non-allergic vasomotor rhinitis.  The research methodology included: anamnesis, otolaryngologic examination, rhino-manometer test, performed before and 3 months after the cryoablation of nasal turbinates , which was performed under local anesthesia, with a xylocaine solution using the Cryo-S device.  Following cryoablation, both groups exhibited statistically significant improvements in the subjective assessment of symptoms of nasal obstruction and in the mean rhino-manometry of air flows through the nasal passages during inspiration and exhalation.  The authors concluded that cryoablation was not the 1st-line treatment for the treatment of allergic and non-allergic vasomotor rhinitis, it did not remove the causes of the disease.  However, they stated that this approach may be an effective method of treatment for some patients and a supplement to existing treatment.

Kompelli and associates (2018) stated that chronic rhinitis impacts 60 million Americans and is associated with significant costs for patients.  Although medical treatments are 1st-line, some patients require surgical intervention such as vidian or posterior nasal neurectomy.  Previous reviews have examined the role of surgical management in chronic rhinitis, but none has investigated a long-standing treatment with recent interest: cryotherapy.  These investigators evaluated the safety, efficacy, and durability of treatment response of cryotherapy in treating chronic rhinitis.  They carried out a systematic literature review to identify studies that investigated the utility of cryotherapy in chronic rhinitis.  Only studies with the primary objective of assessing the efficacy of cryotherapy on chronic rhinitis were included.  Patients were classified as allergic rhinitis, non-allergic rhinitis (vasomotor rhinitis), or mixed rhinitis using the original author's criteria.  Data were extracted regarding reported complications, treatment efficacy, and length of follow-up.  A total of 110 abstracts were identified, of which 15 were included in this review.  Epistaxis and nasal obstruction were commonly reported complications; no serious AEs were reported.  For obstructive symptoms, "reduced" symptoms were reported in 63.4 % to 100 % of patients.  In regard to rhinorrhea, reports of reduced symptoms were experienced from 77 % to 100 % of patients; 7 studies used only patient-reported improvements without stratifying results based on symptom type; general improvements ranged from 67 % to 100 %; 9 studies noted symptom improvement in non-allergic cohorts ranging from 67 % to 97.5 % of patients; 4 studies noted improvement in allergic cohorts ranging from 63.4 % to 80 % of patients; 2 studies noted improvement in patients with mixed pictures ranging from 92.5 % to 100 %.  The authors concluded that a although cryotherapy appeared safe and effective, heterogeneous past investigations with low-quality evidence made strong, evidence-based recommendations difficult to make.  These researchers stated that further study with validated metrics and controlled populations is needed and should be encouraged.

Furthermore, UpToDate reviews on “Clinical presentation, diagnosis, and treatment of nasal obstruction” (Bhattacharyya, 2018), “Chronic rhinosinusitis: Management” (Hamilos, 2018), and “Chronic nonallergic rhinitis” (Lieberman , 2018) do not mention cryoablation as a therapeutic option.

Cancer Pain

In a systematic review, Ferrer-Mileo and colleagues (2018) evaluated the current scientific evidence on the use of cryoablation to control cancer pain.  These researchers carried out a systematic search of the Scopus, PubMed, and Cochrane databases.  All articles published before December 31, 2015, whose title or abstract specified cancer pain control as the end-point were selected.  Articles without abstracts and all non-systematic reviews were excluded.  A total of 22 articles were included: 1 RCT, 2 non-RCTs, 1 ambispective study, 9 retrospective studies, 2 non-specified cohort studies, 3 case series, and 4 case reports.  A total of 496 patients with 580 lesions were treated.  Lung cancer was the most common primary tumor; 82.8 % of the metastases were bone metastases, with or without soft tissue involvement.  Cryoablation decreased mean pain scores by 62.5 % at 24 hours post-cryoablation, by 70 % at 3 months, and by 80.9 % at 6 months.  Cryoablation was associated with a 44.2 % improvement in quality of life (QOL) after 4 weeks and a 59.6 % improvement at 8 weeks.  The need for opioids decreased by 75 % at 24 hours and by 61.7 % at 3 months.  Cryoablation in combination with radiotherapy, vertebroplasty, or bisphosphonates appeared to be better than cryoablation alone.  Complications were highly variable among the studies, but no fatal complications were reported.  The authors concluded that cryoablation was effective in controlling cancer pain without relevant side effects; however, they stated that more studies are needed to confirm these findings.

Cutaneous Sporotrichosis in Pregnant Women

Fichman and colleagues (2018) noted that pregnant women with sporotrichosis should not receive systemic anti-fungal therapy except in severe cases when amphotericin B is recommended.  Thermotherapy is the most reported treatment described in this group of patients.  It entails weeks of daily self-application of heat to the lesions, requires that the patient faithfully apply it, and it could cause skin burns.  Cryosurgery is a useful therapeutic tool for many cutaneous infectious diseases, safe for pregnant women, but not well-evaluated for sporotrichosis treatment in this group.  In a retrospective study, these investigators reviewed the clinical records of 4 pregnant patients diagnosed with cutaneous sporotrichosis and treated with cryosurgery.  Treatments were performed monthly up to clinical cure.  Molecular identification of the Sporothrix species was performed in 2 cases using T3B PCR fingerprinting assays.  All patients were in the 2nd trimester of pregnancy and their age ranged from 18 to 34 years.  With regard to clinical presentation, 2 patients had lympho-cutaneous and 2 had the fixed form; S. brasiliensis was identified in 2 cases as the causative agent.  Cryosurgery was well-tolerated and the number of sessions ranged from 1 to 3.  All the patients reached a complete clinical cure.  The authors concluded that these findings suggested that cryosurgery is a safe and well-tolerated; it is a promising alternative in the treatment of cutaneous sporotrichosis in pregnant women.  Moreover, these researchers stated that further studies with a larger number of patients are needed to confirm efficacy of cryosurgery for sporotrichosis in pregnant patients.

Fibro-Adipose Vascular Anomaly (FAVA) Lesion

Shaikh and colleagues (2016) noted that fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms.  There are no minimally invasive treatment options to effectively control these symptoms.  Image-guided percutaneous cryoablation, which has been used to control pain in people with cancer, could be used for similar indications in FAVA.  In a retrospective cohort study, these researchers examined the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions.  A total of 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015 were included in this analysis.  The outcome was based on the brief pain inventory scoring (BPI), concurrent symptoms, clinical response and patient satisfaction.  After cryoablation, there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24 hours).  Most patients indicated that pain interfered less in their everyday social life.  Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved.  Clinical response was greatest at 2 to 5 months follow-up after cryoablation, with acceptable patient satisfaction thereafter.  Technical response was 100 %; there were no major complications.  The authors concluded that image-guided percutaneous cryoablation was a safe and effective option for treatment of symptomatic FAVA lesions.  This was a small (n = 20) retrospective study with short-term follow-up (2 to 5 months); its findings need to be validated by well-designed studies.

