Malignant pleural effusions are common complications of advanced malignancies and are associated with significant morbidity and compromised quality of life. They constitute a marker of advanced disease, with a median survival after diagnosis ranging from 3 to 12 months.1–7 Given this limited survival, treatment should aim at relieving symptoms and improving function while minimizing the need for hospitalization.
The optimal strategy remains controversial and the choice of treatment may be dictated by several factors including symptoms and performance status of the patient, primary tumor cell type, and possibility of lung reexpansion after pleural fluid evacuation. The least invasive option consists of repeated thoracenteses, but their effect is usually of short duration and therefore most appropriate for frail or terminally ill patients with limited survival expectancy.8–10 Other options include talc pleurodesis (via talc slurry administered using a chest tube or talc insufflation by thoracoscopy), or indwelling pleural catheters. Although both interventions appear equivalent in terms of symptom control, the long-term complication rate, specifically with regards to infectious complications, may be higher with tunnelled indwelling pleural catheters (TIPCs).10–13 In addition, the presence of an indwelling pleural catheter is often considered a relative contraindication to chemotherapy owing to a perceived risk of increased infections in this context. Although this may not be supported by existing data, the immunosuppressive effects of chemotherapy are well recognized, and practice with regards to TIPC placement in these patients varies widely. To clarify this point, we sought to evaluate the incidence of TIPC-related infections in patients who underwent chemotherapy compared with those who did not.
Study Design and Patients
The study was designed as a retrospective cohort study and was conducted at Mayo Clinic, Rochester, MN. This study was approved by the Mayo Clinic Institutional Review Board (IRB#11-008258). All patients meeting the eligibility criteria between November 2005 and March 2011 were included in the study. Patients were included in the study if they underwent TIPC placement for malignant pleural effusion. Patients were excluded from the study if they were below 18 years or if they were unable to give informed consent. We also excluded those patients who died within 1 week of insertion of the TIPC (as we thought that those patients would not have had time to develop infection) and patients without follow-up.
Data were extracted by chart review for all patients included in the study. Data extracted were as follows: age, sex, side of catheterization, type of primary cancer, incidence of infection, type of infection, duration of the TIPC in place, and chemotherapy treatment. Chemotherapy was considered a potential risk factor for infection in TIPC patients if it occurred within 6 weeks of TIPC placement or at any time while the TIPC was in place.
Two types of infection were presumed to be related to TIPC placement: empyema (pleural fluid infection) and soft tissue infection (eg, cellulitis). For the purpose of this study empyema was defined as aspiration of frank pus from the pleural space, positive pleural fluid gram stain for bacteria, or positive pleural fluid culture in the correct clinical setting (all patients who had pleural infection presented with systemic symptoms of infection such as fever, chills, hypotension, and sepsis). Cellulitis was defined as swelling, redness, and warmth of the skin around the TIPC exit site and the catheter tract, or purulent discharge from the catheter exit site.
Primary outcome was development of infection. Patients were followed from the admission time until December 31, 2012 or death, whichever happened first. Statistical analyses were performed using SAS (version 9.1, SAS Institute, Cary, NC). Binary variables are presented as percentages. Continuous data are summarized as median [25% to 75% interquartile range (IQR)] or percentages. We used unpaired Student t test to compare continuous variables with normal distribution and Mann-Whitney U test for variable with skewed distribution.
A total of 391 TIPC were placed in 371 patients during the period of our study. Of these, 113 TIPC were placed for benign pleural effusion and were therefore excluded from the analyses. A further 16 patients (1 TIPC each) died within 1 week of catheter placement and were therefore excluded from this study. No patient was lost to follow-up. A total of 206 patients had died at the time of last follow-up (85%). A total of 262 TIPC placed in 243 patients were included in the study. Patients median (IQR) age was 69 (59 to 77) years and there were 123 (51%) females (Table 1). The most common primary cancer was lung cancer 41% (n=99), followed by breast 16% (n=39), lymphoma and ovarian cancer were both 7% (N=17). Patient demographics are presented in Table 1.
Using TIPCs as the unit measure, there was an approximately equal split between catheterization of the right 49% (n=129) and left 51% (n=133) side. A total of 19 patients had bilateral TIPC placement, the other 224 patients had a single TIPC placed. None of the patients with bilateral TIPC developed infection. The median catheter duration was 77 days (IQR=30 to 150). Chemotherapy was administered within 6 weeks of placement or while the TIPC was in place in 173 of the 262 TIPCs (66%). The median catheter duration in days (IQR) was 90 days (38 to 162 d) in patients receiving chemotherapy and 42 days (20 to 116 d) in patient not receiving chemotherapy, a difference that was statistically significant (P<0.01).
