hyperthermic intrathoracic chemotherapy for treatment of cancer

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)

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.