Endobronchial Cryotherapy

Cryotherapy has been used for several years in treatment of various types of cancers. This chapter describes the use of cryotherapy in the treatment of lung cancer. Various different treatment modalities have been used for the palliation of endo bronchial tumors. Cryotherapy offers a cytotoxic method for removing endobronchial le sions. Cryotherapy has also been used in addition to chemotherapy and radiotherapy in treatment of lung cancer.


HISTORY AND DEVELOPMENT
The analgesic and anti-inflammatory properties of low temperatures have been known for several centuries, 1-3 but therapeutic applications of freezing as applied to tissue destruction for the management of malignancy date from the work of Arnott 4,5 between 1845 and 1851. Arnott used direct application of salt solutions in crushed ice to treat advanced uterine tumors, resulting in a regression in tumor size and effective symptom control with local tissue temperatures of between -8 and -20°C.
Developments in the physical sciences, mainly pioneered by Carnot, Joule, Thompson, and Linde used the thermodynamic properties of gases under restricted expansion to generate the lowest artificially produced temperatures at that time. The Joule-Thompson effect, as this controlled adiabatic expansion is now known, became available to a variety of applications, including commercial refrigeration, by the end of the 19th century and began to find therapeutic uses by the beginning of the 20th century. It demonstrated that liquefied air could be used to treat dermatologic lesions by the early 1900s, and by the 1940s a number of other applications for lesions in other internal organs had appeared. Similarly, after being frozen in several organs, necrotic lesions were characterized by the absence of suppuration or sequestration and a slow accompanying healing process.
Over the next few years, a parallel development in cryosurgical apparatus occurred that facilitated improved treatment of pathologies in the central nervous system, alimentary canal, urogenital system, and hepatic metastasis and in musculoskeletal and dermatologic tissues. [6][7][8][9][10][11][12] Endobronchial disease remained somewhat inaccessible due to the relative difficulty of reaching the components of the tracheobronchial tree with the tools available, however, and also due to concerns regarding the extent of healing in tissues with ciliated endothelia, such as the trachea and bronchi. The restoration of normal epithelia after cryotreatment in experimental studies of dogs was later reported by several workers, [13][14][15][16][17][18][19] and later Sanderson et al 20 reported the first instance of the use of cryotherapy for the amelioration of obstructive airway tumors, followed shortly by another case reported by Sanderson in 1975. By 1977, the first quantitative study of 28 patients treated in this way concluded that cryotherapy could serve as a useful palliative treatment for endoluminally obstructive tracheobronchial carcinoma. 18 During the decade that followed, endobronchial cryotherapy reappeared in Europe. By June 1986 in the United Kingdom, new probes had been developed by M. O. Maiwand 21 that were specifically designed to combat the difficulties of access to the tracheobronchial tree. Similar developments were reported in France and in Italy by the end of that year by J. P. Homasson. 22 Since that time, cryotherapy has been used in nearly all areas of modern surgery, and the literature contains considerable quantitative evidence of the efficacy of the technique wherever it has been applied. 23,30 In addition, it is now being used commonly in combination with other modalities such as radiotherapy 31 and chemotherapy 32 and is now routinely considered for integration into the palliative treatment plans for obstructive tracheobronchial malignancies.

BIOPHYSICAL BASIS OF CRYOAPPLICATION
The biologic damage caused by freezing occurs at several levels-molecular, cellular, structural, and macroscopic-and the method of cryoapplication used has significant implications for the intended end point of the procedure. The processes that occur during freezing have been identified by fundamental research in a number of areas of the biologic sciences, and a number of common factors have been described that differentiate the destructive from the conservative effects of low temperatures. Generally, the extent and permanence of a freeze injury is determined by the rate of cooling and of thawing, [33][34][35] the lowest temperature achieved, 36 the number of freeze-thaw cycles performed, 37,38 and the type of tissue being frozen. 39 The cryosensitivity of tissues is directly related to the free water content of the constituent cells and interstices; consequently, skin, mucosa, and granulation tissue tend to be cryosensitive, whereas bone, fat, cartilage, and fibrous or connective tissue tend to be cryoresistant by comparison. It has been suggested that tumor cells may be more cryosensitive than the normal cells of the host tissue. 39

