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* From the Department of Thoracic Surgery, Harefield Hospital, Harefield, UK.
Correspondence to: M. Omar Maiwand, MD, Consultant Thoracic Surgeon, Department of Thoracic Surgery, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK; e-mail: cryotherapy{at}rbh.nthames.nhs.uk
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Abstract |
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Design: Retrospective analysis of data extracted from a prospective computerized database.
Setting: Tertiary referral thoracic surgical center.
Patients: Data of the 172 patients who underwent at least two sessions of endobronchial cryosurgery (group A) were compared with 157 patients who underwent one session of cryosurgery (group B) for malignant primary or metastatic obstructive lung carcinoma over a 5-year period.
Intervention: Endobronchial cryosurgery is performed under general anesthesia. A nitrous oxide cryoprobe is inserted through a rigid bronchoscope. The probe achieves a temperature of – 70°C at its tip and is applied to the tumor for two 3-min periods. Statistical analysis assessed the effects of cryosurgery on symptoms, lung function, Karnofsky performance score, and survival.
Results: Symptoms of dyspnea, cough, and hemoptysis were significantly reduced in both groups after cryosurgery (p < 0.001), although group A benefited more than group B. Lung function test results improved significantly in group A. The mean Karnofsky performance score (± SD) increased from 67 ± 9 to 74 ± 10 (group A) and from 67 ± 10 to 73 ± 11 (group B). The mean survival was 15 months (median, 11 months) for group A and 8.3 months (median, 6 months) for group B (p = 0.006). Univariate regression analysis showed that no particular patient or tumor characteristic was associated with reduction of symptoms. Patients who had cryosurgery and external beam radiotherapy showed longer survival (p < 0.01). Females and patients with stage IIIa and IIIb tumors achieved significantly improved Karnofsky scores (p < 0.02). Female sex was also a factor for increase in FEV at 1 min (p = 0.003) and FVC (p < 0.001).
Conclusions: Cryosurgery is a safe method for palliation of endobronchial malignancies causing airway obstruction. Statistical analysis showed improvement of dyspnea, cough, and hemoptysis. Cryosurgery can be considered in patients with inoperable obstructive endobronchial carcinoma.
Key Words: bronchial tumor • bronchoscopy • lung cancer • regression analysis
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Introduction |
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Cryosurgery is the controlled application of extreme cold for local destruction of abnormal living tissue. Attempts to treat malignant tumors with local application of cold were made in the mid-19th century, although manufacturing of reliable cryosurgery equipment was not achieved until a century later.4 Cryosurgery for the palliative treatment of endobronchial tumors was first reported in Europe by our group in 19865 and has since been used in > 1,000 patients. Endobronchial cryosurgery is performed on patients under general anesthesia using a rigid bronchoscope. Temperature of – 70°C at the end of a cryoprobe causes destruction of the tumor. A course of cryosurgery usually consists of two sessions with a 2- to 6-week interval. Often, however, clinical condition of patients prevents them from undergoing more than one session. Patient-specific information and postcryosurgery clinical data have been placed prospectively in a computerized database since 1995. In this study, we analyzed the effects of palliative endobronchial cryosurgery on symptoms, performance status, lung function, and survival in patients with malignant lung tumors who underwent at least two cryosurgery sessions. We compared these findings with a group of patients who underwent only one session of cryosurgery. Furthermore, we analyzed patient-specific and specific-specific characteristics in relation to outcome.
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Materials and Methods |
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Patient Groups
Three hundred twenty-nine new patients underwent cryosurgery for obstructive, symptomatic, malignant endobronchial tumors by the senior author of this article (M.O.M.) from January 1996 to December 2000. Patients were classified into two groups for the purpose of this study. Group A included the 172 patients who underwent at least two sessions of cryotherapy. The common feature of these patients was that their selection was based on completion of the standardized cryosurgery protocol, including the two sessions. Group B included 157 patients who underwent only one session of cryosurgery. Group B included a more diverse patient group, most of which were presented in a condition that did not allow them to undergo a second session of cryosurgery. All patients included in the analysis had 100% completion of data collection during the study period. Analyzed outcome variables were measured at follow-up appointments at 2 weeks and 8 weeks after the second session of cryosurgery.
