Mesothelioma, Hope and HITHOC

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

Is there hope?

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


“Dismal” prognosis of malignant mesothelioma

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

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

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

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

Migliore et al. 

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

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

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

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

Anesthesia and HITHOC 

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

Recommended reading

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

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

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


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

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

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

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

Extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma revisited: the Australian experience

A discussion of and link to the Yan et. al (2011) article, “Improving survival rates after surgical management of pleural malignant mesothelioma: an australian institutional experience” as part of a series of posts on mesothelioma and extrapleural pneumonectomy (EPP).

A recent study by Yan et al. (2011) conducted at the Royal Prince Alfred Hospital in Sydney, Australia does more than look at the outcomes of the aforementioned treatment for malignant pleural mesothelioma.  This study, involving 540 patients, over 25 years also gives us a primer on the evolving treatment therapies for this condition.  As newer treatment therapies emerged, these therapies were given to eligible patients, starting with extrapleural pneumonectomy itself, in 1994 and extending to include both radiotherapy and chemotherapy. Chemotherapy consisted of a combination of pemtrexed, carboplatin and cisplatin.  While this alters the results significantly it also provides for an interesting introspective on the treatment of malignant pleural mesothelioma.

This study is noteworthy for both this reason, and as a study looking at a larger set of patients than many of the other studies on this topic.

Study Design: consecutive, non-randomized.

Patient population:  540 patients; organized into two groups for statistical analysis.  Group I – 270 patients (consecutive patients from March 1984 to September 1999.)  Group II – consecutive patients September 1999 to Jan 2008.  As the authors noted, due to the rarity of this condition in Australia, it took 25 years to recruit 540 patients for treatment.

Patient characteristics: the vast majority were male (455 patients)  with a mean age of 66 (+/- 11 years).  315 patients with right-sided disease, the remaining 225 with left-sided disease.

Disease subtypes:

235 patients with epithelial subtype, 212 with sarcomoid/ biphasic  (type determined by tissue pathology)

Treatments received:

69 patients had extrapleural pneumonectomy

269 patients received pleurectomy/ decortication

202 patients received pleurodesis

62 patients received post-operative radiotherapy starting 8 to 12 weeks after surgery. This treatment was added in 2002.

65 of the patients received adjunctive chemotherapy

Notably, as mentioned above, there was a distinct difference in the treatment allocation for groups I and II due to changing treatment protocols, and the development of new therapies.  While 22% of patients in group II received EPP, only 5% of patients in group I received the same surgical procedure.

Treatment strategies were also limited by patient factors; namely the patient’s physical condition / functional status as being considered able to withstand the proposed treatment therapy.  As mentioned in a previous post, extrapleural pneumonectomy is an extensive surgical procedure which requires significant patient reserves and pre-existing functional abilities for anticipated recovery.  In frail or debilitated patients, (as defined by criteria set forth by Yan et. al) EPP was not attempted.  Some of these patients received either pleurectomy with decortication.  In patients deemed too fragile to withstand either of these procedures, a talc pleurodesis (either by VATS or tube thoracostomy) was performed as a palliative procedure.  Unsurprisingly, the patients receiving palliative treatment options had shorter median survival periods.


18 patients died in the perioperative period, including 3 EPP patients.

Median follow-up period for the study was ten months.  At the time of follow-up the majority of patients (433 patients, 80%) had died with a median survival time of nine months for group I (range 0 – 115 months).

In group II, the median survival time was 13 months.  (range 0 – 72 months).

Long term survival by group:

Group   I                                                  Group II

1 year      35%                                                     50 %

2 year     16%                                                     22%

3 year       9 %                                                      12%

5 year        2 %                                                       9 %

These five-year survival rates highlight the importance of continued studies for the advancement of treatment therapies for this condition.

Factors associated with greater survival:

In reviewing their research, the authors were able to identify four independent factors that increased the likelihood of survival in this population. (See original article for discussion in further depth.)

1. Yan et. al found that the epithelial subtype was more favorable for patient survival, and that this subtype was more common in the patients in group II.

2.  The surgeon’s experience (of greater than 100 cases) was positively correlated with greater survival.  Surgeon expertise has been shown to be a factor for better patient outcomes in multiple procedures.

3. Patients who received EPP had improved survival compared to patients who received other treatments.  However, this also reflects a selection bias, since the patients who were eligible for EPP had better pre-operative functional status than patients who received other treatments.

4.  Premetrexed chemotherapy – patients who received this chemotherapy regimen had greater survival.

blog author’s note:

Despite dismal five year survival rates for treatment of malignant pleural mesothelioma by a multitude of treatment methods, extrapleural pneumonectomy (with adjuvant chemotherapy) appears to be the most effective cytoreductive surgery for this condition. ( As noted in related posts, HITHOC is an emerging therapy that combines the principles of both.) We will continue to follow research in these areas for the treatment of malignant pleural mesothelioma and invite the experts to add their comments.

Original article:   Yan, T. (2011). Improving survival rates after surgical management of malignant pleural mesothelioma: an australian institutional experienceAnn Thorac Cardiovasc Surg 2011; 17: 243-249.  Primary author: Dr. Tristan Yan.