MECHANISMS OF CELLULAR CRYODESTRUCTION
During experimental freezing, the following features and changes are visible in cells in suspension 40 : (1) At -5°C, the system remains in a liquid state, despite the cytoplasmic freezing point of -2.2°C. (2) Between -5 and -15°C, extracellular ice crystals form from free water in the interstitial spaces while the intracellular medium remains liquid and supercooled, the cell membrane and the intracellular inclusions and macromolecules forming a barrier to immedi-ate crystallization. The rate of cooling is a determinant of the processes that follow. (3) If the cooling is slow enough, osmotic migration of water from the cell to the interstices (arising from the increasing extracellular solute concentration as the ice forms) begins the dehydration of the cell, further damping any potential intracellular crystallization. Beyond -15°C a transitional state develops in which increases in solute concentration arising from cellular dehydration and ionic diffusion from the interstices further depress the freezing point of the intracellular medium. (4) As the temperature falls further, the eutectic point is reached by the intracellular medium, and complete internal solidification occurs via spontaneous crystallization causing complete cellular destruction. If the cell is cooled too rapidly, however, there will be insufficient time for the migration of water to begin and hence there will be little cellular dehydration before intracellular ice formation occurs. This is significantly less cryodestructive and is the basis for the cryopreservation of living tissues. Thawing damage is also determined by the rate of the effect, such that 41,42 (1) suboptimal (rapid) thawing exposes the cell to a high electrolyte concentration and elevated temperature that may or may not spawn intracellular or extracellular recrystallization, (2) optimal (slow) thawing induces recrystallization with large, thermodynamically stable crystals able to destroy the cellular contents and membranes through a grinding, abrasive, "pack ice" effect. Both mechanical and biochemical factors interact with varying degrees, depending on the cryoregime being used, to produce cellular death. The principal determinants of the extent of these factors, however, are the rate of cooling with respect to time and the lowest temperature achieved. Clearly, for the surgeon or practitioner, the optimal freezing rate will be slow enough to generate the fully destructive effects described above, although rapid enough to make the procedure time efficient.

FREEZING RESPONSES OF TISSUES
At the microscopic level, the freezing process depends upon the physicochemical interaction between the ice crystals, the cellular contents, and the solution occupying and surrounding the cells in the target area. A factor that influences further the sensitivity of the tissue to cold is the extent of microcirculation in the area being treated. After cryotreatment, it is usually possible to discern a line of demarcation 546 between treated and nontreated tissues, with frozen cells appearing clearly disrupted almost immediately and with ischemia and infarction visible shortly after wards. Following thaw, vascular flow ceases rapidly, the thrombosis seemingly resulting from an interac tion of 43 (1) arteriolar vasoconstriction (induced by even slight hypothermia), (2) modifications to the vascular endothelium, (3) an increasing permeability of the vascular walls, (4) an elevation in blood viscosity, (5) a decrease in intracapillary hydrostatic pres sure, (6) a decrease in blood flow, (7) the formation of platelet plugs.
At the periphery of the treatment area, the ef fects of freezing are more heterogeneous, 32,44,45 and this has been exploited for the application of other treatment modalities in combination with cryother apy, namely chemotherapy and radiotherapy. It has been shown that cryotreated tissues, frozen at a suit ably slow rate, exhibit enhanced cytotoxin reten tion despite enhanced plasma clearance rates and consequently shorter half-lives compared with normothermic tissues. This entrapment may result from the vascular damage to the entire target area arising from impairment of blood flow and throm bosis at peripheral hypothermic areas more distal to the center. Hence, ischemic damage occurs over the entire frozen region to varying degrees, deny ing blood to any remaining tumor cells, while trap ping cytotoxic drugs at the same time where chemotherapy has also been applied.
All of the cellular changes described occur in the first few days after cryotherapy, cellular necrosis eventually resulting in an acidophilic slough de rived from the formerly treated tumor tissue. Histo logically, however, the cellular characteristics of the tumor are unchanged by freezing, cryolesions gen erally only being visible under the electron micro scope. This delay in the response of the tissues to freezing explains the later appearance of necrotic tissue and slough.
There is also some documentary evidence that cryotherapy may elicit an immunologic response via the direct application of cold to living tissue. 46,47 It is recognized that there is a distinct involvement of the immune system in the response to cancer and that natural immune responses to tumor infiltra tion can limit locally the spread of the disease, cer tainly in breast tumor and in some other lym phomas. Indeed, the presence of mononuclear tissue infiltration in breast cancer is seen as prognostically favorable for future treatment, indicating measurable natural immunocompetence. There is strong evidence from both clinical and animal stud ies that cryotreatment can influence the immune system response beneficially, although the mecha nisms remain largely conjectural. In our experi ence, we have noted that patients with tracheo bronchial malignancies presenting without supraclavicular node enlargement often do not fol low this generally observed clinical pattern as the disease advances postcryotreatment. We have also recently discovered that there are some phenotypically distinct populations of natural killer cells that are elevated following cryotherapy in certain groups of patients and that these same phenotypes have been implicated in the immune response to carcinogenesis. Furthermore, cryotherapy applied to some primary prostatic tumors has been ob served to result in the resolution of more distant metastatic regions of the disease. 46,47,48 It has been suggested that the local destruction of tumor tissues releases enzymes and other cellular contents that in some way enhances or potentiates the immune re sponse, possibly via the cloning of phenotypically distinct lymphocyte populations. 48 Other studies of prostatic cancer and of malignant melanoma have indicated that there may be increased lymphocyte activation in the peripheral circulation of patients following cryosurgery. 46,47,48 This is an area of signif icant clinical promise; we are investigating the clini cal possibilities of this form of treatment with great interest and curiosity.

