HITHOC – Thoracic Surgery

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.

Results

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.

HITHOC & the guidelines for management of malignant pleural mesothelioma: Why inclusion matters

Dr. Marcelo Migliore, Dr. Stefan Hoffman and several other thoracic surgeons who spearhead large HITHOC (Hyperthermic intrathoracic chemotherapy) research programs have just authored an editorial for the latest December 2020 issue of the Annals of Translational Medicine.

In this thoughtful article, the authors comment on the absence of any mention or consideration of HITHOC for the treatment of malignant Pleural Mesothelioma (MPM) despite multiple studies showing as survival advantage for patients receiving HITHOC*.

You can read the editorial here.

Migliore et al. point out a couple of things in their arguments for inclusion:

Stating (paraphrasing for brevity) that given the current level of evidence for most of the existing treatments of MPM are rated as weak, it is difficult to understand why HITHOC remains excluded from consideration. This gives the erroneous impression that HITHOC is a new, untried/ untested experimental treatment with little to no evidentiary support. This is false. Even a cursory overview of the data shows this is clearly not the case.

Why is this important, you ask??

Doctors, (at least credible ones), don’t offer or refer patients for treatments that fall outside the approved guidelines. Referring patients for treatments outside of the approved guidelines is considered charlatanism at best, and medical malpractice at worst. It’s akin to giving your patient megavitamin supplements and sending them to a Laetrile clinic, instead of an oncologist. This is particularly unethical when dealing with cancer patients because the direness of their prognosis can make them susceptible to the worst medical scams in our society. But this also means that doctors are hesitant to send their patients for legitimate treatments such as HITHOC because it isn’t “recommended.”

-And.. and it’s not a small AND.. the current “recommended” treatments don’t have strong evidence supporting their use (or a lot of good outcomes.)

Now as the editor of thoracics.org, I am going to take argument this a little bit farther than the authors did in their article.

Migliore and his fellow authors are European.. So they and the majority of their patients don’t fall victim to the “American medical insurance conundrum”, where Americans pay enormous sums of money to insurance carriers who then turn around and deny payment for necessary medical treatments. But, most of my patients are American, so inclusion matters a lot to me, because inclusion or specifically, the lack of inclusion drives a lot of insurance payment decisions.

One of the ways insurance companies save money is by denying payment for any treatment that is considered experimental. (What an insurance company deems experimental can also be controversial but that’s another conversation). Whether that so-called experimental treatment has a high probability of saving or prolonging your life is not important to the insurance company. (In fact, for decades after bone marrow transplant was shown to be a very effective form of treatment for several types of cancers, insurance companies continued to deny coverage – because bone marrow transplant is expensive.)

In fact, this scenario was the basis for a very popular 1997 movie based on the John Grisham novel, “The Rainmaker.”

(In the movie, Danny Davito and Matt Damon are in my hometown of Memphis, fighting for a client whose insurance has denied him a life-saving bone marrow transplant. )

As mentioned by the authors in the editorial, the omission of HITHOC from the guidelines suggests that it’s experimental. But as we’ve shown in multiple reviews of the data surrounding HITHOC, it’s been around for over 20 years and has a lot of data to support it’s use.

Even when a treatment isn’t deemed “experimental”, insurance companies don’t have to cover it. They routinely deny payments for treatments that are not part of standard treatment guidelines, so Inclusion in clinical guidelines is the first step to having the treatment included as part of Medical coverage.

In the case of HITHOC, inclusion in the clinical guidelines is critical. Patients with malignant pleural mesothelioma (and other cancers that are treated with HITHOC), don’t have a lot of time – and frankly, without HITHOC, their prognosis, and estimated survival time are both measured in single digits.

Without inclusion – patients never make it from their doctor’s office to the research program. Even if they somehow did find their way there (thru google, word-of-mouth or other means), most patients don’t have the means to pay for it, if insurance won’t help. (Even European programs, which are much more affordable than American programs, HITHOC can cost from 40,000 to 80,000 dollars. In the USA, the cost has been quoted as around a quarter of a million dollars.) So, inclusion matters.

For more information about any of the things we’ve talked about above: (about criteria for recommendations, current malignant pleural mesothelioma guidelines and all things HITHOC)

If you’ve never read a paper reviewing the guidelines for treatment of a medical condition, then you should know a couple of things first.

in these papers, multiple strategies or treatment options are listed
each of these treatments is then given a letter grade of A, B, or C based on the amount of scientific evidence that it works. (For more about the levels of evidence, see this article on the evidence pyramid).
A treatment with a high level of evidence (lots of scientific data, meta-analyses, double-blinded studies with large numbers of participants, etc.) would be ranked as 1A.
If we had another treatment, that seemed really effective, but maybe the evidence wasn’t quite as strong for that exact circumstance, it might be listed as 1B. As the supporting evidence for the treatments is reduced, treatments are graded as B, C and X. Level B recommendations are still things we still might consider using for patients, but less so for level C. Level X means that the treatment may actually cause harm. (Level X is often applied to treatments that were used historically, but are later found not to work. This happens quite a bit if you look at treatments used in the 1960’s versus now.)

So the authors are asking for HITHOC be mentioned in these guidelines, to be then ranked based on evidence. Since the evidence is graded, as we explained above, the authors aren’t asking for HITHOC to replace other treatments. They are merely asking for it to be listed as an option.

What are the current guidelines for treatment of MPM?

The current European guidelines for treatment of MPM are here. (In this guideline, they dispense with the standard grades of A, B, C and basically skip to palliative treatments in most cases. For example, they “recommend” talc pleurodesis as the first line surgical treatment – which as readers know, is a palliative treatment based on symptom management only.

The American recommendations also eshew the standard grading nomenclature, but A, B, C are merely substituted with srong, moderate and weak.

What about HITHOC? What is HITHOC?

*Many of those studies have been reviewed here at Thoracics.org: we have a whole section dedicated to cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITHOC).

HITHOC review of the literature (2018)

HITHOC: the Indian experience

This 2019 article from the Indian Journal of Surgical Oncology covers a very tiny group of patients undergoing HITHOC during an 8 1/2 year period has serious limitations (with a total of only seven patients having HITHOC) but it’s still worth a few minutes of our readers time, particularly if the reader’s interest in HITHOC hasn’t translated into practice yet.

Patel et. al. do a very nice job of describing their inclusion criteria, as well as the surgical techniques utilized in this study, where patients underwent either pleurectomy/ decortication (P/D) or extrapleural pneumonectomy (EPP) with/ without HITHOC.

In fact, it’s one of the better overviews of the procedure that’s been published in recent years. This praise must be tempered by the fact that HITHOC is paired with two very high morbidity/ mortality procedures in this study. P/D and EPP alone are difficult-to-tolerate procedures, and for that reason, are limited to a small subset of eligible patients. Multiple studies by the leaders in the area of HITHOC such as Reid, Isik etc. have already demonstrated that HITHOC can be effective without EPP.

For readers, there are some other serious limitations in their study. Despite having a tiny sample size, the HITHOC and non-HITHOC groups are not comparable. It is figuratively; apples to oranges.

The non-HITHOC group was primarily made up of pleural mesothelioma patients, and based on that diagnosis alone – would have been expected to do worse post-operatively. Yet, we don’t know if they did (do worse or not).

One of the reasons that we don’t know if the pleural mesothelioma patients outlived the HITHOC treatment group is that measurements were discordant as well. The authors talk about 24 month and 36 month survival in the non-HITHOC group, but apparently, didn’t even follow the HITHOC group after 9 months. (Or chose not to present their data after nine months, which is, worse. )

The authors do acknowledge this, in their discussion, but also point out that two of the HITHOC patients (one a 40 year old female*) had extensive, infiltrating disease processes and poor pre-operative functional statuses.

It’s an interesting read for the most part, but it begs for follow-up so we will reach out to Patel etl. al. and update readers with any response.

