Use of Small-Bore vs Large-Bore Chest Tubes for Treatment of Malignant Pleural Effusions^*

Materials and Methods

We conducted a retrospective review of patients treated at a tertiary hospital between 1986 and 1995. This time period allowed us to maximize the size of the study cohorts, and it corresponded to a period when there were no dramatic changes in the systemic treatment of advanced solid tumors that would have significantly influenced the outcome variables chosen for this study. The potential study population was determined by reviewing all charts, which indicated discharge diagnostic codes for pleural effusion, chest tube insertion, pleurodesis, or sclerotherapy. This identified patients admitted to the thoracic surgery, oncology, and respirology services. Individual patient charts were then reviewed, and only symptomatic patients with confirmed malignancy, no clear nonmalignant etiology for the effusion (eg, congestive heart failure), and adequate follow-up chest radiographs were included in the final study population.

Information collected for each patient included demographics, date of initial diagnosis, type of malignancy, treatment status (ie, prior or ongoing chemotherapy), and the presence of other concurrent illness predisposing to a pleural effusion. Biochemical and cytological characteristics of the pleural effusion were recorded when available. For all patients, recurrences were determined by blinded examination of all postpleurodesis radiographs by two independent chest radiologists. Recurrence was defined as re-accumulation of pleural fluid greater than that seen on the baseline post-pleurodesis chest radiograph. When lack of agreement occurred, a consensus opinion was obtained between the two radiologists. Follow-up time was calculated from the date of pleurodesis to the date of last radiograph or recurrence of the effusion. The actuarial method was used to compare time to recurrence between groups. Patients without evidence of recurrence on the last known chest radiograph were censored at that point in time.

Statistical Analysis

Results were analyzed as follows: time-dependent data (time to failure of pleurodesis, survival data) was generated using the Kaplan-Meier product limit method.²⁷ All time dependent outcomes were calculated from the date of tube insertion. Patient data were censored where the outcome of interest had not yet occurred at last follow-up. Univariate analyses for comparing baseline characteristics of the two groups were performed using χ² analysis. Univariate analyses for time-dependent events were performed using a univariate Cox proportional hazards model.²⁸ Multivariate analysis using stepwise regression analysis and the Cox proportional hazards model was performed to identify factors independently associated with time to event outcomes. Statistical software used included BMDP for Windows (descriptive statistics, χ² analysis), BMDP Classic (BMDP Statistical Software; Cork, Ireland), and Graphpad Prism (generation of survival curves, log-rank tests) [Graphpad Software; San Diego, CA].

Results

Of 159 cases of pleural effusion initially identified, 57 cases were excluded from analysis for the following reasons: empyema, 14; pleural effusion related to alcoholic cirrhosis, 1; pleurodesis not performed, 30; early death unrelated to tube insertion and prior to pleurodesis, 3; lack of follow-up chest radiographs, 8; lost to follow-up, 1. The final study group was formed from the remaining 102 cases. The median age was 65 (range, 44 to 92) years. Fifty-eight patients were treated with small-bore catheters, and 44 patients received conventional large-bore chest tubes. The most common diagnoses were breast cancer (56 patients, 55%) and non-small cell lung cancer (28 patients, 27%). Sixty-seven patients (66%) had received prior systemic therapy. Fifty-nine patients (58%) were receiving ongoing chemotherapy. Seven (7%) had other concurrent nonmalignant disease that may have predisposed to a pleural effusion. Cytologic evaluation was performed on 70 patients and was positive in 56 patients (80%). Table 1 reveals the baseline characteristics of the two groups. After adjusting for the statistical effect of multiple testing, no significant differences were found between the groups with respect to these characteristics.

Agents used for sclerotherapy were: talc, 27 patients (26%); tetracycline/doxycycline, 72 (70%); bleomycin, 2 (2%); and interferon, 1 (1%). There were no differences between the two groups with respect to the agent used for sclerotherapy (χ² = 0.91, degrees of freedom [df] = 3, p = 0.82). Talc was administered in the form of a slurry to patients treated with small-bore catheters and via insufflation to patients treated with large-bore chest tubes. All patients included in this analysis had pleurodesis performed only once on the side (left or right) in which response was measured.