Metastatic Hepatocellular Carcinoma

Gosalia and colleagues (2017) stated that stated that hepato-cellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths worldwide.  Treatment of HCC has rapidly evolved with interventional radiology.  Percutaneous ethanol injection (PEI), radio-frequency ablation (RFA), microwave ablation (MWA), cryoablation, and trans-arterial chemo-embolization (TACE) are the major modalities utilized to control growth of HCC lesions.  Cryoablation has been less utilized as more advanced ablative techniques have emerged, but still plays a role in select patients.  The technique requires laparoscopy with direct application of a cryoprobe, with either liquid nitrogen or argon gas placed on the HCC lesion.  Freezing induces irreversible damage to the tissue.  Typically, 2 to 3 cycles are performed in a single session, and intra-operative ultrasound (US) is used to monitor tumor destruction in real time.  Cryoablation can be used as monotherapy or as part of a multi-modal therapeutic approach.  There are no RCTs evaluating the effectiveness of cryoablation compared to other ablative modalities, although retrospective trials and case-series studies have evaluated the efficacy of cryoablation.  One large series of patients receiving cryotherapy demonstrated a 39.8 % 5-year survival rate, and among the subset of patients with lesions less than 5 cm, survival was 55.4 %.  The main disadvantage of cryoablation is that it is most often performed laparoscopically and may cause morbidity in patients with advanced cirrhosis.  Complication rates have been reported to be upwards of 50 % and include coagulopathy, cardiac arrhythmia, and liver fracture.  However, percutaneous application of cryoablation may mitigate these risks.  The authors stated that cryoablation may have a role in special situations, such as treatment of residual disease at resection margins, but is rarely considered as a 1st-line therapy in the treatment of HCC.

Furthermore, an UpToDate review on “Nonsurgical local treatment strategies for colorectal cancer liver metastases” (Venook, 2018) states that “There is insufficient evidence to conclude that cryotherapy is of any benefit in patients with liver metastases from various primary sites.  Because of the availability of newer and safer modalities, cryotherapy is rarely used in this setting”.

Osteoid Osteoma

In a prospective, phase-I clinical trial, Miyazaki and colleagues (2018) evaluated the safety of percutaneous cryoablation for osteoid osteoma (OO).  A total of 9 patients with OO (mean tumor size of 5.9 mm; tibia, n = 5; femur, n = 2; lumbar spine, n = 2) were enrolled and treated with percutaneous cryoablation.  The primary end-point was the evaluation of the treatment safety as determined using step-by-step registration.  The secondary end-points were the incidence and grade of AEs by CTCAE version 4.0, and the short-term efficacy of this treatment.  Based on a decrease in the numerical rating scale (NRS) score, efficacy was classified as significantly effective (SE greater than or equal to 5 or reached 0 to 2), moderately effective (ME 2 to 4), or not effective (NE less than 2 or increase).  Cryoablation was completed in all patients; major AEs (greater than or equal to grade 3) related to the procedure were not observed; minor AEs (less than or equal to grade2) were observed in 22 to 67 %.  The mean NRS score was 7 before treatment, 0.6 at 4-week, 0.1 at 6-month, and 0 at 1-year post-treatment.  All procedures were classified as SE.  The authors concluded that percutaneous cryoablation is a safe treatment for OO.  Moreover, they stated that future phase-II clinical trials with large patient cohorts are needed.

Reduction of Pain or Opioid Consumption after Total Knee Arthroplasty

Tedesco et al (2018) stated there is increased interest in non-pharmacological treatments to reduce pain after total knee arthroplasty (TKA).  However, little consensus supports the effectiveness of these interventions.  These investigators systematically reviewed and meta-analyzed evidence of non-pharmacological interventions for post-operative pain management after TKA.  Database searches of Medline (PubMed), Embase (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Web of Science (ISI database), Physiotherapy Evidence (PEDRO) database, and ClinicalTrials.gov for the period between January 1946 and April 2016 were performed.  Randomized clinical trials comparing non-pharmacological interventions with other interventions in combination with standard care were included.  Two reviewers independently extracted the data from selected articles using a standardized form and assessed the risk of bias.  A random-effects model was used for the analyses.   Of 5,509 studies, 39 randomized clinical trials were included in the meta-analysis (2,391 patients).  The most commonly performed interventions included continuous passive motion (CPM), pre-operative exercise, cryotherapy, electrotherapy, and acupuncture.  Moderate-certainty evidence showed that electrotherapy reduced the use of opioids (mean difference [MD], -3.50; 95 % CI: -5.90 to -1.10 morphine equivalents in mg/kg/ 48 hours; p = 0.004; I2 = 17 %) and that acupuncture delayed opioid use (MD, 46.17; 95 % CI: 20.84 to 71.50 mins to the first patient-controlled analgesia; p < 0.001; I2 = 19 %).  There was low-certainty evidence that acupuncture improved pain (MD, -1.14; 95 % CI: -1.90 to -0.38 on a VAS at 2 days; p = 0.003; I2 = 0 %).  Very low-certainty evidence showed that cryotherapy was associated with a reduction in opioid consumption (MD, -0.13; 95 % CI: -0.26 to -0.01 morphine equivalents in mg/kg/48 hours; p = 0.03; I2 = 86 %) and in pain improvement (MD, -0.51; 95 % CI: -1.00 to -0.02 on the VAS; p < 0.05; I2 = 62 %).  Low-certainty or very low-certainty evidence showed that CPM and pre-operative exercise had no pain improvement and reduction in opioid consumption: for CPM, the MDs were -0.05 (95 % CI: -0.35 to 0.25) on the VAS (p = 0.74; I2 = 52 %) and 6.58 (95 % CI: -6.33 to 19.49) opioid consumption at 1 and 2 weeks (p = 0.32, I2 = 87 %), and for pre-operative exercise, the MD was -0.14 (95 % CI: -1.11 to 0.84) on the Western Ontario and McMaster Universities Arthritis Index Scale (p = 0.78, I2 = 65 %).  The authors concluded that in this meta-analysis, electrotherapy and acupuncture after TKA were associated with reduced and delayed opioid consumption.

