This literature reappraisal will research the applications of cryosurgery in lung malignant neoplastic disease, discoursing its efficaciousness, restrictions and benefits when compared to other intervention option. Lung malignant neoplastic disease is the most common type of malignant neoplastic disease in the universe ( 38 ) with a normally inexorable forecast. Between 2005 and 2009 merely 9 % of grownups in England had survived their lung malignant neoplastic disease for 5 old ages or longer ( 57 ) . Harmonizing to a survey by Maiwand et Al. merely 20 % of lung malignant neoplastic disease patients are suited for traditional surgery as a consequence of hapless respiratory status or other wellness concerns ( 3 ) . In this respect cryosurgery may keep the reply as an effectual, cost-efficient, healing and alleviative intervention option, but how does it do when compared to other intervention methods?
Lung malignant neoplastic disease can be classified into two chief classs:
Small cell lung malignant neoplastic disease ( SCLC ) is unluckily a fast-spreading malignant neoplastic disease, which has frequently spread to other parts of the organic structure by the clip that it is diagnosed. When observed under a microscope these malignant neoplastic disease cells appear comparatively little and the bulk of the cell infinite is taken up by the karyon. Around 18 out of every 100 lung malignant neoplastic disease instances in the UK are of this type ( 32 ) .
Non-small cell lung malignant neoplastic disease ( NSCLC ) is a less aggressive malignant neoplastic disease that spreads more easy than SCLC. It is more common, being involved in about 78 out of every 100 instances of lung malignant neoplastic disease in the UK. There are several types of NSCLC including squamous cell, glandular cancer and big cell carcinoma, but type does non find the intervention administered ( 32 ) .
What is cryosurgery?
Cryosurgery or cryoablation employs the usage of really low temperatures to destruct tissue in a controlled mode and can be used to handle a figure of conditions. These include tumors, but besides benign skin lesions such as keratosis, solar freckle, warts and dermatofibroma for illustration ( 49 ) . The first usage of cold to destruct tissue came about with James Arnott, a doctor in the nineteenth century. He used a mixture of salt and ice for the palliation of several malignant neoplastic diseases. He was able to make temperatures of -24 & A ; deg ; C. However, this is non equal for tumour devastation, where temperatures of at least -50 & A ; deg ; C is required ( 48 ) .
Several promotions have been made in cryosurgical equipment since, with the development of investigations that utilise the Joule-Thompson rule. Pressurised gases such as C dioxide, azotic oxide and Ar, which are used as cryogens today, are passed through an gap in a heat money changer in the investigation. The rapid enlargement of the gases as they pass through this gap from a high force per unit area zone to a low force per unit area zone leads to chilling at the investigation tip due to the Joule-Thompson rule. They can accomplish temperatures every bit low as -70 & A ; deg ; C, -70 & A ; deg ; C and -135 & A ; deg ; C severally at the tip ( 3,20,50 ) . Even lower temperatures can be achieved utilizing pressurised liquid N that is supercooled via a heat money changer and so circulated to the cryoprobe tip, which can make temperatures between -195 & A ; deg ; C and -165 & A ; deg ; C. The cryoprobe tip is applied to the lesion taking to cell devastation. For processs carried out on splanchnic constructions, the procedure is normally monitored utilizing ultrasound or CT with thermosensors to corroborate that a sufficient country and temperature of freeze has been achieved ( 50 ) .
Mechanism of Action
The construct of cryosurgery is based on stop deading the mark tissue quickly, followed by slow melt to maximize harm to the cells ( 50 ) . This is achieved by the formation of ice-crystals inside the cells, which disrupt enzyme activity and the cell membrane of the cells. Formation of ice outside the cells consequences in desiccation and melt afterwards leads to a rapid motion of H2O back into the cells by osmosis, doing lysis. Destruction of the blood vass providing the tumor due to these factors besides contributes to tumour cell decease ( 33 ) .
Cryosurgery for Lung Cancer
Cryosurgery is suited for patients with lung malignant neoplastic disease who are unable to undergo surgery for several grounds ; if the malignant neoplastic disease is in a late phase, the patient would hold unequal respiratory map after resection, if the tumor has returned after already having chemotherapy, radiation therapy or lung resection or if the patient does non wish to hold surgery ( 7 ) .