Technical Aspects of Endobronchial Cryosurgery
The technical aspects of endobronchial cryosurgery have been described previously.58 Indications for endobronchial cryosurgery include endobronchial, obstructive tumors that cause symptoms or that are likely to result in the immediate development of symptoms. The majority of these tumors are regarded as inoperable based on the advanced stage of the disease or the lung function and performance status of the patient. Before endobronchial cryosurgery, the procedure, benefits, and risks are explained to the patient, and informed consent is obtained. The procedure is performed under short-acting IV general anesthesia, using a large rigid (9.2 mm) and a flexible bronchoscope (2.4 mm). Oxygenation is maintained with Venturi positive pressure ventilation. A Joule-Thomson-type probe (Spembly Medical; Hampshire, United Kingdom) with nitrous oxide as the cryogen is used. A temperature of approximately – 70°C is achieved at the probe tip. The distal tip of the bronchoscope is placed about 5 mm above the lesion, and the cryoprobe is inserted through the bronchoscope and applied to the tumor. Tissue samples for histologic examination are obtained before each cryosurgery. Bleeding from the site of a biopsy or cryosurgery is contained by the local application of epinephrine (adrenaline) 1:1,000. The tumor is frozen for 3 min and then allowed to thaw until the probe separated from the tissue. If the tumor covered wider areas of the bronchial tree, multiple cryoapplications of epinephrine are made during the same treatment session. Necrotic tumor material, when present, was removed after each cryoapplication of epinephrine using a biopsy-type clamp. Patients often report that additional necrotic-appearing material is coughed out 24 to 48 h after cryosurgery. More than 95% of patients are discharged to home on the same day. Patients are reviewed in the outpatient clinic 2 weeks after each cryosurgery session and every 6 weeks thereafter. In view of the nature of the disease, regrowth of the endobronchial portion of the tumor is often rapid. Although quantification of tumor recurrence is difficult, medium-term outcome is reflected by survival reported in this study. Contraindications of cryosurgery include inability of the patient to undergo general anesthesia or previously observed poor tumor response to the procedure.
Statistical Analysis
Age, sex, site of tumor, histologic type, stage, and adjuvant treatment were used as explanatory variables of interest. These were related to outcome variables such as dyspnea class, severity of cough, hemoptysis, Karnofsky score, lung function tests (FEV1 and FVC), and survival (time between cryosurgery and death). A Wilcoxon-matched pairs signed-rank sum test was carried out for each outcome variable to determine whether there was a difference between before and after cryosurgery measurements. Categorical data were compared between groups using Fisher Exact Test or the 
2 test. Distributions of continuous data were observed, and t tests or Mann-Whitney U tests were performed accordingly for comparisons of groups. Univariate Cox regression analysis, with calculation of hazard ratio, was performed for each variable of interest to assess their association with survival. Ordered logistic regression analysis, with calculation of odds ratio, was used to assess the association of variables of interest with all other outcome variables. Univariate regression analysis was followed by multivariate analysis. Actuarial survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Results are expressed as mean ± SD or as the appropriate ratio at 95% confidence interval. A p value of < 0.05 was considered significant.
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Results |
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All patients were discussed at multidisciplinary meetings. Palliative or adjuvant treatment was decided according to stage of the tumor, histologic type, performance score of the patient, and wish of the patient. Of the 172 patients in group A, 101 patients underwent adjuvant radiotherapy, and 20 patients underwent lung resection, whereas chemotherapy was administered to 12 patients. The 20 patients who underwent lung resection had their tumor stage revised after surgical assessment and lymph node sampling. The timing of applying adjuvant therapy varied considerably among the patients because radiotherapy, surgery, or chemotherapy may have been applied before or after cryosurgery. Furthermore, a small number of patients underwent more than one mode of adjuvant treatment. Rates of palliative or adjuvant radiotherapy were significantly lower in group B. The relatively low number of patients undergoing radiotherapy in both groups (101 of 172 patients [59%] in group A, and 45 of 157 patients [29%] in group B) is explained by the fact that some of the patients were referred for cryosurgery with acute dyspnea but despite symptom relief, did not survive long enough.
Effects of Cryosurgery on Outcome Measures
Dyspnea:
Of the 172 patients in group A (Table 2
), dyspnea improved by at least one NYHA class in 87 patients (50.5%) and remained unchanged in 50 patients (29.0%), whereas 25 patients (14.5%) experienced deterioration by at least one NYHA class at their first follow-up after cryosurgery. These figures were lower after the second follow-up. Patients referred to as "not applicable" were not able to attend follow-up after cryosurgery or did not experience dyspnea. Overall, there was a statistically significant chance (p < 0.001) that dyspnea would improve by at least one NYHA class at 2 weeks after the second session of cryosurgery. Patients in group B benefited to a lesser degree from cryosurgery.
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Hemoptysis: This was an infrequent symptom in this patient population (Table 2). Only 78 of the 172 patients (43.3%) in group A reported episodes of hemoptysis before or after treatment. Of these patients, however, 36 patients (20.9%) reported reduction in hemoptysis by at least one class, whereas 14 patients (22%) improved by two classes, and 12 patients (19%) improved by three hemoptysis classes. This reduction in hemoptysis was statistically significant (p < 0.001) overall. Figures in group B remained small due to limited follow-up attendance.
