Lung carcinoma is the most frequently diagnosed malignancy in the world, with the incidence increasing through the 20th century. It divides into small cell lung cancer(SCLC) and Non-small cell lung cancer (NSCLC).
NSCLCis a heterogeneous aggregate of histologies. The most common histologies are epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Treatment review

At diagnosis, patients with NSCLC can be divided into 3 groups that reflect both the extent of the disease and the treatment approach.
The first group of patients has tumors that are surgically resectable (generally stage I, stage II, and selected stage III patients). Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy. Adjuvant cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage IB, stage II, or stage IIIA NSCLC.

The second group includes patients with either locally (T3-T4) and/or regionally (N2-N3) advanced lung cancer. This group has a diverse natural history. Selected patients with locally advanced tumors may benefit from combined modality treatments. Patients with unresectable or N2-N3 disease are treated with radiation therapy in combination with chemotherapy. Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.

The final group includes patients with distant metastases (M1) that were found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status, women, and patients with distant metastases confined to a single site live longer than others. Currently, no single chemotherapy regimen can be recommended for routine use. Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitor.

In NSCLC, results of standard treatment are poor except for the most localized cancers. At diagnosis, about 85% of patients are in an advanced stage of the disease. Only 20% of patients are considered suitable for surgery ,of patients with operable tumors,about 20% are unable to undergo curative surgical treatment because of poor respiratory function or other major organ dysfunction. A further 2% -11% of these patients who are considered to be operable are found to have unresectable malignancies at thoracotomy. Therefore, overall 5-year survival is only 15%.For patients with stage Ⅲa, Ⅲb and Ⅳ disease, the 5-year survival rate falls to 13%,5% and 1% respectively. These figures have changed little over recent years in spite of advances in radiotherapy and chemotherapy.

During the past years, some new modalities have been used for unresectable lung cancer especially for NSCLC. Current areas under evaluation include combining local treatment (cryosurgery, radiofrequency, photodynamic therapy), regional treatment (radiation therapy, invasive therapy), and systemic treatments (chemotherapy, immunotherapy, and targeted agents).

For SCLC, chemotherapy has been the main therapeutic modality for the 15 years.The poor survival time after locoregional treatment,such as surgery and radiotherapy,underlines the fact that this is a systemic disease.Introducing active cytotoxic drugs has dramatically increased survival time.Two meta-analysis evaluated the role of radiotherapy in limited disease patients and showed that radiation improved 3-year survival rate by 5.4% and tumor control by 25.3%.

Since survival rates are so poor, the issue of quality of life for these patients becomes paramount. Around 30% of patients with lung cancer present with central airway obstruction, which itself causes significant morbidity and mortality (28) and causes distressing symptoms of cough, breathlessness, hemoptysis and recurrent infection which in extreme cases may lead to gradual asphyxiation where central airways are obstructed. Therefore, it is essential to improve these distressing symptoms by local ablation therapies,such as cryosurgery.

History of cryoablation for lung cancer

The goal of cryotherapy in pneumology is based on the freezing of tissues of specific areas in lungs through a probe, with optical control and through impedance, reaching deep low temperatures in order to obtain a specific cellular destruction (cryodestruction).

The history of cryotherapy for tracheo-bronchial-lung lesions has been relatively short due to the difficulty of anatomic accessibility. A limited amount of experimental work was carried out in the USA from about 1975 with the first study at the Mayo Clinic, with 28 patients with malignant and benign lesions treated with a rigid probe with liquid nitrogen as the cryogen, achieving probe tip temperatures of -160 C (12). A further study by Rodgers used a nitrous oxide cooled probe with a tip temperature of -80 C to treat a group of 27 patients (13).

In Europe, it was only in 1977 that first applications in pneumology appeared with Carpenter and later with Sanderson in 1981 and Rogers in 1983. In 1985, thanks to the work of J.P. Homasson in France and O. Maiwand in England the peak of this treatment was reached due to the perfecting of probes of small caliber-rigid, semi-rigid, and flexible (Le Pivert 1980). In France, there are over 100 units actively using this method.