Appendix

Stages of prostate cancer

Stage I (A)

Prostate cancer can not be felt by digital rectal exam, causes no symptoms, and is only in the prostate, usually found incidentally in a prostatectomy specimen when surgery is done for benign prostatic hyperplasia.

Stage II (B)

Cancer confined to the prostate gland found by a needle biopsy done for an elevated PSA level or after rectal examination reveals a mass in the prostate.

Stage III (C)

Cancer cells have spread outside the capsule of the prostate to tissues around the prostate, e.g., seminal vesicles.

Stage IV (D)

Cancer cells have metastasized to lymph nodes or to organs and tissues such as the bone, liver, or lungs.


Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

0441T Ablation, percutaneous, cryoablation, includes imaging guidance, lower extremity distal/peripheral nerve
20982 Ablation therapy for reduction or eradication of 1 or more bone tumors (eg, metastasis) including adjacent soft tissue when involved by tumor extension, percutaneous, including imaging guidance when performed; radiofrequency
20983 Ablation therapy for reduction or eradication of 1 or more bone tumors (eg, metastasis) including adjacent soft tissue when involved by tumor extension, percutaneous, including imaging guidance when performed; cryoablation
31641 Bronchoscopy (rigid or flexible); with destruction of tumor or relief of stenosis by any method other than excision (e.g., laser therapy, cryotherapy)
32994 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, including imaging guidance when performed, unilateral; cryoablation
33254 Operative tissue ablation and reconstruction of atria, limited (eg, modified maze procedure)
33256 Operative tissue ablation and reconstruction of atria, extensive (eg, maze procedure); with cardiopulmonary bypass
+ 33257 Operative tissue ablation and reconstruction of atria, performed at the time of other cardiac procedure(s), limited (eg, modified maze procedure) (List separately in addition to code for primary procedure)
+ 33259 Operative tissue ablation and reconstruction of atria, performed at the time of other cardiac procedure(s), extensive (eg, maze procedure), with cardiopulmonary bypass (List separately in addition to code for primary procedure)
50250 Ablation, open, 1 or more renal mass lesion(s), cryosurgical, including intraoperative ultrasound guidance and monitoring, if performed
50593 Ablation, renal tumor(s), unilateral, percutaneous, cryotherapy
55873 Cryosurgical ablation of the prostate (includes ultrasonic guidance for interstitial cryosurgical probe placement)
57511 Cautery of cervix; cryocautery, initial or repeat
64600 Destruction by neurolytic agent, trigeminal nerve; supraorbital, infraorbital, mental, or inferior alveolar branch [cryoablation of chronic headaches]
+93657 Additional linear or focal intracardiac catheter ablation of the left or right atrium for treatment of atrial fibrillation remaining after completion of pulmonary vein isolation (List separately in addition to code for primary procedure)

CPT codes not covered for indications listed in the CPB:

Cryoablation, Cryoablation with ClariFix device - no specific code:

19105 Ablation, cryosurgical, of fibroadenoma, including ultrasound guidance, each fibroadenoma
32998 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, radiofrequency, unilateral [cryoablation for nonobstructive non-small cell lung cancer]
43229 Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [not covered for cryoablation of Barrett's esophagus or malignant neoplasm of esophagus]
43270 Esophagogastroduodenoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [not covered for cryoablation of Barrett's esophagus or malignant neoplasm of esophagus]

Other CPT codes related to the CPB:

17000 - 17286 Destruction, benign or premalignant lesions, or malignant lesions, any method
47371 Laparoscopy, surgical, ablation of one or more liver tumor(s); cryosurgical
47381 Ablation, open, of one or more liver tumor(s); cryosurgical
58353 Endometrial ablation, thermal, without hysteroscopic guidance
58356 Endometrial cryoablation with ultrasonic guidance, including endometrial curettage, when performed
58563 Hysteroscopy, surgical; with endometrial ablation (e.g., endometrial resection, electrosurgical ablation, thermoablation)
77013 Computed tomography guidance for, and monitoring of, parenchymal tissue ablation
77022 Magnetic resonance guidance for, and monitoring of, parenchymal tissue ablation

Other HCPCS codes related to the CPB:

C1886 Catheter; extravascular tissue ablation, any modality (insertble)
C2618 Probe/needle, cryoablation

ICD-10 codes covered if selection criteria are met:

C34.00 - C34.92 Malignant neoplasm of bronchus and lung [malignant endobronchial obstruction]
C44.01
C44.111 - C44.119
C44.211 - C44.219
C44.310 - C44.319
C44.41
C44.510 - C44.519
C44.611 - C44.619
C44.711 - C44.719
C44.81
C44.91
Basal cell carcinoma [covered for low risk, superficial basal cell carcinoma where surgery or radiation is contraindicated or impractical]
C49.10 - C49.6 Malignant neoplasm of connective and other soft tissue [soft tissue sarcoma of extremities and trunk in symptomatic persons with disseminated metastases] [not covered for leiomyosarcoma]
C61 Malignant neoplasm of prostate
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis [renal cell carcinoma - see criteria]
C78.00 - C78.02 Secondary malignant neoplasm of lung
C79.82 Secondary malignant neoplasm of genital organs [prostate]
D02.20 - D02.22 Carcinoma in situ of bronchus and lung
D04.0 - D04.9 Carcinoma in situ of skin [covered for squamous cell - Bowen's disease where surgery or radiation is contraindicated or impractical]
D06.0 - D06.9 Carcinoma in situ of cervix uteri [cervical intraepithelial neoplasia III (CIN III)]
D07.5 Carcinoma in situ of prostate
I48.0 - I48.2, I48.91 Atrial fibrillation
N87.0 - N87.1 Mild and moderate dysplasia of cervix (cervical intraepithelial neoplasia I and II [CIN Iand CIN II])

ICD-10 codes not covered for indications listed in the CPB:

