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Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review
Journal Pre-proof Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review Ioana Baiu, MD MPH, Elorm Yevudza, BS, Joseph B. Shrager, MD PII:
S0003-4975(19)31549-8
DOI:
https://doi.org/10.1016/j.athoracsur.2019.08.104
Reference:
ATS 33127
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 June 2019 Revised Date:
13 August 2019
Accepted Date: 29 August 2019
Please cite this article as: Baiu I, Yevudza E, Shrager JB, Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.08.104. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review Ioana Baiu MD MPH1, Elorm Yevudza BS2, Joseph B. Shrager MD2
1
Stanford University School of Medicine, Department of General Surgery, Stanford, CA Stanford University School of Medicine, Department of Cardiothoracic Surgery, Division of Thoracic Surgery 2
Corresponding Author: Ioana Baiu, MD MPH 300 Pasteur Dr., H3653 Stanford, CA 94305 [email protected]
1
Abstract Background: Talcum has been used in pleurodesis for over eight decades. Despite a wealth of research, controversy remains over the optimal sclerosant for pneumothorax and pleural effusions. Talc’s historical primacy has been challenged due to its potential for pulmonary toxicity, possible carcinogenicity, and recent concerns surrounding availability and legal liability, making an ideal time for a review. Methods: This is a systematic review of the talc literature, focused on publications after the year 2000 evaluating mechanism of action, efficacy, side-effect profile, and alternative sclerosants; included is an overview of current socioeconomic and legal controversies. Results: The data support talc as the most effective agent for pleurodesis. There is evidence to suggest that mean particle size has a direct relationship to the side-effect profile and that significant hypoxemic events following talc administration are exceedingly rare using available graded talc preparations. Concerns regarding the development of malignancies following topical talc application remain incompletely resolved but appear related to cosmetic powder preparations that were contaminated with asbestos. Purified talc in the pleural space has not been implicated. Recent difficulties accessing commercial talc preparations have been solved. Although safe and effective talc alternatives do exist, these agents are not as well studied. Conclusions: Talc pleurodesis with modern, purified, graded talc preparations is safe and highly effective. Talc is an inexpensive and accessible option that remains appropriate for pleurodesis despite existing controversies.
2
Despite several decades of clinical experience and an abundance of research on the subject, there remains substantial controversy surrounding the use of the mined mineral, talcum, as a sclerosant to achieve pleurodesis. Talc, or hydrated magnesium silicate (Mg3Si4O10(OH)2), is mined around the world and used for a variety of purposes (plastic production, paint, ceramics, paper, cosmetics, medicine). Medical talc is purified to contain >95% talcum.
Thoracoscopic talc poudrage was first reported by
Bethune in 1935 to induce adhesions following lobectomy1. In 1958, Chambers described the use of talc for treatment of malignant pleural effusions (MPE)2. While other agents have been used for pleurodesis, strong evidence shows talc to be the most effective and economical agent for MPE3,4,5. Talc also remains widely used in primary spontaneous pneumothorax (PSP), for which modest evidence suggests its superiority to mechanical pleurodesis6. The uncommon occurrence of a substantial systemic inflammatory response (SIR) to intrapleural talc, which may rarely result in Acute Respiratory Distress Syndrome (ARDS), has ignited recent reexamination of talc for pleurodesis. This re-evaluation is occurring despite correlation of small talc mean particle size (MPS) with SIR/ARDS, which can be avoided with modern talc preparations. Nevertheless, interest has grown in alternative sclerosants. Recent shortages of talc, and an emerging fear that talc use could result in litigation over a possible association between ovarian cancer and perineal talc, has furthered recent controversy. Given the above, this is an appropriate time for a review of the role, indications, risks, and potential legal and socioeconomic ramifications of talc pleurodesis.
I.
Patients and Methods We performed a literature review in PubMed of research involving agents for pleurodesis for
pleural effusion and pneumothorax. We included systematic review articles and original research. We limited reference to case series with at least 30 subjects, published after the year 2000, other than papers establishing “firsts”. The legal/socioeconomic review is based on publicly available documents and media.
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II.
Mechanism of Action
Pleurodesis creates an inflammatory response to encourage the symphysis of the parietal and visceral pleurae, eliminating the potential space created by pneumothorax or effusion.
Animal models
demonstrate that talc creates inflammation, edema, cellular proliferation, and dose-dependent fibrosis when applied intrapleurally as powder or slurry7,8. Talc pleurodesis has local and systemic effects. In both animal and human models there is a notable increase in serum and pleural fluid levels of leukocytes, percentage of neutrophils, macrophages, lactate dehydrogenase (LDH), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP)9,10,11. Studies also show a potential antineoplastic effect via apoptosis of cancer cells12,13.
III.
Clinical Effectiveness The efficacy of talc as a chemical sclerosant in both MPE and, to a lesser extent, PSP has been
well established, and it appears to be the most effective agent available. A Cochrane review of MPE concluded that talc was the most efficacious and least likely to result in recurrence versus bleomycin, tetracycline, and mustine3. Furthermore, the relative risk of death in the talc group was not statistically different compared to other agents, and all of the deaths were found to be related to the underlying disease 3
. Other systematic reviews also support that patients treated with talc had fewer MPE recurrences
compared to bleomycin (RR 0.64) or tetracycline (RR 0.5) as well as compared to Corynebacterium parvum, mustine, mitoxantrone, mepacrine4,14. The reported effectiveness of talc in pleurodesis for MPE ranges from 70-100%, assuming a fully expansile lung15. For primary spontaneous pneumothorax, talc pleurodesis is safe and has minimal side-effects apart from pain and fever16. A systematic review showed that talc pleurodesis is more effective than pleurectomy or mechanical pleural abrasion, with recurrence rates of 0.4-1.8%6. Although there no prospective randomized trials comparing talc pleurodesis with pleural abrasion, the former does appear to be associated with lower morbidity, shorter in hospital length-of-stay, and lower reintervention rates in retrospective cohorts17. Talc poudrage is far more effective than chest tube drainage alone18.
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IV.
Particle Size and Dose Depending on its region and even its mine of origin, talc characteristics can vary widely, and it
has been well-established that variation in particle size and contaminants can lead to different side-effect profiles in patients19. The concept of “graded” or “calibrated” talc refers to preparations that have been processed into a powder of a certain particle size and filtered to remove smaller particles. The mean particle size of different preparations of “graded talc” nevertheless differ substantially, between approximately 10 and 25 µm. Talc mined in the United States has traditionally been processed to a mean particle size of 10.8 µm, as compared to >30 µm in France and Taiwan19. SIR associated with talc has stimulated research on the role of particle size and dosage. There are two proposed mechanisms by which talc particles migrate systemically: lymphatic absorption or induced changes in alveolar-capillary membrane permeability.