Cryosugery is currently used widely around the world for treatment of lung cancer. The advancement of this therapy is related to experimental work on animals (6-11) and the improvement of cryoprobes.

The first large scale study in Europe involved treating bronchial carcinoma with a specially designed rigid probe (Fig. 11.1.1) and was published by Maiwand in July 1986 (14), followed by a paper by Homasson in August of the same year (15) and Asteriano in November (16). All three authors used nitrous oxide cooled cryoprobes for palliation or treatment of malignant and benign endobronchial lesion.

Direct cryosurgery at exploratory thoracotomy was reported by Maiwand and Asimakopoulos in1980’s.

Recently, percutaneous cryoablation has been used for treatment of locally advanced lung cancer mainly in China. Preliminary experience shows that the modality is an effective method for the destroying cancerous masses in lungs, and often leads to sufficient improvement in the patients' condition such that they can tolerate further treatments, such as radiotherapy or chemotherapy, thus providing a better outcome and improved quality of life and survival.

Indications of cryosurgery

• These patients who are not considered for lung resection because of the advanced stage of the disease or the patient’s general condition or poor respiratory function.
• These patients with tumor recurrence following radiotherapy, chemotherapy or lung resection.
• These patients who have localized lung cancer but refuse to receive operative therapy.
• Endobronvhial cryosurgery is used primarily to treat inoperative obstructive central bronchial lung cancer.
• The cryosurgery is mainly limited to NSCLC. But in some cases of SCLC, cryoablation may use aimed to decrease tumor loading and to improve symptoms.

Apart from lung cancer,cryosurgery has been used in the treatment of a number of benign and low malignancy conditions including carcinoid tumors, granulation tissue following heart/lung transplant (34), amyloidosis (35), tracheobronchopathia osteochondroplasticz (TBOCP), sarcoid, lipoma, polyps, post-intubation tubal stenosis, leiomyoma, hemangioma and Wegener’s granulomatosis.

Pre-procedure study

• Patients are assessed clinically, radiologically, and for performance status.
• Respiratory function tests, forced expiratory volume in one second(FEV1),and forced vital capacity (FVC) are measured.
• Bronchoscopy should be performed.

Procedures of cryosurgery

Equipment of cryosurgery for lung cancer

The equipment required for endobronchial cryosurgery consists of a cryosurgical console, a selection of probes and source of cryogen. Cryomachines or consoles are manufactured by several companies, including Spembly Medical in the UK, Endocare and Cryomedical Scoiences in USA, Erbe in Germany, DATE in France and MST in the Czech Republic. The main differences among them are the method of temperature control and the cryogen used. Most consoles regulate the supply of cryogen by means of a foot controlled pedal and monitor cryogen cylinder pressure, time of application and probe tip temperature.

Two types of bronchoscope can be used for cryosurgical procedures, rigid and flexible. Rigid bronchoscopes have the advantage that they can accommodate a fine suction catheter, which can be used to remove secretions and debris so that they do not accumulate and insulate the target area. The rigid bronchoscope also allows for larger biopsies, bleeding control and oxygen provision. The model of rigid bronchoscope is not critical so long as it has sufficient diameter to allow the insertion of the cryoprobe. The flexible bronchoscope has the advantage that it can be used under local or general anesthesia, but it is less robust and there is a possibility that the cryoprobe may cause it to become blocked or damaged by ice crystals forming in the return channel.

Cryoprobes for endobronchial use have been specially designed to fit the internal anatomy of the trachea, main bronchi and of the lobar and segmental divisions of the bronchial tree and must fit within the bronchoscope. The cryoprobe may be a rigid or flexible one, and rigid probes may be straight or have a rigid-angled tip. A probe with an angled tip is used for lesions of the trachea, main bronchi, and basal segments of the lower lobe, and a probe with a right angled tip for lesions in the upper lobes and apical segments of the lower lobes. Probe diameter is an important factor in the effectiveness of cryosurgery and while smaller diameter probes (2.2mm) cool more rapidly, their area of treatment is limited and so can only be used for small to moderately sized lesions. Smaller probes also take a longer time to thaw. Larger diameter probes (5.5mm) are most effective for larger tumor masses. The rigid probe has a number of advantages over the flexible probe in that it is more robust and can be used to treat a much larger area and allows for more rapid thawing.

