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This literature review will explore the applications of cryosurgery in lung cancer, discussing its efficacy, limitations and benefits when compared to other treatment option. Lung cancer is the most common type of cancer in the world (38) with a usually grim prognosis. Between 2005 and 2009 only 9% of adults in England had survived their lung cancer for 5 years or longer (57). According to a study by Maiwand et al. only 20% of lung cancer patients are suitable for traditional surgery as a result of poor respiratory condition or other health concerns (3). In this regard cryosurgery may hold the answer as an effective, cost-effective, curative and palliative treatment option, but how does it fare when compared to other treatment methods?
Lung cancer can be classified into two main categories:
Small cell lung cancer (SCLC) is unfortunately a fast-spreading cancer, which has often spread to other parts of the body by the time that it is diagnosed. When observed under a microscope these cancer cells appear relatively small and the majority of the cell space is taken up by the nucleus. Around 18 out of every 100 lung cancer cases in the UK are of this type (32).
Non-small cell lung cancer (NSCLC) is a less aggressive cancer that spreads more slowly than SCLC. It is more common, being involved in around 78 out of every 100 cases of lung cancer in the UK. There are several types of NSCLC including squamous cell, adenocarcinoma and large cell carcinoma, but type does not determine the treatment administered (32).
What is cryosurgery?
Cryosurgery or cryoablation employs the use of very low temperatures to destroy tissue in a controlled manner and can be used to treat a number of conditions. These include tumours, but also benign skin lesions such as keratosis, solar lentigo, warts and dermatofibroma for example (49). The first use of cold to destroy tissue came about with James Arnott, a physician in the 19th century. He used a mixture of salt and ice for the palliation of several cancers. He was able to reach temperatures of -24 °C. However, this is not adequate for tumour destruction, where temperatures of at least -50 °C is required (48).
Several advancements have been made in cryosurgical equipment since, with the development of probes that utilise the Joule-Thompson principle. Pressurised gases such as carbon dioxide, nitrous oxide and argon, which are used as cryogens today, are passed through an opening in a heat exchanger in the probe. The rapid expansion of the gases as they pass through this opening from a high pressure zone to a low pressure zone leads to cooling at the probe tip due to the Joule-Thompson principle. They can achieve temperatures as low as -70°C,-70°C and -135°C respectively at the tip (3,20,50). Even lower temperatures can be achieved using pressurised liquid nitrogen that is supercooled via a heat exchanger and then circulated to the cryoprobe tip, which can reach temperatures between -195°C and -165°C. The cryoprobe tip is applied to the lesion leading to cell destruction. For procedures carried out on visceral structures, the process is usually monitored using ultrasound or CT with thermosensors to confirm that a sufficient area and temperature of freezing has been achieved (50).
Mechanism of Action
The concept of cryosurgery is based on freezing the target tissue rapidly, followed by slow thawing to maximise damage 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 results in dehydration and thawing afterwards leads to a rapid movement of water back into the cells by osmosis, causing lysis. Destruction of the blood vessels supplying the tumour due to these factors also contributes to tumour cell death (33).
Cryosurgery for Lung Cancer
Cryosurgery is suitable for patients with lung cancer who are unable to undergo surgery for several reasons; if the cancer is in a late stage, the patient would have inadequate respiratory function after resection, if the tumour has returned after already receiving chemotherapy, radiotherapy or lung resection or if the patient does not wish to have surgery (7).
Depending on the location of the tumour and circumstance, three types of procedure can be carried out. They include endobronchial, direct intrathoracic or percutaneous cryoablation (7). Endobronchial cryosurgery is used for tumours in the tracheobronchial region (6). It is performed under a local or short-lived general anaesthetic. A rigid 9.2mm or a flexible 2.4 mm bronchoscope is employed. It is positioned 5mm above the tumour and following this, a cryoprobe is placed through the bronchoscope directly into the tumour. The liquid that is frequently used for cooling, the cryogen, is either argon or nitrous oxide. Freezing of the tumour lasts 3 to 5 minutes, after which the tumour is allowed to thaw. When the cryoprobe becomes detached from the tissue, a second cycle of freeze/thawing is usually carried out. Necrotic material formed during the process is removed with forceps. (1,3,5,6).
