HITHOC goes head to head with VATS talc pleurodesis for treatment of Malignant Pleural Mesothelioma

Here’s an update on our 2016 article: Q & A with Migliore et al. about HITHOC and mesothelioma in Catania, Italy.

Migliore et. al at the University of Catania, Italy have just published the first randomized pilot study that directly compares hyperthermic intrathoracic chemotherapy with VATS pleurectomy / decortication with VATS talc pleurodesis. This is important because it represents a shift in the thinking surrounding treatment of Malignant Pleural Mesothelioma (MPM). For too long, too many surgeons have automatically shunted these patients into the palliative care treatment algorithm, which includes talc pleurodesis.

As we have discussed on multiple previous posts on this topic; treatments like talc pleurodesis are mainly performed for symptom relief. (The instillation of talc into the pleural space does nothing to treat the underlying cancer, but the talc pleurodesis slows the re-accumulation of pleural effusions which are a common cause of shortness of breath in these patients). HITHOC is different; it’s an active treatment aimed at treating the mesothelioma. A related treatment, called HIPEC (which is the same treatment aimed at cancers in the abdominal cavity) has rapidly become the standard of care for carcinomatosis, malignant peritoneal mesothelioma and other abdominally-based cancers.

Another important difference between this study and prior work in this area is the use of minimally invasive surgery for both groups. In several prior research studies, the use of large open operations in combination with HITHOC is believed to have contributed to an increased morbidity and mortality.

Multiple small studies (featured on this site) have shown increased survival and longevity for patients receiving HITHOC but these studies were not randomized. Randomization (while sometimes seeming to be cruel to enrolled patients) is important to eliminate conscious or unconscious treatment bias, and randomized control trials (RCT) are considered the highest level of evidence.

Why randomize?

Treatment bias is when researchers consciously or unconsciously select patients that they think will do better to place into one treatment group versus another. Sometimes this treatment bias is built into the study (ie. sicker patients enrolled into a palliative care arm of a study).

As you can imagine, if all of the high functioning, ambulatory, well-nourished patient with earlier stage cancers go into the treatment arm, and all the cachectic, bedridden patients with advanced cancer go into the other arm of the study, the results are more likely to favor the first group. Surprisingly, this sort of sorting strategy is not uncommon, and is sometimes used along with ‘non-inferiority’ trials to push expensive treatments and technologies. Migliore et al. lessen this by using patients at 3 separate study sites and randomizing them into two groups.

However, some selection bias will usually still exist, particularly when involved in a study in a specialized area like this – meaning that patients have to be referred to the study center in the first place. Hopefully, if the program is large enough and well-publicized in the local medical communities, referring physicians will send any and all of their patients with malignant pleural mesothelioma to be evaluated for enrollment. Once the researchers start receiving the referrals, then they use standardized inclusion criteria to enroll patients. This way, the patients selected are similar to each other, in cancer staging, functional status, age etc. Apples to Apples, so to speak.

How is a pilot study different from a ‘regular’ study?

As a pilot study, the main aim of the study was to recruit patients (to see if a larger future trial is practical or feasible). If you can’t get eligible patients into your studies, it doesn’t matter what medical breakthrough you might be working on.

This pilot study also have secondary goals; determining statistical significance (how many patients do we need to treat to show a statistically significant difference aka Number Needed to Treat (NNT), Survival rates at specific fixed intervals, length of stay, rate of peri and postoperative complications.

Who could participate (aka inclusion criteria)

In this particular study, all of the participants had to have a pleural effusion along performance status equal or below 2. This means that the patients had to be fairly functional and independent.

ECOG/WHO Performance Status (borrowed from verywellhealth.com)

0: Fully active, no restrictions on activities. A performance status of 0 means no restrictions in the sense that someone is able to do everything they were able to do prior to their diagnosis.

1: Unable to do strenuous activities, but able to carry out light housework and sedentary activities. This status basically means you can’t do heavy work but can do anything else.

2: Able to walk and manage self-care, but unable to work. Out of bed more than 50% of waking hours. In this category, people are usually unable to carry on any work activities, including light office work.