Lung Function Tests: A significant increase in mean PEF from 170 ± 79 to 181 ± 73 L (p = 0.03) at first follow-up was recorded in group A patients (Table 3 ). This benefit was lost by the second follow-up appointment. Patients attending follow-up clinics in group B did not show improved PEF rates. FEV1 increased from 1.36 ± 0.63 to 1.43 ± 0.47 L and was recorded following cryosurgery in group A patients, although the difference did not reach statistical significance. There was also a small but statistically significant increase in FVC from 1.89 ± 0.63 to 2.02 ± 0.72 L at first follow-up (p = 0.001). Patients in group B attending follow-up did not show improved performance in lung function tests after cryosurgery.
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Univariate Regression Analysis
Univariate regression analysis was performed only in group A patients (Table 4
).
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Dyspnea: Ordered logistic regression was used for analysis of data related to the effect of explanatory (patient) variables to dyspnea, cough, hemoptysis, and Karnofsky score. Ordered logistic regression analysis is an extension of logistic regression analysis and allows modeling of ordered categorical response variables. It is used when more than two different outcomes are analyzed. With regard to the present study, we used the model to compare "improvement" to "no change" or "deterioration" after cryosurgery. The model assumes that the odds ratio comparing improvement and no change is the same as that comparing no change and deterioration. There is borderline evidence that advanced age (p = 0.08) and stage IIIa (p = 0.06) are associated with alleviation of dyspnea.
Cough: Regression analysis correlating variables to improvement of cough was performed similarly to the analysis of dyspnea. There was also borderline evidence that cough is more likely to be reduced by cryosurgery in advanced age (p = 0.07).
Hemoptysis: There is borderline association between advanced age and clinical improvement of hemoptysis (p = 0.07). There is also weak evidence that hemoptysis related to adenocarcinoma or other histologic type of lung malignancy is more likely to improve compared with squamous cell or small cell carcinoma (p = 0.08).
Karnofsky Performance Score: Results displayed in Table 4 show that the Karnofsky performance score is particularly likely to improve by at least 10% in female patients (p = 0.05) and in patients with cancer at stage IIIa and IIIb (p = 0.02).
Lung Function Tests: Ordinary, least squares regression analysis was used to examine the relationship between FEV1 or FVC and each variable. Female patients benefit significantly more than male patients from cryosurgery with regards to FEV1 (p = 0.003) and FVC (p < 0.001).
Multivariate Regression Analysis
In view of the small number of patient variables that are associated with significantly positive results, as shown in the univariate analysis, multivariate analysis is of relatively minor relevance. Stepwise regression was used to find the best multivariate model for each outcome variable. A cutoff point of p = 0.05 was used for adding variables and of p = 0.1 for removing variables. The only multivariate models of significance were the following: (1) age (p = 0.003) and site (p = 0.08) for hemoptysis; (2) sex (0.04), site (0.009), and stage (p < 0.001) for Karnofsky score; and (3) age (p = 0.04), sex (p < 0.01), and stage (p = 0.04) for FVC.
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Discussion |
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Cryosurgery was shown to be associated with significant reduction in dyspnea, cough, and hemoptysis. It was also shown to be associated with improvement in the Karnofsky performance score, whereas the effect on PEF, FEV1, and FVC was moderate. Univariate Cox regression analysis demonstrated correlation between the use of external beam radiotherapy and prolonged survival. Although difficult to quantify, application of radiotherapy has undoubtedly contributed to patients’ survival. Because the opening of the airways by cryosurgery may allow many patients to undergo radiotherapy or other procedures, it may serve as a mechanism of prolonging survival. No particular patient or tumor characteristic, however, was shown to strongly affect symptoms such as dyspnea, cough, or hemoptysis. Karnofsky performance score, however, improved significantly more in patients with stage III carcinoma. Female sex was the only variable associated with improvement in lung function tests. Expectedly, the benefits of endobronchial destruction of tumor were more significant in group A. Patients in group B did not complete two cryosurgery sessions and displayed significantly shorter survival.
Cryosurgery achieves destruction of the endobronchial element of the tumor and recanalization of tracheobronchial obstruction. The effect on dyspnea and lung function tests can therefore be explained by the mechanical removal of the tumor. These findings are in agreement with previously reported results. In a small study, Mathur et al11 demonstrated dyspnea improvement in 12 of 17 patients treated with endobronchial cryosurgery, whereas similar results were produced in a larger trial.12 The related improvement in the Karnofsky performance score, an indicator of quality of life, may be attributable to the reduction of symptoms. Indeed, cough and hemoptysis were also reduced after two sessions of cryosurgery. It was inevitable that most patients’ symptoms deteriorated at a later stage in view of the very advanced nature of the disease.