Reference article

Patel MD, Damodaran D, Rangole A, et al. (2019). Hyperthermic Intrathoracic Chemotherapy (HITHOC) for Pleural Malignancies-Experience from Indian Centers. Indian J Surg Oncol. 2019;10(Suppl 1):91–98. doi:10.1007/s13193-018-0859-y [link to free full text].

*There are two charts that nicely display all the characteristics of patients in both groups. Interestingly, in this HITHOC group, both of the female patients presented with more advanced disease many, many months after initial diagnosis. The 40F patient is clearly a last ditch ‘salvage’ patient, so her six month survival time after surgery would be better measured against more palliative procedures.

A closer look at HITHOC in Germany

A look of HITHOC in two programs in Germany, Freiburg and Regensburg

While there are a reported 17 centers in Germany performing the HITHOC procedure, this, dear readers, is the tale of two cities.

Over the years, finding information and making contact with surgeons performing the HITHOC procedure has been a long, expensive and time-consuming affair. Emails, interview requests and research questions frequently go unanswered. Expensive trips abroad for in-person interviews sometimes end up with all-too-brief meetings with disappointing results. But illuminating, and informative interviews and in-depth discussions about HITHOC are worth the inconvenience.

After the publication of a brief English language abstract for a larger article in German that hinted at research outcomes for multiple facilities, thoracics.org reached out several times to the authors (Ried et al, 2018) for further comment.

Back in 2011, Dr. Ried and his colleague, Dr. Hofmann at the University Medical Center in Regensburg, Germany, briefly discussed their HITHOC program, which was started in 2008.

Now, thoracics.org is in Germany to talk with Dr. Hofmann as well as another thoracic surgeon at a different facility in southwestern Germany.

sign — Heading south to Freiburg im Breisgau

Our journey starts just a few hours south of Frankfurt, in the picturesque city of Freiburg im Breisgau, in the Black Forest region of Germany best known for Cuckoo clocks, the Brothers Grimm fairy tales chocolate cake, and thermal spas. Freiburg is the largest city in this region. It’s a charming locale with a history that extends back to medieval times despite Allied bombing in a more recent century.

church — Freiburg is known for it’s massive cathedral, Munster Unserer Lieben Frau (Cathedral of our Lady). Construction began in 1200 and was completed over 315 years later.

Frieburg is also home to a University Hospital and the Robert Koch clinic of thoracic surgery. Dr. Bernward Passlick is the Director and head surgeon of this department.

clinic sign

Dr. Passlick is the reason thoracics.org has come to this charming but sleepy college town. After several months of written correspondence, thoracics.org arrived in Freiburg to here more about the HITHOC program from Dr. Passlick himself.

However, from the first initial comments from the department secretary who lamented that the length of HITHOC cases was “a waste of operating room time” [because multiple other cases could be done in the time it takes to perform one HITHOC case], to the actual meeting with Dr. Passlick, nothing proceeded as expected. Dr. Passlick was uninterested, and unwilling to discuss HITHOC. He reported that he did approximately 15 cases a year, retains no outcomes data and has no interest in publishing any results from these cases. However, despite the apparent lack of any documentation or statistics on HITHOC cases performed at the facility in Freiburg, he states that the ‘average’ survival is 2 to 3 years with some long-term survivors at six years or more, post-procedure. [When asked when he had no interest in publishing data showing six year survival, Dr. Passlick had no answer. We sat in silence for a few minutes, until I thanked him for his time and left.]

He briefly mentioned that his real interest lay in the area of treating multiple pulmonary metastasis using laser assisted resection via open thoracotomy. The laser resection technique allows for greater lung sparing in patients with multiple (and presumably, bilateral) pulmonary metastases from other primary cancers such as advanced colon, renal or breast cancer. He uses this technique for patients with five or more pulmonary metastasis, and reports he has operated on patients with as many as 20 to 25 metastatic pulmonary lesions. He didn’t have any statistics on this procedure to share, but did offer that he has a paper scheduled for publication soon. So, a bit disheartened, and thus unenlightened, it was time to leave Freiburg.

the canals of Freiburg in the historic district

Leaving the Black Forest, we head east – into Bavaria with miles of rolling hills dotted with windmills, vineyards and solar panels, past Munich and then north into the area where the Danube, the Naab and the Regen rivers meet. This is Regensburg, a city that was founded by the Celts. The Romans later built a fort here in 90 CE. The remains of a later Roman fort are readily seen in the historic city center.

roman ruins — Part of old Roman fortress in the historic quarter of Regensburg

But as charming as the city of Regensburg is, we aren’t here for sightseeing. Our next stop is another HITHOC program. It’s not the biggest in Germany, not by far, but it is a very well established program that is grounded in evidence-based practice, protocols and on-going scientific inquiry and research.

We are here to interview Dr. Hans – Stefan Hofmann, the head of the thoracic surgery department at both the University hospital and the large, private Catholic hospital in town. Dr. Hofmann along with his colleague, Dr. Michael Reid.

Fotor_156010569958864

Re-assuredly, the interviews were more familiar territory. Dr. Hofmann was very friendly, and forth-coming. Dr. Hofmann reports that their HITHOC volumes are fairly small, and attributes this to plateauing rates of pleural mesothelioma. (The majority of the HITHOC cases were initially performed for pleural mesothelioma, but there have been an increasing number of cases treating advanced thymomas (stage IV) with HITHOC as well as limited cases of pleural carcinosis.

In some of these thymoma cases, the patient undergoes a staged procedure, with mediastinal exploration performed as the first step. In some cases, the Regensburg facility receives patients after they have undergo mediastinal lymph node dissection at another facility.

His program has been performing HITHOC for over ten years, using a combination of cisplatin and doxirubin with a cycle time of 60 minutes. He reports a low rate of complications and points to the multiple publications by his colleague, Dr. Reid for outcome data. Dr. Reid has another couple of articles in press including another paper, that explains their renal protection protocol, [in addition to Reid’s earlier work in 2013, listed below].

IMG_20190611_162641_resized_20190614_060212748 — Dr. Michael Reid (left) with Dr. Hans Stephen Hofmann

Of course, the visit wouldn’t be complete without a trip to the operating room. While it wasn’t a HITHOC case, Dr. Hofmann was performing a robotic -assisted thoracoscopic surgery on a patient requiring lung resection for adenocarcinoma. As the patient was already medicated when I entered the operating room – there are no operating room photos. The case proceeded quickly, efficiently with no intra-operative complications and minimal EBL.

As some of our long time readers know, thoracics.org no longer just reports on news and events in thoracic surgery. After multiple requests from our readers, we now facilitate specialty treatment too.

We won’t talk about that a lot here – it’s not the right forum, but for readers who would like more information about Dr. Hofmann, or are interested in surgery with Dr. Hofmann (or Dr. Gonzalez Rivas, Dr. Sihoe or any of the other modern Masters of thoracic surgery), we are happy to assist you. Contact me at kristin@americanphysiciansnetwork.org

thoracics OR Regensburg — In the operating room, with the robot behind me (case is over).

Selected citations

Both surgeons are widely published on multiple thoracic surgery topics. This is a limited selection of citations related to HITHOC.

Ried M, Hofmann HS, Dienemann H, Eichhorn M. (2018). [Implementation of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Germany]. Zentralbl Chir. 2018 Jun;143(3):301-306. doi: 10.1055/a-0573-2419. Epub 2018 Mar 12. German. PMID: 29529693 It was an article similar to this that started thoracics.org journey to Germany.

Ried M, Marx A, Götz A, Hamer O, Schalke B, Hofmann HS. (2016). State of the art: diagnostic tools and innovative therapies for treatment of advanced thymoma and thymic carcinoma. Eur J Cardiothorac Surg. 2016 Jun;49(6):1545-52. doi: 10.1093/ejcts/ezv426. Epub 2015 Dec 15. Review. PMID:26670806

Hofmann HS, Wiebe K. (2016). [Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion]. Chirurg. 2010 Jun;81(6):557-62. doi: 10.1007/s00104-010-1926-2. Review. German. PMID: 20454769

Ried M, Lehle K, Neu R, Diez C, Bednarski P, Sziklavari Z, Hofmann HS. (2015). Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure. Eur J Cardiothorac Surg. 2015 Mar;47(3):563-6. doi: 10.1093/ejcts/ezu217. Epub 2014 May 28. PMID: 24872472

Ried M, Potzger T, Braune N, Neu R, Zausig Y, Schalke B, Diez C, Hofmann HS. (2013). Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: perioperative management and clinical experience. Eur J Cardiothorac 2013 Apr;43(4):801-7. doi: 10.1093/ejcts/ezs418. Epub 2012 Aug 10. Early article on their HITHOC results with 8 patients.