3: Confined to bed or a chair more than 50 percent of waking hours.Capable of limited self-care.

4: Completely disabled. Totally confined to a bed or chair. Unable to do any self-care.

5: Death

In addition to this, and patient participant consent, the participants had to agree to undergo VATS pleurodesis. (This last inclusion criteria may sound obvious, but if all your enrollees only agree to take the ‘experimental’ treatment, then the study isn’t random).

Patients with advanced disease, and patients who were too sick/ debilitated to undergo surgery/ anesthesia were excluded.

Potential limitations to randomization with this study design

In this pilot study, the randomization strategy is one of limited utility. In this study, recruited patients were ‘randomized’ based on which medical center they presented to. Now, that probably worked just fine when they were only recruiting 3 to 5 patients per year but this presents a potential problem for future, larger studies. Imagine, dear reader, after reading numerous articles here at thoracics.org, your loved one, family member, or even a neighbor is diagnosed with malignant pleural mesothelioma. Well, as an educated reader, and patient advocate, you are going to send your loved one to the treatment center that you know does the procedure you want. Depending on your oncologist, they might do the same. (We do it all the time in medicine when we refer patients to specific hospitals for “a higher level of care”/ surgical evaluation etc.). It wouldn’t take very long or very many patients for much of the medical community and the educated public to know patients enrolled in the trial at the University of Catania are in the treatment arm of the study, and getting HITHOC (Group B) and that the patients at Morgagni Hospital and University Hospital of Palermo (Group A) receive palliative treatment with talc pleurodesis. But given the relative scarcity of published information on HITHOC for the general public and in Italian, we can argue that for this small pilot study, this strategy worked. As long as the patients in the treatment groups look about the same, it shouldn’t affect the outcomes (that’s where performance status, and degree of disease comes in.)

Also, I would like to point out – that in this study, all of the patients continued to receive adjuvant therapy, which I think is really the only ethical option available. (If you know that talc pleurodesis is only of palliative value, it’s very questionable to require study participants to discontinue adjuvant chemotherapy, which may help slow the spread of their disease. We already know adjuvant chemotherapy doesn’t work that well, (hence the need for discovery of new treatments) but it seems almost punitive to make participants discontinue chemotherapy. So, while some many argue that this adjuvant treatment may impact results, the authors opted to take the more ethical route. Since everyone in the study was getting the adjuvant treatment, it can be factored into the study results.

As a pilot study, comparison groups are small. As we discussed before, one of the primary aims of this study was the recruitment of eligible patients – and it took several years (almost six) for the authors to recruit enough patients to be able to extrapolate data and publish this study. In this study, Group A had 14 people, group B had 13. As a pilot study, that is a respectable size (many pilot studies have groups in the single digits). However, this study size highlights one of the biggest limitations of pilot studies – and it’s also the reason that these authors don’t suggest changes to the treatment algorithm based on their results. Pilot studies are not designed to change treatment regimens – they are designed to see if there is enough of a reason to investigate further. (aka Is there something there? )

It’s just not enough people to make broad statements or changes to current treatment. The authors of this study acknowledge this.

A word about study size

Readers need to be careful to make sure they don’t fall into the trap of forgetting the importance of study and treatment group size. (This commonly occurs when the general media reports on medical findings. One of the best examples is the widespread reporting in the early 2000’s on the use of cinnamon as a treatment for diabetes. Millions of people at home adopted this as a more ‘holistic’ alternative, despite the fact that the preliminary studies had very few patients in the treatment (cinnamon arm). It wasn’t until 2013, that the first meta-analysis was published showing many of these claims to be misleading and exaggerated, and this meta-analysis was still based on multiple small size studies (see figure below)

Looking at these numbers, no one should abandon their medications in favor of cinnamon

So now that we’ve discussed study size for this pilot study, let’s look at their findings and determine, Is there something there – an apparent difference in outcomes between the small groups important enough that a larger study should be conducted.

What were the actual treatments performed?