CRYOGENS
Gases used specifically for the purpose of gen erating low temperatures are termed cryogens. Most cryogens are used in the liquid phase during the transition to a gaseous state in order to generate the low temperatures required via the specific latent heat of evaporation. According to the Joule-Thompson effect, the cooling rate is potentiated if the expanding fluid is exposed to increased pres sures and also to a restricted path of flow such as through a small orifice or via a capillary system. This essentially simple process is used as the physi cal basis for modern commercial and scientific re frigeration. An adaptation of the principle, the Linde process, in which the expanded cooling gas is directed to flow back along a countercurrent system cyclically reducing the temperature of the circulat ing fluid, is employed commercially to produce liq uefied cryogens for use in many fields of applica tion such as refrigeration.
Studies have shown that a lesion can be de stroyed between -20 and -40°C. Freezing to -40°C or below at -KXTCmin -1 will cause ≥90% 547 cell death. Hence the cryogen used is extremely crucial to the effective function of the treatment. Carbon dioxide has been popular because it can generate temperatures of -79°C at equilibrium, but it tends to produce "snow" when it expands at atmospheric temperatures that can block the transmission system of finer-bore cryoprobes. This makes it inappropriate for tracheobronchial treatments, but it is still used dermatologically. The most frequently used endothoracic cryogen is nitrous oxide, although liquid diatomic nitrogen is growing in popularity due to its lower equilibrium temperature and, hence, greater cryodestructive potential, despite its slightly higher cost.
The process by which these cryogens are used in the operation of a medical cryoprobe is effectively very simple. In the case of nitrous oxide, the cryogen is maintained in its liquid form at room temperature but in high-pressure cylinders. When required, it is transferred to the probe tip via a system of capillary tubes surrounded by either a metal or a plastic sheath. There is little need for thermal insulation, and as the cryogen reaches the tip, it expands and forms a vapor haze of gaseous nitrous oxide. As this occurs, an equilibrium temperature of -89°C is achieved that reduces the cryogen temperature within the tube for up to 2 cm from the expansion nozzle, a process that is extremely rapid. In slight contrast, liquid diatomic nitrogen is maintained in a vacuum-insulated container because of the high evaporization rate of the fluid. Transfer to the cryoprobe is achieved by a line placed at the bottom of the container. This is allowed to cool to a temperature where the nitrogen remains liquid as it flows along the probe to the distal tip, where it evaporates to produce rapid cooling to an equilibrium temperature of -187°C.
The process is economical due to the fact that only a relatively small mass of cryogen is required to expand in order to cool only the metallic mass of the probe tip. The initial cycle of freezing is perhaps the longest (up to a minute for nitrogen before the equilibrium of -187°C is reached) due to the time taken to cool the interior of the length of the supply system, after which the time falls to about 20 to 30 seconds as the cooler surfaces accelerate the drop in temperature of the liquid cryogen traveling toward the tip. Because of this, the cooling power of the probe is precise: it is present when it is needed, where it is needed, and exactly for how long it is needed.