In animal models,
intrapleural instillation of small particles leads to a more robust SIR compared to large particles, with small particle deposits found in the liver and kidneys20,21.
Other studies show that although the
pleurodesis created is equivalent, smaller particle formulations produce more inflammation and are more likely to deposit in distant organs22. A randomized, blinded clinical trial in MPE evaluated small and large particle talc and found worse alveolar-arterial (A-a) gradient, reduction of PaO2, fever, and increased serum CRP level in the former group23. Another study comparing small and large particle formulations in MPE found similar rates of pain, fever, and successful pleurodesis; the former group had higher levels of serum and pleural fluid inflammatory markers and a higher risk of death attributed to a variety of causes24. One large study in patients with MPE confirmed efficacy and safety using largeparticle talc (MPS 24.5 µm), with zero incidence of ARDS25. Systemic deposition of talc is also dose-dependent. In rabbit models, pleurodesis with small MPS talc (8.36 µm) revealed dose-dependent deposition in other organs, in contrast to large-particle talc (MPS 33.6 µm), which had minimal spread26,27. Several studies published before the year 2000 suggest that
5
higher doses of talc are associated with more complications in patients, but the dose-dependent sideeffect profile has not been systematically studied in humans28. In conclusion, there is strong animal-based and clinical evidence that mean particle size and dose are important determinants of systemic distribution and inflammation following talc pleurodesis. Spread to distant sites has been considered a proxy for the systemic effects of talc, and thus, presumably, the SIR and the rare ARDS responses. In the clinical application of talc, it is clear that one must take into consideration the variability of particle size across different manufacturers and talc sources, as graded talc with larger mean particle sizes is less likely to have systemic effects. The medical talc from Lymol, Inc that was widely used in the U.S. until recently was considered “graded”, but the FDA did not disclose an exact particle size. Novatech, a European company that now sells Sclerosol in the U.S. and Steritalc in Europe, supplies graded talc with MPS > 31.3 µm. The dose of talc that appears to provide effective pleurodesis with a low risk of ARDS is generally agreed among experts to be 4-5 grams, instilled unilaterally, in a 70 kg adult, in agreement with the American Thoracic Society 2000 Consensus recommendations28.
V.
Talc Side-Effects
Despite the proven efficacy of talc pleurodesis for both pneumothorax and MPE, talc has been associated with potentially serious systemic complications. As the most studied pleural sclerosant, talc’s side-effect profile is better documented than that of other agents. Common reactions include chest pain and fevers.
The more feared complications include a SIR syndrome that can be accompanied by
respiratory distress that may progress to ARDS. Furthermore, weak associations between topical perineal talc powder and gynecologic malignancies have been elucidated, begging the question of whether intrapleural talc could increase the risk of cancers. Notably, pulmonary function tests (PFT’s) are not affected by talc pleurodesis in long-term follow-up29.
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1. ARDS
The true association of talc pleurodesis with ARDS is difficult to elucidate due to its low incidence. The earliest report described 3 patients with ARDS and 1 death after instillation of 10g of nongraded talc slurry via chest tube30. However, a multicenter prospective cohort study of talc poudrage using graded Steritalc (MPS 24.5 µm) had an ARDS incidence of zero, in agreement with other large trials25,16. A small study using non-graded talc slurry for MPE or PSP reported a rate of complications of 15% (tachycardia, pain, fever or dyspnea) with one death attributed to ARDS; however, the study lacked conclusive evidence for ARDS31. De Campos and Light reported a 1.3% incidence of ARDS with 50% mortality with non-graded talc (PS 5-70 µm)32.
A retrospective review from Japan found a 15%
incidence of ARDS when large PS talc (>25 µm) was used, however, the description of ARDS was not consistent with the widely-accepted 2012 Berlin criteria, thus raising validity concerns33,34. Throughout the literature, the definition of ARDS, as well as the dosages and particle size of talc used vary considerably, making the incidence of this syndrome difficult to establish.
The debate
continues, and some contend that even a rare case of ARDS is not a risk worth taking, others argue that the high efficacy and low cost of talc trumps the minimal risks35,36. The authors of this review do not find the evidence for the risk of ARDS when using large-particle, graded talc to be sufficiently compelling to require a change in practice towards other sclerosing agents.
2. Malignancy
Recently, concerns have arisen regarding a potential association of topical talc usage with malignancy. Prior to 1970, talc was frequently contaminated by asbestos, a known carcinogen. Since
7
then, talc used in cosmetic powders or for any medical purpose has undergone purification intended to eliminate such contamination. The Nurses’ Health Study (NHS), a prospective cohort comprising of 121,700 women enrolled in 1976, revealed a small increase in risk of invasive serous ovarian cancer (RR 1.4, 95% CI 1.02-1.92)37. There was no increased risk of other types of ovarian cancer or ovarian cancer risk overall. A 24% increase in endometrial cancer risk was noted, accentuated by increased usage frequency37,38.
The
Women's Health Initiative Observational Study failed to demonstrate any association between perineal powder use and ovarian cancer39. Nevertheless, a large meta-analysis showed a small increase in the risk of ovarian cancer with OR 1.31 (95% CI 1.24-1.39)40.
Endometrial cancer has also been weakly
associated with use of perineal talc, although the Australian National Endometrial Cancer Study, a casecontrol study of 1,399 women with endometrial cancer and 740 controls, revealed no association41. The National Cancer Institute currently maintains that the suggestion of perineal talc usage causing inflammation of the ovaries is not supported by “the weight of the evidence.” To summarize, there is perhaps a weak association between perineal talc use and increased risk of female genital malignancies. However, the data has not been clearly elucidated and many controversies still exist. Importantly, we identified no reports of talc causing malignant mesothelioma; nor any literature linking intrapleural talc to any non-thoracic malignancies. Surgeons should, therefore, be mindful of patient concerns regarding the potential risk of malignancy with topical talc application, but they can reassure patients that intrapleural talc use has not been linked to any malignancies.
VI.
Alternatives to Talc Over the years, alternatives to talc have been studied including: silver nitrate (SN), tetracycline
and derivatives, erythromycin, TGF-β2, tigecycline, bleomycin, iodopovidone, quinacrine, ethanolamine oleate, blood, OK-432, NaOH, and Helixor-M. Several studies have compared talc formulations (powder vs slurry) and instillation methods (video-assisted thoracoscopic surgery (VATS) versus chest tube). Lastly, tunneled pleural catheters (TPC) have been studied as an alternative for MPE. A 2003 survey of
8
physicians identified talc slurry as the most-used agent (56%), followed by tetracycline and its derivatives (26%), talc powder (12%) and bleomycin (7%).