The patients in Group A had a talc pleurodesis via the Uniportal VATS approach that included a surgical biopsy for final diagnosis and tissue type.

Patients in group B underwent tissue biopsy prior to the procedure to confirm the diagnosis of Malignant Pleural Mesothelioma and tissue type. These patients then underwent pleurectomy / decortication via the VATS approach with mini-thoracotomy followed by the instillation of chemotherapy. The surgeons removed all of the parietal and visceral pleural as well as any visible tumor tissue (debulking). Then cisplatin, diluted with 2-3 liters of saline was heated to 41 degrees in temperature, and then circulated through the chest cavity for 60 minutes.


Since I’ve included the link to the reference article, I am going to skip a lot of the discussion of group comparisons, (they were very similar), hospital stay (very similar) and the rates of post-operative complications were very similar (group A 8 patients, group B 7 patients).

Let’s look at the big question for the participants in the study and their families – and the real reason Dr. Migliore and all of his colleagues are investigating HITHOC as treatment.

Patient survival

Look at the last column – at 36 months (3 year survival):

4 patients in the HITHOC treatment group were still alive versus just one in the talc pleurodesis cohort. The authors note that this survival for the HITHOC group might even be skewed a little, in that some of the patients in the HITHOC group didn’t receive treatment until SIX months after diagnosis (and all survival rates are calculated as length of survival after diagnosis).

So, yes, even with these small, small numbers, these findings are important enough for researchers to continue investigate in this area. It certainly warrants a larger study, research grants/ and other financial support.

However, it also needs to be noted, that researchers in this study found that the tumor tissue type had a major impact on outcomes. Patients with epithelioid MPM lived on average of 15 months after talc pleurodesis ( 9 patients) versus 45 months after HITHOC ( 9 patients). Patients with biphasic tumor type, or sarcomatoid type were less frequent in this study, but it appears to carry a poorer prognosis.

Reference article:

Migliore, M. et. al. (2021). Comparison of VATS Pleurectomy/Decortication Surgery plus Hyperthermic Intrathoracic Chemotherapy with VATS talc pleurodesis for the treatment of Malignant Pleural Mesothelioma: a randomized pilot study. MedRxIV, 28 Nov 2021.

For more about HITHOC, please see our archives.

Blebs, Bullae and Spontaneous Pneumothorax

Overview of spontaneus pneumothorax and treatment modalities.

There are multiple classifications of pneumothoraces – primary, secondary, iatrogenic, traumatic, tension etc.  This article is a limited overview of the most common type(s) of pneumothorax, and methods of treatment.

What are blebs? 

The lung is made up of lung tissue itself (consisting of alveoli, bronchi and bronchioles) and a thin, membranous covering called the pleura.  This covering serves to prevent inhaled air from travelling from the lung to the area inside the thoracic cavity.  ‘Blebs’ are blister-like air pockets that form on the surface of the lung.  Bulla (or Bullae for pleural) is the term used for air-filled cavities within the lung tissue.

Who gets/ who has blebs and/or bullae?

Blebs and bullae may be related to an underlying disease process such as emphysema / chronic obstructive pulmonary disease, but they (blebs in particular) may also be found in young, healthy people with no other medical issues.  Indeed, the ‘classic’ scenario for a primary spontaneous pneumothorax is a young adult male (18 – 20’s), tall and thin in appearance and no other known medical history who presents with complaints of shortness of breath or dyspnea.

Smoking, and smoking cannabis have been implicated in the development of spontaneous pneumothorax in young (otherwise healthy) patients.

Bullae, or air pockets within the lung tissue are more commonly associated with chronic disease processes such as chronic obstructive pulmonary disease (emphysema).  It can be also part of the clinical picture in cystic fibrosis and other lung diseases.

How do blebs cause a pneumothorax?

When these blebs rupture or ‘pop’ inhaled air is able to travel from the airways to the thoracic cavity, creating a pneumothorax or lung collapse.