Direct intrathoracic cryoablation of the tumour is carried out if the patient is found to be inoperable during the lung resection surgery after thoracotamy. In preparation for this outcome patients are told beforehand about the use of cryosurgery and informed consent for the procedure is obtained. The size of the tumour, its location in the lungs and its relation to nearby structures will have been identified prior to surgery. After needle aspiration has been carried out to confirm the location of major blood vessels, the cryoprobe is inserted into the tumour and freezing commences. Freezing continues until the resultant iceball covers the tumour entirely and also a 5mm margin around the tumour. Multiple cryoprobes may have to be used if the tumour is large enough. Again a second cycle of freezing and thawing is often performed. Necrotic tissue is removed, but a layer is left on the margin of healthy lung tissue to reduce the risk of air-leak. (1,2,3,4)
Percutaneous cryoablation is carried out under the influence of a local or general anaesthetic (9,42). Under CT guidance a cryoprobe is inserted through the skin and thorax into the tumour. Pressurised argon gas is used for freezing and pressurised helium is used for thawing. Initially there is a 5 minute cycle of freezing, followed by thawing up to 20 °C. This cycle is repeated again and then followed by a longer 10 minute cycle of freezing before thawing once more. During the first freezing an area of only 1 cm can be frozen as the insulating air in the lung parenchyma prevents the conduction of low temperatures. As a result consecutive cycles of freezing and thawing are required to freeze a larger area. For tumours smaller than 2 cm one cryoprobe is used, whereas larger tumours require the use of multiple cryoprobes at the same time in order to achieve a margin of freezing around the tumour (9).
In addition to the direct destruction of tumour cells, there are in-vitro studies which suggest that cryosurgery can modulate the immune system to act against tumour cell replication (35-37). However, these findings are inconclusive and require further investigation.
Other Treatment Options
Treatment options depend on the stage of the cancer, its location and the health of the patient. Surgery is a viable option for stage 1, 2 or some stage 3a NSCLC and also SCLC if caught very early as the cancer can be removed completely. There are several surgical procedures that can be performed. A wedge resection involves removal of a small segment of the lung, where the cancer is thought to be localised. A lobectomy involves removing a single lobe of the lung if the cancer is contained in a single lobe, whereas pneumonectomy is the complete removal of a lung in the event that all of the lobes of that particular lung are affected by the cancer. Removal of lymph nodes near the lungs is also carried out as a preventative measure in case cancer cells have spread there. In SCLC the cancer is likely to have already spread upon diagnosis. As a result surgery is not usually viable as a method of removing the cancer completely (43).
There are also other situations where surgery is not a recommendable option; for instance if the cancer is located in close proximity to vital organs such as the heart, windpipe or major blood vessels or if the patient has other conditions that render them unfit for surgery. (43)
Post operative recovery time will be around 10 days for pneumonectomy and 5 to 7 days for lobectomy (43). During this time patients will remain in ICU followed by the wards. The patient will also be required to undertake breathing and leg exercises to prevent infections and blood clots. Painkillers may also be required to alleviate pain after the surgery to help with breathing. In contrast endobronchial and percutatneous cryotherapy are usually an outpatient procedure, warranting a lower recovery period and are less invasive procedures. Cryosurgery could potentially save money on patient care due to this lower recovery period and free up space in wards for other patients.
Local anaesthesia can also be used with the cryotherapy procedures stated above, whereas surgery facilitates the need for an anaesthetist and additional equipment as general anaesthesia is used (20). This can account for a higher cost for lung resection compared with cryosurgery.
An investigation by Du et al. looked at and compared the results of direct intrathoracic cryotherapy and lung resection in 26 and 18 patients respectively with tumours located near the periphery of the lungs. The cancer returned in fewer patients that underwent cryotherapy than in resection. In addition 1- and 3-year survival were both found to be higher in the cryotherapy patients- 75% and 58.3% compared to 58.3% and 0% respectively, suggesting that cryosurgery may be more effective than resection when treating lung cancer. It is difficult to draw a general conclusion from these results due to the small non-randomised sample, which does not reflect on tumours located more deeply (10).
SCLC is treated primarily by chemotherapy, which utilises cytotoxic drugs to destroy the cancer cells. Cell death is caused by the action of drugs on different parts of the cell cycle (56). For example the drug Cisplatin forms platinum complexes with nucleophilic groups in DNA, resulting in cross-links in the DNA that lead to apoptosis and inhibit cell growth (55). Chemotherapy may also be used to treat early stage NSCLC after surgery to prevent the cancer from returning. A combination of drugs including one of either Cisplatin or carboplatin is often used. Treatment can last for 4 to 6 months with 3 to 4 weeks in between each treatment. SCLC is very responsive to chemotherapy and because the drug can be distributed around the body in the circulation, it can act at multiple sites that the cancer cells may have spread to, even if these cancer cells are not visible on scans (44). Cryosurgery on the other hand relies on identifying tumour cells on scans prior to treatment and administering the cryoprobe to the target area. Therefore it cannot effectively treat tumours that have just metastasized and are not yet visible on imaging scans.