Ried M, Hofmann HS. (2013). [Intraoperative chemotherapy after radical pleurectomy or extrapleural pneumonectomy]. Chirurg. 2013 Jun;84(6):492-6. doi: 10.1007/s00104-012-2433-4. Review. German. PMID: 23595855

Ried M, Hofmann HS. (2013). The treatment of pleural carcinosis with malignant pleural effusion. Dtsch Arztebl Int. 2013 May;110(18):313-8. doi: 10.3238/arztebl.2013.0313. Review. PMID: 23720697 Link to article in english discussing limited utility of HITHOC for pleural carcinosis.

Ried M, Neu R, Schalke B, Sziklavari Z, Hofmann HS. (2013). [Radical pleurectomy and hyperthermic intrathoracic chemotherapy for treatment of thymoma with pleural spread]. Zentralbl Chir. 2013 Oct;138 Suppl 1:S52-7. doi: 10.1055/s-0033-1350869. Epub 2013 Oct 22. German. PMID: 24150857

Ried M, Potzger T, Braune N, Diez C, Neu R, Sziklavari Z, Schalke B, Hofmann HS. (2013). Local and systemic exposure of cisplatin during hyperthermic intrathoracic chemotherapy perfusion after pleurectomy and decortication for treatment of pleural malignancies. J Surg Oncol. 2013 Jun;107(7):735-40. doi: 10.1002/jso.23321. Epub 2013 Feb 5. PMID: 23386426. Discussed the effects of cisplatin on tissue.

Ried M, Speth U, Potzger T, Neu R, Diez C, Klinkhammer-Schalke M, Hofmann HS. (2013). [Regional treatment of malignant pleural mesothelioma: results from the tumor centre Regensburg]. Chirurg. 2013 Nov;84(11):987-93. doi: 10.1007/s00104-013-2518-8. German. PMID: 23743993

HITHOC in 2018 – Where are we now?

We’ve come along way when discussing Mesothelioma and the use of hyperthermic intrathoracic chemotherapy (HITHOC) since this site was started back in 2010. In fact, for our first discussions about this technique, we had to travel to Ganziantep, Turkey

Back then, Dr. Isik was one of very few researchers to be actively looking, investigating and performing research in this area. So, when thoracics.org wanted to report about HITHOC – we had to go to the source. There were a few other researchers, in scattered locations across the globe, such as the Nara experiment in Japan, a couple of case reports out of Germany, but otherwise, it was a barren landscape in thoracic research.

Then came Dr. Marcello Migliore and the Italian research teams.. and then everyone else. HITHOC has expanded from the treatment of malignant pleural mesothelioma to a viable treatment for malignant pleural effusions from almost any kind of primary cancer (including lung, breast, thymoma).

So now that Thoracics.org is preparing to return to Italy for VATS International 2018 – it’s time to check in one the state of HITHOC in 2018.

Germany

It seems the Germans have the answer. Unfortunately, they are keeping it to themselves, because Reid et. al’s most recent article that sums up state of HITHOC in over 116 German institutions is published only in german. Thoracics.org has attempted to contact the lead author for more details, but at the time of this publication, we are still awaiting a reply.

The English version abstract gives us a tiny sliver – of the results of the authors survey of german thoracic surgery practices. Ried et al. reports that of the 116 facilities they surveyed, 17 thoracic surgery departments in Germany are performing HITHOC. All of these facilities perform HITHOC for malignant pleural mesothelioma, with 11 facilities including patients with thymoma with pleural metastasis. Only 7 facilities report performing HITHOC on patients with other secondary pleural carcinosis. While the inclusion criteria doesn’t appear to be the same throughout Germany, the procedural protocol appears to be fairly universal – hyperthermic (42 centigrade) application of cisplatin or cisplatin combinations for a 60 minute cycle. But that tiny scrap of an abstract still leaves thoracics.org with so many questions. Enough in fact, that we promise the authors their own feature article, if we get a reply.

Italy

Migliore’s recent editorial, while interesting, doesn’t really add much to our current landscape. On the thoracics.org wishlist instead is a more step-by-step discussion of the Catania University thoracic surgery department’s HITHOC treatment algoriths and review of research results.

Luzzi et al. out of Siena, Italy published a small-scale study on the physiologic effects of HITHOC after pleurectomy and decortication. Notably, these patients are undergoing an more extensive operation than HITHOC alone, and there are part of a smaller subset of patients with a more aggressive cancer than some of our other studies, namely malignant pleural mesothelioma (MPM). While the authors followed 41 patients undergoing HITHOC at their facility, only ten patients were enrolled in their study looking at hemodynamics.

This study which included 10 patients, looked at the hemodynamics of patients before, during the HITHOC procedure, and the early post-operative procedure. The authors were trying to address possible causes of the high rate of complications cited in previous researchers studies. These studies also showed that adequate fluid hydration intra-operatively reduced many of these complications such as hypotension and acute renal injury. The authors hypothesized that microvascular changes (namely systemic vasodilation and with a capillary leak syndrome) contributed to the development of these operative complications. They used both vasopressors and specific fluid volume resuscitation recipes to reduce these microvascular changes during and after the procedure but also observed that colloid and blood transfusions had similar effects. The authors call for the adoption of hemodyanamic monitoring parameters similar to those used in cardiac surgery (Swan Ganz, SvO2 monitoring) for better detection and treatment of these microvascular changes to limit the development of complications.

China

Chinese authors offer us the most comprehensive view of HITHOC up-to-date. Not through newly published results or an original work, but through a comprehensive meta-analysis of previously published works. Zhou et. al do a nice job of reviewing the existing research and discussing the different applications of HITHOC (outside of malignant pleural mesothelioma for malignant pleural effusions of any underlying etiology. Unfortunately, Thoracics.org has covered many of these articles before – so while it’s a good overview article for HITHOC novices, long-term readers already know the in-depth details of the Isik study, Zhang’s results, and several of the other major studies discussed in Zhou et. al. But the authors make a very salient point – that while several of the programs have formalized and standardized HITHOC protocols, these protocols often differ from hospital to hospital, with no set universal chemotherapeutic regimen in place. A universal protocol would make it easier to conduct additional meta-analyses and RCTs to determine if HITHOC for malignant pleural effusions are as promising as they appear to be. A HITHOC registry, anyone?

References

Luzzi, et. al. (2018). Hyperthermic intrathoracic chemotherapy after extended pleurectomy and decortication for malignant pleural mesothelioma: an observational study on outcome and microcirculatory changes. Journal of thoracic disease, vol 10, supp 2.

Migliore, M. (2017). Debulking surgery and hyperthermic intrathoracic chemotherapy (HITHOC) for lung cancer. Chinese Journal of Cancer Research, 2017, Dec; 29 (6): 533-534. Editorial.

Reid, M., Hofmann, H. S., Dienemann, H. & Eichorn, M. (2018). Implementation of hyperthermic intrathoracic chemotherapy in Germany. [article in german]. Zentralbl Chir. 2018 Jun, 143 (3): 301-306. Ried et al. are also the authors of that 2014 article, we discussed in a previous post about anesthesia during HITHOC.

Zhou et. al. (2017). Effect of hyperthermic intrathoracic chemotherapy on the malignant pleural effusion. Medicine, 96:1.