Light and Dikensoy argue that SN, quinacrine,
iodopovidone, and doxycycline are reasonable, inexpensive alternatives to talc42.
Although not
exhaustive, this section will review the main alternatives to talc.
a.
Silver nitrate (SN)
SN (1-10% solution) was among the first agents employed for pleurodesis43. The strong local inflammatory response and pain associated with SN at higher doses initially made it unpopular. Studies using lower concentrations have shown promising results with less pain44.
In animal models, SN
produces faster and more robust adhesions and alveolar collapse vs. talc, but with time this difference fades45,46. Low doses of SN can lead to intense pleural inflammation with fewer side effects compared to higher doses11,9. The one-year success rate is similar between SN and talc in animal models47. The only prospective randomized trial in patients with MPE using SN vs. talc administered via chest tube found equivalent rates of pain and successful pleurodesis at 30 days, with no incidence of ARDS48. A literature review on pleurodesis using 0.5% SN in patients with MPE concluded similar short-term success rates to talc, but with a guarded recommendation for use given the lack of long-term follow-up49. There are substantial systemic effects in patients treated with SN, including dose-related hypoxia and acute kidney injury50. Data like this have led researchers to try lower doses with repeated treatments, but, to our knowledge, this approach has not been studied in humans. Overall, the literature suggests that SN may be a reasonable alternative to talc, but the optimal dose and long-term results remain incompletely defined.
b.
Tetracycline derivatives
9
Tetracycline is no longer available for pleurodesis in the U.S., but its derivatives (minocycline, doxycycline) are still used. In animal models, these agents led to higher rates of hemothorax, fibrosis, and local tissue damage compared to talc7,8. In patients treated with tetracycline, blood patch, or talc instilled via chest tubes for PSP, the success of tetracycline was 63%, blood 75%, and talc 84%51.
A
retrospective study in patients with recurrent MPE looking at tetracycline or bleomycin instilled via chest tube vs. talc instilled via VATS or thoracotomy, found talc to be superior with lower drainage and earlier chest tube removal52. Two small randomized trials comparing tetracycline with talc in MPE showed that talc created a higher local and systemic inflammatory response23. In a meta-analysis, RR for nonrecurrence of MPE after talc vs tetracycline was 1.34, in favor of talc3. The data for tetracycline derivatives in chemical pleurodesis thus does not support these agents over talc.
c.
Bleomycin
When bleomycin is compared against talc and tetracycline derivatives, it usually underperforms with respect to pleurodesis success and recurrence53,54.
In multiple prospective randomized trials,
bleomycin is less effective or, at best, as effective as talc or tetracycline derivatives. In a meta-analysis, RR for non-recurrence of MPE was 1.34 for talc compared to bleomycin3. While bleomycin has a good side-effect profile, it is more expensive than other options. The evidence of reduced rates of successful pleurodesis with bleomycin and its cost do not support its use over talc.
d.
Iodopovidone
When compared to talc, iodopovidone produces similar results, with a low side-effect profile and less pain55,56. A meta-analysis showed success rates of iodopovidone as high as 89-95% in MPE and PSP with pain and hypotension as the most notable side-effects57. When compared directly to bleomycin,
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iodopovidone has similar rates of success but is significantly cheaper58. A multicenter prospective trial of 10% iodopovidone used in patients with recurrent MPE reported a 96% efficacy59. Concerns about the safety of iodopovidone causing hypothyroidism do not appear to be clinically significant60,61. However, with doses greater than 600-1,200mg of iodate (well above the dose for pleurodesis), ocular toxicity may occur62. More data is needed to evaluate iodopovidone’s dosing and safety profile, but results are promising.
e.
Blood
Autologous blood has been reported as a sclerosant in patients with pneumothorax, postoperative air leak, and hydrothorax complicating peritoneal dialysis63. The mechanism of action is unclear, but likely explained by the formation of adhesions as well as a presumed “patch” effect leading to resolution of postoperative air leaks. Post-lobectomy patients with air leaks on post-operative day 5 showed a benefit of intrapleural instillation of 120 mL of autologous blood via chest tube55. However, empyema has been reported to occur in up to 9% of cases63. The data for blood pleurodesis in PSP is weak; the existing trials are small, heterogeneous and unblinded. It is probable that the “pleurodesing” effect of pleurectomy results in part from the blood spillage. Autologous blood has not been studied in the setting of MPE. Given other more easily available, better-studied, effective alternatives, we do not recommend the use of blood as a first choice for pleurodesis in PSP or MPE.
f.
Others
Many other substances have been tested as potential alternatives to talc for pleurodesis. Quinacrine, an anti-malarial drug, has shown a poor side-effect profile (pain and fever) vs. tetracycline, and an increased need for repeat treatments vs. talc65. OK-432 has been extensively studied in rats and
11
humans with MPE and shown to result in less fibrosis compared to talc in rats66. In humans, the efficacy and safety profiles appear to be similar, but larger trials are needed67. In animals, TGF-β2 induces more collage deposition, higher pleural fibrosis and pleural thickness, with a lower WBC and LDH compared to talc68.
In vitro, TGF-β2 upregulates mesothelial cell collagen synthesis and increases VEGF
production, while in vivo it creates less pleural inflammation in comparison to talc and doxycycline69. All of the above agents provide intriguing alternatives to talc, but they are more expensive, less available, and require further investigation in humans.
g.
Tunneled Pleural Catheters
Any discussion of talc’s role in MPE must at least briefly consider the relatively recent, successful application of tunneled pleural catheters (TPC). These provide immediate symptom palliation in 89% of patients with a mean duration of 56 days70. They create pleurodesis in 42-60% of patients with MPE, depending in part on whether the lung is fully expansile70,71. TPCs have the advantage of being able to be placed on an outpatient basis without general anesthesia. Empyema is rare (1-5% of patients), but can be quite morbid. Notably, a hybrid approach using VATS talc pleurodesis and TPC placement at the same time provides a higher rate of pleurodesis, with 92% of patients with MPE achieving pleurodesis at 6 months, a median inpatient stay of 2 days and 7 days of outpatient TPC use72. A randomized study in MPE showed a higher rate of successful pleurodesis in patients with TPC who received outpatient talc instillation 2 weeks later compared to placebo instillation73.
Treatments centered on IPCs are thus certainly
reasonable for patients who are not averse to a potentially permanent external device. IPC use should be an individualized decision made by each patient together with their physicians.
VIII.
