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.

canals
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.

Hofmann
Dr. Hans – Stephan Hofmann, Director of Thoracic Surgery

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.

HofmannOR
Outside the operating room

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

CT scans for the early detection of lung cancer: new recommendations

Article re-post on the newest recommendations for screening guidelines for early detection of lung cancer. Second in a series on lung cancer related topics as part of Lung Cancer Month.

As reported in multiple journals – a large, randomized study showed a significant mortality benefit from periodic low dose CT scans for the early detection of lung cancer in high risk individuals.  Since this data was published, the National Comprehensive Cancer Network has begun recommending annual CT scans in high risk people.  (High risk is defined as 55 – 74 years of age with 30 or more pack years of smoking*.)  Since lung cancer screening is independent of symptomatology, this allows lung cancer in asymptomatic patients to be discovered – at earlier stages (which hopefully allows for more effective [i.e. surgical resection] treatment.

However, this recommendation is not without its detractors (due to cost, radiation exposure, etc.) as discussed in the article below.

Article re-post from Medscape.com:

Screening for Lung Cancer Based on ‘Strongest Evidence’

Zosia Chustecka

November 17, 2011 — The brand-new guidelines from the National Comprehensive Cancer Network (NCCN), the first to be published by a national advisory group, strongly recommend the use of low-dose computed tomography (LDCT) screening for select individuals at high risk for the disease. For the target group of heavy smokers 55 to 74 years of age, regular annual LDCT scans are recommended.

This is a category 1 recommendation, which is based on high-level evidence (i.e., a randomized controlled trial) and uniform NCCN consensus that the intervention is appropriate.

“A category 1 recommendation is very uncommon,” said Arnold J. Rotter, MD, from the City of Hope Hospital in Duarte, California, who was one of the members of the NCCN panel that wrote the  guidelines. “The vast majority of clinical medicine wouldn’t be considered category 1,” he told Medscape Medical News. “Both mammography and colonoscopy, commonly performed cancer screenings, are only category 2A per the NCCN,” he pointed out.

For high-risk individuals, the recommendation is the strongest that it can be because it is based on a large randomized clinical trial, Dr. Rotter explained.

These high-risk individuals are defined as adults 55 to 74 years of age with a 30 pack-year or more history of smoking tobacco (i.e., smoking 1 pack a day for 30 years), even if they have stopped smoking within the past 15 years.

This is the same as the inclusion criteria for the National Lung Screening Trial (NLST), which was halted early last year after showing a significant lung-cancer-specific mortality benefit. An interim analysis from this trial showed that screening heavy smokers with LDCT significantly reduced deaths from lung cancer, compared with screening with chest x-ray. In the LDCT group, the reduction in lung-cancer-specific death was 20%, and there was a 7% reduction in all-cause mortality, Dr. Rotter noted.

“This was a large randomized clinical trial and it provides the strongest level of evidence that can be obtained,” Dr. Rotter emphasized.

The answer is yes.

“The question of CT screening for people at high risk for lung cancer has been answered, and the answer is yes,” he told Medscape Medical News. “Of course, further research can be done to clarify the optimal timing, size, criteria for follow-up, and many other details, but the crucial issue of lung cancer mortality has been answered in the affirmative,” he said.

The  guidelines recommend regular LDCT screening for another group of high-risk individuals — those who are slightly less-heavy smokers (a 20 pack-year or more history of smoking) but who have an additional risk factor, such as cancer history, lung disease history, family history of lung cancer, radon exposure, and occupational exposure. This is a category 2B recommendation for LDCT screening. It is based on lower-level evidence and NCCN consensus, but not  uniform consensus (as in category 2A), which signifies that there was some debate about this recommendation.

Concern Over How to Proceed

Earlier this year at the World Lung Cancer Conference in Amsterdam, the Netherlands, lung cancer experts heaped praise on the NLST results, but at the same time expressed concern about how to proceed with this finding in clinical practice. Who should be screened? How often? What should be done about unclear findings? How should intervention be minimized for patients who turn out not to have lung cancer? One issue specific to lung cancer screening is that the lung is a vital organ, so biopsies carry a greater risk than biopsies of other organs that are screened for cancer, such as the breast, cervix, and prostate.

More recently, at the Tenth Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research, experts declared that lung cancer screening is “not yet ready for prime time.”

There are a number unresolved issues with respect to CT screening for lung cancer, said John L. Field, MA, PhD, BDS, FRCPath, director of research at the Roy Castle Lung Cancer Research Programme, University of Liverpool, United Kingdom. “These need to be resolved before a national screening program can be implemented in any country,” he said at that meeting.

“These issues include defining optimal risk populations, cost effectiveness, and harmonization of CT screening protocols; the whole area of work-up techniques is still an open question,” he explained. In addition, “optimal surgical management…screening intervals, and screening rounds” must still be defined for Europe, he noted. There are several European studies  ongoing, including the NELSON (Nederlands-Leuvens Longkanker Screenings Onderzoek) trial.

I don’t know quite what their beef is.

When asked about these opinions, Dr. Rotter said: “There is tremendous push back from all of academia about cancer screening. I don’t know quite what their beef is.” This applies to all screening, he said, including mammography for breast cancer, colonoscopy for colon cancer, prostate-specific antigen testing for prostate cancer, and LDCT scans for lung cancer.

