With an estimated 2.1 million cases and 1.8 million deaths per year, lung cancer remains one of the leading causes of cancer mortality worldwide due to inadequate tobacco control polices. The geographic patterns of lung cancer mortality copy those of incidence due to the relatively poor prognosis of the disease after diagnosis [5]. Nearly a third of cancer patients are dying with evidence of pulmonary metastases; those patients satisfying the criteria for surgical resection represent a much smaller subgroup. Pulmonary metastases in adults are usually from breast, GI tract, kidney, testes, head, and neck tumors or from a variety of bone and soft tissue sarcomas [6].
The need for immunohistochemistry and genetic studies is crucial to help personalize treatment strategies for advanced lung cancer patients. The new classification for small biopsies and cytology as proposed by the 2011 IASLC/ATS/ ERS Classification was a different approach in classification of lung cancers compared to the prior classification of resected lung cancers [7].
The most commonly recorded complication post-biopsy was pneumothorax, needing chest tube insertion [8]. In spite of being relatively safe procedure with low rates of morbidity and mortality, great interest has been propagating since 1970s in reducing post-procedural complications and thus hospital expenditure and stay [4].
A meta-analysis published by Huo et al. [8] pooling results from 21 articles on 8133 patients showed pneumothorax to be the most frequent complication of CT-guided lung biopsy cases. The pooled rates of pneumothorax were between 12 and 45%, and the chest tube placement was 5.6% according to some studies and as high as 17% in others.
Our study is a prospective randomized control study where 138 patients underwent CT-guided percutaneous thoracic tru-cut biopsies. Seventy cases underwent biopsy track embolization by Gelfoam slurry, and 68 cases were non-embolized.
Gelfoam is a porcine gelatin material prepared either in a Gelfoam injectable slurry [9], or prepared from gelatin powder into a thick injectable paste [1]. Being a viscous material more than air, it absorbs fluid from the surrounding tissue to seal the biopsy tract [1].
Similar materials for lung sealants (autologous blood patch, saline, gelatin, hydrogel plugs, or fibrin glue) have been proposed, but none of them gained popular use nor have been added to the international guidelines [8].
The best comparable studies regarding the utilization of Gelfoam material in track embolization after biopsy and statistical models of analysis were done by Tran et al. [4], Baadh et al. [1], and Renier et al. [9]. Although retrospective, they all were case–control studies where non-embolized control cases were compared to Gelfoam-embolized lung biopsy cases. Tran et al. [4] and Renier et al. [9] used Gelfoam in slurry form, while Baadh et al. [1] used gelatin powder. The rates of pneumothorax and chest tube insertion were then recorded and correlated with the pre-procedural and procedure-related risk factors in univariate and multivariate analytical models.
Our study was able to fulfill the homogenous risk factor representation with no statistical significance regarding most of the risk factors studied. However, more cases with central lung lesions were allocated to the embolized group in contrary to control cases with significant p value of 0.007. The patients in the embolized group were significantly older than those in the control group. In addition, more patients with pericardial invasion were noted in the control cases than in the embolized cases.
In our study, a total of 50 out of 138 patients (i.e., 36%) developed at least one complication during or after the biopsy. A total of 90 complications were recorded. The majority (45%) were pneumothoraces, 20% required chest tube, 12.2% had hemothorax, and only a total of 17.8% required hospital admission. These findings were in total keeping with the Society of Interventional Radiology (SIR) quality improvement guidelines; the suggested threshold rates for image-guided percutaneous needle biopsy in adults are 45% for all pneumothorax, 20% for all thoracostomy tube placement for pneumothorax [10].
In general, our study showed same proportions of patients suffered pneumothorax complications in both embolized and control cases, where 30% had pneumothoraces of the embolized group compared to 35% of the controls, yet this reduction was insignificant p = 0.507.
Tran et al. [4] showed in their study till no significant reduction in pneumothorax rates; however, most of them were small pneumothoraces in both cases and controls requiring no intervention p = 0.06.
On the contrary, Renier et al. [9] study successfully showed a reduction in the rates of pneumothorax occurrence with only 10% of the embolized group compared to 25.8% in control with a significant p value of 0.0001.