Depending on the location of the tumor and circumstance, three types of process can be carried out. They include endobronchial, direct intrathoracic or transdermal cryoablation ( 7 ) . Endobronchial cryosurgery is used for tumors in the tracheobronchial part ( 6 ) . It is performed under a local or ephemeral general anesthetic. A stiff 9.2mm or a flexible 2.4 millimeter bronchoscope is employed. It is positioned 5mm above the tumor and following this, a cryoprobe is placed through the bronchoscope straight into the tumor. The liquid that is often used for chilling, the cryogen, is either Ar or azotic oxide. Freeze of the tumor lasts 3 to 5 proceedingss, after which the tumor is allowed to dissolve. When the cryoprobe becomes detached from the tissue, a 2nd rhythm of freeze/thawing is normally carried out. Necrotic stuff formed during the procedure is removed with forceps. ( 1,3,5,6 ) .
Direct intrathoracic cryoablation of the tumor is carried out if the patient is found to be inoperable during the lung resection surgery after thoracotamy. In readying for this result patients are told beforehand about the usage of cryosurgery and informed consent for the process is obtained. The size of the tumor, its location in the lungs and its relation to nearby constructions will hold been identified prior to surgery. After needle aspiration has been carried out to corroborate the location of major blood vass, the cryoprobe is inserted into the tumor and freeze commences. Freezing continues until the attendant iceball covers the tumor wholly and besides a 5mm border around the tumor. Multiple cryoprobes may hold to be used if the tumor is big plenty. Again a 2nd rhythm of freeze and melt is frequently performed. Necrotic tissue is removed, but a bed is left on the border of healthy lung tissue to cut down the hazard of air-leak. ( 1,2,3,4 )
Transdermal cryoablation is carried out under the influence of a local or general anesthetic ( 9,42 ) . Under CT counsel a cryoprobe is inserted through the tegument and thorax into the tumor. Pressurised Ar gas is used for stop deading and pressurised He is used for dissolving. Initially there is a 5 infinitesimal rhythm of freeze, followed by dissolving up to 20 & A ; deg ; C. This rhythm is repeated once more and so followed by a longer 10 infinitesimal rhythm of stop deading before dissolving one time more. During the first stop deading an country of merely 1 centimeters can be frozen as the insulating air in the lung parenchyma prevents the conductivity of low temperatures. As a consequence back-to-back rhythms of freeze and dissolving are required to stop dead a larger country. For tumors smaller than 2 cm one cryoprobe is used, whereas larger tumors require the usage of multiple cryoprobes at the same clip in order to accomplish a border of stop deading around the tumor ( 9 ) .
In add-on to the direct devastation of tumor cells, there are in-vitro surveies which suggest that cryosurgery can modulate the immune system to move against tumor cell reproduction ( 35-37 ) . However, these findings are inconclusive and necessitate farther probe.
Other Treatment Options
Surgery
Treatment options depend on the phase of the malignant neoplastic disease, its location and the wellness of the patient. Surgery is a feasible option for phase 1, 2 or some phase 3a NSCLC and besides SCLC if caught really early as the malignant neoplastic disease can be removed wholly. There are several surgical processs that can be performed. A wedge resection involves remotion of a little section of the lung, where the malignant neoplastic disease is thought to be localised. A lobectomy involves taking a individual lobe of the lung if the malignant neoplastic disease is contained in a individual lobe, whereas pneumonectomy is the complete remotion of a lung in the event that all of the lobes of that peculiar lung are affected by the malignant neoplastic disease. Removal of lymph nodes near the lungs is besides carried out as a preventive step in instance malignant neoplastic disease cells have spread at that place. In SCLC the malignant neoplastic disease is likely to hold already spread upon diagnosing. As a consequence surgery is non normally feasible as a method of taking the malignant neoplastic disease wholly ( 43 ) .
There are besides other state of affairss where surgery is non a recommendable option ; for case if the malignant neoplastic disease is located in close propinquity to critical variety meats such as the bosom, trachea or major blood vass or if the patient has other conditions that render them unfit for surgery. ( 43 )
Post operative recovery clip will be about 10 yearss for pneumonectomy and 5 to 7 yearss for lobectomy ( 43 ) . During this clip patients will stay in ICU followed by the wards. The patient will besides be required to set about external respiration and leg exercisings to forestall infections and blood coagulums. Analgesics may besides be required to relieve hurting after the surgery to assist with external respiration. In contrast endobronchial and percutatneous cryotherapy are normally an outpatient process, justifying a lower recovery period and are less invasive processs. Cryosurgery could potentially salvage money on patient attention due to this lower recovery period and free up infinite in wards for other patients.
