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

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

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).