Talc slurry vs powder
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The method by which talc is instilled intrapleurally appears to have a small impact on the efficacy of pleurodesis. Talc poudrage is achieved via VATS, while talc slurry is typically instilled via chest tube. These result in superimposable recurrence rates, except breast and lung cancer subgroups, where poudrage has a slight advantage74,75. In severely debilitated patients with MPE, performing a bedside talc slurry eliminates the risks of anesthesia76. Patient-centered outcomes in patients with MPE were similar between TPCs, talc poudrage, and talc slurry, but talc poudrage produced the most durable results77. Patient satisfaction was highest (but insignificantly different) in those who had VATS poudrage and lowest in those who had the slurry. Certainly, bedside chest tube placement and talc instillation is less comfortable than similar procedures done under general anesthesia; however, the risks of general anesthesia and the cost must also be considered. When pleural biopsy is required to establish a diagnosis, VATS is indicated. We will not broach the topic of VATS biopsy or talc poudrage under sedation only, although this has been demonstrated possible78. In summary, talc poudrage and slurry pleurodesis offer nearly equivalent results and, therefore, the choice should be grounded in a discussion of goals of care between the physician and the patient.
IX.
Cost of Talc Given that there is solid data supporting several chemical sclerosants, their cost and availability
should be taken into consideration. Analyzing the costs of talc can be challenging, as numbers quoted the literature vary greatly by institution and source. The overall consensus among studies is that talc is less costly than other agents, but povidone iodine and SN are similarly affordable. Biologic agents (e.g. OK432, TGF-B) are more expensive. In patients with PSP, thoracoscopic talc poudrage is more costeffective than bedside drainage even in patients with a first episode of a pneumothorax18,79. In the treatment of MPE, cost-effectiveness appears dependent on expected survival time80. In 3-month survival analyses, TPCs were found to be cheap and effective. Repeated thoracentesis was the least expensive ($4,946) but provided the lowest quality-adjusted-life-years (QALYs), followed in cost by TPC ($6,450), bedside pleurodesis ($11,224) and thoracoscopic pleurodesis ($18,604). In 12-month survival analyses,
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bedside pleurodesis was the least expensive and provided the most QALYs, while repeat thoracentesis was the most expensive. VATS pleurodesis was the most effective, but the incremental cost-per-QALYs gained over lifetime was estimated >$250,000. Therefore, the most recent cost-effectiveness analyses suggest that in patients with limited survival, TPCs are favored from a cost-effectiveness perspective; by contrast, in patients with more prolonged expected survival, bedside talc pleurodesis provides the most cost-effective alternative.
X.
Shortages of Talc The privately-owned company Lymol Medical (formerly Bryant Corp) had been the main
supplier of sterile talc powder in the U.S. In 2016, there was a recall of Lymol’s aerosolized talc when the Food and Drug Administration (FDA) cited inappropriate sterilization techniques, leading to a national shortage. The company pleaded guilty to selling incorrectly sterilized talc from 1997 to 2007. U.S. centers urgently needed a new source. At our center, we contracted with a compounding pharmacy to sterilize and filter talc to our specifications due to the shortage.
In August 2017, Novatech
collaborated with Boston Medical Products and began importing FDA-approved sterile graded talc [Steritalc (MPS > 25 µm)], essentially solving the previous national shortage.
XI.
Talc Litigation The putative association between perineal talc powder and the risk of developing gynecologic
cancers (mesothelioma in a few cases) has led to over 12,000 plaintiffs suing Johnson&Johnson, the primary maker of talc for home use. In 2016, the company was ordered to pay a total of $127 million in cases in Alabama and Missouri. In 2017, 4,800 women with ovarian cancer requested that Johnson&Johnson replace its baby powder with one made exclusively of cornstarch or place a carcinogenicity warning on the product. In 2018, a jury awarded $4.69 billion to women claiming that asbestos in the powder caused their ovarian cancer (currently under appeal). Other lawsuits are pending.
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Most recently, jurors in Missouri cleared the company of any responsibility, arguing that the causal association between talc and malignancy is not sufficiently strong. Talc contaminated with asbestos, prior to the institution of purification in the 1970’s, would have the hypothetical potential to cause mesothelioma if instilled into the pleural space. However, there are no reports in the medical literature of this occurring. The litigation on ovarian cancer, however, has raised the question as to whether even “asbestos-free”, purified talc could cause pleural malignancy (or even non-thoracic malignancies, as intrapleural talc does result in some systemic absorption). Notably, we found no such documented cases in the literature. The only long-term (118 months) outcome study after talc pleurodesis showed no increased risk of cancer, but the study was underpowered and with insufficient follow-up time29. There are several undecided tort cases (and two decided – one for each side) against Johnson&Johnson for mesothelioma claimed to have been caused by inhaled asbestos fibers in talc for home use. We are not aware of any talc lawsuits that name physicians as defendants. Overall, any concern by surgeons that their use of medical talc powder in the pleural space could lead to litigation on the basis of the development of future cancers is currently unfounded.
XII.
Conclusions Talc has been used for more than 80 years and is clearly established as an efficacious and cost-
effective agent in the management of pneumothorax and pleural effusions. The systemic risks associated with its use are almost always tolerable, with an extremely low risk of clinically significant pulmonary dysfunction when using large-particle, graded talc. While this latter complication has been observed by most thoracic surgeons at some point during their career, this was almost certainly prior to the consistent institution of graded talc with particle sizes in the safe range. Several of the sclerosant alternatives to talc are promising (in particular, SN and iodopovidone), but these have not been sufficiently well-studied in prospective, randomized trials to allow us to make a strong recommendation with regard to the use of any particular agent over talc.
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There is weak statistical evidence implicating perineal talc use in the development of ovarian cancer. Although no studies have specifically evaluated the risk of ovarian cancer following talc pleurodesis, there are no reports of this occurring, and it seems unlikely that such a relationship would exist given the limited systemic distribution of talc with large particle formulations. More research is needed to fully elucidate the relationship between talc and gynecologic cancers. Similarly, there is neither evidence for, nor reason to believe that, talc pleurodesis causes mesothelioma. Given the existing evidence, we believe that, among the agents available for pleurodesis, purified graded talc is the most reliable and efficacious agent, along with clearly defined optimal dosing, a good side-effect profile, and reasonable cost.
The existing literature reveals minimal risk of serious
complications such as ARDS with large-particle, graded talc – a rate of occurrence so low that we cannot make a compelling argument for routine use of talc-alternatives at this time. The recently experienced talc shortages in the U.S. are now resolved.
We see no reason that recent talc litigation surrounding
malignancy should dissuade surgeons. Although other agents such as silver nitrate and iodopovidone are also not unreasonable to employ, talc currently remains the gold standard agent for pleurodesis.