*Thoracics.org has a particular interest in the area of HITHOC. Researchers and HITHOC programs are always invited to submit research, and other materials for for review here at Thoracics.org

Q and A with Migliore et al.. about Hithoc and Mesothelioma in Catania, Italy

Thoracics.org follows up with Dr. Marcello Migliore from the University of Catania, on his work in the area of HITHOC and malignant pleural mesothelioma

Dr. Migliore and his team performing HITHOC

As discussed in a previous post on HITHOC and Mesothelioma, Dr. Marcello Migliore and his colleagues in Catania, Italy have published results from a small pilot study on the use of HITHOC (cytoreductive surgery and intrathoracic chemotherapy) to treat malignant pleural mesothelioma.

Thoracics.org contacted Dr. Migliore to find out more about that study as well as his on-going research in this area. He was also kind enough to offer his opinions on Hope and the diagnosis of malignant mesothelioma.

On-going research on HITHOC

Thoracics.org: Dr. Migliore, woud you tell us more about your current research on HITHOC and mesothelioma?

Dr. Migliore: We are conduction a pilot study to compare pleurodesis with talc vs HITHOC in mesothelioma patients. Goals are quality of life and survival.

Thoracics.org: How many more patients are you hoping to enroll ?

Dr. Migliore: we hope to enroll at least 12 patients (unfortunately in almost 2 years we enrolled only 6 patients)

Thoracics.org: Would you tell us more about eligibility criteria?

Dr. Migliore: All patients with mesothelioma will enter the study protocol except those who cannot undergo surgery for poor performance status.

Thoracics.org: Would you describe the procedures for our readers?

Dr. Migliore: Talc pleurodesis is performed using the uniportal VATS technique (2 cm skin incision), which is a concept that was introduced by us already in 1998 (and published in 2001 and 2003). As you know, Gonzalez- Rivas is now well known worldwide for using the concept of uniportal technique to perform major lung resection. Pleuerectomy and decortication with HITHOC is performed using the bi-portal VATS technique but with an skin incision of around 8 cm.

Thoracics.org: In your preliminary paper on your last pilot study, there were a couple patients with lung cancer who were included in the HITHOC trials. Is that the same for your current study?

Dr. Migliore: While I feel that some patients with lung cancer could have benefited from HITHOC, for this study, the indications must be strictly limited [to patients with malignant mesothelioma only].

As you know, the largest group of patients with lung cancer are patients with more advanced cancer; stage IV lung cancer patients, and because survival is dismal, the standard practice is no surgery except palliative procedures. But, there are selected patients in whom there is some evidence that surgery could help. For this reason my personal reaction is that, in the near future, we should aim to prolong survival in stage IV lung cancer patients also by surgery. We are in mind to start a new study on the role of surgery in selected stage IV lung cancer patients.

Migliore and colleagues — Dr. Migliore and his colleagues from the University of Catania, Policlinico Hospital, Catania, Italy

Technical Aspects on HITHOC

Thoracics.org: Does previous pleurodesis make surgery more difficult?

Dr. Migliore: Yes, due to the development of adhesions between parietal pleura and the chest wall, as well as between the parietal and the visceral pleura, which are really difficult to remove. It requires delicate work using the fingers ( at the end of the operation you can have pain in fingers and fingertips!)

Thoracics.org: Does it lead to increased operating room time, or increased bleeding from adhesions?

Dr. Migliore: While is certainly increases operating time but there is no evidence of increased bleeding but air leaks are more frequent. Intraoperatively, it is imperative to put attention to every single detail to avoid postoperative complications.

Thoracics.org: Do you find that patients with diaphragm involvement develop more post-operative complications or are more likely to develop disseminated disease ?

Dr. Migliore: That has not occurred in this group of patients but the number of patients is small, and therefore it is impossible to answer.

Other considerations

Thoracics.org: What has been the biggest obstacle in your research?

Dr. Migliore: Certainly living in a “rural” region with cultural dogmas and financial restriction for research are probably the most common obstacles to speedy clinical surgical research.

On Hope & Malignant Mesothelioma

[During a related study] “We operated two patients and one is alive after 3 years. She was 40 y.o. lady with a 15 year-old child. She had malignant pleural effusion with a peripheral lung tumor and was treated elsewhere with talc pleurodesis alone, and 6 months survival was given. We performed a parietal and visceral pleurectomy with HITHOC. She is alive (with recurrence) and her son is now 18 yo. This simple case give an explanation that an operation although “experimental, gives hope (we should not give false hope) and permits to these unfortunate patients to see light in the dark”.

Dr. Marcello Migliore, MD

Thoracic Surgeon

Section of Thoracic Surgery

Department of General Surgery & Medical Specialities

University of Catania, Policlinico Hospital

Catania, Italy

Editor’s note: Some minor edits have been made for the sake of formatting. Thank you to Dr. Migliore and his team.

Mesothelioma, Hope and HITHOC

Is there hope? Thoracics.org discusses hope and mesothelioma along with the most recently published work in the area of cytoreductive surgery and intrathoracic chemotherapy (HITHOC).

Is there hope?

In a recent article in Future Oncology, Dr. Maat and his colleagues explore the question of whether hope exists for patients with malignant pleural mesothelioma (MPM). The authors acknowledge the difficulties for patients and providers alike in maintaining hope when the odds are against it. Dr. Maat also discusses the differences between offering false hope and belief in the possibilities of emerging therapies.

“Dismal” prognosis of malignant mesothelioma

This brings to the forefront one of the biggest failures in thoracic surgery and oncology; malignant mesothelioma. While great strides have been made in the last fifty years in the treatment of many other cancers, malignant mesothelioma continues to carry a dismal prognosis with a lifespan measured in months. Not only that, but even the great “wins” in this area, like pleural decortication, are often only viewed as such when measured against palliative treatment (Zahid, Sharif, Routledge & Scarci, 2011).

This is one of the reasons Thoracics. org has taken such an interest in emerging therapies and research in areas such as HITHOC, and will continue to do so. Sometimes even the most promising data takes a dead-end, like in the case of Dr. Isik in Ganziantep, Turkey, where HITHOC and mesothelioma research have been forced to take a backseat to ISIS and the Syrian refugee crisis. This along with financial limitations (unfunded research) have threatened a promising program.

Dr. A. Feridun Işık and his team perform cytoreductive surgery and the HITHOC (HIPEC) procedure (in 2014)

In situations like Dr. Isik’s, it is easy for readers and other researchers themselves to lose hope. If programs showing favorable results like Dr. Isik’s can not survive, how can we expect support for additional research in this area? But just as Dr. Maat advocates for hope among patients, and providers, we here at Thoracics.org continue to advocate for a hopeful future in the area of HITHOC; not just for malignant pleural mesothelioma, but for a whole spectrum of cancers that remain frustratingly difficult to treat.

Migliore et al.

As such, Thoracics.org would like to highlight some of the most recent HITHOC publications. Two of these studies are from Dr. Migliore and his colleagues at Catania, Italy. The first paper, describes their preliminary experiences with eight patients (6 patients with MPM and 2 patients with lung cancer). The authors discuss inclusion criteria, methodology and surgical technique (uniportal VATS/ and mini-thoracotomes) including one hour of chemoperfusion with cisplatin at 42.5 degrees centigrade. Interestingly, in this tiny subset of patients, the surgeons included one patient who underwent diaphragmatic resection, which is usually considered a contraindication to the procedure according to most researchers*. When we review the post-operative survival of these patients in this and the subsequent publication, it is worth asking about the specific survival time of the patient with diaphragmatic resection, and whether disease recurred in this specific patient.

The authors also included 2 patients with adenocarcinoma of the lung with pleural metastases in their priliminary series. One of these patients had previously undergone talc pleurodesis.

Consistent with other recently published reports, mortality for this limited study was 0% (or much lower than what was previously reported during the “first generation” of cytoreductive surgery with hyperthermic chemotherapy in the early 2000’s). Additional post-operative complications included 2 cases of post-operative nausea/ vomiting and one patient with acute kidney injury (post-operative creatinine 2.0).

The second publication by Migliore et al., also in Future Oncology is an expanded discussion of the six malignant pleural mesothelioma patients with better survival outcomes as 4 patients survival extended past the time of publication (one death at 6 months post-operative, one death at 24 months).

