How to find treatment for malignant pleural mesothelioma

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

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.

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

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.