Local anesthesia can besides be used with the cryotherapy processs stated above, whereas surgery facilitates the demand for an anesthesiologist and extra equipment as general anesthesia is used ( 20 ) . This can account for a higher cost for lung resection compared with cryosurgery.
An probe by Du et Al. looked at and compared the consequences of direct intrathoracic cryotherapy and lung resection in 26 and 18 patients severally with tumors located near the fringe of the lungs. The malignant neoplastic disease returned in fewer patients that underwent cryotherapy than in resection. In add-on 1- and 3-year endurance were both found to be higher in the cryotherapy patients- 75 % and 58.3 % compared to 58.3 % and 0 % severally, proposing that cryosurgery may be more effectual than resection when handling lung malignant neoplastic disease. It is hard to pull a general decision from these consequences due to the little non-randomised sample, which does non reflect on tumors located more deeply ( 10 ) .
Chemotherapy
SCLC is treated chiefly by chemotherapy, which utilises cytotoxic drugs to destruct the malignant neoplastic disease cells. Cell decease is caused by the action of drugs on different parts of the cell rhythm ( 56 ) . For illustration the drug Cisplatin forms Pt composites with nucleophilic groups in DNA, ensuing in cross-links in the Deoxyribonucleic acid that lead to apoptosis and suppress cell growing ( 55 ) . Chemotherapy may besides be used to handle early phase NSCLC after surgery to forestall the malignant neoplastic disease from returning. A combination of drugs including one of either Cisplatin or carboplatin is frequently used. Treatment can last for 4 to 6 months with 3 to 4 hebdomads in between each intervention. SCLC is really antiphonal to chemotherapy and because the drug can be distributed around the organic structure in the circulation, it can move at multiple sites that the malignant neoplastic disease cells may hold spread to, even if these malignant neoplastic disease cells are non seeable on scans ( 44 ) . Cryosurgery on the other manus relies on placing tumour cells on scans anterior to intervention and administrating the cryoprobe to the mark country. Therefore it can non efficaciously handle tumors that have merely metastasized and are non yet seeable on imaging scans.
However, there are disadvantages to chemotherapy in the signifier of several side effects. Equally good as aiming malignant neoplastic disease cells, normal organic structure cells such as white blood cells, ruddy blood cells, thrombocytes, tegument and hair cells are besides affected by the drugs. Due to this deficiency of specificity patients can see inauspicious effects such as hair loss, increased exposure to infections, fatigue, sickness, alterations to savor, tinnitus and diarrhea depending on the drugs used.
Chemotherapy has limited success opening up air passages blocked by tumors ( 3,46 ) . This is an country where cryosurgery would be more utile.
Radiotherapy ( 45 )
Another intervention option is radiotherapy. It can be used for phase 1 or 2 NSCLC where surgery can non – if the patient is unfit due to an bing status, a phase 3 malignant neoplastic disease is near to the bosom or another country where it is hard to run, the patient does non wish to hold surgery, or if the malignant neoplastic disease is stage 3a or 3b NSCLC and the patient can non undergo chemotherapy ( 7,45 ) . Radiotherapy can besides be used efficaciously for SCLC with or after chemotherapy intervention ( 53 ) . Contraceptive cranial radiation therapy is sometimes carried out as a safeguard to forestall malignant neoplastic disease cells that may hold spread to the encephalon from turning farther ( 45 ) . However, radiation therapy besides portions limited effectivity in opening up air passages that are blocked by tumors, with cryosurgery being a more successful option in this respect ( 3,46 ) .
There are two signifiers of radiation therapy: external-beam radiation therapy ( EBRT ) and brachytherapy. Both types rely on radiation to kill tumour cells alternatively of the low temperatures used in cryosurgery. Cell decease occurs by harm to the tumor cell DNA caused by the ionising radiation, which leads to a arrest in cell division and finally cell decease.
