HIPEC Treatment for Mesothelioma Patients

Hyperthermic intraperitoneal chemotherapy (HIPEC) is part of a multimodal treatment plan for peritoneal mesothelioma and other abdominal cancers. The procedure is combined with surgery and a special approach to chemotherapy. Cytoreduction and HIPEC have significantly improved survival for peritoneal mesothelioma patients, but the role of heated chemotherapy in pleural mesothelioma treatment is less clear.

Unlike standard chemotherapy, doctors do not offer HIPEC in pill form or inject it into an IV (intravenous) line. Instead, they add the drugs to a heated solution and pump the mixture directly into the patient’s abdomen. This phase of the procedure, similar to a hot water bath for cancer-laden tissues, is performed immediately after cytoreductive surgery.

Doctors developed HIPEC to improve the relatively poor results of traditional chemotherapy treatment. Although many patients respond well to chemotherapy drugs, the effects are often short-lived.

Boosting Peritoneal Mesothelioma Survival

The vast majority of mesothelioma patients who receive heated chemotherapy suffer from peritoneal mesothelioma, the disease’s second most common type. For many years, doctors did not believe the procedure was effective for treating pleural mesothelioma. The topic remains controversial today.

HIPEC can provide drastic improvements to life expectancy, with some peritoneal patients surviving years after the procedure. In one study involving more than 100 peritoneal mesothelioma patients, 26 patients survived for more than five years after the procedure. Remarkably, 19 patients were alive seven years later. The authors claim these long-term survivors appear to be cured.

Survival After HIPEC

In one of the largest multicenter studies on HIPEC for peritoneal mesothelioma patients to date, Dr. Tristan Yan and colleagues confirmed the treatment can significantly extend survival for select patients.

After follow-up with more than 400 patients, the researchers reported an overall median survival of 53 months — nearly 4.5 years. One patient survived for more than 19 years after the procedure.

Survival rates of one, three and five years, which describe the percentage of patients who survived after that much time has passed, were 81 percent, 60 percent and 47 percent, respectively.

Benefits of Heated Chemotherapy

Aside from the growing number of studies reporting better survival after cytoreduction and HIPEC, one of the procedure’s main draws is its less severe side effects.

With traditional chemotherapy, drugs enter the bloodstream and travel throughout the entire body. The drugs kill any cells that rapidly multiply — a key characteristic of cancer. A major downside of this approach is that it harms healthy cells that also multiply quickly, causing well-known chemotherapy side effects like hair loss and nausea.

• Improved survival
• Fewer side effects
• Safe delivery of higher drug doses
• Prevents chemotherapy resistance

HIPEC, on the other hand, is a locoregional therapy, which is a technical way of saying it only treats the surfaces that come into contact with the chemotherapy. Because heated chemotherapy drugs stay within the abdominal cavity, the approach minimizes the rest of the body’s exposure to chemotherapy. This allows doctors to give higher doses of drugs safely, with the added benefit of reduced side effects.

Temperature Benefits

In the lab, researchers discovered a variety of drugs worked better when raised to a higher temperature (mild hyperthermia). Doctors believe the heated drugs may penetrate deeper into tumors.

Overcoming Resistance

Additionally, researchers learned they could overcome resistance to chemotherapy treatments in several cancers by exposing a greater number of diseased cells to drugs that kill cancer in the body.

Complications

Most are related to surgery. Common risks are bleeding and infection, but patients may also develop blood clots, pneumonia or a fistula (a connection between the skin and intestines).

Which Patients Are Eligible?

The ideal HIPEC patient has several important characteristics. Because cytoreductive surgery is required before chemotherapy, only patients healthy enough for this extensive procedure will qualify.

Doctors also look for patients with a good performance status, which means they are otherwise healthy except for their cancer diagnosis. Surgery is often too risky for patients with heart disease or other chronic illnesses.

HIPEC is best for patients who:

• Are healthy enough for surgery
• Have a good performance status
• Do not have advanced cancer spread

HIPEC doctors only select patients who will benefit from surgery. If the extent of tumor growth is too far advanced, or the cancer has spread beyond the abdomen, HIPEC is no longer an effective treatment option.

There is always a chance that doctors begin surgery only to find it is impossible to remove enough tumor growth to make HIPEC worthwhile. In cases like this, the procedure will not be effective.

Clinical studies have shown that patients who receive complete or near complete removal of tumors before HIPEC have the best outcomes.