Complications of Therapy

We examined the complication rate of patients in each group with emphasis on the following: (1) the development of intercurrent infection during the time that the tube was in place, (2) the incidence of radiographically evident pneumothorax, and (3) the probability of death during the procedure. In total, 11 patients developed infection; 6 (14%) in the large tube group and 5 (9%) in the small tube group. This difference was not statistically different (χ² = 0.65, df = 1, p = 0.42). Radiographically evident pneumothoraces were seen in 28 patients—16 (36%) patients from the large-bore group vs 12 patients (21%) of the small-bore group. This difference was of borderline significance (χ² = 3.08, df = 1, p = 0.08). There was no difference in the probability of death during the time that the tube was in place. Three patients (7%) in the large tube group died, compared with 4 (7%) in the small tube group.

Differences in Time of the Procedure

We examined various timelines associated with the procedures. These included time from tube insertion to pleurodesis, average total duration of tube placement, time to discharge after removal of the tube, and the total length of stay. These results are summarized in Table 2 . Although there were trends suggesting shorter times to pleurodesis for patients with large tubes and shorter times to discharge and total length of stay for patients with the smaller tubes, none of these reached statistical significance after adjusting for multiple testing.

Response to Sclerotherapy

The actuarial method was used to compare differences between groups in time to recurrence. This method treats follow-up time as a confounding variable and allows all patients to contribute to the outcome measure whether they have recurred or not (those who had not recurred at last follow-up or who were lost to follow-up were censored at that point in time). This increases the sensitivity to show a difference in efficacy between the two methods of pleurodesis.

Duration of Response

Time to recurrence was assessed in a blinded manner by two independent radiologists. Lack of agreement occurred in < 10 cases and was easily resolved by consensus opinion.

The actuarial probabilities of recurrence at 6 weeks and at 4 months were 45% and 53% for the small-bore catheters, compared with 41% and 51% for the large-bore chest tubes. Although as a single point on the curve the median time to recurrence was longer for the large-tube group when compared to the small-catheter group (19 weeks vs 7 weeks, respectively), the overall probability of recurrence over time was not different between the two groups (Fig 1 , p = 0.43 by log-rank).

To evaluate the effect of multiple potential confounding variables on duration of response, we examined the effect of both baseline and treatment related variables on duration of response using univariate and multivariate analyses. In univariate analysis, age (p = 0.50), diagnosis (p = 0.25), prior systemic therapy (p = 0.26), current systemic therapy (p = 0.32), concurrent disease predisposing to an effusion (p = 0.36), sclerosing agent (p = 0.17), and the size of tube (p = 0.42) all had no predictive effect on duration of response to sclerotherapy. Neither time to pleurodesis (p = 0.18) nor duration of tube placement (p = 0.65) had any significant effect on duration of response to sclerotherapy. In univariate analysis, male gender was a predictor of shorter time to recurrence (p = 0.04). In multivariate analysis, the effect of all of the above potential confounding variables was examined by generating a Cox proportional hazards stepwise regression analysis. In the model using all patients, both gender (for men, relative risk [RR] = 2.5, 95% confidence interval [CI] = 1.8 to 3.2, p = 0.03) and a history of prior systemic therapy (RR = 1.8, 95% CI = 1.1 to 2.5, p = 0.02) had independent significant effects on the probability of recurrence. No other variables had significant effects on the probability of recurrence, including size of tube used (p = 0.30).

We also reviewed outcomes in the subset of patients (n = 70) for whom information on cytology was available. This analysis revealed that the presence of malignant cells in the effusion was a highly significant independent predictor of a shorter time to recurrence (Fig 2 , RR = 12.2, 95% CI = 10.2 to 14.3, p = 0.007) as was gender (for men, RR = 5.3, 95% CI = 4.2 to 6.4, p = 0.02), and perhaps the use of current systemic therapy (RR = 1.8, 95% CI = 0.9 to 2.7, p = 0.06). However, even in this subset of patients, multivariate analysis revealed that tube size was not significant (p = 0.27).