EBRT uses high energy X raies or gamma beams produced by a machine called a additive gas pedal ( LINAC ) . three-dimensional conformal radiation therapy ( 3D-CRT ) is the most common signifier of EBRT ; by utilizing package, radiation is administered to a specific country ( 54 ) . Extremist EBRT therapy used to bring around malignant neoplastic disease can follow two different intervention governments. Patients can have radiotherapy 5 yearss a hebdomad for 4 to 7 hebdomads. The weekends are excluded to give patients a opportunity to retrieve and understate side effects. The other regimen is called Continuous Hyperfractionated Accelerated Radio Therapy ( CHART ) where 3 interventions are given daily for 12 yearss ( 45 ) . Endobronchial and transdermal cryosurgery are similar to radiotherapy in that they are normally carried out on an outpatient footing as is the instance with the former regimen, whereas CHART requires the patient to stay in infirmary during the class of the intervention ( 45 ) . In add-on radiation therapy does non necessitate the usage of anesthetic while local anesthesia is used for cryosurgery. However, radiation therapy can do harm to the healthy lung tissue environing the tumor and lessening lung map of the patient ( 15 ) , whereas this is non the instance with cryosurgery because gristle environing the wall of the windpipe and bronchial tube is immune to stop deading and the air in the alveoli Acts of the Apostless as an dielectric, forestalling the cold temperatures from badly impacting local countries near the tumor ( 3, 41 ) .
The combined usage of radiation therapy and chemotherapy are sometimes employed provided the patient is fit plenty. This might propose that a combined intervention of cryosurgery with other methods may supply even more benefit to the patient. However, one analysis of several surveies suggests that a combination of cryosurgery with radiation therapy and chemotherapy will non supply such benefit and that it may even take down the quality of life for the patient ( 14 ) . Other studies struggle with this decision, proposing that cryotherapy before chemotherapy may assist increase the sum of cytotoxic drugs taken up by the tumor and better the result of the patient farther ( 21, 22 ) and combination with radiation therapy may besides better efficaciousness ( 24 ) .
Brachytherapy is a signifier of radiation therapy where a radioactive beginning is placed near to or into the tumor. That beginning is frequently iridium-192 ( 20 ) . Fatal hemoptysis and fistula formation look to be the biggest concerns ; one study found an overall happening of 10 % for these jobs. There is an extra hazard factor of radiation exposure to staff members over clip ( 30 ) . In comparing no long-run safety concerns are present for staff administrating cryosurgery.
Radiofrequency Ablation ( RFA )
The usage of electrical currents can be used to bring forth heat that can kill tumour cells. This process is performed under local or general anesthesia. A investigation is inserted through the tegument and guided utilizing CT into the tumor ( 12 ) . As a consequence it is less invasive than lung resection, like endobronchial and transdermal cryosurgery ( 34 ) .
Photodynamic Therapy ( PDT )
This intervention option uses a drug such as Porfimer Na ( 20 ) to sensitize the cells of the organic structure to visible radiation and uses a optical maser thenceforth to kill the tumor cells. As with cryosurgery it can be used when lung resection surgery is non an option and can besides be used for alleviative intents if a tumor is barricading the air passages and curtailing air flow ( 14 ) .
The light-sensitising drug is given 48 hours before the process to let it to be absorbed ( 8 ) . In this respect it is unsuitable if gap of the air passages is required in an exigency obstructor ( 5,20 ) . However, it is an outpatient process and can be performed under local anesthesia like endobronchial and transdermal cryosurgery. The drug leaves the tegument medium for up to 6 hebdomads after disposal. During this clip the patient will hold to be careful of sunshine and indoor visible radiation and avoid traveling outside or put on the lining skin harm ( 14, 20 ) . This may be more inconvenient for the patient when compared with cryosurgery.
Similarly to endobronchial cryosurgery, entree to the tumor is gained through a bronchoscope. In PDT a fiber-optic bronchoscope is used to aim the tumor with visible radiation that will be absorbed by the photosensitising drug. These drugs are non specific to the tumor cells so the possibility of harm to healthy lung tissue exists, whereas the lungs are reasonably resilient to stop deading from cryosurgery and a border of healthy tissue is deliberately frozen ( 14, 17, 20 ) .
PDT, Brachytherapy therapy and cryotherapy require a period of clip before their effects are seen in endobronchial obstructor ( 20 ) . In state of affairss where there is a terrible obstruction in the air passages that requires pressing action, Nd-YAG optical maser resection has been used foremost to supply immediate alleviation followed with effectual usage of brachytherapy or PDT afterwards ( 20,26-28 ) .