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18
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Vargas FS, Teixeira LR, Antonangelo L, Vaz MA, Carmo AO, Marchi E, et al. Experimental
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Paschoalini M da S, Vargas FS, Marchi E, Pereira JR, Jatene FB, Antonangelo L, et al.
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24
S0003-4975(19)31549-8
DOI:
https://doi.org/10.1016/j.athoracsur.2019.08.104
Reference:
ATS 33127
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 June 2019 Revised Date:
13 August 2019
Accepted Date: 29 August 2019
Please cite this article as: Baiu I, Yevudza E, Shrager JB, Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.08.104. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review Ioana Baiu MD MPH1, Elorm Yevudza BS2, Joseph B. Shrager MD2
1
Stanford University School of Medicine, Department of General Surgery, Stanford, CA Stanford University School of Medicine, Department of Cardiothoracic Surgery, Division of Thoracic Surgery 2
Corresponding Author: Ioana Baiu, MD MPH 300 Pasteur Dr., H3653 Stanford, CA 94305 [email protected]
1
Abstract Background: Talcum has been used in pleurodesis for over eight decades. Despite a wealth of research, controversy remains over the optimal sclerosant for pneumothorax and pleural effusions. Talc’s historical primacy has been challenged due to its potential for pulmonary toxicity, possible carcinogenicity, and recent concerns surrounding availability and legal liability, making an ideal time for a review. Methods: This is a systematic review of the talc literature, focused on publications after the year 2000 evaluating mechanism of action, efficacy, side-effect profile, and alternative sclerosants; included is an overview of current socioeconomic and legal controversies. Results: The data support talc as the most effective agent for pleurodesis. There is evidence to suggest that mean particle size has a direct relationship to the side-effect profile and that significant hypoxemic events following talc administration are exceedingly rare using available graded talc preparations. Concerns regarding the development of malignancies following topical talc application remain incompletely resolved but appear related to cosmetic powder preparations that were contaminated with asbestos. Purified talc in the pleural space has not been implicated. Recent difficulties accessing commercial talc preparations have been solved. Although safe and effective talc alternatives do exist, these agents are not as well studied. Conclusions: Talc pleurodesis with modern, purified, graded talc preparations is safe and highly effective. Talc is an inexpensive and accessible option that remains appropriate for pleurodesis despite existing controversies.
2
Despite several decades of clinical experience and an abundance of research on the subject, there remains substantial controversy surrounding the use of the mined mineral, talcum, as a sclerosant to achieve pleurodesis. Talc, or hydrated magnesium silicate (Mg3Si4O10(OH)2), is mined around the world and used for a variety of purposes (plastic production, paint, ceramics, paper, cosmetics, medicine). Medical talc is purified to contain >95% talcum.
Thoracoscopic talc poudrage was first reported by
Bethune in 1935 to induce adhesions following lobectomy1. In 1958, Chambers described the use of talc for treatment of malignant pleural effusions (MPE)2. While other agents have been used for pleurodesis, strong evidence shows talc to be the most effective and economical agent for MPE3,4,5. Talc also remains widely used in primary spontaneous pneumothorax (PSP), for which modest evidence suggests its superiority to mechanical pleurodesis6. The uncommon occurrence of a substantial systemic inflammatory response (SIR) to intrapleural talc, which may rarely result in Acute Respiratory Distress Syndrome (ARDS), has ignited recent reexamination of talc for pleurodesis. This re-evaluation is occurring despite correlation of small talc mean particle size (MPS) with SIR/ARDS, which can be avoided with modern talc preparations. Nevertheless, interest has grown in alternative sclerosants. Recent shortages of talc, and an emerging fear that talc use could result in litigation over a possible association between ovarian cancer and perineal talc, has furthered recent controversy. Given the above, this is an appropriate time for a review of the role, indications, risks, and potential legal and socioeconomic ramifications of talc pleurodesis.
I.
Patients and Methods We performed a literature review in PubMed of research involving agents for pleurodesis for
pleural effusion and pneumothorax. We included systematic review articles and original research. We limited reference to case series with at least 30 subjects, published after the year 2000, other than papers establishing “firsts”. The legal/socioeconomic review is based on publicly available documents and media.
3
II.
Mechanism of Action
Pleurodesis creates an inflammatory response to encourage the symphysis of the parietal and visceral pleurae, eliminating the potential space created by pneumothorax or effusion.
Animal models
demonstrate that talc creates inflammation, edema, cellular proliferation, and dose-dependent fibrosis when applied intrapleurally as powder or slurry7,8. Talc pleurodesis has local and systemic effects. In both animal and human models there is a notable increase in serum and pleural fluid levels of leukocytes, percentage of neutrophils, macrophages, lactate dehydrogenase (LDH), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP)9,10,11. Studies also show a potential antineoplastic effect via apoptosis of cancer cells12,13.
III.
Clinical Effectiveness The efficacy of talc as a chemical sclerosant in both MPE and, to a lesser extent, PSP has been
well established, and it appears to be the most effective agent available. A Cochrane review of MPE concluded that talc was the most efficacious and least likely to result in recurrence versus bleomycin, tetracycline, and mustine3. Furthermore, the relative risk of death in the talc group was not statistically different compared to other agents, and all of the deaths were found to be related to the underlying disease 3
. Other systematic reviews also support that patients treated with talc had fewer MPE recurrences
compared to bleomycin (RR 0.64) or tetracycline (RR 0.5) as well as compared to Corynebacterium parvum, mustine, mitoxantrone, mepacrine4,14. The reported effectiveness of talc in pleurodesis for MPE ranges from 70-100%, assuming a fully expansile lung15. For primary spontaneous pneumothorax, talc pleurodesis is safe and has minimal side-effects apart from pain and fever16. A systematic review showed that talc pleurodesis is more effective than pleurectomy or mechanical pleural abrasion, with recurrence rates of 0.4-1.8%6. Although there no prospective randomized trials comparing talc pleurodesis with pleural abrasion, the former does appear to be associated with lower morbidity, shorter in hospital length-of-stay, and lower reintervention rates in retrospective cohorts17. Talc poudrage is far more effective than chest tube drainage alone18.
4
IV.
Particle Size and Dose Depending on its region and even its mine of origin, talc characteristics can vary widely, and it
has been well-established that variation in particle size and contaminants can lead to different side-effect profiles in patients19. The concept of “graded” or “calibrated” talc refers to preparations that have been processed into a powder of a certain particle size and filtered to remove smaller particles. The mean particle size of different preparations of “graded talc” nevertheless differ substantially, between approximately 10 and 25 µm. Talc mined in the United States has traditionally been processed to a mean particle size of 10.8 µm, as compared to >30 µm in France and Taiwan19. SIR associated with talc has stimulated research on the role of particle size and dosage. There are two proposed mechanisms by which talc particles migrate systemically: lymphatic absorption or induced changes in alveolar-capillary membrane permeability.