The symptoms of a pneumothorax depend on the amount of lung collapse and the baseline respiratory status of the patient.   In young, otherwise healthy patients, the symptoms may be more subtle even with a large pneumothorax.  In patients with limited reserve (chronic smokers, COPD, pulmonary fibrosis, sarcoidosis) patients may experience shortness of breath, dyspnea/ difficulty breathing, chest and chest wall pain.  With large pneumothoraces or complete collapse of a lung, patients may become cyanotic, or develop respiratory distress.

In cases of pneumothorax caused by external puncture of the lung, or other traumatic circumstances, a patient may develop a life-threatening condition from a tension pneumothorax.  This can happen with a simple, primary lung collapse from bleb rupture, but it is uncommon. 

How is this treated?

Simple (or first-time) pneumothorax

Oxygen therapy – traditional treatment for small pneumothorax in asymptomatic or minimally symptomatic patients was oxygen via a face mask or non-rebreather.  Much of the more recent literature has discredited this as an effective treatment.

Tube thoracostomy  (aka chest tube placement) – a chest tube is placed to evacuate air from the thoracic cavity, to allow the lung to re-expand.  The chest tube is initially placed to suction until the lung surface heals, and the lung is fully expanded.  After a waterseal trial, the chest tube is removed.

Recurrent pneumothorax / other circumstances;

Blebectomy via:

  1. VATS (video-assisted thoracoscopy)
  2. Open thoracotomy or mini-thoracotomy

As we have discussed previously, the VATS procedure / open thoracotomy and mini-thoracotomy are not really stand alone procedures but are the surgical approaches or techniques used to gain entry into the chest.  Using a VATS technique involves the creation of one or more ‘ports’ or opening for the use of thoracoscopic surgical tools, and a thoracoscope (or camera.)  There are rigid and flexible scopes available; but most thoracic surgeons prefer the rigid scopes for better visibility and control of tissue during the operation[1].

blebs seen during VATS procedure

Open thoracotomy or mini-thoracotomy incisions may be used to gain access to the lung, particularly for resection of bullae (lung volume reduction) surgeries for the treatment of chronic disease.

During this procedure, fibrin sealants may be used.  Investigational use of both radio-frequency and other ablative therapies have also been used (Linchevskyy, Makarov & Getman, 2010, Funai, Suzuki, Shimizu & Shiiya 2011**).

Treatment Guidelines

British Thoracic Surgeons 2010 treatment guidelines

American College of Chest Physicians – a bit dated (2001)

Linchevskyy, Makarov & Getman, 2010.  Lung sealing using the tissue-welding technology in spontaneous pneumothorax.  Eur J Cardiothorac Surg (2010) 37(5): 1126-1128.

Funai, Suzuki, Shimizu & Shiiya (2011).  Ablation of weak emphysematous visceral pleura by an ultrasonically activated device for spontaneous pneumothorax. Interact CardioVasc Thorac Surg (2011) 12(6): 908-911. 

Pleurodesis may also be used – in combination with either tube thoracostomy or surgical resection.  Pleurodesis can be performed either mechanically, chemically or both.  Mechanical pleurodesis is accomplished by irritated the pleura by physical means (such as scratching or rubbing the pleura with the bovie scratch pad or surgical brushes.  A chest tube also produces a small amount of mechanical pleurodesis as the tube rubs on the chest wall during patient movement.

Chemical pleurodesis is the instillation of either sterile talc or erythromycin to produce irritation or inflammation of the pleura.  With bedside pleurodesis or tube thoracostomy pleurodesis, sterile talc is mixed with lidocaine and sterile water to create a talc slurry.  (If you like your patient, carry it in your pocket for 10 – 20 minutes to allow the solution to warm to at least room temperature.  This will help reduce the discomfort during instillation.)  The mixture should be in a 60cc syringe or similar delivery device – shake briskly before use.  The mixture is then instilled via the existing thoracostomy tube.  The chest tube is clamped for 30 – 60 minutes (dwell time) and the patient is re-positioned every 10 to 20 minutes. Despite the lidocaine, the talc will produce a burning sensation, so pre-medication is desirable.  This procedure has largely fallen out of fashion in many facilities.  Post-pleurodesis, pleural inflammation may cause a brief temperature elevation.  This is best treated with incentive spirometry, and pulmonary toileting.