Endobronchial cryosurgery

Anatomical knowledge and the practical ability to perform rigid and flexible bronchoscopy are essential requirements for performing tracheobronchial cryosurgery. Tracheobronchial cryosurgery is performed under direct vision via the bronchoscope, using a rigid or flexible cryoprobe. The flexible cryoprobe is designed to be used through a fibreoptic bronchoscope under local or general anesthesia. The much larger rigid cryoprobe (5.5mm diameter) requires the use of a rigid bronchoscope under general anesthesia. General anesthesia has the advantage that it provides complete relation of the patient giving maximum mobility to the neck. This facilitates the accurate positioning of the long cryoprobes to the trachea, main bronchus or lower lobes (Fig. 11.1.2). An additional advantage of the use of a rigid bronchoscope is that it allows for positioning a 3 mm catheter close to the lesion, which facilitates continuous suction of blood and secretions and provides better probe to tumor contact.

Before general anesthesia an intravenous access site is established with a plastic cannula typically 21g or similar size. Monitoring includes a three lead ECG to monitor lead V5 non-invasive blood pressure recording and arterial oxygen saturation using a pulse oximeter.

Following a period of preoxygenation, anesthesia is induced with propofol (0.75 to 1.8mg/kg) administered over a 30-120 second period. Following the loss of the eyelash reflex, relaxation is provided with succinylcholine (0.5 to 1.0mg/kg) or mivacurium (150ug/kg). The airway is controlled and intermittent positive pressure ventilation is provided with 100% oxygen by means of a Sander’s injector. Eye protection is applied at this point.

The patient is placed in the supine position with the head fully extended so that the chin points vertically upwards in a mid line position. The upper jaw should be protected from trauma with a swab or sponge. The rigid bronchoscope should be supported by the left forefinger and thumb to protect the teeth and gums. The operator should perform an initial visual assessment of the lesion, as site and macroscopic characteristics of the tumor can affect the choice of cryoprobe. The distal tip of the rigid bronchoscope should be placed about 5mm above the lesion. With the lesion in direct vision, the appropriate probe is inserted on or into the tumor mass. It is important to excise any necrotic tissue or slough to prevent insulation of the target tumor.

Cryogen is supplied to the probe by the compression of the foot operated pedal and cooling is initiated for a period of 3 minutes after which thawing is allowed until the probe separates from the tissue. A second freeze-thaw cycle may then be carried out. If the lesion covers a large area of the bronchial tree, multiple applications may be necessary during the session. It is essential that the whole area affected by the tumor is frozen in order to achieve maximum tumor destruction. If the trachea or bronchi are blocked by a tumor mass, then as much of the tumor as possible is removed with forceps and the area refrozen for 3 minutes. At the end of the procedure the lumen frequently opens satisfactorily. Excessive bleeding from the tumor surface can be controlled by the application of adrenaline solution 1:1000. The procedure generally takes about 20 minutes and patients can usually be discharged home on the same day. A repeat treatment is carried out after 2 weeks and also where indicated after 6 weeks. Tissue samples for histological examination are taken before each cryosurgical treatment.

Second treatment is carried out two weeks later.The procedure is repeated if symptoms recur.