In animal models,
intrapleural instillation of small particles leads to a more robust SIR compared to large particles, with small particle deposits found in the liver and kidneys20,21.
Other studies show that although the
pleurodesis created is equivalent, smaller particle formulations produce more inflammation and are more likely to deposit in distant organs22. A randomized, blinded clinical trial in MPE evaluated small and large particle talc and found worse alveolar-arterial (A-a) gradient, reduction of PaO2, fever, and increased serum CRP level in the former group23. Another study comparing small and large particle formulations in MPE found similar rates of pain, fever, and successful pleurodesis; the former group had higher levels of serum and pleural fluid inflammatory markers and a higher risk of death attributed to a variety of causes24. One large study in patients with MPE confirmed efficacy and safety using largeparticle talc (MPS 24.5 µm), with zero incidence of ARDS25. Systemic deposition of talc is also dose-dependent. In rabbit models, pleurodesis with small MPS talc (8.36 µm) revealed dose-dependent deposition in other organs, in contrast to large-particle talc (MPS 33.6 µm), which had minimal spread26,27. Several studies published before the year 2000 suggest that
5
higher doses of talc are associated with more complications in patients, but the dose-dependent sideeffect profile has not been systematically studied in humans28. In conclusion, there is strong animal-based and clinical evidence that mean particle size and dose are important determinants of systemic distribution and inflammation following talc pleurodesis. Spread to distant sites has been considered a proxy for the systemic effects of talc, and thus, presumably, the SIR and the rare ARDS responses. In the clinical application of talc, it is clear that one must take into consideration the variability of particle size across different manufacturers and talc sources, as graded talc with larger mean particle sizes is less likely to have systemic effects. The medical talc from Lymol, Inc that was widely used in the U.S. until recently was considered “graded”, but the FDA did not disclose an exact particle size. Novatech, a European company that now sells Sclerosol in the U.S. and Steritalc in Europe, supplies graded talc with MPS > 31.3 µm. The dose of talc that appears to provide effective pleurodesis with a low risk of ARDS is generally agreed among experts to be 4-5 grams, instilled unilaterally, in a 70 kg adult, in agreement with the American Thoracic Society 2000 Consensus recommendations28.
V.
Talc Side-Effects
Despite the proven efficacy of talc pleurodesis for both pneumothorax and MPE, talc has been associated with potentially serious systemic complications. As the most studied pleural sclerosant, talc’s side-effect profile is better documented than that of other agents. Common reactions include chest pain and fevers.
The more feared complications include a SIR syndrome that can be accompanied by
respiratory distress that may progress to ARDS. Furthermore, weak associations between topical perineal talc powder and gynecologic malignancies have been elucidated, begging the question of whether intrapleural talc could increase the risk of cancers. Notably, pulmonary function tests (PFT’s) are not affected by talc pleurodesis in long-term follow-up29.
6
1. ARDS
The true association of talc pleurodesis with ARDS is difficult to elucidate due to its low incidence. The earliest report described 3 patients with ARDS and 1 death after instillation of 10g of nongraded talc slurry via chest tube30. However, a multicenter prospective cohort study of talc poudrage using graded Steritalc (MPS 24.5 µm) had an ARDS incidence of zero, in agreement with other large trials25,16. A small study using non-graded talc slurry for MPE or PSP reported a rate of complications of 15% (tachycardia, pain, fever or dyspnea) with one death attributed to ARDS; however, the study lacked conclusive evidence for ARDS31. De Campos and Light reported a 1.3% incidence of ARDS with 50% mortality with non-graded talc (PS 5-70 µm)32.
A retrospective review from Japan found a 15%
incidence of ARDS when large PS talc (>25 µm) was used, however, the description of ARDS was not consistent with the widely-accepted 2012 Berlin criteria, thus raising validity concerns33,34. Throughout the literature, the definition of ARDS, as well as the dosages and particle size of talc used vary considerably, making the incidence of this syndrome difficult to establish.
The debate
continues, and some contend that even a rare case of ARDS is not a risk worth taking, others argue that the high efficacy and low cost of talc trumps the minimal risks35,36. The authors of this review do not find the evidence for the risk of ARDS when using large-particle, graded talc to be sufficiently compelling to require a change in practice towards other sclerosing agents.
2. Malignancy
Recently, concerns have arisen regarding a potential association of topical talc usage with malignancy. Prior to 1970, talc was frequently contaminated by asbestos, a known carcinogen. Since
7
then, talc used in cosmetic powders or for any medical purpose has undergone purification intended to eliminate such contamination. The Nurses’ Health Study (NHS), a prospective cohort comprising of 121,700 women enrolled in 1976, revealed a small increase in risk of invasive serous ovarian cancer (RR 1.4, 95% CI 1.02-1.92)37. There was no increased risk of other types of ovarian cancer or ovarian cancer risk overall. A 24% increase in endometrial cancer risk was noted, accentuated by increased usage frequency37,38.
The
Women's Health Initiative Observational Study failed to demonstrate any association between perineal powder use and ovarian cancer39. Nevertheless, a large meta-analysis showed a small increase in the risk of ovarian cancer with OR 1.31 (95% CI 1.24-1.39)40.
Endometrial cancer has also been weakly
associated with use of perineal talc, although the Australian National Endometrial Cancer Study, a casecontrol study of 1,399 women with endometrial cancer and 740 controls, revealed no association41. The National Cancer Institute currently maintains that the suggestion of perineal talc usage causing inflammation of the ovaries is not supported by “the weight of the evidence.” To summarize, there is perhaps a weak association between perineal talc use and increased risk of female genital malignancies. However, the data has not been clearly elucidated and many controversies still exist. Importantly, we identified no reports of talc causing malignant mesothelioma; nor any literature linking intrapleural talc to any non-thoracic malignancies. Surgeons should, therefore, be mindful of patient concerns regarding the potential risk of malignancy with topical talc application, but they can reassure patients that intrapleural talc use has not been linked to any malignancies.
VI.
Alternatives to Talc Over the years, alternatives to talc have been studied including: silver nitrate (SN), tetracycline
and derivatives, erythromycin, TGF-β2, tigecycline, bleomycin, iodopovidone, quinacrine, ethanolamine oleate, blood, OK-432, NaOH, and Helixor-M. Several studies have compared talc formulations (powder vs slurry) and instillation methods (video-assisted thoracoscopic surgery (VATS) versus chest tube). Lastly, tunneled pleural catheters (TPC) have been studied as an alternative for MPE. A 2003 survey of
8
physicians identified talc slurry as the most-used agent (56%), followed by tetracycline and its derivatives (26%), talc powder (12%) and bleomycin (7%).