Overall Survival

A comparison of overall survival between the two groups revealed no significant difference (Fig 3 , p = 0.29 by log-rank test). The median survival for the group receiving the large tube was 4.43 months and for the group receiving the small tube was 3.17 months. The 12- and 24-month survival rates for each group were 23% and 15% for the large tube group and 20% and 7% for the small tube group.

Discussion

In the vast majority of patients, the treatment of malignant pleural effusions is palliative and, therefore, should be associated with a low morbidity and mortality rate. Recent interest in the use of small-bore catheters for effusion drainage and sclerotherapy is based on the premise that it may be less invasive as a procedure and thus better tolerated by patients compared to standard large-bore chest tubes, with no compromise in efficacy. The literature examining the use of catheters for management of diseases of the pleural space is encouraging.

One case series examined the efficacy and complication rate of 133 percutaneous pigtail catheters placed in 91 children in a pediatric ICU.²⁹ The majority of patients had congenital heart disease. Eighty-five percent of the catheters were placed for pleural effusion drainage, the remainder for treatment of pneumothorax. The catheter was found to be highly effective for drainage of serous and chylous effusions, less so for hemothorax or empyema. Five percent of catheter placements were associated with serious complications (hemothorax, pnuemothorax, and hepatic perforation). Complications of catheter use occurred in 20% of patients and included failure to drain, dislodgement, kinking, empyema, and disconnection.

Other studies demonstrated the efficacy and safety of small-bore catheters in the adult population for treatment of pneumothorax and uncomplicated pleural effusion due to various conditions.²¹³⁰³¹ Gammie et al³¹ retrospectively reviewed the outcome of 109 consecutive pigtail catheters placed at the bedside (ie, without radiographic guidance). No complications of placement were seen, despite the fact that 24% of patients had laboratory evidence of coagulopathy. Another study demonstrated that the use of a small indwelling pleural catheter was more cost-effective when used in place of a closed tube thoracostomy for drainage of large-volume pleural effusions.³⁰

Others have evaluated the use of small-bore percutaneous catheters in combination with sclerotherapy (using tetracycline or bleomycin). Walsh et al³² treated 15 consecutive patients with disseminated disease and symptomatic pleural effusion using a 9F catheter. Eleven of 12 patients who lived for > 4 weeks had objective clinical responses. Five patients had complete roentgenographic responses; another 5 had only slight reaccumulation or thickening. Complications were minimal. Spontaneously resolving, small, apical pneumothoraces developed in 4 of the 15 patients. One patient experienced re-expansion pulmonary edema before pleurodesis. Efficacy of this method was confirmed in two other studies, both involving 21 patients.²³³³ Each study demonstrated a success rate of 71% with minimal treatment-related morbidity.

The largest case series was reported by Seaton et al.²⁴ Forty-seven patients underwent small tube drainage and doxycycline sclerotherapy. Twenty-one patients had radiographic follow-up at 30 days and formed the study group. Seventeen patients (81%) had a complete response and three patients (14%) had a partial response based on the 30-day chest radiograph. Again, the complication rate was low and consisted of symptoms such as pain and fever.

The incidence and significance of pneumothorax after small-bore catheter placement for malignant pleural effusions was examined by Chang et al²⁵ in a retrospective review of 88 patients treated over a 2-year period. Twenty-seven patients with 28 catheters developed a pneumothorax. Resolution occurred in 22 patients; in the remaining 6, the pneumothorax was stable. No complications such as tension pneumothorax, or respiratory distress were reported.

Parker et al²² compared the efficacy of small-bore catheter drainage and sclerosis to traditional drainage with standard chest tube in a retrospective single institution review involving 20 patients with a total of 24 malignant pleural effusions. Treatment consisted of drainage with a pigtail catheter or standard chest tube followed by tetracycline sclerotherapy. Success was determined by the status of the pleural effusion at 30 days. Eight of 13 effusions were adequately treated using the small-bore catheter, compared with 4 of 11 effusions treated with the standard chest tube. The authors concluded that the pigtail catheter drainage and sclerosis was at least as successful as the more traditional drainage with standard chest tube.