“Eliminating screening and depending on improved chemotherapy to optimize health for the population does not make sense to me,” he said.

Part of the issue is that some of the early evidence supporting these interventions came from nonrandomized clinical trials, Dr. Rotter said. This was the case with lung screening, he admitted, and was the main criticism directed at the International Early Lung Cancer Action Program (I-ELCAP) study, headed by Claudia Henschke, MD, which Dr. Rotter was involved in during the early years.

The I-ELCAP study showed that lung cancer can be diagnosed with LDCT at a much earlier stage than usual, he explained. Without screening, 85% of lung cancers are diagnosed at stage III and IV; only 15% are diagnosed at stage I.

The I-ECLAP study inverted this staging, so that 85% of lung cancers were diagnosed at stage I, he said. “But this wasn’t a randomized trial, and that was an issue,” he acknowledged. And some researchers suggested that some of the early-stage lung cancers were indolent.

“Our overwhelming experience in every area of cancer is that people with earlier stages do better and have better survival,” Dr. Rotter said. There was pressure from the research community to prove that lung-cancer-specific mortality could be reduced with LDCT screening, so the huge NLST, funded by the US National Cancer Institute, was launched. There was some controversy over the comparison of LDCT with chest x-ray; some researchers questioned whether the use of chest x-rays was ethical in light of the benefits already documented for LDCT.

Now that the NLST results are in and are overwhelmingly positive for lung cancer screening with LDCT in high-risk individuals, there should be an end to these debates, Dr. Rotter said. “I think that the antiscreening groups are struggling to find a way to minimize these very significant findings,” he added.

“I believe that lung screening is ready for prime time,” Dr. Rotter said. “In fact, the recommendations are conservative; they limit screening to only the highest-risk group,” he noted, in contrast to screening for other cancer types, which is aimed at all people.

Not a Test, Part of a Process

Lung cancer screening should not be conducted in isolation, Dr. Rotter emphasized. It should be part of a multidisciplinary program with primary care doctors, pulmonologists, radiologists, thoracic surgeons, medical oncologists, and pathologists, as specified in the NCCN guidelines. In addition,  smoking-cessation counseling should be an integral part of the  screening process, he noted.

This sentiment was echoed by Michael Unger MD, FACP, FCCP, director of the pulmonary cancer detection and prevention program and of the pulmonary endoscopy and high-risk lung cancer program at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Screening is not a test but a process.

“I maintain that screening is not a test but a process requiring a multidisciplinary approach with adequate resources for appropriate follow-up and algorithms of the best available additional tests and procedures,” Dr. Unger told Medscape Medical News. “Without this, it is a financially driven sham that exploits public ignorance; it has some personal benefits but also potential damage.”

Dr. Unger was on the panel of experts that authored the  NCCN guidelines. “By definition, it is a consensus, and is not necessarily a rigorous, methodologically strict, and categorically graded guideline. Thus, it has strength and weaknesses,” he said. However, he added, the results from the NLST randomized controlled trial “are solid.”

“The consensus recommended proceeding with the process of screening in a specific high-risk population that, essentially, is not different from the population criteria for inclusion in the NSLT study,” he said.

Dr. Unger agrees that there are many unanswered questions. “For example, assuming a negative study on initial and repeat LDCT in a subject 57 years of age: Do we stop (and if so, on what basis) or continue until age 74? Or should we do it every 2 years? If so, what is the evidence?”

Another important point is that in the United States, where lung cancer screening is already being offered at some centers, the process is not covered by medical insurance companies, Dr. Unger noted. “Patients are asked to pay (around $300 to $350) out of pocket…. This might introduce the problem of disparities.”

For the time being, Dr. Unger sees lung cancer screening as more of personalized rather than a population-based approach. “We are dealing then with 2 issues — medical practice and public policy,” he said. [article end].

* How to calculate pack years:  pack years are the number of years smoking multiplied by the amount of cigarettes (ppd) per day.  For example, a person who smokes two packs per day for 15 years would have 30 pack years – same as someone who smoked 1 pack per day for thirty years. When trying to calculate years smoking (if patient isn’t sure) – take the age of the patient and assume initiation of smoking at the age of 15 to 20.  It is rare for mature adults to start smoking.

Update: 25 May 2012: The American College of Chest Physicians and the American Society of Clinical Oncology (ASCO) recently released lung cancer screening guidelines recommending low-dose CT scans.  These guidelines were endorsed by the American Thoracic Society.   These guidelines recommend yearly CT screening for smokers and former smokers 55 years and older with heavy smoking habits.  More about the pros and cons associated with these guidelines can be found here.

Additional Resources

A blog by a thoracic surgeon discussing the effect of Japan’s long standing lung cancer screening program (which dates back to the 1940’s).

National Comprehensive Cancer Network – screening recommendations.

Updated:  3/24/2012 : More on the screening guidelines as presented at a recent cancer conference in Florida.  NCCN annual conference presentation, March 2012

Ferketich AK, Otterson GA, King M, Hall N, Browning KK, Wewers ME.  A pilot test of a combined tobacco dependence treatment and lung cancer screening program.  Lung Cancer. 2011 Nov 14.

Note:  article re-posts are for the benefit of readers who do not have subscriptions or access to medical journals.