Direct intrathoracic cryosurgery (at exploratory thoracotomy)

The procedure is performed at thoracotomy. The tumor are found to be more advanced than expected, and the patients, and the patient is deemed unresectable. The tumor is precisely located, its size measured, and its relation to vital structures documented. Prior to cryosurgery insertion, needle aspiration is performed to confirm the position of major blood vessels. An Argon-helium cryosystem (Endocare, Irine, CA,USA) or a nitrous oxide cooled cryoprobe (Spembly Medical, Andover, UK) or are used. The probe is introduced into the tumor mass and the freezing continued until the ice-ball was large enough to cover it. For larger tumors, multiple applications are made with the aim to destroy all macroscopically visible tumor. A 5 mm margin of normal lung tissue is included in the freezing process and necrotic tissue that formed intra-operatively is removed mechanically (usually with a biopsy instrument).A layer of necrotic material covering the free margin of healthy-appearing lung tissue is often left in situ in order to minimize the risk of air-leak.

Percutaneous cryoablation

The procedure is often performed under CT guiding.Patient is placed nto the CT gantry to allow easier access for needle and cryoprobe placement. Generally, argon gas or liquid nitrogen are used as the cryogenic material. After the tumors are localized by CT, an 18-gauge needle is placed in the tumor center in lungs, and the needle position is confirmed in both imaging planes. The general approach is to avoid direct puncture of the tumor and to try to have some noncancerous tissue interposed between entry point and the tumor tissue. A J-shaped guide wire is positioned in the tumor through the needle. A sheathed dilator (3-8mm) is introduced into the tumor over the guide wire. The dilator is removed, and the sheath is left in place. Cryogenic probes are then placed into tumor through the sheath. The sheath is then pulled back. Cryogenic material is circulated through the probes. The iceball created by this treatment is visualized and monitored by CT. The tumors are frozen at maximum flow rate for 15 minutes, and are thawed for 5 minutes, and then refrozen for another 10 minutes. Normally, there is a 5- to 10 mm ablation margin of normal tissue surrounding the targeting tissue(tumor).

If the initial ice balls are not large enough to encompass the entire length of the tumor, then the probes are pulled back for 2-5cm, depending on the length of the tumors. The cryogenic probes are turned on maximum flow rate for an additional 15 minutes, thawed for 5 minutes, and then refrozen for 10 minutes. The entire process may be repeated for very large tumors.

For tumor <1.5 cm in diameter, a 3-mm probe is placed at the center of the tumor. For tumors larger than 3 cm, multiple combinations of 3- or 5-,or 8 mm cryogenic probes are placed around the periphery and in the center of the tumor to insure freezing of the entire tumor. The goal is to destroy the tumor plus a 1-cm margin around the tumor.

Clinical therapeutic efficacy

Presentation of tracheobronchial cancer may be as a tumor mass primarily obstructing the central bronchial lumen, or a mass infiltrating lung tissue. Endobronchial cryosurgery can be used as a method of palliative treatment for endobronchial presentation.A number of studies have shown that endobronchial cryosurgery is a safe and effective palliation for malignant obstructive lesions (14,30-33). Maiwand showed a study consisted of 305 consecutive patients with histologically proven carcinoma, who were treated between January 1995 and December 1999. Patients received an average of 2.51 cryotreatments. This was an elderly and late stage group of patients, with 80% of patients 70 or older and over 90% at stage III or IV. Results (Table 11.13) showed that cryosurgery effectively reopened blocked endobronchial lumina (Figs. 11.1.3-11.1.5) and provided improvements in performance status respiratory function and symptom quantification.

Later,Maiwand and Asimakopoulos reported the results of 521 consecutive patients with a mean age of 67.9 years who had advanced obstructive tracheobronchial malignant tumors underwent cryosurgery, with a mean of 2.4 treatments per patient during a nine-year period. Pathological findings were:squamous cell carcinoma 68.3%,adenocarcinoma 15.2%,large cell 2.6%,unclassified non-small cell carcinoma5.2% and small cell carcinoma 8.7%. The TNM staging for NSCLC was: stage Ⅱb 6.7%,Ⅲa 21%,Ⅲb 23.9% and Ⅳ48.4%.Of these patients,39% had previously received radiotherapy and 9% chemotherapy.Hemoptysis, cough, dyspnoea and chest pain improved by at least one class in 76.4%, 69.0%, 59.25% and 42.6% (p<0.01) of symptomatic patients respectively,and improvement in one or more symptoms was demonstrated in 86% of patients. Quality of life studies showed that the mean Karnofsky score improved from 60 to 75 and the mean WHO score from 3.04 to 2.20. There were 7 (1.2%) in-hospital deaths, median survival was 8.2 momths and 2-year survival was 15.9%.