Light and Dikensoy argue that SN, quinacrine,
iodopovidone, and doxycycline are reasonable, inexpensive alternatives to talc42.
Although not
exhaustive, this section will review the main alternatives to talc.
a.
Silver nitrate (SN)
SN (1-10% solution) was among the first agents employed for pleurodesis43. The strong local inflammatory response and pain associated with SN at higher doses initially made it unpopular. Studies using lower concentrations have shown promising results with less pain44.
In animal models, SN
produces faster and more robust adhesions and alveolar collapse vs. talc, but with time this difference fades45,46. Low doses of SN can lead to intense pleural inflammation with fewer side effects compared to higher doses11,9. The one-year success rate is similar between SN and talc in animal models47. The only prospective randomized trial in patients with MPE using SN vs. talc administered via chest tube found equivalent rates of pain and successful pleurodesis at 30 days, with no incidence of ARDS48. A literature review on pleurodesis using 0.5% SN in patients with MPE concluded similar short-term success rates to talc, but with a guarded recommendation for use given the lack of long-term follow-up49. There are substantial systemic effects in patients treated with SN, including dose-related hypoxia and acute kidney injury50. Data like this have led researchers to try lower doses with repeated treatments, but, to our knowledge, this approach has not been studied in humans. Overall, the literature suggests that SN may be a reasonable alternative to talc, but the optimal dose and long-term results remain incompletely defined.
b.
Tetracycline derivatives
9
Tetracycline is no longer available for pleurodesis in the U.S., but its derivatives (minocycline, doxycycline) are still used. In animal models, these agents led to higher rates of hemothorax, fibrosis, and local tissue damage compared to talc7,8. In patients treated with tetracycline, blood patch, or talc instilled via chest tubes for PSP, the success of tetracycline was 63%, blood 75%, and talc 84%51.
A
retrospective study in patients with recurrent MPE looking at tetracycline or bleomycin instilled via chest tube vs. talc instilled via VATS or thoracotomy, found talc to be superior with lower drainage and earlier chest tube removal52. Two small randomized trials comparing tetracycline with talc in MPE showed that talc created a higher local and systemic inflammatory response23. In a meta-analysis, RR for nonrecurrence of MPE after talc vs tetracycline was 1.34, in favor of talc3. The data for tetracycline derivatives in chemical pleurodesis thus does not support these agents over talc.
c.
Bleomycin
When bleomycin is compared against talc and tetracycline derivatives, it usually underperforms with respect to pleurodesis success and recurrence53,54.
In multiple prospective randomized trials,
bleomycin is less effective or, at best, as effective as talc or tetracycline derivatives. In a meta-analysis, RR for non-recurrence of MPE was 1.34 for talc compared to bleomycin3. While bleomycin has a good side-effect profile, it is more expensive than other options. The evidence of reduced rates of successful pleurodesis with bleomycin and its cost do not support its use over talc.
d.
Iodopovidone
When compared to talc, iodopovidone produces similar results, with a low side-effect profile and less pain55,56. A meta-analysis showed success rates of iodopovidone as high as 89-95% in MPE and PSP with pain and hypotension as the most notable side-effects57. When compared directly to bleomycin,
10
iodopovidone has similar rates of success but is significantly cheaper58. A multicenter prospective trial of 10% iodopovidone used in patients with recurrent MPE reported a 96% efficacy59. Concerns about the safety of iodopovidone causing hypothyroidism do not appear to be clinically significant60,61. However, with doses greater than 600-1,200mg of iodate (well above the dose for pleurodesis), ocular toxicity may occur62. More data is needed to evaluate iodopovidone’s dosing and safety profile, but results are promising.
e.
Blood
Autologous blood has been reported as a sclerosant in patients with pneumothorax, postoperative air leak, and hydrothorax complicating peritoneal dialysis63. The mechanism of action is unclear, but likely explained by the formation of adhesions as well as a presumed “patch” effect leading to resolution of postoperative air leaks. Post-lobectomy patients with air leaks on post-operative day 5 showed a benefit of intrapleural instillation of 120 mL of autologous blood via chest tube55. However, empyema has been reported to occur in up to 9% of cases63. The data for blood pleurodesis in PSP is weak; the existing trials are small, heterogeneous and unblinded. It is probable that the “pleurodesing” effect of pleurectomy results in part from the blood spillage. Autologous blood has not been studied in the setting of MPE. Given other more easily available, better-studied, effective alternatives, we do not recommend the use of blood as a first choice for pleurodesis in PSP or MPE.
f.
Others
Many other substances have been tested as potential alternatives to talc for pleurodesis. Quinacrine, an anti-malarial drug, has shown a poor side-effect profile (pain and fever) vs. tetracycline, and an increased need for repeat treatments vs. talc65. OK-432 has been extensively studied in rats and
11
humans with MPE and shown to result in less fibrosis compared to talc in rats66. In humans, the efficacy and safety profiles appear to be similar, but larger trials are needed67. In animals, TGF-β2 induces more collage deposition, higher pleural fibrosis and pleural thickness, with a lower WBC and LDH compared to talc68.
In vitro, TGF-β2 upregulates mesothelial cell collagen synthesis and increases VEGF
production, while in vivo it creates less pleural inflammation in comparison to talc and doxycycline69. All of the above agents provide intriguing alternatives to talc, but they are more expensive, less available, and require further investigation in humans.
g.
Tunneled Pleural Catheters
Any discussion of talc’s role in MPE must at least briefly consider the relatively recent, successful application of tunneled pleural catheters (TPC). These provide immediate symptom palliation in 89% of patients with a mean duration of 56 days70. They create pleurodesis in 42-60% of patients with MPE, depending in part on whether the lung is fully expansile70,71. TPCs have the advantage of being able to be placed on an outpatient basis without general anesthesia. Empyema is rare (1-5% of patients), but can be quite morbid. Notably, a hybrid approach using VATS talc pleurodesis and TPC placement at the same time provides a higher rate of pleurodesis, with 92% of patients with MPE achieving pleurodesis at 6 months, a median inpatient stay of 2 days and 7 days of outpatient TPC use72. A randomized study in MPE showed a higher rate of successful pleurodesis in patients with TPC who received outpatient talc instillation 2 weeks later compared to placebo instillation73.
Treatments centered on IPCs are thus certainly
reasonable for patients who are not averse to a potentially permanent external device. IPC use should be an individualized decision made by each patient together with their physicians.
VIII.