Anesthesia and HITHOC

While this article dates back to mid 2014, Kerscher et al. is one of the only authors to investigate and describe the unique challenges for anesthesiologists managing these patients during the intra-operative and post-operative period. Kerschner and colleagues report on their experiences with 20 patients undergoing cytoreductive surgery and HITHOC at the University Medical Center in Regensberg, Germany from 2008 to 2013. In addition to describing the intra-operative anesthetic and post-operative analgesic techniques used as their institution, Kerscher et. al also delve into the specific management strategies related to the use of HITHOC, such as the addition of ventilatory peep during the cycling of hyperthermic chemotherapy to increase the amount of lung surface area exposed to the chemotherapeutic agents (cisplatin in this study).

Recommended reading

Their discussion of the management of intra-operative challenges caused by the infusion of chemotherapy such as low cardiac output, hypotension, pulmonary edema and coagulopathies along with an in-depth look at hemodynamics, volume resuscitation, challenges in ventilation and normothermia make this paper recommended reading for any surgeons or institutions interested in piloting their own HITHOC program. This article also serves as a reminder that while many small studies report minimal complications, there can and are serious and potentially fatal intra-operative complications in patients undergoing HITHOC.

Like Dr. Hung and Dr. Chen, this paper serves an important reminder that all advancements and discoveries in thoracic surgery require a cohesive, teamwork approach.

*Most surgeons who perform HITHOC / HIPEC exclude patients with diaphragmatic involvement because this is believed to make it impossible to prevent widespread dissemination of disease – since the diaphragm is the physical, tissue barrier that separates the chest cavity from the abdomen.

References

Maat, A., Cornelissen, R., Bogers, J. & Takkenberg, J. (2015). Is the patient with mesothelioma without hope? Future Oncol., 2015, 11 (24s), 11-14.

Migliore M, Calvo D, Criscione A, Viola C, Privitera G, Spatola C, Parra HS, Palmucci S, Ciancio N, Caltabiano R, Di Maria G. (2015). Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases: preliminary experience. Future Oncol. 2015;11(2 Suppl):47-52. doi: 10.2217/fon.14.256.

Migliore M, Calvo D, Criscione A, Palmucci S, Fuccio Sanzà G, Caltabiano R, Spatola C, Privitera G, Aiello MM, Parra HS, Ciancio N, Di Maria G. (2015). Pleurectomy/decortication and hyperthermic intrapleural chemotherapy for malignant pleural mesothelioma: initial experience. Future Oncol. 2015 Nov;11(24 Suppl):19-22. doi: 10.2217/fon.15.286.

Kerscher C, Ried M, Hofmann HS, Graf BM, Zausig YA. (2014). Anaesthetic management of cytoreductive surgery followed by hyperthermic intrathoracic chemotherapy perfusion. J Cardiothorac Surg. 2014 Jul 25;9:125. doi: 10.1186/1749-8090-9-125. An excellent overview of intra-operative management considerations for patients undergoing HITHOC procedures. Recommended reading.

Dr. Ahmet F. Işık talks about pleural mesothelioma, HITHOC, and thoracic surgery in Gaziantep, Turkey

updates on the on-going HITHOC project, war surgery, foreign body obstructions and bronchoscopy for infants

Gaziantep, Southeastern Anatolia

It’s been over a year since I first read Dr. Isik’s work on treating pleural mesothelioma. Since that time, Dr. Işik has continued his research into HITHOC and has now enrolled over 79 patients into the hyperthermic treatment group including one of the patients I met during my visit. (There are 29 surviving patients in the study, 13 in the mesothelioma group, the remainder are secondary pleural cancers.).

(If you are a patient seeking treatment, or would like more information about Dr. Isik (or Dr. Gonzalez Rivas, Dr. Sihoe or any of the other modern Masters of thoracic surgery), we are happy to assist you. Contact me at kristin@americanphysiciansnetwork.org

First impressions are deceiving

I don’t know what I expected Gaziantep to look like as one of the world’s oldest cities, but from the moment the airplane begins its descent into a beige dust cloud, to the desolate brush and dirt of the airport outside the city, it isn’t what I expected. Much of the antiquity of the biblical city of Antiochia has been replaced by a bustling modern city. Historic ruins and ancient Roman roads marking this as part of the original Silk Road are conspicuous, only by their scarcity.

modern Gaziatep is featureless at first glance — modern Gaziantep is featureless at first glance

There are a handful of museums and monuments to the area’s rich history, but like the new name of Gaziantep (replacing Antep after the first world war), Turkey’s sixth largest city is modern; a collection of traffic and squat square buildings of post-modern architecture.

The city is also a mosaic of people. There are groups of foreign journalists in the lobby of our hotel, and convoys of United Nations vehicles cruising the streets. Crowds of Syrian children play in the park, calling out in Arabic to their parents resting on the benches nearby. There is a smattering of Americans and English speakers interspersed, many are college students and other foreign aid workers on humanitarian missions to help alleviate the strain caused by large numbers of people displaced by the Syrian civil war.

Gaziantep is famed for their copper work

But like a mosaic, there is always more to see, the closer you look. For me, as I look closer, I just want to see more. I feel the same about Dr. Elbeyli’s thoracic surgery department.

The closer you look, the more you see. photo courtesy of wiki-commons — The closer you look, the more you see.
photo courtesy of wiki-commons

The border (and the largest Syrian city of Aleppo) lies just to the south – and the impact of the Islāmic militants is felt throughout the region. No where is this more evident than at the local university hospital, where I meet Dr. Ahmet Işık and the Chief of Thoracic Surgery, Dr. Levent Elbeyli.

Dr. Ahmet Feridun Işık

I like Dr. Işık immediately. He is friendly and appears genuinely interested by my visit. He’s from Giresun in the Black Sea region of northern Anatolia of Turkey. He attended medical school at Ankara University and completed his thoracic surgery training in Ankara before going to Adiyaman State Hospital in the bordering Turkish province of Adiyaman in southeastern Turkey.

He was an associate professor of thoracic surgery at Yuzuncu Yil University in the far eastern province of Van, Turkey before coming to Gaziantep in 2005. He became a full professor at the University of Gaziantep in 2013. In additional to authoring and contributing to his own publications, he also served as a reviewer for the Edorium series of open access journals.

It helps that his English is miles better than my non-existent Turkish. (Reading about the Turkish language in phrase books is one thing, pronouncing words correctly is another.)

He doesn’t seem to mind my questions tumbling out one after another. I’d like to be the cool, sophisticated visitor, but I’ve been waiting so long to ask some of these questions – and frankly, I am just excited to be there.

Dead-ends in medicine

There are a lot of “dead ends” in medicine – treatments that at first appear promising, but then end up being either impractical or ineffective. In fact, for the first ten years of HIPEC, most surgeons dismissed it as a ‘dead-end’ treatment; the surgery was too radical and mortality too high. But researchers kept trying experimental protocols; tweaking medications (less toxic) and procedures – and finding the right patients (not too frail prior to surgery) – and the literature shifted; from a largely useless ‘last ditch’ salvage procedure to a large, but potentially life-saving treatment. HITHOC is HIPEC in another color…

So I fire away –

Since our last post about Dr. Işık – he has performed several more cases of HITHOC on patients with pleural mesothelioma, pleural based cancers and advanced lung cancers. He now has 79 patients in the HITHOC treatment group. He has been receiving patients from all over Turkey, including Istanbul to be evaluated for eligibility for this procedure. While the majority of patients are referred by their oncologists, others come to Gaziantep after reading about Dr. Işık on the internet.

None of the original patients (from 2009) are still alive, but their survival still exceeded all expectations, with 13 patients (of 14 HITHOC patients) living 24 to 36 months after the procedure. (I don’t mean to be vague – but I was asking some of these questions in the operating room and I forgot to stuff my little notebook in my scrub pocket.)