Direct cryosurgery to carcinoma of the lung was performed on 15 patients at exploratory thoracotomy. Results showed an increase in FEV1 from 1.80 +/- 0.6 liters to 1.95 +/- 0.8 (8.3%) liters and in FVC from 2.50 +/- 0.8 to 2.68 +/- 0.8 liters (7.2%). The Karnofsky score improved from 68 +/- 9 to 78 +/- 10 and the WHO score from 2.63 +/- 0.81 to 2.38 +/- 0.78 (9.6%). Major symptoms including cough, dyspnoea, and hemoptysis were assessed and showed improvement in 77.8%, 66.7%, and 100% (p<0.01) of symptomatic patients respectively. Patients were followed for a mean period of 18 months (range 4-84 months). Median survival from the date of surgery (Kaplan-Meier, 95%Cl) was 11.6 (6.8 to 18.2) months, range 1 to 84 months. Cryosurgery provides a safe and effective method for the palliation of advanced central bronchial obstructive tumors, and compares favorably with other methods in terms of safety, cost, and complications. Initial experience suggests that similar palliation may be achieved by cryosurgery applied to advanced parenchymal tumor masses.

Wang et al reported from China that 40 cancer patients with 80 lesions of the metastatic lung cancer underwent percutaneous cryosurgery in between Aug 2001 and Nov 2002. The percentage of iceball covered lung masses was 98. 9 % and 87%, and the efficacy rate was 100 % and 86.2% in 51 lesions ( < 4 cm in diameter) and in 29 lesions ( > 4 cm in diameter), respectively. Slight haemoptysis occurred in 46. 8 % of patients , fever in 16. 1 % , pneumothorax in 25. 8 % and pleural effusion in 19. 4 % after cryoablation. 66. 7 % of the masses were enlarged and cavities developed after one week of cryosurgery. The masses shrank after 1～3 month. 9. 5 % of lesions ( < 3 cm in diameter) disappeared after three months. The masses were stable after 6 months. A median survival period was 5 months in the follow up for 15 months. The 6- and 15- month survival rate was 66 % and 50 % respectively.

During from March 2001 to Feb 2006, 625 patients with NSCLC were received percutaneous cryoablation in Fuda Cancer Hospital Guangzhou.There were 120 patients who received follow up for more than 2 years. Argon-helium cryosystem（Endocare,CA,USA）was used.The trocar was inserted into tumor center under CT. Results: Posttherapeutic improvement rates were 78.5% for chest pain,79.2% for hemotoptysis,69.1% for cough,and 72% for breathing difficulty. Improvement of above symptoms lasted for 1-21 months with median of 13 months.In 98 patients with CT review data,25 patients (25.5%) got CR,41(41.8%) PR,21(21.4%)MR and 11(11.2%) NC at three months after therapy.84 patients are alive up to now, being the longest life-span of 24 months. Survival rates were 64% for 6 months,55% for 12 months,44% for 18 months and 36% for 24 months. Complications: Air-thorax in 2 cases, bloody thorax in 4 cases and pulmonary infection in 5 cases, being recovering with symptomatic management. Conclusions: Cryoablation with argon-helium system can improve symptoms, promote shrinking of tumor, prolong life-span and raise survival for patients with locally advanced non-small cell lung cancer who can’t be resected by operation.