CRYOEQUIPMENT
The equipment has three components: the console, the cryoprobe, and the transfer line con-necting the probe with the cryogen. Cryoprobes are rigid, semirigid, and flexible and can be employed through either a fiberoptic bronchoscope in the case of flexible probes or a rigid bronchoscope. The use of direct visualization of the sites of tracheal and endobronchial lesions during bronchoscopy involving fiberoptic probes linked to a video imaging system has proved invaluable for teaching purposes. Nevertheless, this generates a considerable need for the operator to be familiar with the use of the instrument, as well as imposing the need for extensive acquired experience in the identification of both normal variation and abnormalities in the appearance of various tracheal and endobronchial topographies. To a certain extent, these difficulties have been ameliorated by the development of a variety of cryoprobes, designed using the internal anatomy of the trachea, principal bronchi, and lobar and segmental divisions of the bronchial tree as main production constraints.
Rigid bronchoscopes are largely unaffected by the low temperatures maintained during the procedure, whereas flexible bronchoscopes may be damaged by ice droplets forming in the return channel of the apparatus, such that distortional damage of the probe may occur. In addition, suitably large bronchoscopes can also accommodate a fine suction catheter that can be positioned adjacent to the tip of the cryoprobe in order that secretions and debris may be removed. It is desirable that these tissues are cleared, because they may accumulate and freeze, insulating the target tumor from the effects of the probe and decreasing the efficacy of the procedure. If the probe tip diameter is kept as small as practically possible, allowing for the constraints of pressure maintenance and of cryogen supply, lower temperatures can be achieved and a more rapid freezing rate attained. Probe tip diameter limits the effective treatment area in one session, however, and so a compromise between probe size and treatment area is necessary. It has been observed that a probe diameter of 2.2 mm is suitable for the destruction of small or moderately sized obstructions, whereas a larger bore of 5.5 mm is more suitable for larger tumor masses. Rigid bronchoscopy using a larger probe obviates the additional use of fine suction catheters, larger biopsies, removal of necrotic tissue, bleeding control, and oxygen provision. These constraints will achieve maximal cryodestruction and, therefore, maximal efficacy of treatment.
Modern cryoequipment provides facilities for monitoring accurately the time of application, cylinder pressure, and probe tip temperature. Monitoring of freezing is a problem that, to a certain extent, is a function of operator experience and can be judged by the color change in the treated tissue and the length of freeze. 49 In clinical studies with all 548 Figure 1. The currently available cryoprobes. The middle probe is flexible probe and the two on the side are rigid probes. three forms of probe, each freeze-thaw cycle is about 30 seconds. Rigid probes have a reheating system that enables the thaw phase to begin immediately after freezing, but flexible probes rely on spontaneous thawing that increases the cycle length ( Fig. 1). 50 Thermocouples have been used to monitor temperatures via impedance variation related to state changes in the water comprising the extracellular medium. 51 The cryoprobe represents one electrode, with a second formed from a metallic plate in contact with the patient's body. Ice ball formation breaks the current at a resistance of 200 to 500 kW, indicating that the device is functioning correctly.

PATIENT SELECTION AND INDICATIONS FOR CRYOTHERAPY
Endobronchial cryotherapy is indicated for the palliation of symptoms in, mainly, unresectable patients with histologically proven carcinoma of the trachea and bronchi. Surgery in these cases has been deemed inappropriate and cryosurgery indicated because (a) of the position of the tumor; (b) the disease is in an advanced state; (c) of poor lung function; (d) of recurrence of the disease following treatment using other modalities; (e) the tumor is intraluminal or, if extraluminal, occludes less than 75% of the lumen; (f) hemoptysis is caused by a visible benign or malignant lesion. Cryotherapy can also be indicated for situations in which (g) the carcinoma is microinvasive; (h) granulation tissue stenosis occurs iatrogenically to lung transplantation; (i) foreign bodies become lodged in the trachea or bronchi.
Patients for whom cryotherapy is indicated must also satisfy the general clinical criteria for treatment suitability arising from the use of general anesthetic for all procedures involving rigid bronchoscopy and hence for a reasonable prognosis for postoperative survival.