B42.89 Other forms of sporotrichosis [in pregnancy]
B76.0 - B76.9 Hookworm diseases
C15.3 - C15.9 Malignant neoplasm of esophagus
C22.0 Liver cell carcinoma
C48.0 Malignant neoplasm of retroperitoneum [retroperitoneal soft-tissue sarcoma]
C49.0
C49.8 - C49.9
Malignant neoplasm of connective and other soft tissue [leiomyosarcoma, lipoma/neuroma]
C50.011 - C50.929 Malignant neoplasm of breast
C79.00 - C79.02 Secondary malignant neoplasm of kidney and renal pelvis
C79.81 Secondary malignant neoplasm of breast
D05.00 - D05.92 Carcinoma in situ of breast
D16.0 - D16.9 Benign neoplasm of bone and articular cartilage
D17.0 - D17.9 Lipoma
D21.0 - D21.9 Other benign neoplasm of connective and other soft tissue [plantar fibroma] [neuroma] [bone and soft tissue tumors]
D24.1 - D24.9 Benign neoplasm of breast
D33.3 Benign neoplasm of cranial nerves [acoustic neuroma]
D48.1 Neoplasm of uncertain behavior of connective and other soft tissue [extra-abdominal desmoid tumor]
D49.2 Neoplasm of unspecified nature of bone, soft tissue, and skin [extra-abdominal desmoid tumor]
F52.4 Premature ejaculation
G44.021 - G44.029 Chronic cluster headache
G44.221 - G44.229 Chronic tension-type headache
G56.00 - G57.93 Mononeuropathies
G89.3 Neoplasm related pain (acute) (chronic) [Pain after total knee arthroplasty]
H35.101 - H35.179 Retinopathy of prematurity
I47.0 - I47.9 Paroxysmal tachycardia [post-infarction, idiopathic]
I80.00 - I80.3 Phlebitis and thrombophlebitis of superficial and deep vessels of lower extremities
I82.401 - I82.4Z9 Acute embolism and thrombosis of deep veins of lower extremity
I82.501 - I82.5Z9 Chronic embolism and thrombosis of deep veins of lower extremity
I82.811 - I82.819 Embolism and thrombosis of superficial veins of lower extremity
I83.001 - I83.029 Varicose veins of lower extremities with ulcer
I83.10 - I83.12 Varicose veins of lower extremities with inflammation
I83.201 - I83.229 Varicose veins of lower extremities with ulcer and inflammation
I83.811 - I83.899 Varicose veins of lower extremities with other complications
I87.001 - I87.099 Postphlebitic syndrome
I87.2 Venous insufficiency (chronic) (peripheral)
J30.0 - J30.9 Vasomotor and allergic rhinitis
J31.0 - J31.2 Chronic rhinitis, nasopharyngitis and pharyngitis
K11.7 Disturbances of salivary secretion[drooling]
K22.10 - K22.11 Ulcer of esophagus
L92.0 - L92.9 Granulomatous disorders of skin and subcutaneous tissue [talc granuloma pain]
M45.0 - M54.9 Dorsopathies [facet or sacroiliac joint pain]
M72.2 Plantar fascial fibromatosis [plantar fibroma]
N40.0 - N40.3 Enlarged prostate
O99.711 –O99.719 Diseases of the skin and subcutaneous tissue complicating pregnancy [sporotrichosis]
Q27.30 - Q27.9 Arteriovenous malformation [peripheral] [not covered for residual facial arterio-venous malformations]
Q85.00 - Q85.09 Neurofibromatosis [multiple neuroma]
S84.00xA - S84.92xS Injury of nerves at lower leg level
T87.30 - T87.34 Neuroma of amputation stump
Z96.651 - Z96.659 Presence of artificial knee joint [Pain after total knee arthroplasty]

The above policy is based on the following references:

Cryoablation of the Prostate

  1. Onik GM, Cohen JK, Reyes GD, et al. Transrectal ultrasound-guided percutaneous radical cryosurgical ablation of the prostate. Cancer. 1993;72:1291-1299.
  2. Cohen JK, Miller RJ, Rooker GM, et al. Cryosurgical ablation of the prostate: Two year prostate-specific antigen and biopsy results. Urology. 1996;47(3):395-401.
  3. Miller RJ, Cohen JK, Shuman B, et al. Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma. Cancer. 1996;77:1510-1514.
  4. Carroll PR. Prostate cancer - many treatments but not enough answers. J Urol. 1995;154:454-455.
  5. Cox RL, Crawford ED. Complications of cryosurgical ablation of the prostate to treat localized adenocarcinoma of the prostate. Urology. 1995;45:932-935.
  6. Long JP, Fallick ML, LaRock DR, et al. Preliminary outcomes following cryosurgical ablation of the prostate in patients with clinically localized prostate carcinoma. J Urol. 1998;159(2):477-484.
  7. Wong WS, Chinn DO, Chinn M, et al. Cryosurgery as a treatment for prostate carcinoma: Results and complications. Cancer. 1997;79(5):963-974.
  8. Shinohara K, Connolly JA, Presti JC Jr, et al. Cryosurgical treatment of localized prostate cancer (stages T1 to T4): Preliminary results. J Urol. 1996;156(1):115-121.
  9. Cohen JK, Rooker GM, Miller RJ Jr, et al. Cryosurgical ablation of the prostate: Treatment alternative for localized prostate cancer. Cancer Treat Res. 1996;88:167-186.
  10. Bales GT, Williams MJ, Sinner M, et al. Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology. 1995;46(5):676-680.
  11. Zippe CD. Cryosurgical ablation for prostate cancer: A current review. Semin Urol. 1995;13(2):148-156.
  12. Saliken JC, Donnelly BJ, Brasher P, et al. Outcome and safety of transrectal US-guided percutaneous cryotherapy for localized prostate cancer. J Vasc Interv Radiol. 1999;10(2 Pt 1):199-208.
  13. Derakhshani P, Neubauer S, Braun M, et al. Cryoablation of localized prostate cancer. Experience in 48 cases, PSA and biopsy results. Eur Urol. 1998;34(3):181-187.
  14. Schmidt JD, Doyle J, Larison S. Prostate cryoablation: Update 1998. CA Cancer J Clin. 1998;48(4):239-253.
  15. Chin JL, Downey DB, Mulligan M, et al. Three-dimensional transrectal ultrasound guided cryoablation for localized prostate cancer in nonsurgical candidates: A feasibility study and report of early results. J Urol. 1998;159(3):910-914.
  16. Chuang CK, Chu SH, Chen HW, et al. Application of cryoablation in the management of prostate cancer. Chang Keng I Hsueh. 1997;20(3):201-206.
  17. Patel BG, Parsons CL, Bidair M, et al. Cryoablation for carcinoma of the prostate. J Surg Oncol. 1996;63(4):256-264.
  18. Corral DA, Pisters LL, von Eschenbach AC. Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am. 1996;23(4):677-684.
  19. de la Taille A, Hayek O, Benson MC, et al. Salvage cryotherapy for recurrent prostate cancer after radiation therapy: The Columbia experience. Urology. 2000;55(1):79-84.
  20. Drachenberg DE. Treatment of prostate cancer: Watchful waiting, radical prostatectomy, and cryoablation. Semin Surg Oncol. 2000;18(1):37-44.
  21. Erlichman M, Handelsman H, Hotta SS. Cryosurgery for recurrent prostate cancer following radiation therapy - systematic review. Health Technology Assessment No. 13. AHCPR Pub. No. 99-0004. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); June 1999.
  22. BlueCross BlueShield Association (BCBS), Technology Evaluation Center. Cryoablation for the primary treatment of clinically localized prostate cancer. TEC Assessment Program. Chicago IL: BCBSA; 2001;16(6).
  23. Alberta Heritage Foundation for Medical Research (AHFMR). Cryosurgery for prostate cancer. Technote TN 16. Edmonton, AB: AHFMR; 2002.
  24. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60(2 Suppl 1):3-11.
  25. Donnelly BJ, Saliken JC, Ernst DS, et al. Prospective trial of cryosurgical ablation of the prostate: Five-year results. Urology. 2002;60(4):645-649.
  26. Katz AE, Rewcastle JC. The current and potential role of cryoablation as a primary therapy for localized prostate cancer. Curr Oncol Rep. 2003;5(3):231-238.
  27. Foster KN. Cryotherapy for prostatic cancer. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian Ltd., eds. London, UK: Wessex Institute for Health Research and Development, University of Southampton; 2001;1(4):1-10.
  28. L'Agence Nationale d'Accreditation d'Evaluation en Sante (ANAES). Treatment of localised prostate cancer. Paris, France: ANAES; 2001:4.
  29. Feldman M. Cryoablation of the prostate for the treatment of primary and recurrent localized prostate cancer. Technology Assessment. San Francisco, CA: California Technology Assessment Forum: June 15, 2005. Available at: http://www.ctaf.org/ass/viewfull.ctaf?id=54588264128. Accessed January 13, 2006.
  30. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Cryotherapy for prostate cancer. Pre-Assessment No. 32. Ottawa, ON: CCOHTA; February 2004.
  31. Alberta Heritage Foundation for Medical Research (AHFMR). Cryotherapy as primary treatment for localized prostate cancer (update). Technote TN 54. Edmonton, AB: AHFMR; 2005.
  32. National Institute for Health and Clinical Excellence (NICE). Cryotherapy as a primary treatment for prostate cancer. Interventional Procedure Guidance 145. London, UK: NICE; November 2005.
  33. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for recurrent prostate cancer. Interventional Procedure Guidance No. 119. London, UK: NICE; May 2005.
  34. Hummel S, Paisley S, Morgan A, et al. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: A systematic review. Health Technol Assess. 2003;7(33):1-170.
  35. Grubb RL 3rd, Vardi IY, Bhayani SB, Kibel AS. Minimally invasive approaches to localized prostate carcinoma. Hematol Oncol Clin North Am. 2006;20(4):879-895.
  36. Shelley M, Wilt TJ, Coles B, Mason MD. Cyrotherapy for localised prostate cancer. Cochrane Database Syst Rev. 2007;(3):CD005010.