In a study, fifteen patients with histologically proven endobronchial carcinoid tumors (12 typical, 3 atypical) were treated with cryosurgery. Of the 12 patients with typical carcinoid tumor, all but one, who died accidentally, are still alive with a mean follow–up of 49.4 months. Nine of these, treated with cryosurgery only (mean 3.4 treatments) showed no tumor present on histological and radiological examination at follow-up. For the patient who died accidentally, post-modern examination reported no residual tumor. For the other three patients, cryosurgery downstaged the tumor from the main bronchus to lobar bronchus, allowing resection by lobectomy rather than pneumonectomy. There was a significant improvement in respiratory function tests and performance status after treatment.

Two of the three patients with atypical carcinoid tumors had good endobronchial palliation with cryosurgery but subsequently died due to metastasis. The third is still alive and well after 49 months. The results suggest that cryosurgery is an effective palliative and potentially curative treatment for carcinoid tumors deemed inoperable because of the extent of their disease or co-morbid conditions. Cryosurgery can also be considered as a treatment for downstaging endobronchial carcinoid tumors to allow for less radical resection.

Discussion

Clinical comment of therapeutic efficacy

For patients with bronchial malignancy, cryosurgery will destroy the visible endobronchial portion of tumor, and yield a palliative efficacy. Overall, the results have been favorable in 70 to 80% of patients treated, providing excellent symptom relief and improved quality of life (11).

The major symptom amenable to cryosurgery is hemoptysis caused by a visible lesion. The hemostatic effect of cold causing vasoconstriction, capillary occlusion and rapid slowing of the circulation is well known (1) Although this effect is not immediate, and electrocautery is certainly more appropriate even if both techniques should be consecutively used during the same endoscopic session,all those who have tried cryosurgery alone have obtained a significant improvement or disappearance of hemoptysis. In general, hemoptysis stopped in 80% of cases and similar good results are generally reported.

Dyspnea is also a frequent symptom due to an obstructing lesion. Cryosurgery is not indicated in case of acute respiratory distress.However an overall improvement of dyspnea (37%-66%) after cryosurgery is reported in different series (2-4).

Following cryosurgery the patients have less cough (64%) and stridor (70%) (5-7). Disappearance of wheeze and thoracic pain is sometimes reported.

Objective improvement of pulmonary function was seen in 58% of patients, and the changes in lung function corrected with symptoms (3-8).

Tumors of intermediate malignancy, incuding carcinoids, cylindromas, papillomatosis, mucosquamous (12), have been successfully treated with
cryosurgery when conventional surgery is contraindicated.

Some benign lesions constitute a small percentage of pathology seen in the tracheo-bronchial tree. Granulation tissue is very sensitive to the effect of cold. Cryosurgery has also been successful in treating tumors or granulation tissue regrowth around both silicone or wire mesh stents without the loss of the integrity of the stent. Cryosurgery is an effective therapeutic option to deal with bronchial stenosis secondary to excess granulation tissue following lung transplantation (4). Good results have been obtained when treating myomas, including leiomyomas, although several sessions may be needed. Less vascularized lesions, such as amyloidosis, fibromas, lipomas, hamartochondromas or fibrous stenosis, are rarely influenced by cryosurgery (7-13), but there is no risk in attempting treatment.

Combination of cryosurgery and chemotherapy or radiotherapy

At the edge of the frozen area the hypothermia causes a heterogeneous destructive effect, and it is in this area that chemotherapy or radiotherapy has a complementary destructive effect. For this reason, this area is called the combined therapeutic area (Fig. 11.2.4). Experimental studies and clinical results show that the combination of cryosurgery and chemotherapy or radiotherapy is more effective than either therapy alone.