Treatment Efficacy
Endobronchial cryosugery
A instance survey in 2004 by Maiwand et Al. looked at 521 patients that received endobronchial cryosurgery with an norm of 2.4 interventions. The bulk of patients had non-small cell lung carcinoma with a minority that had little cell lung malignant neoplastic disease. A followup of these patients after the first intervention revealed that there was a general betterment in respiratory map. Mean forced expiratory volume in one minute had increased from 1.39 liters to 1.51 liters and intend forced critical capacity had increased from 1.93 liters to 2.13 liters. There were besides betterments in symptoms after cryosurgery. Cough, dyspnea, hemoptysis, and chest hurting had improved in 69 % , 59.2 % , 76.4 % and 42.6 % of diagnostic patients severally. These betterments appear to warrant the higher quality of life signalled by a important addition in the mean Karnofsky mark from 60 to 75 and a important decrease in the mean WHO score from 3.04 to 2.20. The happening of complications was besides low at 9 % of all instances. These included hemoptysis, atrial fibrillation, respiratory hurt and hapless gas exchange, which were attributable to 4 % , 2 % ,3 % and 1.2 % of the instances severally. ( 3,8 )
Another survey by Askimakopoulou et Al. suggests that increasing the figure of interventions improves the effects of endobronchial cryosurgery. Two similar size groups were compared ; group A patients ( 172 instances ) had received two interventions of cryosurgery at least, whilst group B patients ( 157 instances ) received a individual intervention. Although symptoms improved in both groups, the benefit was greater for group A. There was besides a important difference for average survival clip post-therapy. This was 15 months and 8.3 months for group A and group B severally. Perceptibly patients with phase 3a and 3b tumors displayed significantly improved Karnofsky tonss, foregrounding the benefit of cryosurgery in alleviative attention of late phase malignant neoplastic disease ( 4 ) . Although these consequences appear to be promoting the sample sizes involved are excessively little to do a unequivocal decision.
A study by Lee et Al. found encouraging consequences for RFA. Two groups of patients with NSCLC or metastatic lung tumors that underwent RFA were investigated. 10 patients were holding the intervention to bring around the malignant neoplastic disease, whereas 20 were having the intervention for palliation of symptoms. In entire 32 tumors were involved- 10 for the former and 22 for the latter group. 38 % of the tumors were destroyed wholly. The probe found that RFA was really effectual for tumors smaller than 3 centimeter in diameter, with 100 % of the tumors being wholly destroyed. However, the consequences were far less successful for larger tumor with 38 % and 8 % complete devastation of tumors that were 3.1-5cm and 5cm or greater severally ( 11 ) .
Improvement of patients ‘ symptoms was besides noted. Cough, dyspnea, hemoptysis and thorax hurting improved in 25 % ,36 % , 80 % and 36 % of diagnostic patients severally. In comparing, Maiwand ‘s survey of endobronchial cryosurgery showed that the per centum of patients who saw an betterment in these symptoms was significantly higher with cryosurgery. The exclusion was dyspnea, which saw a somewhat higher per centum betterment with RFA. Complications with this process besides included minor pneumothorax and pleural gush nowadays in some instances of transdermal cryosurgery. They occurred in 23 % and 6.7 % of patients severally. The frequence is similar to that seen in Maiwand ‘s study for endobronchial cryosurgery ( 3 ) . RFA was besides responsible for other complications including clogging pneumonia, febrility and haemotysis, which were all uncommon and mild in nature. However, there were 3 instances of major complication, 2 of which involved a major pneumothorax. The staying instance involved a patient who was diagnosed with pneumonia prior to RFA and died 30 yearss afterwards ( 11 ) .
A survey by Yoshihiro Hayata et Al. followed 57 lesions that were treated with PDT at Tokyo Medical College and 70 lesions at Hayata Cancer Research Group centres. They were all early phase tumors and a bulk were squamous cell carcinoma- a type of NSCLC. Complete devastation of the tumor was achieved in 71.9 % and 82 % of lesions at the two establishments severally. However, the sample was non randomised at Tokyo Medical College as all except 1 of the 48 instances were male. In contrast the male to female ratio in Maiwand ‘s survey was 1.8: 1, giving a better representation of the population. While these consequences appear to be much more successful than those of Niu ‘s transdermal cryosurgery, where merely 14.4 % complete remittal of all tumors was achieved, the bulk of good consequences for PDT were confined to tumors smaller than 1 centimeter in diameter and wholly seeable by endoscope ( 18 ) . The sample besides consisted of merely early phase malignant neoplastic disease patients, whereas Niu ‘s sample included patients with a assortment of malignant neoplastic disease phases.