Infections related to TIPC occurred in a total of 16 of the 243 patients (6.6%), all of whom had a single TIPC placed. Hence, infections complicated the course of 16 of the 262 TIPCs (6.1%). These infections consisted of empyema for 10 TIPCs (3.8%) and cellulitis/soft tissue infection in 6 cases (2.3%; Fig. 1). Of the patients who developed an infection, 9 were either receiving chemotherapy during the period of catheter placement or had received chemotherapy within 6 weeks before catheter placement (9/173, 5.2%) and 7 were not receiving chemotherapy (7/89, 7.9%). The difference between these infection rates was not statistically different (P=0.42). The median follow-up between patients undergoing chemotherapy and those who did not was not statistically significant. No patient was lost to follow-up. Two patients with infection had documented neutropenia at the time of infection (cellulitis, n=2), as defined by neutrophil count <500/μL. Microbiological studies were positive in 6 patients with empyema and consisted of methicillin sensitive Staphylococcus aureus in 3 patients, methicillin resistant S. aureus in 1 patient, Klebsiella pneumonia in 1 patient, and Corynebacterium species in 1 patient.
Treatment consisted of intravenous antibiotics in all patients and TIPC removal in 11 patients, whereas the TIPC could be maintained after successful antibiotic treatment in 5 patients. Antibiotic treatment consisted of cefazolin in 7 patients; vancomycin in 3; levofloxacin in 3; and ceftriaxone, ceftazidime, and ertapenem in 1 patient each.
In patients with advanced malignancy, drainage of pleural effusions provides palliative relief of dyspnea. In the past, definitive treatment of malignant pleural effusions required hospitalization for pleurodesis or repeated therapeutic thoracenteses. However, TIPCs now offer the attractive option of an outpatient procedure providing long-lasting relief with minimal complications or need for hospitalization.13–15 As patients with advanced malignancies frequently receive chemotherapy treatment, providers often worry about the theoretically increased infectious risk while the indwelling pleural catheter is in place. We therefore performed a retrospective analysis of our experience with TIPC to compare the rates of infectious complications depending on whether or not patients underwent chemotherapy with a TIPC in place. We found no increased risk of infection with chemotherapy in our cohort, suggesting that TIPC may remain a safe option in patients with malignant pleural effusion, even when chemotherapy is still considered as an option.
The infection rate in our study falls within the range of 1% to 12% infection rate reported in previous studies. The rate of infection was not higher among patients undergoing chemotherapy, although the numbers were small and the study may not have been sufficiently powered to detect a difference. In addition, only 2 patients undergoing chemotherapy had neutropenia, which may explain the low observed infectious rate. We only reported neutropenia when severe, as defined by an absolute neutrophil count of <500/μL. Five patients received monotherapy (as opposed to combination cytotoxic chemotherapy) which may also explain the relatively low incidence of neutropenia in our cohort.
There are very limited data in the literature and conflicting reports as to whether concurrent chemotherapy treatment increases the complication risk. Morel et al16 found no significant difference in infection rates for patients receiving chemotherapy while the TIPC was present and those who did not receive chemotherapy and argued that chemotherapy should not be withheld from patients with a TIPC for malignant pleural effusion. In contrast, Sioris et al17 suggest that chemotherapy may be a predisposing factor both for infection and for catheter dislodgment.
We observed similar infection rates irrespective of whether patients were receiving chemotherapy or not. In addition, we found no difference in the incidence of different types of infection, specifically skin infection and empyema, in the 2 groups of patients. These results are in line with those of Morel et al16 who also reported no difference in infection rate between those who received chemotherapy while the TIPC was present and those who did not. The patient characteristics in these 2 groups were similar, with similar median duration of TIPC in place and a similar spread of underlying malignancies. The combined results of these studies, therefore, suggest that chemotherapy does not increase the risk of infectious complications in patients with TIPC in place.
Although 16 patients were excluded from the study due to death within 1 week of the TIPC placement, we could not find a relationship between TIPC placement and the death of these patients. Previous studies have demonstrated no-treatment–related deaths,18 suggesting that TIPC use does not compromise survival compared with alternative treatment options.
There are a number of limitations to our study. Because of the retrospective study design, our data analysis is based on the data extracted from chart review and therefore relies on the accuracy and completeness of the medical records. Although few patients were lost to follow-up, it is possible that some patients could have sought medical attention elsewhere for infectious reasons and treated without acknowledgement in the patients’ medical records. As the study was conducted in a single center, the data may be biased by local practices. In addition, there were relatively low number of patients who developed infection, which likely limited the power of our study and did not allow for meaningful subgroup analyses (such as influence of cancer type or chemotherapy regimen). Our data suggest that TIPC placement may be a safe option in patients eligible for chemotherapy. Future prospective studies would be helpful in confirming these findings.
In conclusion, we confirm that the incidence of infection in patients with malignant pleural effusion receiving TIPC is fairly low and does not appear dependent on whether patients receive chemotherapy at the time of catheterization. TIPC therefore remains a treatment option to palliate respiratory symptoms in patients with advanced malignancy with the need for only minimal or no hospitalization. Chemotherapy should not be viewed as a contraindication for indwelling pleural catheter insertion and similarly chemotherapy should probably not be withheld from patients who have a TIPC in place.
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