Maiwand(22) carried out a prospective study on twelve patients with bronchogenic cancer at an advanced stage of illness,no amenable to surgical resection. The patients received 15mg bleomycin i.v. labelled with cobalt 57 and were then placed under a gamma camera and a region of interest was drawn over the left ventricle in order to plot a time activity curve corresponding to the disappearance of the radiolabelled bleomycin from the blood. A uptake ratio of tumor to normal tissue was then calculated. As the wash-out time of radiolabelled bleomycin was about 10 days, the same protocol was performed 15 days later, one hour after the cryosurgery procedure. The endoscopic treatment was carried out using either rigid or flexible probes, and nitrous oxide was the cooling agent. A significant difference was found in the tumoral uptake of radiolabelled bleomycin before and after cryosurgery with a mean increase in uptake of 30% following cryosurgery. The pharmacokinetic parameters demonstrate that after cryotherapy there was accelerated plasma clearance and it can be postulated that bleomycin is trapped in the tumor as a consequence of the vascular disruption caused by freezing(Fig. 11.2.9). These clinical results confirm that the concentration of the anticancer drug was higher in the frozen zone and adjoining hypothermic area compared to untreated surrounding tissue, and tumor destruction is superior to that normally found with chemotherapy alone.

It is suggested that tumor debulking prior to irradiation helps improve survival and avert local complications.The “curative” local efficacy induced by the vascular effects of the cryosurgery. raises the possibility of increased tumor radiosensitivity,

In a prospective but not randomized series, Maiwand enrolled 29 inoperable patients with NSCLC in a protocol of cryosurgery associated with radiotherapy (25). Two weeks after cryosurgery, radiotherapy was performed. One or two sessions of cryosurgery were performed.Cryosurgery was considered satisfactory in 16 cases, who had more than 50% tumor destruction, and unsatisfactory in 13 cases with persistent tumor lesions. 21 patients received 65 Gy and 8 patients with a poor general condition received 45 Gy. In the satisfactory group, the median survival was 11 months and a significant improvement in survival was obtained (Fig. 11.2.10),in contrast to patients in the unsatisfactory cryosurgery group, who died quickly of local complications, with a median survival of 5 months.

Combination of percutaneous cryoablation and brachytherapy

Brachytherapy is an implantation with iodine-125 or palladium-103
seeds into targeting tumor masses. Seed implantation with iodine-125 seed gives a lower dose rate of radiation than palladium-103 but works in body longer than the latter. This modality has been used to treat solid tumors of many organs and tissues, including lung cancer.
Before an implantation, a CT volume study to see the size and location of the cancerous mass in lungs as well as the surrounding organs. A predetermination is made of see how many seeds a patient will need and exactly where they should be placed based on the size and shape of the cancerous mass. The implantation is usually performed via percutaneous route, under local anesthesia. Normally, 20 to 100 seeds are placed inside needles that are inserted in to the masses.
Combination of brachytherapy and cryoablation has a complementary efficacy each other. Both therapies may be performed in same session. In general, seeds implant into the peripheral zone of freezed cancerous tissues after finishing percutaneous cryoablation. This is because that cytotoxic effect from rapid cooling is the greatest in the center of the iceball, while cells at the periphery of the iceball may survive, particularly if the tumor abuts a larger blood vessel that abrogates the effects of tissue cooling. The surviving tumor cells result in the recurrence of the disease. Seed implantation may be treated tumors in lungs amenable to cryoablation,for central lung cancer which abuts large blood vessel and heart, as well.
During from Jul 2002 to Feb 2006,fifty five patients with NSCLC were received combination of cryoablation and brachytherapy in Fuda Cancer Hospital Guangzhou. The cancerous masses in lungs which were implanted with seeds were larger than 5 cm in size.The 1-,2-,and 3-year survival rates were 78%,63% and 54%.

Combination of cryosurgery and photodynamic therapy

Photodynamic therapy(PDT), as a scientific, appropriate, noninvasive or microinvasive therapy, developed at the beginning of the 21st century. It is a non-thermal light chemical reaction and need oxygen, photosensitive substance (photosensitizer) and laser simultaneously to participate in. Photosensitizer is absorbed by neoplasm tissue and accumulates in the cells for a long time. Photosensitizer is activated with the appropriate wavelength of light and reacts with oxygen to generate reactive single state oxygen and photochemical substance that are toxic to cells ,can leads to apoptosis and necrosis of cancer, can result in local vascular lesion of tumor and tumor tissue ischemic necrosis, and can initiate an antitumor immune reaction.