Chemical pleurodesis can also be performed in the operating room.  Loose sterile talc can be insufflated, or instilled using multiple delivery devices including aerosolized talc.  As discussed in previous articles, pleurodesis can also be used for the treatment of pleural effusions.

Sepehripour, Nasir and Shah (2011).  Does mechanical pleurodesis result in better outcomes than chemical pleurodesis for recurrent primary spontaneous pneumothorax?  Interact CardioVasc Thorac Surg ivr094 first published online December 18, 2011 doi:10.1093/icvts/ivr094

Alayouty, Hasan,  Alhadad Omar Barabba (2011).  Mechanical versus chemical pleurodesis for management of primary spontaneous pneumothorax evaluated with thoracic echography.                     Interact CardioVasc Thorac Surg (2011) 13(5): 475-479 

Special conditions and circumstances related to Pneumothorax:

Catamenial pneumothorax – this a pneumothorax that occurs in menstruating women.  It usually occurs on the right-side and is associated with endometriosis, and defects in the diaphragm. A related case study can be viewed here.  Several recent studies suggest catamenial pneumothorax may be more common that previously believed and should be suspected in all women presenting with right-sided pneumothorax, particularly if pneumothorax occurs within 48 – 72 hours of menstrual cycle.  This may be the first indication of underlying endometrial disease.

Additional References

For more reference citations and articles about the less common causes  – see More Blebs, Bullae and Spontaneous Pneumothorax

Pneumothorax: an update – gives a nice overview of the different types of pneumothorax, and causes of each.

Medscape overview of pneumothorax – this is a good article with radiographs with basic information about pneumothoraces.

More on the difference between blebs and bullae – from learning radiology.com

Lung resection for bullous emphysema

Japanese study suggesting Fibulin-5 protein deficiency in young people with pneumothoraces.

VATS versus tube thoracostomy for spontaneous pneumothorax

What’s worse than a spontaneous pneumothorax?  Bilateral pneumothoraces – a case report.

Early article suggesting VATS for treatment of spontaneous pneumothorax (1997)

Blebs, Pneumothorax and chest drains

[1] Flexible scopes are usually preferred for GI procedures such as colonoscopy, where the camera is inserted into a soft tissue orifice.  By comparison, the thoracic cavity with the bony rib cage is more easily navigated with the use of a firm instrument.

** I have contacted the primary authors on both of these papers for more information.

Like all materials presented on this site, this paper is presented for information only.  It should not be considered medical advice or treatment.  Also, all information provided is generalized information and (outside of clinical case presentations) is not intended to treat of diagnose any disease or condition.  If you have questions about the content, please contact us.  If you have medical questions, please consult your thoracic surgeon or pulmonologist.

Case report: Blebectomy with talc pleurodesis after spontaneous pneumothorax

Case report of spontaneous pneumothorax followed by bleb resection and talc pleurodesis.

During my various travels and interviews, I have had the opportunity to meet and talk with thoracic patients from around the world.  During a recent trip, I encountered a very nice young woman (in her early 20’s**).  This is her story below:

The patient, the aforementioned young woman had no significant past medical history.  She initially presented to a small tertiary facility with chest pain.  She was evaluated for acute coronary syndrome and discharged from the emergency department.  She subsequently miscarried an early pregnancy.

Several days later, her symptoms intensified, and she became short-of-breath so she returned to the emergency department.  On chest radiograph, she was found to have a large left-sided pneumothorax.  A chest tube was placed but subsequent radiographs showed a persistent pneumothorax.  The nearest trauma facility was notified and the patient was transferred for further evaluation and treatment.

On arrival, the patient who was experiencing significant chest and LUQ pain, and breathlessness received a second chest tube.  Following chest tube placement in the emergency room, chest radiograph showed the pneumothorax to be unchanged.  The patient was admitted to the hospital for further testing.

A CT scan (TAC) of the chest showing chest tubes in good position and several large blebs.  Following the CT scan, thoracic surgery was consulted for further treatment and management.