Talc slurry vs powder
12
The method by which talc is instilled intrapleurally appears to have a small impact on the efficacy of pleurodesis. Talc poudrage is achieved via VATS, while talc slurry is typically instilled via chest tube. These result in superimposable recurrence rates, except breast and lung cancer subgroups, where poudrage has a slight advantage74,75. In severely debilitated patients with MPE, performing a bedside talc slurry eliminates the risks of anesthesia76. Patient-centered outcomes in patients with MPE were similar between TPCs, talc poudrage, and talc slurry, but talc poudrage produced the most durable results77. Patient satisfaction was highest (but insignificantly different) in those who had VATS poudrage and lowest in those who had the slurry. Certainly, bedside chest tube placement and talc instillation is less comfortable than similar procedures done under general anesthesia; however, the risks of general anesthesia and the cost must also be considered. When pleural biopsy is required to establish a diagnosis, VATS is indicated. We will not broach the topic of VATS biopsy or talc poudrage under sedation only, although this has been demonstrated possible78. In summary, talc poudrage and slurry pleurodesis offer nearly equivalent results and, therefore, the choice should be grounded in a discussion of goals of care between the physician and the patient.
IX.
Cost of Talc Given that there is solid data supporting several chemical sclerosants, their cost and availability
should be taken into consideration. Analyzing the costs of talc can be challenging, as numbers quoted the literature vary greatly by institution and source. The overall consensus among studies is that talc is less costly than other agents, but povidone iodine and SN are similarly affordable. Biologic agents (e.g. OK432, TGF-B) are more expensive. In patients with PSP, thoracoscopic talc poudrage is more costeffective than bedside drainage even in patients with a first episode of a pneumothorax18,79. In the treatment of MPE, cost-effectiveness appears dependent on expected survival time80. In 3-month survival analyses, TPCs were found to be cheap and effective. Repeated thoracentesis was the least expensive ($4,946) but provided the lowest quality-adjusted-life-years (QALYs), followed in cost by TPC ($6,450), bedside pleurodesis ($11,224) and thoracoscopic pleurodesis ($18,604). In 12-month survival analyses,
13
bedside pleurodesis was the least expensive and provided the most QALYs, while repeat thoracentesis was the most expensive. VATS pleurodesis was the most effective, but the incremental cost-per-QALYs gained over lifetime was estimated >$250,000. Therefore, the most recent cost-effectiveness analyses suggest that in patients with limited survival, TPCs are favored from a cost-effectiveness perspective; by contrast, in patients with more prolonged expected survival, bedside talc pleurodesis provides the most cost-effective alternative.
X.
Shortages of Talc The privately-owned company Lymol Medical (formerly Bryant Corp) had been the main
supplier of sterile talc powder in the U.S. In 2016, there was a recall of Lymol’s aerosolized talc when the Food and Drug Administration (FDA) cited inappropriate sterilization techniques, leading to a national shortage. The company pleaded guilty to selling incorrectly sterilized talc from 1997 to 2007. U.S. centers urgently needed a new source. At our center, we contracted with a compounding pharmacy to sterilize and filter talc to our specifications due to the shortage.
In August 2017, Novatech
collaborated with Boston Medical Products and began importing FDA-approved sterile graded talc [Steritalc (MPS > 25 µm)], essentially solving the previous national shortage.
XI.
Talc Litigation The putative association between perineal talc powder and the risk of developing gynecologic
cancers (mesothelioma in a few cases) has led to over 12,000 plaintiffs suing Johnson&Johnson, the primary maker of talc for home use. In 2016, the company was ordered to pay a total of $127 million in cases in Alabama and Missouri. In 2017, 4,800 women with ovarian cancer requested that Johnson&Johnson replace its baby powder with one made exclusively of cornstarch or place a carcinogenicity warning on the product. In 2018, a jury awarded $4.69 billion to women claiming that asbestos in the powder caused their ovarian cancer (currently under appeal). Other lawsuits are pending.
14
Most recently, jurors in Missouri cleared the company of any responsibility, arguing that the causal association between talc and malignancy is not sufficiently strong. Talc contaminated with asbestos, prior to the institution of purification in the 1970’s, would have the hypothetical potential to cause mesothelioma if instilled into the pleural space. However, there are no reports in the medical literature of this occurring. The litigation on ovarian cancer, however, has raised the question as to whether even “asbestos-free”, purified talc could cause pleural malignancy (or even non-thoracic malignancies, as intrapleural talc does result in some systemic absorption). Notably, we found no such documented cases in the literature. The only long-term (118 months) outcome study after talc pleurodesis showed no increased risk of cancer, but the study was underpowered and with insufficient follow-up time29. There are several undecided tort cases (and two decided – one for each side) against Johnson&Johnson for mesothelioma claimed to have been caused by inhaled asbestos fibers in talc for home use. We are not aware of any talc lawsuits that name physicians as defendants. Overall, any concern by surgeons that their use of medical talc powder in the pleural space could lead to litigation on the basis of the development of future cancers is currently unfounded.
XII.
Conclusions Talc has been used for more than 80 years and is clearly established as an efficacious and cost-
effective agent in the management of pneumothorax and pleural effusions. The systemic risks associated with its use are almost always tolerable, with an extremely low risk of clinically significant pulmonary dysfunction when using large-particle, graded talc. While this latter complication has been observed by most thoracic surgeons at some point during their career, this was almost certainly prior to the consistent institution of graded talc with particle sizes in the safe range. Several of the sclerosant alternatives to talc are promising (in particular, SN and iodopovidone), but these have not been sufficiently well-studied in prospective, randomized trials to allow us to make a strong recommendation with regard to the use of any particular agent over talc.
15
There is weak statistical evidence implicating perineal talc use in the development of ovarian cancer. Although no studies have specifically evaluated the risk of ovarian cancer following talc pleurodesis, there are no reports of this occurring, and it seems unlikely that such a relationship would exist given the limited systemic distribution of talc with large particle formulations. More research is needed to fully elucidate the relationship between talc and gynecologic cancers. Similarly, there is neither evidence for, nor reason to believe that, talc pleurodesis causes mesothelioma. Given the existing evidence, we believe that, among the agents available for pleurodesis, purified graded talc is the most reliable and efficacious agent, along with clearly defined optimal dosing, a good side-effect profile, and reasonable cost.
The existing literature reveals minimal risk of serious
complications such as ARDS with large-particle, graded talc – a rate of occurrence so low that we cannot make a compelling argument for routine use of talc-alternatives at this time. The recently experienced talc shortages in the U.S. are now resolved.
We see no reason that recent talc litigation surrounding
malignancy should dissuade surgeons. Although other agents such as silver nitrate and iodopovidone are also not unreasonable to employ, talc currently remains the gold standard agent for pleurodesis.
16
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