PATIENT PREPARATION
After admission, a full clinical history is taken as well as a full blood count, any histologic or cytologic information, a chest x-ray, respiratory function tests, quality of life questionnaire, and possibly a CT scan, or bone scan if metastases are indicated. 549 Following histologic and clinical diagnosis, the full procedure is explained to the patient and written informed consent obtained. The patient receives no oral intake for 6 hours prior to the procedure, and anticoagulant therapy, if applied, is discontinued prior to surgery. Reactive edema is rare and never severe; hence, corticosteroid application is not generally indicated unless tracheal or subglottic lesions are involved.
For rigid bronchoscopy, the patient is given general anesthesia following preoxygenation via an indwelling intravenous cannula with the induction agent propofol, either intermittently or via continuous infusion at 0.7 to 1.5 mg . kg -1 . Muscle relaxation is provided with suxamethonium or, more frequently, with mivacuronium. Nitrous oxide, oxygen, and isoflurane are administered intermittently until the patient is fully relaxed. The procedure lasts from 20 to 30 minutes, and intravenous naloxone at 1 to 2 g . kg -1 is then administered to reverse the effects of anesthesia and sedation.
For flexible bronchoscopy, intravenous drug and oxygenation routes are established as above, after which the patient is sedated with a benzodiazepine (e.g., midazolam). A 5% lignocaine spray and gargle provides local nasophyarngeal and oropharyngeal anesthesia. The fiberoptic bronchoscope is then passed via the nose into the pharynx and guided via the larynx into the trachea. Further administration of lignocaine is provided as it is required during the course of the procedure.

CLINICAL PROCEDURES FOR RIGID AND FOR FLEXIBLE BRONCHOSCOPY
Probe temperatures, three-lead ECG readings on lead V5, and noninvasive blood pressure and oxygen saturation measurements are monitored throughout both rigid and flexible bronchoscopies, and additional data gathered include impedance measurements and videographic images. In a supine position with the head fully extended such that the chin is pointing vertically, the patient's upper jaw is protected from trauma using a sponge or swab, and the bronchoscope itself is supported with the forefinger or thumb to protect the teeth and gums. The operator assesses the visible characteristics of the lesion before proceeding because the site of the tumor and also, to a degree, its macroscopic characteristics can limit the effect and, maybe, the advisability of cryotreatment. Cavitated lesions, for example, which can arise after radiotherapy, should not be treated inside the cavity to avoid the risk of excessive bleeding. For the upper lobes, apical segments of the lower lobes, and where there are severe patho-logic distortions of the bronchial tree, lesions can be accessed using right-angled rigid probes.
In general, with the lesion in direct vision, the distal tip of the apparatus is placed on or within the tumor bulk. The probe can also be used tangentially if any lateral infiltrating lesions around the tracheobronchial walls or junctions are targeted. Any necrotic tissue or slough can be removed to prevent unwanted insulation of the tumor target. Using a foot-pedal control, the cryogen is supplied to the probe until an ice ball forms at the tip, proximal to the tumor site. The tissue is frozen for a period lasting approximately 3 minutes and involving a number of 30-second freeze-thaw cycles; larger or more dispersed lesions may require multiple treatments as several locally diseased sites in the same cyrosession. In these cases, cryotherapy can be applied in staggered, overlapping zones so that the contiguous frozen volume can be maximized over the entire affected area. Before moving the probe to another site, sufficient time should be allowed to thaw the tip of the probe after foot-pedal deactivation to prevent unwanted cryoadhesive tearing of the tissues.
It has been suggested that with nitrous oxide the 30-second cycle is optimal for cryodestructive damage and that the effect of the treatment is potentiated by increasing the number of freeze-thaw cycles rather than by lengthening the freeze-time per se. Our collaborative work in China as well as our own clinical experience with the rigid probe, however, has indicated that a 3-minute freeze-thaw cycle accentuates the destructive effect of the treatment optimally, which would be expected given the previously documented effects of freezing at the microscopic level discussed earlier. The lower equilibrium temperature of liquid nitrogen may justify a somewhat longer period of freeze (up to 1 minute for the first cycle), although subsequent freezes can be shorter in length. Bronchoscopy, if indicated, can be performed again after 2 weeks and again after a further 4 weeks if necessary. At this time, tumor debulking of earlier necrotic tissue can be performed using forceps or by the cryoadhesive properties of the probe.