While much of the literature surrounding the procedure cites renal failure as one of the major complications of the procedure, Dr. Işık has had one case of renal failure requiring dialysis. Any other instances of elevated creatinine were mild and transient. He doesn’t use any chemical renal prophylaxis but he does use fluid rehydration to limit nephrotoxicity.

He reports that while many surgeons consider sarcomas to be a contraindication to this procedure, he has had good outcomes with these patients.

He does state that diaphragmatic involvement in mesothelioma is an absolute contraindication because while the diaphragm can be resected / patched etc, it is almost impossible to guarantee or absolutely prevent the seeding of microscopic cancer cells from the diaphragm to the abdominal cavity – which increases the risk of disseminated disease.

He still uses Cisplatin – since that is what the original HITHOC researchers were using, but he uses a slightly higher dose of 300mg. He’d like to do some prospective studies utilizing HITHOC (these have all been retrospective in nature – comparing today’s patients with past patients that received PDD and pleurodesis for similar conditions). Prospective studies would allow him to better match his patients and to compare treatments head to head. It would also allow him to compare different techniques or chemotherapeutic agents.

Unfortunately, as he explained, many of these types of studies of ineligible for government funding in Turkey because the government doesn’t want to pay for experimental / unproven treatments for patients even if there are few or no alternatives for treatment. He is hoping to appeal this regulation so that he can continue his research since there is such a high rate of mesothelioma, that disproportionately affects rural Turkish patients.

The University of Gaziantep Hospital

The University Hospital is one of several hospitals in Gaziantep. The academic institution has over 900 beds and 20 operating rooms spread out over three floors. There is a large 24 bed surgical ICU which includes 4 dedicated thoracic surgery beds.

Thoracic surgery may not be the advertised superstar of the hospital but it is the backbone of patient care. There are three full-time professors of surgery; Dr. Ahmet Isik, Dr. Levent Elbeyli and Dr. Bulent Tunçözgür, along with an associate professor, Dr. Maruf Sanli, several thoracic surgery fellows and research assistants. Together the thoracic surgery team performs over 1000 cases a year.

Dr. Levent Elbeyli is the driving force for thoracic surgery. A Gaziantep native, he founded the department in 1992, and has seen it grow from a few scattered beds to a full-fledged program with a full-time clinic, 2 dedicated operating rooms, 4 ICU beds and 15 to 20 cases a week.

Dr. Levent Elbeyli (in loupes) in the operating room

For the thoracic nurse, the department of Thoracic Surgery is a dream come true; tracheal cases, surgical resections, esophagectomies, thoracic trauma – all of the bread and butter that makes our hearts go pitter-pat. But then there is also plenty of pediatric cases, pectus repair, foreign body removal (oro-esophageal) and on-going surgical research. They do a large amount of pediatric and infant bronchoscopies (for foreign body obstructions, tracheal malformations etc).

There is the slightly exotic hydatid cysts and the more mundane (but my personal favorite) empyema thoracis to be treated. Cancers to be staged, and chest wall resections to undertake. I feel almost overwhelmed in my own petite version of a candy store; everywhere I turn I see opportunities to learn, case reports to write and new things to see.

Dr. Levent Elbeyli operates as Dr. Isik observes.

My non-medical readers might be slightly repulsed by my glee – but it is this intellectual interest that keeps me captivated, engaged and enamored with thoracic surgery and caring for thoracic surgery patients. And then there is the HITHOC program. With a large volume of mesothelioma and pleural based cancers due to endemic environmental asbestos in rural regions of Turkey, there is an opportunity to bring hope and alleviate suffering on a larger level. (Dr. Isik sees more cases here in his clinic in one year than I have seen in my entire career).

What’s not to love about that?

Article updates:

Since our original visit to Dr. Isik, he has continued his work on HITHOC for malignant pleural mesothelioma and other cancers. You can read his latest paper, “Can hyperthermic intrathoracic perfusion chemotherapy added to lung sparing surgery be the solution for malignant pleural mesothelioma?”

In this study, Dr. Isik and hs team looked at 73 patients with malignant pleural mesothelioma (MPM) who were in three different treatment groups. Group 1 received surgery only (extrapleural pneumonectomy). Group 2 received palliative treatment only. Group 3 received lung sparing surgery with hyperthermic chemotherapy (HITHOC). Lung sparing surgery included pleural decortication.

While the treatment groups are small, the results show a clear survival benefit to the patients receiving HITHOC. Surprisingly, the palliative group lived longer than the surgery alone group.

Survival based on treatment modality:

Surgery only: 5 months average surgery. 15% survival at 2 years

Palliative treatment only: 6 months average survival 17.6% at 2 years

HITHOC group: 27 months average survival 56.5% at 2 years

Selected Bibliography for Dr. Işık

Işık AF, Sanlı M, Yılmaz M, Meteroğlu F, Dikensoy O, Sevinç A, Camcı C, Tunçözgür B, Elbeyli L (2013). Intrapleural hyperthermic perfusion chemotherapy in subjects with metastatic pleural malignancies. Respir Med. 2013 May;107(5):762-7. doi: 10.1016/j.rmed.2013.01.010. Epub 2013 Feb 23. The article that brought me to Turkey, and part of our series of articles on the evolving research behind HITHOC.

Isik AF, Tuncozgur B, Elbeyli L, Akar E. (2007). Congenital chest wall deformities: a modified surgical technique. Acta Chir Belg. 2007 Jun;107(3):313-6.

Isik AF, Ozturk G, Ugras S, Karaayvaz M. (2005). Enzymatic dissection for palliative treatment of esophageal carcinoma: an experimental study. Interact Cardiovasc Thorac Surg. 2005 Apr;4(2):140-2. Epub 2005 Feb 16.

Er M, Işik AF, Kurnaz M, Cobanoğlu U, Sağay S, Yalçinkaya I. (2003). Clinical results of four hundred and twenty-four cases with chest trauma. Ulus Travma Acil Cerrahi Derg. 2003 Oct;9(4):267-74. Turkish.

Sanli M, Arslan E, Isik AF, Tuncozgur B, Elbeyli L. (2013). Carinal sleeve pneumonectomy for lung cancer. Acta Chir Belg. 2013 Jul-Aug;113(4):258-62.

Maruf Şanlı, MD, Ahmet Feridun Isik, MD, Sabri Zincirkeser, MD, Osman Elbek, MD, Ahmet Mete, MD, Bulent Tuncozgur, MD and Levent Elbeyli, MD (2008). Reliability of positron emission tomography–computed tomography in identification of mediastinal lymph node status in patients with non–small cell lung cancer. The Journal of Thoracic and Cardiovascular Surgery, Volume 138, Issue 5, Pages 1200–1205, November 2009.

Sanlı M, Isik AF, Tuncozgur B, Elbeyli L. (2009). A new method in thoracoscopic inferior mediastinal lymph node biopsy: a case report. J Med Case Rep. 2009 Nov 3;3:96. doi: 10.1186/1752-1947-3-96.

Sanli M, Isik AF, Zincirkeser S, Elbek O, Mete A, Tuncozgur B, Elbeyli L. (2009). The reliability of mediastinoscopic frozen sections in deciding on oncological surgery in bronchogenic carcinoma. J Thorac Cardiovasc Surg. 2009 Nov;138(5):1200-5. doi: 10.1016/j.jtcvs.2009.03.035. Epub 2009 Jun 18.

Sanli M, Işik AF, Tunçözgür B, Arslan E, Elbeyli L. (2009). Resection via median sternotomy in patients with lung cancer invading the main pulmonary artery. Acta Chir Belg. 2009 Jul-Aug;109(4):484-8.

Sanli M, Isik AF, Tuncozgur B, Elbeyli L. (2010). Successful repair in a child with traumatic complex bronchial rupture. Pediatr Int. 2010 Feb;52(1):e26-8. doi: 10.1111/j.1442-200X.2009.03000.x

Sanli M, Işik AF, Tunçözgür B, Meteroğlu F, Elbeyli L. (2009). Diagnosis that should be remembered during evaluation of trauma patients: diaphragmatic rupture]. Ulus Travma Acil Cerrahi Derg. 2009 Jan;15(1):71-6. Turkish.