Cryoablation for Malignant Endobronchial Obstruction

  1. Wood DE. Management of malignant tracheobronchial obstruction. Surg Clin North Am. 2002;82(3):621-642.
  2. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for malignant endobronchial obstruction. Interventional Procedure Guidance No. 142. London, UK: NICE; November 2005. Available at: http://www.nice.org.uk/page.aspx?o= 280075. Accessed January 13, 2006.

Cryoablation of the Kidney

  1. Uchida M, Imaide Y, Sugimoto K, et al. Percutaneous cryosurgery for renal tumours. Br J Urol. 1995;75(2):132-137.
  2. Delworth MG, Pisters LL, Fornage BD, et al. Cryotherapy for renal cell carcinoma and angiomyolipoma. J Urol. 1996;155(1):252-255.
  3. Cozzi PJ, Lynch WJ, Collins S, et al. Renal cryotherapy in a sheep model: A feasibility study. J Urol. 1997;157(2):710-712.
  4. Campbell SC. Renal cryosurgery: Experimental evaluation of treatment parameters. Urology. 1998;52(1):29-34.
  5. Gill IS, Novick AC, Soble JJ, et al. Laparoscopic renal cryoablation: Initial clinical series. Urology. 1998;52(4):543-551.
  6. Bishoff JT, Chen RB, Lee BR, et al. Laparoscopic renal cryoablation: Acute and long-term clinical, radiographic, and pathologic effects in an animal model and application in a clinical trial. J Endourol. 1999;13(4):233-239.
  7. Long JP. Percutaneous cryoablation of the kidney in a porcine model. Cryobiology. 1999;38(1):89-93.
  8. Rukstalis DB, Khorsandi M, Garcia FU, et al. Clinical experience with open renal cryoablation. Urology. 2001;57(1):34-39.
  9. Harada J, Dohi M, Mogami T, et al. Initial experience of percutaneous renal cryosurgery under the guidance of a horizontal open MRI system. Radiat Med. 2001;19(6):291-296.
  10. Janzen N, Zisman A, Pantuck AJ, et al. Minimally invasive ablative approaches in the treatment of renal cell carcinoma. Curr Urol Rep. 2002;3(1):13-20.
  11. Chin JL, Pautler SE. New technologies for ablation of small renal tumors: Current status. Can J Urol. 2002;9(4):1576-1582.
  12. Desai MM, Gill IS. Current status of cryoablation and radiofrequency ablation in the management of renal tumors. Curr Opin Urol. 2002;12(5):387-393.
  13. Lee DI, McGinnis DE, Feld R, Strup SE. Retroperitoneal laparoscopic cryoablation of small renal tumors: Intermediate results. Urology. 2003;61(1):83-88.
  14. Lowry PS, Nakada SY. Renal cryotherapy: 2003 clinical status. Curr Opin Urol. 2003;13(3):193-197.
  15. Shingleton WB, Sewell PE Jr. Cryoablation of renal tumours in patients with solitary kidneys. BJU Int. 2003;92(3):237-239.
  16. Moon TD, Lee FT Jr, Hedican SP, et al. Laparoscopic cryoablation under sonographic guidance for the treatment of small renal tumors. J Endourol. 2004;18(5):436-440.
  17. Johnson DB, Solomon SB, Su LM, et al. Defining the complications of cryoablation and radio frequency ablation of small renal tumors: A multi-institutional review. Urol. 2004;172(3):874-877.
  18. Cestari A, Guazzoni G, dell'Acqua V, et al. Laparoscopic cryoablation of solid renal masses: Intermediate term followup. J Urol. 2004;172(4 Pt 1):1267-1270.
  19. Desai MM, Aron M, Gill IS. Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology. 2005;66(5 Suppl):23-28.
  20. Aron M, Gill IS. Renal tumor ablation. Curr Opin Urol. 2005;15(5):298-305.
  21. Silverman SG, Tuncali K, vanSonnenberg E, et al. Renal tumors: MR imaging-guided percutaneous cryotherapy--initial experience in 23 patients. Radiology. 2005;236(2):716-724.
  22. Powell T, Whelan C, Schwartz BF. Laparoscopic renal cryotherapy: Biology, techniques and outcomes. Minerva Urol Nefrol. 2005;57(2):109-118.
  23. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation: Outcome at 3 years. J Urol. 2005;173(6):1903-1907. 
  24. Kaouk JH, Aron M, Rewcastle JC, Gill IS. Cryotherapy: Clinical end points and their experimental foundations. Urology. 2006;68(1 Suppl):38-44.
  25. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for renal cancer. Interventional Procedure Guidance 207. London, UK: NICE; January 2007. Available at: http://guidance.nice.org.uk/IPG207/guidance/pdf/English. Accessed March 12, 2007.
  26. Mouraviev V, Joniau S, Van Poppel H, Polascik TJ. Current status of minimally invasive ablative techniques in the treatment of small renal tumours. Eur Urol. 2007;51(2):328-336.
  27. Thiel DD, Winfield HN. State-of-the-art surgical management of renal cell carcinoma. Expert Rev Anticancer Ther. 2007;7(9):1285-1294.
  28. Klingler HC. Kidney cancer: Energy ablation. Curr Opin Urol. 2007;17(5):322-326.