The results of our study support this conclusion. We were unable to detect a significant difference in recurrence rates between small-bore catheters compared with large-bore chest tubes in cancer patients with symptomatic effusions. Using the actuarial method, no significant difference in time to recurrence was found between the two groups. To control for potential confounding factors (eg, primary diagnosis, prior or concurrent therapy, etc.), univariate and multivariate analyses were performed. Again, tube size remained nonsignificant. It is worth noting that male gender (RR = 2.5) and previous systemic therapy (RR = 1.8) were found to be significant predictors of relapse. The latter result may be explained by the fact that prior therapy may be a marker for more advanced or aggressive disease. For those patients who underwent cytologic testing, a positive result was found to be highly significant as a predictor of failure (RR = 5.3). The use of concurrent systemic therapy was of borderline significance.

As expected, the complication rates associated with the chest tube insertions and sclerotherapy were low. There were no significant differences in the rates of infection or radiographically detected pneumothoraces. Although the latter achieved borderline statistical significance (p = 0.08), the clinical significance remains doubtful. As anticipated, there was no difference in survival between the two groups. In fact, the similar median survival of both groups (4.4 months and 3.2 months for the large-bore and small-bore tubes, respectively) suggests that the groups were comparable with respect to disease-related prognosis.

The issue of relative efficacy and safety of small-bore catheters compared to chest tubes is unresolved. Interpretation of the current literature is problematic due to various methodologic issues, the principal issue being a lack of prospective randomized trials comparing the two methods of treatment. Other criticisms include small patient numbers, heterogeneous patient populations, lack of documentation of coexisting heart or lung disease (when defining subjective response), failure to define the criteria for diagnosis of malignant pleural effusion, and a lack of standardized follow-up and definition(s) of response.

We were able to address some but not all of these issues. Cytologic confirmation of malignant pleural effusion was sought in all cases during chart review, although positive results were documented in only 55% of the study population. To minimize this problem, careful chart examination was performed to exclude other causes of pleural effusion such as cardiac or renal failure. In accordance with others,³⁴ we defined response in terms of recurrence rate of the effusion compared to a baseline postpleurodesis chest radiograph rather than the traditional solid tumor response system (ie, complete and partial responses). Another strength of our study was the duration of follow-up. Similar to Morrison et al,³³ we collected clinical and radiologic follow-up to the time of last visit or death rather than using an arbitrary time period such as 4 weeks. In addition, blinded evaluation of all chest radiographs was performed by two independent radiologists in an attempt to minimize bias in assessing response. The major limitation of our study was the retrospective design, which might have amplified the effects of bias and confounding. We were unable to derive information from the chart, which may have influenced the outcome of the intervention such as performance status and prior mediastinal irradiation. Issues of bias with respect to choice of tube size are diminished somewhat by the fact that the majority of large tubes were inserted during the early part of the study (ie, from 1986 to 1992), and the majority of small tubes were inserted during a later period of the study (ie, from 1993 to 1995). This suggests that tube selection was influenced mainly by a time-dependent bias, although other factors likely influenced the choice. Another limitation of the study is the small sample size, which would likely have limited the power to detect anything other than a moderate or large difference in efficacy rates (ie, we could have missed a small difference in effect). Finally, we were unable to derive information on what we consider to be two important endpoints—cost and quality of life. These issues are especially important in light of evidence demonstrating that drainage and sclerotherapy of malignant pleural effusions can be done safely and effectively in the ambulatory setting.³⁵

Conclusion

Ultrasound-guided placement of small-bore catheters appears to be a safe and promising tool in the treatment of malignant pleural effusions. Relative efficacy compared with the traditional large-bore chest tube is unknown and deserves further investigation, preferably in the context of a randomized, prospective trial. Associated morbidity rates and costs also warrant further analysis.