Summer at Cirugia de Torax

Cirugia de Torax criss-crosses the globe to bring you news about the latest and greatest in thoracic surgery

ALAT in Medellin

It’s shaping up to be an exciting summer at Cirugia de Torax. We will be heading to Medellin for the annual conference of the Latin American Association of Thoracics.. The Who’s Who of Latin American thoracic surgeons – so I hope to see some familiar faces and catch up on their ongoing projects..

HITHOC with Dr. Isik

After the conference, it’s a quick trip home before heading over to Turkey to interview Dr. Ahmet Feridun Isik to hear more about his HITHOC program.

Dr. Isik and his colleagues have been very gracious during our correspondence – and I’ve been planning a trip to talk to him in person (and see his program) since I first read his work.

HITHOC in Regensburg, Germany at the University Medical Center

Information about the Thoracic Surgery program at the University Medical Center in Regensburg, Germany – and their research into HITHOC.

After sending out several emails to multiple facilities with published research on HITHOC – Dr. Michael Ried of the University Medical Center in Regensburg, Germany responded with some interesting information about the thoracic surgery program at his facility, led by Dr. Hans Stefan Hofmann (who was cited in previous posts) and is the primary author of an article in German, called “Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion.”

Dr. Ried reports that surgical treatment of thymoma and malignant pleural mesothelioma are two of the procedures their department specializes in. Since 2008, they have been performing HITHOC in these patients in combination with pleurectomy and decortication.

Dr. Reid reports that they will be publishing the results of a prospective study based on their experiences with HITHOC in the near future.

Contact information/ Program Summary details:

(note – site is entirely in German, no English version)

University Medical Center: http://www.barmherzige-regensburg.de

Department of Thoracic Surgery: http://www.barmherzige-regensburg.de/thoraxchirurgie.html

Chief of Thoracic Surgery: Dr. Hans Stefan Hofmann

General Contact information – department of thoracic surgery: http://www.barmherzige-regensburg.de/1772.html?&L=0

Email: thoraxchirurgie@barmherzige-regensburg.de

I’ve included visible link information for your information. Google translate will translate the website, as needed.

I have requested some additional program information, and will update this page, as soon as I receive it.

Additional Resources:

Dr. Hofmann is primary author on more than 40 journal articles on thoracic surgery topics (in English) – several dealing with lung cancer on a cellular level. I have posted just a very small sample of citations here that I have selected among full text articles available on-line. (Names of articles may have been changed).

1. The wind of change in the therapy of lung cancer – in this free full-text article from 2006, Dr. Hofmann talks about the future of treatment for lung cancer.

2. The DNA of lung cancer – this article talks about specific DNA markers for aggressive lung cancers, and how these markers may be useful in targeting / treating disease.

3. Diagnosing lung cancer with DNA

4. While Dr. Hofmann is not the primary author on this article about treating a soldier wounded in Afghanistan with artificial lung therapies – I thought it dovetailed nicely with our recent discussions on artificial lungs/ ecmo and ecmo-like therapies and future developments etc.

HITHOC research and programs

New project here on Cirugia de Torax.org: to compile a list of thoracic surgeons and thoracic surgery programs that are investigating and performing HITHOC procedures, but we need your help. Includes clinical trial information.

Since I’ve had enough web traffic and emails to see that I am not the only person that is interested in more news and research in the area of HITHOC, I have started contacting thoracic surgeons and programs that are doing research and treatment using hyperthermic intrathoracic chemotherapy. (I have identified thoracic surgeons through published literature.)

I’ve already contacted several (by email) and hope to hear back soon – so I can pass it on to interested readers. If you are currently researching this treatment, or know of a thoracic surgery program, please contact me via the site with more specific details.

HITHOC programs – Cytoreductive surgery with Hyperthermic intrathoracic chemotherapy

1. University Medical Center (Department of Cardiothoracic Surgery) and at the Barmherzige Brüder Regensburg (Department of Thoracic Surgery) – Regensburg, Germany (more details pending).

1 July 2011

Running into some roadblocks on this project – having a hard time contacting (and receiving replies) from authors researching HITHOC. Hopefully, I’ll get some more leads soon.

Other Research Programs:

HITHOC (Cytoreductive surgery + hyperthermic chemotherapy

1. Extrapleural Pneumonectomy /Pleurectomy Decortication, IHOC Cisplatin and Gemcitabine With Amifostine and Sodium Thiosulfate Cytoprotection for Resectable Malignant Pleural Mesothelioma – at Brigham & Womens – study led by Dr. David Sugarbaker (who I have attempted to contact on behalf of the site several times.) This looks to be one of several clinical trial arms for HITHOC/ Hyperthermic chemotherapy for malignant chemotherapy at Brigham and Women’s.

Hyperthermic Chemotherapy only:

1. Hyperthermia/Thermal Therapy With Chemotherapy to Treat Inoperable or Metastatic Tumors – at the University of Texas at Houston, Texas. Clinical trial currently recruiting participants.

2. Heated Chemotherapy for Cancers That Have Spread to the Chest Cavity – at St. Luke’s Roosevelt Hospital. Currently enrolling participants.

Intrathoracic Hyperthermic Chemotherapy (Hithoc) in advanced non-small lung cancer: the Nara Experience

As part of a continuing discussion of HITHOC (Hyperthermic IntraThoracic intraOperative Chemotherapy), today we are talking about the results of a small study conducted at the Nara Medical University, School of Medicine in Nara, Japan.

While the study is small (just 19 patients in three groups), it’s important because the patients involved all had advanced lung cancer, with malignant pleural effusions or disseminated disease discovered at the time of surgery. This is important, as readers know, because lung cancers are often diagnosed late, (after patients develop malignant effusions), and that the prognosis for patients with malignant effusions is grim.

Population: 19 patients.

Notably, the treatment group C consisting of seven patients (which received no intrathoracic thermic treatment) who were treated during an earlier period (2001 – 2003). Group C had an average age of 64. Essentially a control group.

The remaining patients were treated during 2006 – 2008 and are divided into two groups;

Group A which received hyperthermic (hot) saline infusion with a 30 minute dwell time – consisted of seven patients. This group was also older (average age 72).

Group B, consisting of five patients who received hyperthermic chemotherapy (cisplatin) infusion into the chest cavity with a 30 minute dwell time.

Note: Infusion in this post refers to instillation of fluid into the chest cavity, not an intravenous treatment. All patients received post-operative adjuvant chemotherapy.

The grouping of A and B serves to distinguish whether the mechanism of treatment is related to the application of heat alone, or the application of heated chemotherapeutic agents. Current theories about the effectiveness of HITHOC suggest that the heat of the chemotherapy allows the drugs to penetrate more deeply into the tissues compared to application of chemotherapy alone, but requires studies such as this to support this theory.

Interestingly, the pre-operative staging of these patients differed significantly from intra-operative findings with 8 patients diagnosed with early disease (stage I), five patients with stage II and only six patients as stage IIIA pre-operatively. (Presence of a pleural effusion denotes stage IV). Malignant effusions were not seen during pre-operative workup. (It is not uncommon to find more advanced cancer at the time of surgery.)

Surgery: All of the patients underwent a VATS procedure (video-assisted thoracoscopy). The majority of patients of patients (16) underwent surgery to remove the primary lesion (cytoreductive surgery) with ten patients undergoing lobectomy and six patients undergoing wedge resection.

Intra-operative findings: 16 patients found to have malignant effusions, 10 patients with disseminated disease.

Results: No intra-operative/ post-operative deaths.

Group A (hot saline group): no deaths during follow-up period, with a median follow-up period of almost 20 months. No recurrence of pleural effusions.

Group B (heated chemotherapy group): 4 deaths in follow-up period; median survival time was 41 months, one patient with recurrent pleural effusion 26 months after treatment.

Group C: (VATs alone): 5 deaths (during follow-up period) median survival 25 months, 4 patients with recurrent pleural effusions (average time to recurrent effusion: 3 months).