  29. Littrup PJ, Ahmed A, Aoun HD, et al. CT-guided percutaneous cryotherapy of renal masses. J Vasc Interv Radiol. 2007;18(3):383-392.
  30. Atwell TD, Farrell MA, Leibovich BC, et al. Percutaneous renal cryoablation: Experience treating 115 tumors. J Urol. 2008;179(6):2136-2140, discussion 2140-2141.
  31. Brett AS. Cryoablation for small renal tumors in older patients. Summary and Comment. JournalWatch General Medicine, July 3, 2008.
  32. Hinshaw JL, Shadid AM, Nakada SY, et al. Comparison of percutaneous and laparoscopic cryoablation for the treatment of solid renal masses. AJR Am J Roentgenol. 2008;191(4):1159-1168.
  33. Finley DS, Beck S, Box G, et al. Percutaneous and laparoscopic cryoablation of small renal masses. J Urol. 2008;180(2):492-498; discussion 498.
  34. Weight CJ, Kaouk JH, Hegarty NJ, et al. Correlation of radiographic imaging and histopathology following cryoablation and radio frequency ablation for renal tumors. J Urol. 2008;179(4):1277-1281; discussion 1281-1283.
  35. National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clinical Practice Guidelines in Oncology v.1.2009. Fort Washington, PA: NCCN; August 2008. Available at: http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed October 27, 2008.
  36. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: A meta-analysis. Cancer. 2008;113(10):2671-2680.
  37. Gulur D, Crow P, Keeley FX. Minimally invasive ablative technique for the treatment of small renal masses. Arch Ital Urol Androl. 2009;81(2):100-106.
  38. Nabi G, Cleves A, Shelley M. Surgical management of localised renal cell carcinoma. Cochrane Database Syst Rev. 2010;(3):CD006579.
  39. National Institute for Health and Clinical Excellence (NICE). Percutaneous cryotherapy for renal cancer. Interventional Procedure Guidance 402. London, UK: NICE; July 2011. Available at: http://www.nice.org.uk/nicemedia/live/13306/55645/55645.pdf. Accessed January 13, 2014.

Cryoablation of the Breast

  1. California Technology Assessment Forum (CTAF). Cryoablation for the treatment of breast fibroadenomas. A Technology Review. San Francisco, CA: CTAF; February 15, 2006. Available at: http://ctaf.org/content/general/detail/497. Accessed February 20, 2008.
  2. Bland KL, Gass J, Klimberg VS. Radiofrequency, cryoablation, and other modalities for breast cancer ablation. Surg Clin North Am. 2007;87(2):539-50, xii.
  3. Kaufman C, Bachman B, Littrup PJ, et al. Office-based ultrasound-guided cryoablation of breast fibroadenomas. Am J Surg. 2002;184(5):394-400.
  4. Simmons R. Ultrasound in the changing approaches to breast cancer diagnosis and treatment. Breast J. 2004;10 Suppl 1:S13-4.
  5. Simmons RM. Freezing breast cancers to enhance complete resection. Ann Surg Oncol. 2003;10(9):999.
  6. Simmons RM. Ablative techniques in the treatment of benign and malignant breast disease. J Am Coll Surg. 2003;197(2):334-338.
  7. Pfleiderer SO, Freesmeyer MG, Marx C, et al. Cryotherapy of breast cancer under ultrasound guidance: Initial results and limitations. Eur Radiol. 2002;12(12):3009-3014.
  8. Hall-Craggs MA, Vaidya JS. Minimally invasive therapy for the treatment of breast tumours. Eur J Radiol. 2002;42(1):52-57.
  9. Singletary SE. Minimally invasive techniques in breast cancer treatment. Semin Surg Oncol. 2001;20(3):246-250.
  10. Caleffi M, Filho DD, Borghetti K, et al. Cryoablation of benign breast tumors: Evolution of technique and technology. Breast. 2004;13(5):397-407.
  11. Kaufman CS, Littrup PJ, Freman-Gibb LA, et al. Office-based cryoablation of breast fibroadenomas: 12-month followup. J Am Coll Surg. 2004;198(6):914-923.
  12. Edwards MJ, Broadwater R, Tafra L, et al. Progressive adoption of cryoablative therapy for breast fibroadenoma in community practice. Am J Surg. 2004;188(3):221-224.
  13. Kaufman CS, Littrup PJ, Freeman-Gibb LA, et al. Office-based cryoablation of breast fibroadenomas with long-term follow-up. Breast J. 2005;11(5):344-350.
  14. Littrup PJ, Freeman-Gibb L, Andea A, et al. Cryotherapy for breast fibroadenomas. Radiology. 2005;234(1):63-72.
  15. Whitworth PW, Rewcastle JC. Cryoablation and cryolocalization in the management of breast disease. J Surg Oncol. 2005;90(1):1-9. 
  16. Nurko J, Mabry CD, Whitworth P, et al. Interim results from the FibroAdenoma Cryoablation Treatment Registry. Am J Surg. 2005;190(4):647-652.
  17. Huston TL, Simmons RM. Ablative therapies for the treatment of malignant diseases of the breast. Am J Surg. 2005;189(6):694-701.
  18. Agnese DM, Burak WE Jr. Ablative approaches to the minimally invasive treatment of breast cancer. Cancer J. 2005;11(1):77-82.