MALIGNANCY
The clinical outcome of the cryotherapy can be judged in a similar manner to those of other local therapies. The parameters used for evaluation include endoscopic (macroscopic) appearance, radiologic changes, respiratory function, histologic 550 evidence, and general clinical characteristics. The effect of cryotherapy upon dyspnea, cough, hemoptysis, and stridor was studied in 33 consecutive patients 26 during 81 sessions, the majority improving in overall symptom scoring, and the group showing significant amelioration of symptoms statistically. Of a further 600 patients treated at Harefield Hospital, London, 26 78% were reported to show subjective overall improvement in symptoms of cough (64%), dyspnea (66%), hemoptysis (65%), and stridor (70%). Hemoptysis was reported as improved or stopped in 80% of cases in a French study, (Fig.  2, 3) 28 with 50% improvement in dyspnea also reported along with minor symptomatic improvement in wheeze, cough, and general thoracic pain. Similar improvement has also been documented in a smaller American study using fiberoptic bronchoscopy, in which objective improvement in pulmonary function was also recorded in 58% of patients, correlating with improvement in other symptoms as shown by other studies.
In endobronchial malignancy, cryotherapy can only obliterate the visible portion of the tumor, the remaining invasive tissue being inaccessible to the cryoprobe (Fig. 4). Hence, overall survival will be more closely correlated with the systemic extent of the disease, rather than the local palliative effects of intraluminal tumor debulking. As a palliative treatment, however, overall results appear very favorable when judged against the criteria for clinical patient selection and the resulting extent of obstruction removal. Invariably, the quality of life of treated pa- Figure 3. Non-small cell lung cancer before and after removal right main stem lesion with a cryoprobe. 551 Figure 4. Endobronchial lesion before and after cryotherapy. tients has been radically improved, and our methods have produced survival indistinguishable from other local therapies. Because we calculate survival times from the time of first treatment and not from diagnosis, however, it is possible that our survival statistics are underestimated compared with other studies.

BENIGN AND LOW MALIGNANCY LESIONS
Cryotherapy has also been used successfully to control benign lesions and low-grade malignancies such as carcinoid tumors, cylindromas, papillomas, polyps, amyloidosis, hemangioma, sarcoidosis, and tracheopathia osteoplastica where conventional surgical intervention is contraindicated due to the location of the tissues, the general pathology, or the nature of the disease.
Cryotherapy has been applied with considerable success in the treatment of granulation tissue iatrogenic to lung transplantation with, in nearly all cases, little or no recurrence for several years after initial treatment. Of 595 anastomoses referred for treatment at Harefield Hospital over a 10-year pe-riod, significant stenosis occurred in 22 cases (3.7%) that were unresponsive to dilatation. In 16 of these cases cryotherapy was used as a first-line treatment, and a patent lumen was restored with a total of 30 applications in 11 patients, the remaining 5 requiring an endobronchial stent. Significant improvements of 20% (range 7 to 56%) in forced expiratory volume over 1 second were seen immediately, with 3-and 5-year actuarial survival rates in this group being 74% and 62%, respectively. These results show that cryotherapy is a viable treatment for iatrogenic bronchial stenosis secondary to lung transplantation, with the additional benefit of potentially enhanced long-term survival in uncomplicated cases.
In a recent study of 11 patients (representing 2.1% of all patients treated at Harefield Hospital with this modality) presenting with a number of broncho-obstructive symptoms arising from endobronchial carcinoid disease between January 1989 and December 1996, it was found that 9 patients had become asymptomatic within 14 months from initial treatment. Of these, 6 presented with negative histologies for carcinoid tissue at later follow-up within the same time frame. In addition, 2 patients, 552 previously unresectable, were later deemed suitable for surgical intervention following preoperative cryotherapy. These 2, as well as the 6 described above, are still in remission. One patient who presented with supraclavicular nodal and osteous metastases, included in the 9 described above, is still asymptomatic although treatment is still given when required to prevent endobronchial recurrence. Two further patients that presented with mediastinal metastases have considerably ameliorated symptoms compared with presentation.