Univariate regression analysis revealed only a weak correlation between demographic characteristics of the patients or characteristics of the tumors and outcome measures. Karnofsky score showed the most significant improvement in patients with stage IIIa or IIIb tumors. One can only postulate that patients with stage IV tumors were too unwell to benefit from endobronchial cryosurgery. The reason for the significantly better improvement on lung function tests results in female patients remains unclear.
Fewer than 25% of patients who received diagnoses of lung cancer have localized disease amenable to surgical treatment. Even patients that are operable have <50% chance to be cured.1 Because prognosis is poor, it is important to ensure alleviation of symptoms and improved quality of life. In cases in which the possibility of surgery has been eliminated, other palliative measures should be considered. These treatments include, apart from cryosurgery, laser therapy, photodynamic therapy, argon plasma coagulation, and brachytherapy. The aim of these treatments is to relieve the distressing symptoms of breathlessness, cough, and obstructive pneumonia and to improve respiratory function, general health, and performance status. Because the clinical benefit of cryosurgery is mainly attributable to tumor debulking, other modalities of endobronchial palliation should be expected to produce comparable results.
Nd-YAG or carbon dioxide laser has become a well-established method of treating endobronchial malignancies, particularly in the United States. Cavaliere et al13 reported a series of nearly 2,000 patients treated with Nd-YAG. Quality of their results depended strongly on the site of the tumor, with tracheal tumors responding to treatment more favorably than more peripheral lesions. Postoperative complication rate was low, and there were 12 in-hospital deaths. Cumulative survival at 6 months was 50%. Other studies141516 on patients treated with endobronchial Nd-YAG laser have shown a median survival of 5 months. Indications for laser therapy are similar to cryosurgery. Although laser treatment may be more effective for emergency treatment due to its presumed greater short-term effects, it is significantly more expensive and carries a higher risk of bronchial perforation.12
Photodynamic therapy has been shown to achieve a median survival of 5 to 7 months.1718 It is most effective on tumors of small size but has considerable cost. Tumors are photoradiated by argon dye laser. Indications are similar to cryosurgery, whereas tumors are often not resectable surgically. When photoradiation is followed by surgical resection, long-term survival is satisfactory.19
Endobronchial argon plasma coagulation is also used for palliation of endobronchial neoplasms. It is particularly effective in the treatment of hemoptysis.20 Bronchoscopic electrocautery is effective and inexpensive and for symptomatic palliation of patients with intraluminal airway obstruction. In a small study,21 mean survival was 11.5 months after electrocautery.
The mechanisms involved in tissue destruction by cryosurgery can be divided into immediate and delayed. Immediate mechanisms include the physical effect of intracellular ice crystal formation, the biochemical effect of cell dehydration and shrinkage, and thawing effects.22 The delayed effect involves vascular stasis and apoptosis.22 Cell destruction is influenced by the freezing regime, the distance from the probe, tissue vascularity, and the type of cell being frozen. Areas close to the probe, with high cooling rates, are more likely to undergo intracellular ice crystal formation.23 During the cooling process, an osmotic potential across the cell membrane is created, leading to withdrawal of water from within the cell into the extracellular spaces and cell shrinkage.24 Further cell damage occurs during thawing as smaller ice crystals recrystallize to form larger, more damaging crystals, with lower surface energy. As the ice crystals thaw, the extracellular spaces will become hypotonic for a brief period of time, and water will move into the cell causing expansion and rupture.22 The delayed effect of freezing involves vascular damage, which can lead to cell schema. The mechanism involves detachment of damaged endothelial cells from inside the vessel, increased permeability of the vessel walls, platelet aggregation, and microthrombus formation.25 There is evidence to suggest that some cells undergo apoptosis (gene-regulated cell death) when exposed to temperatures approximately – 6°C to – 10°C.26
The main weakness of our analysis of results is the absence of a control group of patients with comparable malignancies who did not undergo cryosurgery. A randomized trial comparing patients undergoing external beam radiotherapy and endobronchial cryosurgery vs patients undergoing only radiotherapy is in progress and will address this question. A further weakness is the objective nature of classifying symptoms such as dyspnea, cough, and hemoptysis. Care was taken to use a nominal scale of symptom severity that was marked by the patient to minimize investigator bias.
In conclusion, endobronchial cryosurgery for malignant tumors is associated with significant improvement in dyspnea class, cough, hemoptysis, Karnofsky score, and lung function tests. These effects were achieved after two sessions of cryosurgery. The mean survival time after application of two sessions of cryosurgery was 15 months. Endobronchial cryosurgery is a palliative technique, with the aim of alleviating symptoms and improving the patient’s performance status. Future randomized trials, comparing the results of endobronchial cryosurgery with other forms of palliative treatment for lung cancer, will be needed in support of the above findings.
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Footnotes |
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Received for publication February 25, 2004. Accepted for publication December 2, 2004.
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