Cryoablation for Atrial Fibrillation

  1. Hazel S J, et al. A systematic review of intraoperative ablation for the treatment of atrial fibrillation. ASERNIP-S Report No.38. Stepney, SA: Royal Australasian College of Surgeons, Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S); 2004.
  2. Doll N, Kiaii BB, Fabricius AM, et al. Intraoperative left atrial ablation (for atrial fibrillation) using a new argon cryocatheter: Early clinical experience. Ann Thorac Surg. 2003;76(5):1711-1715; discussion 1715.
  3. Hoyt RH, Wood M, Daoud E, et al. Transvenous catheter cryoablation for treatment of atrial fibrillation: Results of a feasibility study. Pacing Clin Electrophysiol. 2005;28 Suppl 1:S78-S82.
  4. Gaita F, Riccardi R, Caponi D, et al. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: Correlation of electroanatomic mapping and long-term clinical results. Circulation. 2005;111(2):136-142.
  5. Mack CA, Milla F, Ko W, et al. Surgical treatment of atrial fibrillation using argon-based cryoablation during concomitant cardiac procedures. Circulation. 2005;112(9 Suppl):I1-I6.
  6. National Institute for Health and Clinical Excellence (NICE). Cryoablation for atrial fibrillation in association with other cardiac surgery. Interventional Procedure Guidance 123. London, UK: NICE; May 2005. Available at: http://www.nice.org.uk/nicemedia/pdf/ip/IPG123guidance.pdf. Accessed January 28, 2008.
  7. Gillinov AM, Saltman AE. Ablation of atrial fibrillation with concomitant cardiac surgery. Semin Thorac Cardiovasc Surg. 2007;19(1):25-32.
  8. Neuwirth R, Fiala M, Branny P, et al. Long term effectiveness of surgical cryoablation for chronic atrial fibrillation in patients undergoing surgery for severe mitral valve regurgitation. Vnitr Lek. 2007;53(2):151-156.
  9. Blomström-Lundqvist C, Johansson B, et al. A randomized double-blind study of epicardial left atrial cryoablation for permanent atrial fibrillation in patients undergoing mitral valve surgery: The SWEDish Multicentre Atrial Fibrillation study (SWEDMAF). Eur Heart J. 2007;28(23):2902-2908.
  10. Andrade JG et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: A systematic review of published studies. Heart Rhythm. 2011;8:1444-1451.
  11. Calkins H et al. 2012 HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints and research trial design. Heart Rhythm. 2012;9:632-696.
  12. Kojodjojo P et al. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: Medium term outcomes and non-randomized comparison with pulmonary venous isolation by radiofrequency ablation. Heart. 2010;96:1379-1384.
  13. Kuhne M et al. Cryoballoon versus radiofrequency catheter ablation of paroxysmal atrial fibrillation: biomarkers of myocardial injury, recurrence rates and pulmonary vein reconnection patterns. Heart Rhythm. 2010:7:1770-1776.
  14. Linhart M et al. Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: A case control study. J Cardiovasc Electrophys. 2009;20:1343-1348.
  15. Packer DL, Kowal RC, Wheelan KR, et al.; STOP AF Cryoablation Investigators. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: First results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol. 2013;61(16):1713-1723.
  16. Wann LS et al. 2011 ACCF/AHA/HRS Focused update on the management of patients with atrial fibrillation (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice Guidelines. Circulation. 2011;123:104-123.

Cryoablation for Skin Cancers

  1. Telfer NR, Colver GB, Morton CA, British Association of Dermatologists. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159(1):35-48.
  2. National Comprehensive Cancer Network (NCCN). Basal and squamous cell skin cancers. NCCN Clinical Practice Guidelines in Oncology v.1.2009. Fort Washington, PA: NCCN; 2009.
  3. Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol. 2006;142(6):729-735.

Cryoablation for Cervical Intraepithelial Neoplasia

  1. Martin-Hirsch PP, Paraskevaidis E, Bryant A, et al. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2010;(6):CD001318.
  2. Lewis KD, Sellors JW, Dawa A, et al. Report on a cryotherapy service for women with cervical intraepithelial neoplasia in a district hospital in western Kenya. Afr Health Sci. 2011;11(3):370-376.
  3. Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. Int J Gynaecol Obstet. 2013;120(3):218-223.