PDT has advantages, such as ① Relative selectivity and tissue speciality for tumor cells; ② Low toxicity, good safety, no immunosuppression and marrow inhibition; ③ No bad effect on other therapies, complementary to surgery, radiotherapy and chemotherapy; ④Short treatment time; ⑤Initiating therapeutic effect within 48-72 hours.

For early bronchial cancer, PDT has the cure rate of 90%,and for lung cancer with bronchial obstruction, PDT induce improvement of air-way obstruction with the improvement rate of 85%.

It is predictable that combination of both PDT and percutaneous cryosurgery is a good strategy for obstructive lung cancer, as the former can clear the intrabronchial cancerous masses and the latter can destroy the extrabronchial tumor in lungs.

In 2003 Niu et al reported eight-five patients with NSCLC with resistant to routine chemotherapy or/and radiotherapy,and no amenable to operation, who received sequential therapy consisted of transarterial chemotherapy targeted to tumor vessels in lung, percutaneous cryoablation, and photodynamic therapy. Seventy-four patients were entered onto the study in Fuda Cancer Hospital,and received follow-up for duration of 6-21 months. Responses included CR(complete response) in 21 cases (28.4%), PR (partial response), 31cases (41.9%),MR(minor response), 8 cases(10.8%), NC(no change), 9 cases (12.2%), and PD (progressive disease), in 5 cases (6.7%).The pain in patients of 51.2 %(21/41) had complete remmision and in 39.0% (16/41) had partial remmision.75.7% (36/74) of patients had increased body weight, and 10.8 % had stable body weight. 85.7 %(48 cases) of 56 patients were recieved evaluation of performance status had increased Karnovsky score. The 1-year survival rate of 76.2 percent.

Niu and Guo investigate the therapeutic efficacy of combined photodynamic therapy and percutaneous cryoablation with argon-helium system for unresectable,obstructive NSCLC.Forty-one patients, whose tumors were considered nonresectable because of local aggression of tumor (stage Ⅲb on TNM)or poor lung function of patients(severe obstructive lung disease), were given the combination therapy in Fuda Cancer Hospital Guangzhou. At first, photodynamic therapy was performed. Then,percutaneous cryoablation with argon-helium system under CT guidance was given. The therapeutic efficacy was estimated according to changes of symptoms tumor size and survival. Results showed 90.2 %had some improvement of subjective symptoms, significant decrease of symptom score, especially marked relief of dyspnoea. Bronchoscopy showed that endobronchial tumor was ablated on different degrees in all patients, with complete resolution in 41.5 % of patients. CT showed that lung tumor had CR of 34.1% and PR of 41.4%. According to the radiographic evidence, collapse of lung resolved completely in 29.6% of patients with previous collapse, and diminished in 70.4% of patients. The 6- and 12-month survival were 44% and 71% respectively. There were no severe complications in photodynamic therapy or percutaneous cryoablation. They conclude that combination of photodynamic therapy and percutaneous cryoablation can eliminate endo- and extra-bronchial tumor masses, respectively, and is complementary to each other, therefore , raise the therapeutic efficacy for unresectable obstructive NSCLC.

Conclusion

Cryosurgery for lung cancer may be performed through
endobronchial, direct intrathoracic (at exploratory thoracotomy)
and percutaneous routes, and it offers an effective therapy in the
alleviation of distressing symptoms caused by obstructing tracheobronchial
carcinoma. This method rapidly restores the patency of
blocked lumina; therefore, post-procedure recovery is rapid.
As a result, cryosurgery restores pulmonary reserve and respiratory
function to a stage that further treatment such as
radiotherapy and chemotherapy can be tolerated, thus providing
improvement in quality of life and survival. This procedure
is well tolerated, and has little or no side effects for either patients or operators.
It have shown cryosurgery for inoperable lung tumors to be
effective in terms of survival and improvement in quality of