This statistical difference noted in the pneumothorax occurrence by Renier et al. [9] was owing to their exclusion criteria. In their study, they excluded all patients with pneumothorax occurring during the biopsy process and accounted only for post-procedural pneumothoraces. In our study and Tran et al. [4], we did not exclude these patients. It was worthy to mention that we found that some of the pneumothoraces occurring during the biopsy either did not progress to need chest tube insertion or even regressed on 4-h follow-up scans.
Our study was yet able to show a significant reduction in rates of chest tube insertion for pneumothorax occurrence 7.1% (i.e., 5 cases) of the embolized group compared to 19.7% (13 cases) of the controls (p = 0.037).
This finding correlated well with both Tran et al. [4] and Renier et al. [9].
Tran et al. [4] 10.7% of the non-embolized cases required a chest tube, whereas only 6.9% of the patients embolized needed a chest tube (p = 0.01). Renier et al. [9] showed also a reduction from 12.2% of the controls down to 3.5% in the embolized cases (p = 0.0005). Baadh et al. [1] showed statistically significant reduction (p = 0.007) in the total rate of procedure-related pneumothorax in track embolization patients (8.8%) when compared to controls (21%). There was a substantial reduction in the incidence of post-procedure chest tube placement in track embolization patients (4%) compared to controls (8.1%); however, conversely to our study they it did not reach statistical significance (p = 0.195) in their study.
In attempt to compare our results with the available literature, we correlated with a study dehydrated hydrogel done by Grage et al. [11] using prospective randomized control design. They applied it via Bio-seal biopsy seal lung plug deploying system®. Dehydrated hydrogel was close to Gelfoam being a solid material absorbing fluid from the lung interstitium after deployment and thus occluding the pleural puncture by a viscous plug.
Grage et al. [11] showed similar results regarding pneumothorax rates, with pneumothoraces occurring the rates of 29% compared to 31% in the controls. Their study showed a reduction in chest tube insertions from 10 to 2% only with p = 0.032.
Additionally, our study noted a significant reduction in post-procedural hospital admission. 19% of the controls were admitted compared to 4.3% of the embolized group with p = 0.007. These results correlated well with those of Grage et al. [11] study, where they showed reduction in the mean hospital stay from 0.44 nights to 0.07 nights.
An older study on Bio-seal biopsy seal lung plug deploying system® by Zaetta et al. [12] showed that hospitalization post-biopsy track embolization was reduced to 9.4% vs. 13.6% in the control group. Compared to this study our results remain still more significant regarding this aspect.
In our study, we did not witness any features of distant embolization or air embolization from Gelfoam slurry. Gelfoam remains more viscous than air and mixing with CT contrast agent would have enabled us to visualize such a potential hazard.
Baadh et al. [1] agreed that no features of distant (including neurological or peripheral vascular deficits), relative to the hemostat gelatin paste embolization during patient follow-up and clinical assessment.
In our study, a minority cases (8 patients) showed endobronchial leak in relation to cavitary lesions; however, this caused only self-limiting cough and required no management. Owing to the use of small amount of contrast in the slurry mixture, only 2 patients were recognized with minor contrast allergy.
Tran et al. [4] and Renier et al. [9] did not show these complications in their studies because they did not add contrast to the mixture. In spite of that, we still think contrast addition is beneficial in terms of visualization of the slurry throughout the follow-up period.
Univariate analysis was performed for pneumothorax occurrence, chest tube placement, and hospital admission. Multivariable models were developed for variables that were statistically significant at the univariate level or that differed significantly between study groups.
Univariate analysis showed that needle angle more than 70º increased the odds of pneumothoraces and the need for chest tube placement significantly by 2.859 and 3.106, respectively.
Lesion position has been accused of increasing odds of complications. We detected a significant correlation between hospital admission and central lesions and those invading the pericardium where they increased the odds of admission by 4.194 (p = 0.031) and 4.545 (p = 0.006) times, respectively. A number of cases with significant emphysematous lung changes had a minimal rim of pneumothorax prior to biopsy as in Fig. 1. These cases were associated with an increased risk of hospital admission by 8.571 times (p = 0.039). We were faced with some instances where the patients failed to follow respiratory instructions due to large tumor sizes, orthopnea, effusion, or even some cases of parkinsonism-induced truncal tremors. They accordingly required needle manipulation and repositioning. We found that this increased the odds of hospitalization by 3.467 times (p = 0.031).