Cryoablation for Other Indications

  1. Birkenmaier C, Veihelmann A, Trouillier H, et al. Percutaneous cryodenervation of lumbar facet joints: A prospective clinical trial. Int Orthop. 2007;31(4):525-530.
  2. Kujak JL, Liu PT, Johnson GB, Callstrom MR. Early experience with percutaneous cryoablation of extra-abdominal desmoid tumors. Skeletal Radiol. 2010;39(2):175-182.
  3. Greenwald BD, Dumot JA, Abrams JA, et al. Endoscopic spray cryotherapy for esophageal cancer: Safety and efficacy. Gastrointest Endosc. 2010;71(4):686-693.
  4. Timmermans C, Manusama R, Alzand B, Rodriguez LM. Catheter-based cryoablation of postinfarction and idiopathic ventricular tachycardia: Initial experience in a selected population. J Cardiovasc Electrophysiol. 2010;21(3):255-261.
  5. Yamauchi Y, Izumi Y, Hashimoto K, et al. Percutaneous cryoablation for the treatment of medically inoperable stage I non-small cell lung cancer. PLoS One. 2012;7(3):e33223.
  6. Simpson JL, Melia M, Yang MB, et al. Current role of cryotherapy in retinopathy of prematurity: A report by the American Academy of Ophthalmology. Ophthalmology. 2012;119(4):873-877.
  7. Klem TM, Schnater JM, Schütte PR, et al. A randomized trial of cryo stripping versus conventional stripping of the great saphenous vein. J Vasc Surg. 2009;49(2):403-409.
  8. Krummel T, Garnon J, Lang H, et al. Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition. BMC Urol. 2014;14(1):77.
  9. Song ZG, Hao JH, Gao S, et al. The outcome of cryoablation in treatment of advanced pancreatic cancer: A comparison with palliative bypass surgery alone. J Dig Dis. 2014;15(10):561-569.
  10. Cornelis F, Petitpierre F, Lasserre AS, et al. Percutaneous cryoablation of symptomatic abdominal scar endometrioma: Initial reports. Cardiovasc Intervent Radiol. 2014;37(6):1575-1579.
  11. Schwimer SR, Bassett LW, Mancuso AA, et al. Giant cell tumor of the cervicothoracic spine. AJR Am J Roentgenol. 1981;136(1):63-67.
  12. Althausen PL, Schneider PD, Bold RJ, et al. Multimodality management of a giant cell tumor arising in the proximal sacrum: Case report. Spine (Phila Pa 1976). 2002;27(15):E361-E365.
  13. David Prologo J, Snyder LL, Cherullo E, et al. Percutaneous CT-guided cryoablation of the dorsal penile nerve for treatment of symptomatic premature ejaculation. J Vasc Interv Radiol. 2013;24(2):214-219.
  14. Iguchi T, Sakurai J, Hiraki T, et al. Safety of percutaneous cryoablation in patients with painful bone and soft tissue tumors: A single center prospective study (SCIRO-1502). Acta Med Okayama. 2016;70(4):303-306.
  15. Cunningham GR, Khera M. Treatment of male sexual dysfunction. UpToDate Inc., Waltham, MA. Last reviewed September 2016.
  16. Woolen S, Gemmete JJ. Treatment of residual facial arteriovenous malformations after embolization with percutaneous cryotherapy. J Vasc Interv Radiol. 2016;27(10):1570-1575.
  17. Luksanapruksa P, Buchowski JM, Singhatanadgige W, et al. Management of spinal giant cell tumors. Spine J. 2016;16(2):259-269.
  18. Thomas DM, Desai J. Giant cell tumor of bone. UpToDate Inc., Waltham, MA. Last reviewed September 2016.
  19. Buethe JY, Abboud S, Brock K, et al. Percutaneous CT-guided cryoablation of the salivary glands in a porcine model. J Vasc Interv Radiol. 2016;27(12):1907-1912.
  20. Fan WZ, Niu LZ, Wang Y, et al. Initial experience: Alleviation of pain with percutaneous CT-guided cryoablation for recurrent retroperitoneal soft-tissue sarcoma. J Vasc Interv Radiol. 2016;27(12):1798-1805.
  21. Domovitov SV, Chandhanayingyong C, Boland PJ, et al. Conservative surgery in the treatment of giant cell tumor of the sacrum: 35 years' experience. J Neurosurg Spine. 2016;24(2):228-240.
  22. Chen L, Gu YD, Xu L. Clinical application of axonal repair technique for treatment of peripheral nerve injury. Chin J Traumatol. 2004;7(3):153-155.
  23. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines. Ann Oncol. 2016;27(suppl 5):v58-v68.
  24. Coupal TM, Pennycooke K, Mallinson PI, et al. The hopeless case? Palliative cryoablation and cementoplasty procedures for palliation of large pelvic bone metastases. Pain Physician. 2017;20(7):E1053-E1061.
  25. National Comprehensive Cancer Network. Clinical practice guideline: Kidney cancer. Version 1.2018. NCCN: Fort Washington, PA.
  26. Garza I, Schwedt TJ. Overview of chronic daily headache. UpToDate Inc., Waltham, MA. Last reviewed October 2017a.
  27. Bonthius DJ, Lee AG, Hershey AD. Headache in children: Approach to evaluation and general management strategies.  UpToDate Inc., Waltham, MA. Last reviewed October 2017.
  28. Garza I, Schwedt TJ. New daily persistent headache. UpToDate Inc., Waltham, MA. Last reviewed October 2017b.
  29. Weller PF, Leder K. Hookworm infection. UpToDate Inc., Waltham, MA. Last reviewed October 2017a.
  30. Weller PF, Leder K. Hookworm-related cutaneous larva migrans. UpToDate Inc., Waltham, MA. Last reviewed October 2017b.
  31. Shaikh R, Alomari AI, Kerr CL, et al. Cryoablation in fibro-adipose vascular anomaly (FAVA): A minimally invasive treatment option. Pediatr Radiol. 2016;46(8):1179-1186.
  32. Gosalia AJ, Martin P, Jones PD. Advances and future directions in the treatment of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2017;13(7):398-410.
  33. Tedesco D, Gori D, Desai KR, et al. Drug-free interventions to reduce pain or opioid consumption after total knee arthroplasty: A systematic review and meta-analysis. JAMA Surg. 2017;152(10):e172872.
  34. Hwang PH, Lin B, Weiss R, et al. Cryosurgical posterior nasal tissue ablation for the treatment of rhinitis. Int Forum Allergy Rhinol. 2017;7(10):952-956. 
  35. Paprocka-Zjawiona M, Nowosielska-Grygiel J, Kikowski L, et al. Cryosurgery in the treatment of allergic and non-allergic rhinitis. Wiad Lek. 2018;71(6):1135-1140.
  36. Fichman V, Valle ACFD, de Macedo PM, et al. Cryosurgery for the treatment of cutaneous sporotrichosis in four pregnant women. PLoS Negl Trop Dis. 2018;12(4):e0006434.
  37. Venook AP. Nonsurgical local treatment strategies for colorectal cancer liver metastases. UpToDate Inc., Waltham, MA. Last reviewed December 2018.
  38. Bhattacharyya N. Clinical presentation, diagnosis, and treatment of nasal obstruction. UpToDate Inc., Waltham, MA. Last reviewed December 2018.
  39. Hamilos DL. Chronic rhinosinusitis: Management. UpToDate Inc., Waltham, MA. Last reviewed December 2018.
  40. Lieberman PL. Chronic nonallergic rhinitis. UpToDate Inc., Waltham, MA. Last reviewed December 2018.
  41. Ferrer-Mileo L, Luque Blanco AI, Gonzalez-Barboteo J. Efficacy of cryoablation to control cancer pain: A systematic review. Pain Pract. 2018;18(8):1083-1098.
  42. Miyazaki M, Saito K, Yanagawa T, et al. Phase I clinical trial of percutaneous cryoablation for osteoid osteoma. Jpn J Radiol. 2018;36(11):669-675.
  43. Kompelli AR, Janz TA, Rowan NR, et al. Cryotherapy for the treatment of chronic rhinitis: A qualitative systematic review. Am J Rhinol Allergy. 2018;32(6):491-501.