After discussing the risks, benefits and alternatives with the patient and family, the patient elected to proceed with a left-sided VATS (video-assisted thoracoscopic surgery) with blebectomy and talc pleurodesis.

Patient received pre-operative low dose beta blockade for sinus tachycardia.  Patient was intubated with a double lumen ETT for uni-lung ventilation.  The patient was hemodynamically stable intra-operatively, and the case proceed without incidence.

Intra-operative thoracoscopy confirmed the presence of several blebs including a large bleb in the left lower lobe.  These were resected surgically with noncoated endoGIA staples.  (Coated coviden staples have been implicated in several injuries and fatalities previously.)

12 grams of sterile talc was insufflated using an aerosolized technique.  A new chest tube was placed at the conclusion of the case. There was minimal to no operative blood loss.

surgeon performing video-assisted thoracoscopy

The patient was awakened, extubated and transferred to the post-operative recovery unit.  Chest radiograph in recovery showed the lung to be well expanded on -20cm of suction.

Post-operatively the patient had a small airleak.  She was maintained on suction for 48 hours and watersealed.  Waterseal trials were successful, and on post-operative day #4, chest tube was removed.  Subsequent chest x-ray was negative for pneumothorax.  Patient was discharged home with a follow-up appointment and a referral to OB-GYN for additional follow-up.

Discussion: Due to patient’s history of miscarriage in close proximity to first reports of chest pain, special consideration was given to the possibility of catamenial pneumothorax (though this was first instance, and on the left whereas 90% of reported cases occur on the right.)  While the literature reports previous episodes of pneumothorax during pregnancy, these reports occurred in later gestation (37 and 40 weeks, respectively.)  On further evaluation, patient had no history of abnormal vaginal bleeding, pelvic infections, pelvic inflammatory disease or a previous diagnosis of endometriosis.  Thoracoscopic evaluation was negative for the presence of endometrial tissue, and there were no diaphragmatic defects.

Final pathology: no abnormal results, confirming intra-operative findings.

**Note:  Since this is a blog, available for public viewing, patient permission was obtained prior to posting.  All efforts are made to protect patient privacy, and thus details regarding patient demographics have been changed/ omitted.  Also, our gracious thanks to the patient and family for allowing this discussion of the case.  If you have an interesting, educational or informative case, contact Cirugia de Torax for publication.

For additional information and discussion on blebs and bullae, see our related post here.

Additional information and articles on catamenial pneumothorax:

Majak P, Langebrekke A, Hagen OM, Qvigstad E.  Catamenial pneumothorax, clinical manifestations–a multidisciplinary challenge.  Pneumonol Alergol Pol. 2011;79(5):347-50.

Ciriaco P, Negri G, Libretti L, Carretta A, Melloni G, Casiraghi M, Bandiera A, Zannini P.   Surgical treatment of catamenial pneumothorax: a single centre experience.   Interact Cardiovasc Thorac Surg. 2009 Mar;8(3):349-52. Epub  2008 Dec 16.

Sánchez-Lorente D, Gómez-Caro A, García Reina S, Maria Gimferrer J. Treatment of catamenial pneumothorax with diaphragmatic defects.  Arch Bronconeumol. 2009 Aug;45(8):414-5; author reply 415-6. Epub 2009 Apr 29. Spanish.

Alifano M, Jablonski C, Kadiri H, Falcoz P, Gompel A, Camilleri-Broet S, Regnard JF.  Catamenial and noncatamenial, endometriosis-related or nonendometriosis-related pneumothorax referred for surgery.  Am J Respir Crit Care Med. 2007 Nov 15;176(10):1048-53. Epub 2007 Jul 12

Kronauer CM.  Images in clinical medicine. Catamenial pneumothorax.  N Engl J Med. 2006 Sep 7;355(10):e9

Marshall MB, Ahmed Z, Kucharczuk JC, Kaiser LR, Shrager JB.  Catamenial pneumothorax: optimal hormonal and surgical management.  Eur J Cardiothorac Surg. 2005 Apr;27(4):662-6