While this study is too small (with only five patients receiving intrathoracic chemotherapy) to generalize the results – it should prompt researchers into conducting more studies and trials into the use of hyperthermic intrathoracic chemotherapy in patients with late stage lung cancers.

The decreased incidence of pleural effusion in the treatment groups (A and B) is important also for quality of life issues. However, these findings are also limited by the small study size.

I have written to Dr. Naito (corresponding author on this article) for further comment and information.

Reference:

1. Kimura, M., Tojo, T., Naito, H., Nagata, Y., Kawai, N., & Taniquichi, S. (2010). Effects of a simple intraoperative intrathoracic hyperthermotherapy for lung cancer with malignant pleural effusion or dissemination. Interactive Cardiovascular & Thoracic Surgery 2010, April, 10 (4); 568 -71. (linked to pdf).

Cytoreductive Surgery with Intraoperative Hyperthermic Intrathoracic Chemotherapy

An introduction to cytoreductive surgery with hyperthermic intrathoracic chemotherapy administrative for the treatment of malignant pleural mesothelioma.

Cytoreductive surgery with Intraoperative Hyperthermic Chemotherapy (HIPEC) has been used for over a decade now for abdominal cancers including metastatic colon cancer (peritoneal carcinomatosis) and malignant peritoneal mesothelioma. During this lengthy procedure, surgeons remove as much gross disease as possible, and then infuse heated chemotherapy agents directly into the abdominal cavity to kill any residual cancer cells. One of the benefits of this treatment is that by directly administering chemotherapy to the site of disease – the patient experiences less toxic side effects (versus intravenous or oral ingestion) and higher concentrations can be used, which are more effective at killing the malignant cells. Research findings have been encouraging, and have shown significant improvement in median survival in comparison to standard treatment.

During my research in Bogotá, Colombia – I interviewed a general surgeon who was responsible for establishing a HIPEC treatment program in a local hospital there. (There are less than 25 HIPEC treatment centers in the world.) This spurred my interest in thoracic applications of this procedure (called the Sugarbaker procedure after the inventor, Dr. Paul Sugarbaker, an oncologist.)

In recent years, thoracic surgery has investigated and adopted some of this research for use and treatment of thoracic cancers, in a procedure known as HITHOC. In thoracic surgery, intrathoracic (inside the chest) administration of heated chemotherapy in the operating room has been used primarily to treat malignant thymomas and malignant pleural mesothelioma. Results of recent studies have been mixed – with the best results occurring in patients with thymomas. In patients with mesothelioma, prognosis is dependent on stage.

Rutgers and Bree et. al at the Netherlands Cancer Institute published several additional studies on the subject, looking at the effectiveness of different chemotherapeutic agents for HITHOC. Given their extensive experience and knowledge on the subject, I have contacted the researchers at the Netherlands Cancer Institute to invite the authors to submit a guest post. (I’d rather all of you hear from the experts!)

Additional References: (links when possible)

1. Dutch study using the Sugarbaker procedure for intrathoracic infusion for pleural thymomas and malignant pleural mesothelioma. Bree et. al (2000) from Chest. Small study with only 14 patients but a nice discussion of the procedure with graphics. Multiple other studies from these authors, as mentioned above.

2. A nice blog that explains the Sugarbaker procedure.

3. Very small Japanese study from 2003 – five patients. Notably, these patients had a different disease process – lung cancer with pleuritic carcinomatosis. 4 out of five patients demonstrated significant longevity after the procedure with no recurrence.

Extrapleural Pneumonectomy: EPP

Extrapleural pneumonectomy for malignant mesothelioma

Extrapleural Pneumonectomy (EPP) is a radical operation in which the entire lung, and tissues of the lung space (pleura, diaphragm and pericardium) are removed. This is done as part of a cancer operation, often for an aggressive cancer called malignant mesothelioma. During cancer operations, surgeons have to remove all or as much cancer tissue as possible, including microscopic cells that are not visible to the surgeon at the time of surgery. Any tissue that is left behind may have cancer cells which will continue to grow, and spread. Due to the location of the cancer cells (in the lining), surgeons have to remove more tissue than if the cancer was centered in the lung itself. This includes replacing the diaphragm with a synthetic patch during surgery.

Mesothelioma is named after the cells it affects. These mesothelial cells make up the “linings” of the body cavities. For this reason, mesothelioma can affect other areas of the body, in the linings of the abdomen called the peritoneum, the pericardium (the lining around the heart), and most commonly, the pleura.

Inside the chest, coating the chest wall is a thin lining tissue called the pleura. The interior area of the rib cage and chest are thus called the pleural cavity. When mesothelial cancer cells invade this fragile tissue layer, it is called pleural mesothelioma, which is different from peritoneal mesothelioma. (Peritoneal mesothelioma affects the peritoneal cavity, or abdominal cavity.)

Not everyone is a candidate for this surgery. Due to the radical nature of this procedure, patients need to have good pulmonary function and overall functional status prior to surgery. (The patient is going to lose one whole lung during this procedure, so patients that are already oxygen dependent / bedridden or otherwise debilitated won’t be able to tolerate this procedure.) The best patients for this surgery (the patients who will have the best outcomes/ receive the most benefits from surgery) are patients with good functional status (able to perform normal activities of daily living) with earlier stages of the disease. In these patients – this surgery can extend their lives significantly. In patients with more advanced (stage III/ stage IV) disease, the surgery will make them live longer (months) but the quality of life may be worse post-operatively.

Prior to consideration for extrapleural pneumonectomy (or any other treatment) the doctors will want to definitively diagnose (prove the diagnosis through tissue biopsy) and do preliminary staging. (Final staging occurs after the operation when further tissue / lymph node biopsies are evaluated by the pathologist).

Preliminary staging and pre-operative evaluation is the process to try to figure out how much cancer is present (has it spread?) and whether the patient can tolerate a large operation. Mediastinoscopy; a surgical procedure to look at mediastinal lymph nodes (lymph nodes behind the sternum or breast bone), PET scans and blood for tumor markers help determine how much cancer is present. The tumor markers also help the oncologists figure out which chemotherapy drugs will work the best.

Pre-operative testing is looking at lung function, to see how well the patient will do with only one lung. Cardiac testing may be done as well since surgery can be stressful to the heart.

If the disease is controllable with surgery, and the surgeon thinks the patient can withstand surgery – the surgeon will consult with an oncologist about the timing of surgery and adjuvant treatments (chemotherapy/ radiation).

Even with radical surgery, the prognosis for malignant pleural mesothelioma is poor, but improves with combination therapies (surgery with chemotherapy/ radiation.) Currently, surgeons are investigating the use of cytoreductive hyperthermic chemotherapy (HIPEC/ Hithoc) for treatment of pleural based mesothelioma. (Previous studies by Dr. Paul Sugarbaker has shown this treatment to be effective with advanced abdominal cancers including malignant peritoneal mesothelioma.) We will discuss HIPEC further on a future post.

There are numerous studies looking at extrapleural pneumonectomy for treatment of malignant pleural mesothelioma. The links below is just a small sampling.

1. Extrapleural pneumonectomy for malignant pleural mesothelioma (2005) – Argote- Greene, Chang, and Sugarbaker. (Note: this article was co-authored by Dr. David Sugarbaker, Department of Thoracic surgery, Brigham Womens & Children’s, not Dr. Paul Sugarbaker, developer of HIPEC. I am going to attempt to contact Dr. Davis Sugarbaker for commentary for the site since he is the expert on this topic, so hopefully I’ll be able to update the site with his post in the future.

2. Radical surgery for malignant pleural mesothelioma – Japanese study comparing results for EPP versus pleurectomy / decortication. The main points to take away from this study is that stage of disease has a huge impact on prognosis, and outcomes after surgery. (The patients with stage I and II that underwent EPP did fairly well.)

3. Review of 83 cases of EPP – (2009) French study which unintentionally highlights the potential complications of surgery of this magnitude(almost 40% had major complications and had a re-operative rate of almost fifteen percent.)