Another paper by Vergnon et Al. compared the two methods. Cryosurgery and PDT both resulted in similar betterment of symptoms. However, cryosurgery had a higher efficaciousness in uncluttering an obstructed air passage, while PDT appeared to profit the patient over a longer period of clip after the intervention ( 20 ) .
Direct Cryosurgery
Positive consequences for this process were seen in a study by Maiwand et Al. affecting 15 patients who had received direct intrathoracic surgery. Follow up of these patients saw that many of them had improved symptoms. Specifically, cough, dyspnea, and hemoptysis had improved in 77.9 % , 66.7 % , and 100 % of diagnostic patients severally ( 3 ) . The incidence in betterment was higher than that seen in Maiwand ‘s survey of endobronchial cryosurgery, but it is hard to make a decision imputing the direct cryosurgery entirely to these benefits because some of these patients received other interventions including radiofrequency extirpation, which could hold had an consequence. The sample size is besides excessively little to bear statistical significance for the consequences found in comparing to the much larger 521 patient sample in Maiwand ‘s survey.
Transdermal Cryosurgery
Niu et Al. reviewed the instances of 840 patients, who received transdermal cryoablation at Fuda Cancer Hospital in China ( 9 ) . They all had NSCLC of changing phases with the bulk being stage 2a and some patients received up to three separate interventions. The consequences showed that merely a little proportion of patients had no marks of malignant neoplastic disease after follow up ( 14.4 % ) and that the bulk of patients had partial remittal of their malignant neoplastic disease ( 70 % ) . Unfortunately, followup of these patients subsequently on revealed that the malignant neoplastic disease had returned in 44.4 % of the patients, with 28.3 % of these in the same location. This suggests that transdermal cryoablation merely has a moderate opportunity of bring arounding lung malignant neoplastic disease and may be more feasible as a alleviative intervention option that can be repeated in hereafter.
Complications included pneumothorax, pleural gush and hemoptysis, which were common. They occurred in 25.9 % ,16 % and 22.5 % of instances severally. However, this is outweighed by the promoting overall 1- , 2- , 3- , 4- and 5- twelvemonth endurance at 68 % , 52 % , 34 % , 26 % and 21 % , severally. Despite these consequences, differentiation of NSCLC types has non been factored. In add-on none of the patients had SCLC. Therefore, it is hard to to the full reason the efficaciousness of transdermal cryoablation for different types of NSCLC and how it may be received by patients with SCLC ( 9 ) .
A survey by Okunaka et Al. concluded that PDT was healing for peripheral lung tumors that had non spread to other countries of the lung provided they were less than 1 centimeter in diameter. Targeting these tumors involved utilizing a investigation with a catheter that was guided utilizing CT into the tumor via a transdermal path. The survey saw 7 out of 9 instances where partial devastation of the tumor was achieved with PDT. 2 of these patients suffered from pneumothorax, which was 22 % of all instances ( 19 ) . This incidence is really similar to that seen in transdermal cryotherapy.
Decision
Although there are several surveies showcasing the efficaciousness of cryotherapy in the intervention of NSCLC there are few probes in comparing that expression at its public presentation in early phase SCLC. In add-on several of the sample sizes used in the surveies are little and it is hence hard to do sound decisions. Furthermore there are few comparative surveies between cryosurgery and other intervention methods, particularly those that are used with bronchoscopy and few surveies measuring the co-administration of cryosurgery with other intervention options.
Another country necessitating farther research is the immune response associated with cryosurgery. This could be the manner frontward to cut down return rates of tumor. There is besides a big fluctuation in cryosurgery processs in the surveies analysed, refering the temperature achieved at the investigation tip. This will impact the sum of mortification achieved, although it has been suggested that a faster freeze rate could be more utile in accomplishing more mortification, lower temperatures may be more effectual in covering with deeper tumors ( 3,41 ) . This creates the chance to prove the effectivity of different cryogens and farther surveies thenceforth need to utilize larger, randomised samples with a more standardized process. Although there is still much to be determined, cryosurgery offers a minimally invasive option to lung resection surgery, with sufficient grounds to warrant its usage and is more economical than brachytherapy and PDT ( 20 ) .
