Cytoreductive Surgery with Intraoperative Hyperthermic Intrathoracic Chemotherapy

An introduction to cytoreductive surgery with hyperthermic intrathoracic chemotherapy administrative for the treatment of malignant pleural mesothelioma.

Cytoreductive surgery with Intraoperative Hyperthermic Chemotherapy (HIPEC) has been used for over a decade now for abdominal cancers including metastatic colon cancer (peritoneal carcinomatosis) and malignant peritoneal mesothelioma.  During this lengthy procedure, surgeons remove as much gross disease as possible, and then infuse heated chemotherapy agents directly into the abdominal cavity to kill any residual cancer cells.  One of the benefits of this treatment is that by directly administering chemotherapy to the site of disease – the patient experiences less toxic side effects (versus intravenous or oral ingestion) and higher concentrations can be used, which are more effective at killing the malignant cells.  Research findings have been encouraging, and have shown significant improvement in median survival in comparison to standard treatment.

During my research in Bogotá, Colombia – I interviewed a general surgeon who was responsible for establishing a HIPEC treatment program in a local hospital there.  (There are less than 25 HIPEC treatment centers in the world.)  This spurred my interest in thoracic applications of this procedure (called the Sugarbaker procedure after the inventor, Dr. Paul Sugarbaker, an oncologist.)

In recent years, thoracic surgery has investigated and adopted some of this research for use and treatment of thoracic cancers, in a procedure known as HITHOC.  In thoracic surgery, intrathoracic (inside the chest) administration of heated chemotherapy in the operating room has been used primarily to treat malignant thymomas and malignant pleural mesothelioma.  Results of recent studies have been mixed – with the best results occurring in patients with thymomas.  In patients with mesothelioma, prognosis is dependent on stage.

Rutgers and Bree et. al at the Netherlands Cancer Institute published several additional studies on the subject,  looking at the effectiveness of different chemotherapeutic agents for HITHOC.  Given their extensive experience and knowledge on the subject, I have contacted the researchers at the Netherlands Cancer Institute to invite the authors to submit a guest post.  (I’d rather all of you hear from the experts!)

Additional References: (links when possible)

1. Dutch study using the Sugarbaker procedure for intrathoracic infusion for pleural thymomas and malignant pleural mesothelioma.  Bree et. al (2000) from Chest. Small study with only 14 patients but a nice discussion of the procedure with graphics. Multiple other studies from these authors, as mentioned above.

2. A nice blog that explains the Sugarbaker procedure.

3. Very small Japanese study from 2003 – five patients.  Notably, these patients had a different disease process – lung cancer with pleuritic carcinomatosis. 4 out of five patients demonstrated significant longevity after the procedure with no recurrence.

Extrapleural Pneumonectomy: EPP

Extrapleural pneumonectomy for malignant mesothelioma

Extrapleural Pneumonectomy (EPP) is a radical operation in which the entire lung, and tissues of the lung space (pleura, diaphragm and pericardium) are removed.  This is done as part of a cancer operation, often for an aggressive cancer called malignant mesothelioma. During cancer operations, surgeons have to remove all or as much cancer tissue as possible, including microscopic cells that are not visible to the surgeon at the time of surgery.  Any tissue that is left behind may have cancer cells which will continue to grow, and spread.  Due to the location of the cancer cells (in the lining), surgeons have to remove more tissue than if the cancer was centered in the lung itself.  This includes replacing the diaphragm with a synthetic patch during surgery.

Mesothelioma is named after the cells it affects.  These mesothelial cells make up the “linings” of the body cavities.  For this reason, mesothelioma can affect other areas of the body, in the linings of the abdomen called the peritoneum, the pericardium (the lining around the heart), and most commonly, the pleura.

Inside the chest, coating the chest wall is a thin lining tissue called the pleura.  The interior area of the rib cage and chest are thus called the pleural cavity.  When mesothelial cancer cells invade this fragile tissue layer, it is called pleural mesothelioma, which is different from peritoneal mesothelioma.  (Peritoneal mesothelioma affects the peritoneal cavity, or abdominal cavity.)

Not everyone is a candidate for this surgery.  Due to the radical nature of this procedure, patients need to have good pulmonary function and overall functional status prior to surgery.  (The patient is going to lose one whole lung during this procedure, so patients that are already oxygen dependent / bedridden or otherwise debilitated won’t be able to tolerate this procedure.)  The best patients for this surgery (the patients who will have the best outcomes/ receive the most benefits from surgery) are patients with good functional status (able to perform normal activities of daily living) with earlier stages of the disease.  In these patients – this surgery can extend their lives significantly.  In patients with more advanced (stage III/ stage IV) disease, the surgery will make them live longer (months) but the quality of life may be worse post-operatively.

Prior to consideration for extrapleural pneumonectomy (or any other treatment) the doctors will want to definitively diagnose (prove the diagnosis through tissue biopsy) and do preliminary staging.  (Final staging occurs after the operation when further tissue / lymph node biopsies are evaluated by the pathologist).

Preliminary staging and pre-operative evaluation is the process to try to figure out how much cancer is present (has it spread?) and whether the patient can tolerate a large operation.  Mediastinoscopy; a surgical procedure to look at mediastinal lymph nodes (lymph nodes behind the sternum or breast bone), PET scans and blood for tumor markers help determine how much cancer is present.  The tumor markers also help the oncologists figure out which chemotherapy drugs will work the best.

Pre-operative testing is looking at lung function, to see how well the patient will do with only one lung.  Cardiac testing may be done as well since surgery can be stressful to the heart.

If the disease is controllable with surgery, and the surgeon thinks the patient can withstand surgery – the surgeon will consult with an oncologist about the timing of surgery and adjuvant treatments (chemotherapy/ radiation).

Even with radical surgery, the prognosis for malignant pleural mesothelioma is poor, but improves with combination therapies (surgery with chemotherapy/ radiation.)  Currently, surgeons are investigating the use of cytoreductive hyperthermic chemotherapy  (HIPEC/ Hithoc) for treatment of pleural based mesothelioma.  (Previous studies by Dr. Paul Sugarbaker has shown this treatment to be effective with advanced abdominal cancers including malignant peritoneal mesothelioma.)  We will discuss HIPEC further on a future post.

There are numerous studies looking at extrapleural pneumonectomy for treatment of malignant pleural mesothelioma. The links below is just a small sampling.

1. Extrapleural pneumonectomy for malignant pleural mesothelioma (2005) – Argote- Greene, Chang, and Sugarbaker. (Note: this article was co-authored by Dr. David Sugarbaker, Department of Thoracic surgery, Brigham Womens & Children’s, not Dr. Paul Sugarbaker, developer of HIPEC.  I am going to attempt to contact Dr. Davis Sugarbaker for commentary for the site since he is the expert on this topic, so hopefully I’ll be able to update the site with his post in the future.

2.  Radical surgery for malignant pleural mesothelioma – Japanese study comparing results for EPP versus pleurectomy / decortication.  The main points to take away from this study is that stage of disease has a huge impact on prognosis, and outcomes after surgery.  (The patients with stage I and II that underwent EPP did fairly well.)

3. Review of 83 cases of EPP – (2009) French study which unintentionally highlights the potential complications of surgery of this magnitude(almost 40% had major complications and had a re-operative rate of almost fifteen percent.)