However, there are disadvantages to chemotherapy in the form of several side effects. As well as targeting cancer cells, normal body cells such as white blood cells, red blood cells, platelets, skin and hair cells are also affected by the drugs. Due to this lack of specificity patients can experience adverse effects such as hair loss, increased vulnerability to infections, tiredness, nausea, changes to taste, tinnitus and diarrhoea depending on the drugs used.
Chemotherapy has limited success opening up airways blocked by tumours (3,46). This is an area where cryosurgery would be more useful.
Another treatment option is radiotherapy. It can be used for stage 1 or 2 NSCLC where surgery cannot - if the patient is unfit due to an existing condition, a stage 3 cancer is close to the heart or another area where it is difficult to operate, the patient does not wish to have surgery, or if the cancer is stage 3a or 3b NSCLC and the patient cannot undergo chemotherapy (7,45). Radiotherapy can also be used effectively for SCLC with or after chemotherapy treatment (53). Prophylactic cranial radiotherapy is sometimes carried out as a precaution to prevent cancer cells that may have spread to the brain from growing further (45). However, radiotherapy also shares limited effectiveness in opening up airways that are blocked by tumours, with cryosurgery being a more successful alternative in this regard (3,46).
There are two forms of radiotherapy: external-beam radiation therapy (EBRT) and brachytherapy. Both types rely on radiation to kill tumour cells instead of the low temperatures used in cryosurgery. Cell death occurs by damage to the tumour cell DNA caused by the ionising radiation, which leads to a halt in cell division and eventually cell death.
EBRT uses high energy x-rays or gamma rays produced by a machine called a linear accelerator (LINAC). 3-dimensional conformal radiation therapy (3D-CRT) is the most common form of EBRT; by using software, radiation is administered to a specific area (54). Radical EBRT therapy used to cure cancer can adopt two different treatment regimes. Patients can receive radiotherapy 5 days a week for 4 to 7 weeks. The weekends are excluded to give patients a chance to recover and minimise side effects. The other regimen is called Continuous Hyperfractionated Accelerated Radio Therapy (CHART) where 3 treatments are given daily for 12 days (45). Endobronchial and percutaneous cryosurgery are similar to radiotherapy in that they are usually carried out on an outpatient basis as is the case with the former regimen, whereas CHART requires the patient to remain in hospital during the course of the treatment (45). In addition radiotherapy does not require the use of anaesthetic while local anaesthesia is used for cryosurgery. However, radiotherapy can cause damage to the healthy lung tissue surrounding the tumour and decrease lung function of the patient (15), whereas this is not the case with cryosurgery because cartilage surrounding the wall of the trachea and bronchi is resistant to freezing and the air in the alveoli acts as an insulator, preventing the cold temperatures from severely affecting local areas near the tumour (3, 41).
The combined use of radiotherapy and chemotherapy are sometimes employed provided the patient is fit enough. This might suggest that a combined treatment of cryosurgery with other methods may provide even more benefit to the patient. However, one analysis of several studies suggests that a combination of cryosurgery with radiotherapy and chemotherapy will not provide such benefit and that it may even lower the quality of life for the patient (14). Other reports conflict with this conclusion, suggesting that cryotherapy before chemotherapy may help increase the amount of cytotoxic drugs taken up by the tumour and improve the outcome of the patient further (21, 22) and combination with radiotherapy may also improve efficacy (24) .
Brachytherapy is a form of radiotherapy where a radioactive source is placed close to or into the tumour. That source is often iridium-192 (20). Fatal haemoptysis and fistula formation appear to be the biggest concerns; one report found an overall occurrence of 10% for these problems. There is an additional risk factor of radiation exposure to staff members over time (30). In comparison no long-term safety concerns are present for staff administering cryosurgery.
Radiofrequency Ablation (RFA)
The use of electrical currents can be used to generate heat that can kill tumour cells. This procedure is performed under local or general anaesthesia. A probe is inserted through the skin and guided using CT into the tumour (12). As a result it is less invasive than lung resection , like endobronchial and percutaneous cryosurgery (34).
Photodynamic Therapy (PDT)
This treatment option uses a drug such as Porfimer sodium (20) to sensitise the cells of the body to light and uses a laser thereafter to kill the tumour cells. As with cryosurgery it can be used when lung resection surgery is not an option and can also be used for palliative purposes if a tumour is blocking the airways and restricting airflow (14).