The patient group seemed as the common protective factor throughout the univariate analysis of chest tube placement and hospital admission. It reduced chest tube placement by 68% (p = 0.044) and hospitalization by 81% (p = 0.012).
Multivariate regression models were carried out on chest tube insertion and hospital admission. Needle angle still significantly increased chest tube insertion rate by 3.526 times (p = 0.025). While in lesion location being more central or invading the pericardium increased hospitalization by 6.812 and 1.992, respectively.
Lesions close to the rib and peripheral position were significantly protective against chest tube insertion by 83% with a p value of 0.015.
Other risk factors were clinically significant, but as a result of their sparse incidence in the examined patient samples we could not statistically signify for their importance. For example, patients with cavitary lung lesions were more prone to hospitalization by 2.897 (p = 0.144). Multiple pleural punctures increased the risk of pneumothorax and chest tube insertions with an OR of 2.656 and 2.352; however, p values remained insignificant. Further future larger patient samples may help magnify the impact of such factor and assess their relevance (Fig. 2).
On the other hand, similar analysis by Tran et al. [4] showed increased odds of the same adverse events with track length more than 24 mm increased chest tube insertion chances by 262% (p = 0.003). Deep lesions biopsies are often more challenging due to anatomic obstacles and may require multiple adjustments of the needle during advancement or necessitate additional pleural passes [4].
According to logistic regression analysis by Renier et al. [9], they agreed that Gelfoam embolization was a protective parameter against pneumothorax and chest tube insertion in both univariate and multivariate models. In univariate analysis, it reduced the rate of pneumothorax by 68% in their study and chest tube by 74%. In multivariate model, it decreased the rate of pneumothorax by 69% and chest tube by 75% [9].
Although our study did not assess for added cost calculation, Gelfoam is still relatively a minimal added cost and relatively safe maneuver compared to the added cost of chest tube placement and overnight hospital stay. It can be used to finish up a properly planned lung biopsy considering all features of patient positioning to avoid anatomical obstacles. Additionally, we believe it remains more reliable and needs minimal training regarding preparation and deployment after completion of the biopsy. With proper preparation of the material, the odds of pneumothorax requiring chest tube insertion and hospital admission have been shown clinically and statistically to reduce. It was even noted in some patients developing pneumothorax during the biopsy, to regress over the follow-up period; however, we had no attempts of quantification of pneumothorax as its assessment remains still more subjective.
In Baadh et al. [1] study, they showed a marked reduction in cost owing to reduced rates of chest tube placement, resulting in higher costs per patient due to subsequent imaging, procedures, and hospitalization. The average cost per patient utilizing the track embolization technique was $262.40 compared to $352.07 for the non-track embolization group, which was statistically significant (p = 0.044).
Compared to Gelfoam utilizing studies, our study is a prospective randomized control study, assessing the frequency of the same range of complications including pneumothorax, chest tube insertion, hospitalization, and Gelfoam-related hazards. The mode of preparation of Gelfoam slurry was different from Tran et al. [4] and Renier et al. [9]. By adding 4 cc of CT contrast, we improved its visualization in the lung parenchyma over the follow-up period and improved the visualization of any leakage and potential embolization. We injected the slurry throughout the tract not only at the pleural puncture site aiming to seal the pleural puncture site and subcutaneous tissues to avoid external air from being sucked to the potential pleural space.
Our study still showed some drawbacks. In spite of randomization, still some risk factors were more represented in the controls than in the cases group; like the lesion position being more central in the embolized groups, this did not impact the rates of complications reduction. We also did not attempt quantification of time spent during the biopsy to see if Gelfoam was more time-consuming in preparation and injection. In further research, we wish to quantify further details about hospital expenditures in relation to complications and other commercially available sealants in our market, to see how far can Gelfoam stand the comparison and prove helpful financially and clinically.
It is worth noting that our sample size fulfilled our primary research question and gave satisfying results regarding a reduction in post-biopsy adverse events. However, we are still interested in evaluating the risk factors by attempting logistic regression models with a larger sample size.