ASSOCIATIONS AMONG CRYOTHERAPY, CHEMOTHERAPY, AND RADIOTHERAPY
Endobronchial cryotherapy has been demonstrated to amplify the benefits derived from chemotherapy. 44 Experimental studies have suggested that this derives from some mechanism whereby cryotreated tumor cells seem to acquire a greater affinity for trapping anticancer drugs than do untreated cells. 45 In a French study 31 of 12 patients, tumor cells were reported to have a significantly elevated postcryotherapy rate of uptake of 15 mg of 57 Co-radiolabeled bleomycin, with a 30% increase in the normal:tumor tissue ratio 15 days after the treatment. This is supported further by the observation that the plasma clearance of the drug was elevated after cryotherapy, suggesting that the damaged tumor tissue trapped the drug, preventing removal. Because the dose of the drug given was below clinically effective levels, this indicated that the effect was due to cryodamage and not to the cytotoxic effects of bleomycin itself. This observation confirms other findings with mouse tumor cells, and clinical studies of otorhinolaryngeal cancer 44,45 that concentrations of tracer-labeled drugs are significantly elevated in the frozen and adjoining hypothermic tissues compared with peripheral normothermic areas following cryotreatment. As alluded to earlier, it is believed that this may derive from the influence of the ischemic effects of cryotherapy via the deprivation of the target tumor of its blood supply. The indications are that cryochemotherapy presents a valid alternative treatment for bronchial carcinomas, and probably other forms of cancer, when surgical resection is inappropriate.
Cryotherapy, radiotherapy, and brachytherapy have been shown to influence cardiovascular flow through treated tissue, and it is because of this that a potential synergism has been postulated between these forms of treatment. It is possible that neovascularization and hypervascularization of cryogenically treated tissue may influence the incipient radiosensitivity of the tissue. Certainly, neovascularization has been demonstrated microangiographically by LePivert in studies of cryolesions in rabbits, and similar hypervascularity has been demonstrated in rodent studies. 30,51 Radiotherapy per se is an accepted treatment for localized, inoperable cancers, 29 although the mean survival rate of patients is barely 8 months, with local tumor eradication being found in only 35% of cases. 27,28 Regression of atelectasis in obstructive tumors has only been observed in 21% of cases, where there has been no local disease treatment. 28 Improved quality of life prognoses have been achieved when neodymium: yttrium-aluminum-garnet lasers have been used on the tumor site prior to irradiation, however. Similar to laser therapy, cryotherapy will relieve bronchial obstructions and reduce the risk of local complications that are the cause of many deaths.
In our own study, 29 patients with malignant obstructive airway symptoms were treated with cryotherapy for local (18 patients) or functional indications (11 patients). One or two sessions were applied and considered satisfactory in 16 cases and unsatisfactory in 13, with persistent or recurrent lesions. Twenty-one patients received 65 Gy, and 8 patients in poor general condition received 45 Gy. Evaluation with flexible bronchoscopy and biopsy was performed 2 months postirradiation. All patients were alive at 3 months, although patients with unsatisfactory responses to cryotherapy died quickly of local complications with a median survival of 5 months, significantly shorter than the 11 months recorded for those for whom cryotherapy gave a satisfactory response. This was a nonrandomized study and as such cannot be considered unequivocal. Nevertheless, it serves to highlight the relative importance of local obstruction as a prognostic criterion, survival being more strongly correlated with this than with tumor nodes and metastases-classified staging and illustrate the similarity of survivorship rates in patients treated with cryotherapy and laser therapy. 52,53 CONCLUSIONS Cryotherapy offers an effective local therapy for the symptoms of airway obstruction arising from a number of tracheobronchial pathologies. In the case of malignancy, these benefits, which can appear rapidly after treatment, may also confer additional advantages in terms of enhanced short-and long-term survival. Coupled with these factors, the cost effectiveness of the therapy in terms of low expense, fast turnover, and low demand on hospital facilities and convalescence points towards an increasing clinical popularity for this modality in the future. As research continues, long-term results and 553 clinical audit should ensure the stability and establishment of the method as a first-line palliatiave treatment for endobronchial obstructive symptoms.