The light-sensitising drug is given 48 hours before the procedure to allow it to be absorbed (8). In this regard it is unsuitable if opening of the airways is required in an emergency obstruction (5,20). However, it is an outpatient procedure and can be performed under local anaesthesia like endobronchial and percutaneous cryosurgery. The drug leaves the skin sensitive for up to 6 weeks after administration. During this time the patient will have to be careful of sunlight and indoor light and avoid going outside or risking skin damage (14, 20). This may be more inconvenient for the patient when compared with cryosurgery.
Similarly to endobronchial cryosurgery, access to the tumour is gained through a bronchoscope. In PDT a fibreoptic bronchoscope is used to target the tumour with light that will be absorbed by the photosensitising drug. These drugs are not specific to the tumour cells so the possibility of damage to healthy lung tissue exists, whereas the lungs are fairly resilient to freezing from cryosurgery and a margin of healthy tissue is intentionally frozen (14, 17, 20).
PDT, Brachytherapy therapy and cryotherapy require a period of time before their effects are seen in endobronchial obstruction (20). In situations where there is a severe blockage in the airways that requires urgent action, Nd-YAG laser resection has been used first to provide immediate relief followed with effective use of brachytherapy or PDT afterwards (20,26-28).
A case study in 2004 by Maiwand et al. looked at 521 patients that received endobronchial cryosurgery with an average of 2.4 treatments. The majority of patients had non-small cell lung carcinoma with a minority that had small cell lung cancer. A follow-up of these patients after the first treatment revealed that there was a general improvement in respiratory function. Mean forced expiratory volume in one minute had increased from 1.39 litres to 1.51 litres and mean forced vital capacity had increased from 1.93 litres to 2.13 litres. There were also improvements in symptoms after cryosurgery. Cough, dyspnoea, haemoptysis, and chest pain had improved in 69%, 59.2%, 76.4% and 42.6% of symptomatic patients respectively. These improvements appear to justify the higher quality of life signalled by a significant increase in the mean Karnofsky score from 60 to 75 and a significant reduction in the mean WHO score from 3.04 to 2.20. The occurrence of complications was also low at 9% of all cases. These included haemoptysis, atrial fibrillation, respiratory distress and poor gas exchange, which were attributable to 4%, 2%,3% and 1.2% of the cases respectively. (3,8)
Another study by Askimakopoulou et al. suggests that increasing the number of treatments improves the effects of endobronchial cryosurgery. Two similar size groups were compared; group A patients (172 cases) had received two treatments of cryosurgery at least, whilst group B patients (157 cases) received a single treatment. Although symptoms improved in both groups, the benefit was greater for group A. There was also a significant difference for mean survival time post-therapy. This was 15 months and 8.3 months for group A and group B respectively. Noticeably patients with stage 3a and 3b tumours displayed significantly improved Karnofsky scores, highlighting the benefit of cryosurgery in palliative care of late stage cancer (4). Although these results appear to be encouraging the sample sizes involved are too small to make a definitive conclusion.
A report by Lee et al. found encouraging results for RFA. Two groups of patients with NSCLC or metastatic lung tumours that underwent RFA were investigated. 10 patients were having the treatment to cure the cancer, whereas 20 were receiving the treatment for palliation of symptoms. In total 32 tumours were involved- 10 for the former and 22 for the latter group. 38% of the tumours were destroyed completely. The investigation found that RFA was very effective for tumours smaller than 3 cm in diameter, with 100% of the tumours being completely destroyed. However, the results were far less successful for larger tumours with 38% and 8% complete destruction of tumours that were 3.1-5cm and 5cm or greater respectively (11).
Improvement of patients' symptoms was also noted. Cough, dyspnoea, haemoptysis and chest pain improved in 25%,36%, 80% and 36% of symptomatic patients respectively. In comparison, Maiwand's study of endobronchial cryosurgery showed that the percentage of patients who saw an improvement in these symptoms was significantly higher with cryosurgery. The exception was dyspnoea, which saw a slightly higher percentage improvement with RFA. Complications with this procedure also included minor pneumothorax and pleural effusion present in some cases of percutaneous cryosurgery. They occurred in 23% and 6.7% of patients respectively . The frequency is similar to that seen in Maiwand's report for endobronchial cryosurgery (3). RFA was also responsible for other complications including obstructive pneumonia, fever and haemotysis, which were all uncommon and mild in nature. However, there were 3 cases of major complication, 2 of which involved a major pneumothorax. The remaining case involved a patient who was diagnosed with pneumonia prior to RFA and died 30 days afterwards (11).
