Isik et al.. & HITHOC in patients with pleural malignancies

The actual title of the article by Ahmet Feridun Isik and his colleagues at Ganziantep University Medical School in Sejitkamil – Ganziantep, Turkey is “Intrapleural hyperthermic perfusion chemotherapy in subjects with metastatic pleural malignancies.”

As we’ve discussed in previous posts, malignant pleural effusions (MPE) are a devastating diagnosis with an exceedingly poor prognosis.  As stated by the authors, “currently palliative therapy with pleurodesis or pleurectomy / decortication is the treatment of choice in secondary MPEs. Other treatment approaches are chemotherapy and/or radiotherapy.   Unfortunately, none of these approaches provides a significant benefit for survival.”

Length of survival following the development of MPE is related to the underlying primary cancer, and primary lung cancer has the shortest survival.  However, preliminary results of other studies looking at HITHOC have shown promising results.  This is what led Isik and his team to further study the use HITHOC in malignant pleural effusion.  With their permission, and gracious assistance, we have presented information on their study here.

HITHOC or HIPEC is the administration of heated chemotherapy directly to the tissue surfaces.  Scientists believe that the addition of heat, as part of a direct application of a chemotherapeutic solution enhances the cancer-cell killing effects of the agent itself while localizing these effects to the affected body cavity.  (Versus systemic chemotherapy through an IV -into the bloodstream where the chemotherapy has direct effects on other organs like the brain).  While chemotherapy is still absorbed into the system with systemic effects, this is believed to be less than with traditional chemotherapy.

When: Study started in January of 2009 – December 2011 (for data compiled and used for publication).  Protocol is currently on-going.

Who:  Cancer patients with a node status of 1N or less with (pleural) biopsy/ cytology proven metastatic malignancies.  Patients required to have good functional status, and no distant metastases (outside of pleura) at time of inclusion in study.

Of the 19 patients – 10 had primary lung cancers (adenocarcinoma), the remainder included timoma, rabdomyosarcoma, malignant fibrous histiocitoma. (Full information available in original paper, table 1)

Comparison groups: historically matched patients from medical records June 2007 – June 2008.

How many :  19 patients for the HITHOC treatment group original research,  (11 more since paper submission in July 2012 – with a total of 28 patients receiving treatment using the protocol discussed in the study as of June 2013.)  The original group included 14 males, 5 females.

Group 2: 13 patients; 6 males, 7 females

Group 3: 12 patients; 7 male, 5 female

What was the treatment:

HITHOC group (group 1): Pleurectomy / Decortication (PD) with infusion of heated chemotherapy via chest tubes following completion of pleurectomy and decortication.

The HITHOC process:  The patients’ heads were packed with ice to prevent damage to the brain due to hyperthermia.  Normal saline was heated to 42 degrees centigrade, then infused/ circulated through pleural space via the chest tubes (ie. intrapleural infusion) for one hour (using approximately 1.2 – 3.2 liters of saline solution.)  After the saline infusion, patients received an intrapleural infusion of 300mg /m2 of cisplatin for one hour.  Patients received IV hydration for 24 hours after the procedure to prevent nephrotoxicity.  Patients also received FFP.

infusing cisplatin solution via chest tubes
infusing cisplatin solution via chest tubes

Notably, despite the morbidity and mortality of similar procedures, such as HIPEC of the abdominal cavity, none of the HITHOC group patients died intra-operatively.

the machine that regulates the temperature of the chemotherapy (to 42 degrees centigrade)
the machine that regulates the temperature of the chemotherapy (to 42 degrees centigrade)

Comparison groups:

Group 2: Talc pleurodesis – 4.5 gram talc slurry administered thru a small bore chest tube.  Since this treatment is essentially palliative in nature only (to prevent re-accumulation of effusion), we would expect this group to do the worst.

Group 3: Pleurectomy / Decortication by VATS, with excision of all apical and basal parts of parietal pleura except mediastinal and diaphragmatic sides.  Performed with patient under general anesthesia.  This is the current surgical treatment for this condition.

All patients in all groups received cisplatin- based systemic chemotherapy based on primary cancer.

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

Results:  Survival at one year (12 months)

Group 1: (HITHOC with P/D) – 57.4 %  Two patients in this group needed re-operation for additional resection due to cancer recurrence ( 1 completion pneumonectomy and 1 wedge resection).

Group 2: Talc pleurodesis  – 0.6%

Group 3: P/D – 0.8%

Median survival time:

HITHOC group: 15.6 months

Talc group (group 2): 6 months

P/D group (group 3): 8 months

Results since publication – as of June 2013:

10 of the HITHOC patients remain alive to date (6 were primary lung cancers, 4 with other metastatic cancers).

The authors report that the main complication has been  a modest rise in serum creatinine (which may indicate renal impairment/(kidney damage) but that has been remedied with the use of IV hydration.


Işık AF, Sanlı M, Yılmaz M, Meteroğlu F, Dikensoy O, Sevinç A, Camcı C, Tunçözgür B, Elbeyli L. (2013).  Respir Med. 2013 May;107(5):762-7. doi: 10.1016/j.rmed.2013.01.010. Epub 2013 Feb 23. Intrapleural hyperthermic perfusion chemotherapy in subjects with metastatic pleural malignancies.


Update:  In the summer of 2014, traveled to Ganziantep, Turkey to interview Dr. Isik and his colleagues about his research. 

 Additional posts on related topics

Author: K Eckland

World of Thoracic Surgery is a blog about the work, research, and practices of thoracic surgeons around the world. It includes case studies, [sometimes] dry research, interviews with thoracic surgeons along with patient perspectives, and feedback.

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