A study 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 stage tumours and a majority were squamous cell carcinoma- a type of NSCLC. Complete destruction of the tumour was achieved in 71.9% and 82% of lesions at the two institutions respectively. However, the sample was not randomised at Tokyo Medical College as all except 1 of the 48 cases were male. In contrast the male to female ratio in Maiwand's study was 1.8: 1, giving a better representation of the population. While these results appear to be much more successful than those of Niu's percutaneous cryosurgery, where only 14.4 % complete remission of all tumours was achieved, the majority of good results for PDT were confined to tumours smaller than 1 cm in diameter and completely visible by endoscope (18). The sample also consisted of only early stage cancer patients, whereas Niu's sample included patients with a variety of cancer stages.
Another paper by Vergnon et al. compared the two methods. Cryosurgery and PDT both resulted in similar improvement of symptoms. However, cryosurgery had a higher efficacy in clearing an obstructed airway, while PDT appeared to benefit the patient over a longer period of time after the treatment (20).
Positive results for this procedure were seen in a report by Maiwand et al. involving 15 patients who had received direct intrathoracic surgery. Follow up of these patients saw that many of them had improved symptoms. Specifically, cough, dyspnoea, and haemoptysis had improved in 77.9%, 66.7%, and 100% of symptomatic patients respectively (3). The incidence in improvement was higher than that seen in Maiwand's study of endobronchial cryosurgery, but it is difficult to reach a conclusion attributing the direct cryosurgery alone to these benefits because some of these patients received other treatments including radiofrequency ablation, which could have had an effect. The sample size is also too small to bear statistical significance for the results found in comparison to the much larger 521 patient sample in Maiwand's study.
Niu et al. reviewed the cases of 840 patients, who received percutaneous cryoablation at Fuda Cancer Hospital in China (9). They all had NSCLC of varying stages with the majority being stage 2a and some patients received up to three separate treatments. The results showed that only a small proportion of patients had no signs of cancer after follow up (14.4%) and that the majority of patients had partial remission of their cancer (70%). Unfortunately, follow-up of these patients later on revealed that the cancer had returned in 44.4% of the patients, with 28.3% of these in the same location. This suggests that percutaneous cryoablation only has a moderate chance of curing lung cancer and may be more viable as a palliative treatment option that can be repeated in future.
Complications included pneumothorax, pleural effusion and haemoptysis, which were common. They occurred in 25.9 %,16 % and 22.5% of cases respectively. However, this is outweighed by the encouraging overall 1-, 2-, 3-, 4- and 5- year survival at 68%, 52%, 34%, 26% and 21%, respectively. Despite these results, distinction of NSCLC types has not been factored. In addition none of the patients had SCLC. Therefore, it is difficult to fully conclude the efficacy of percutaneous cryoablation for different types of NSCLC and how it may be received by patients with SCLC (9).
A study by Okunaka et al. concluded that PDT was curative for peripheral lung tumours that had not spread to other areas of the lung provided they were less than 1 cm in diameter. Targeting these tumours involved using a probe with a catheter that was guided using CT into the tumour via a percutaneous route. The study saw 7 out of 9 cases where partial destruction of the tumour was achieved with PDT. 2 of these patients suffered from pneumothorax, which was 22% of all cases (19). This incidence is very similar to that seen in percutaneous cryotherapy.
Although there are several studies showcasing the efficacy of cryotherapy in the treatment of NSCLC there are few investigations in comparison that look at its performance in early stage SCLC. In addition several of the sample sizes used in the studies are small and it is therefore difficult to make sound conclusions. Furthermore there are few comparative studies between cryosurgery and other treatment methods, especially those that are used with bronchoscopy and few studies assessing the co-administration of cryosurgery with other treatment options.
Another area requiring further research is the immune response associated with cryosurgery. This could be the way forward to reduce recurrence rates of tumours. There is also a large variation in cryosurgery procedures in the studies analysed, concerning the temperature achieved at the probe tip. This will affect the amount of necrosis achieved, although it has been suggested that a faster freezing rate could be more useful in achieving more necrosis, lower temperatures may be more effective in dealing with deeper tumours (3,41). This creates the opportunity to test the effectiveness of different cryogens and further studies thereafter need to use larger, randomised samples with a more standardised procedure. Although there is still much to be determined, cryosurgery offers a minimally invasive alternative to lung resection surgery, with sufficient evidence to justify its use and is more economical than brachytherapy and PDT (20).