Overview of the Procedure

Although the specific approach to HIPEC can vary depending on the doctor and treatment center, the general concept is always the same. The procedure has two phases: Surgery and a heated chemotherapy bath.

Phase I: Surgery

First, doctors perform cytoreductive surgery to remove as much tumor growth as possible. The procedure can include a wide variety of surgical techniques that aim to rid the abdominal cavity of all visible signs of cancer. HIPEC without surgery is ineffective because the drugs cannot penetrate deep into cancerous tumors.

Cytoreductive surgery can be highly challenging for doctors because the cancer forms thousands of small tumor nodules that can join to cover the entire lining of the abdomen. In some cases, complete removal of the tumors is not possible and you may need to explore other treatment options.

Phase II: Chemotherapy Bath

Even if doctors can remove all visible tumors, microscopic cancer cells will unavoidably remain. These cells pose a serious risk of causing the cancer to return, so doctors target them with heated chemotherapy immediately after surgery. The goal is to destroy as many cancer cells missed by surgery as possible to extend survival and prevent cancer recurrence.

As soon as surgery is complete, doctors insert plastic tubes called catheters into the abdominal cavity. They connect the tubes to the perfusion system, an advanced machine that heats the chemotherapy solution and pumps it to and from the body.

Inflow catheters deliver the medicine to the body and outflow catheters send it back to the perfusion system. Doctors also insert special probes that allow them to monitor the temperature of the solution inside the body.

When all tubes and probes are in place, they close the incision using stitches or staples. Next, they turn on the perfusion system, which begins cycling saline solution between the abdominal cavity and the machine.

As the solution flows through the machine, a heating element raises it to the desired temperature, typically between 105 and 109 degrees Fahrenheit. Cancer cells start to die when heated to around 104 degrees, while normal cells can survive up to 111 degrees.

Once the solution reaches the proper temperature, doctors add high doses of one or more chemotherapy drugs. As the medicine blends with the solution and fills the abdominal cavity, a doctor massages the abdomen by hand. This ensures the solution is fully mixed, and helps the cancer-killing drugs reach every tissue surface that may be hosting microscopic cancer cells.

Doctors allow the chemotherapy drugs to flow between the patient and perfusion system for a set period of time. Some studies describe an exposure time of up to two hours, although doctors rarely perform the chemotherapy bath for longer than one hour.

When the chemotherapy bath is finished, doctors drain the medicated solution from the body. Next, they rinse the cavity with saline solution, this time with no medicine added. Finally, a surgeon reopens the incision and removes the tubes and probes before closing the incision one last time.

The entire procedure, including cytoreductive surgery and HIPEC treatment, may take between six and 18 hours to complete, as surgery times will vary. The more the cancer has spread within the abdomen, the longer surgery will take.

Recovery

After the procedure, you should expect a recovery time of several months. Your treatment team will go over everything you need to know about the recovery process, including how to care for your incision wounds and encourage healing.

The most challenging aspect of recovery will be the fatigue. It will likely take two to three months until you begin to feel back to normal. Until then, it is important to stay active (within your limits) and maintain good nutrition. You should attempt to get up and move around during recovery, each day striving to accomplish a little more.

Drugs Used for Heated Chemotherapy

Patients who opt for HIPEC may be treated with a variety of medicines that can kill cancer cells and halt the growth and spread of tumors. Mesothelioma specialists have spent many years comparing the effectiveness of a wide range of drugs. Study results suggest that patients treated with two drugs rather than one often experience improved survival.

Mainstays of mesothelioma treatment like carboplatin, cisplatin, doxorubicin, gemcitabine and pemetrexed have all been used for heated chemotherapy.

Instead of injecting these drugs into your blood, doctors deliver them directly to the chest or abdomen. Because the medicine doesn’t spread all throughout the body, chemotherapy side effects are less severe.

Effective drug combinations include:

• Gemcitabine and pemetrexed
• Mitomycin c and 5-fluorouracil
• Cisplatin and dimethyl sulfoxide

Other drugs doctors use with heated chemotherapy for pleural and peritoneal mesothelioma include:

• Cytarabine
• Cytosine arabinodide
• Melphalan
• Mitomycin
• Paclitaxel
• Etoposide
• Oxaliplatin

Most Effective HIPEC Drugs

Although a variety of drugs work well for HIPEC, researchers are still looking for the drug or drug combination that offers the greatest survival benefit.

Several leading treatment centers prefer mitomycin, but a 2014 Creighton University Medical Center study reports carboplatin is currently the best option for mesothelioma patients. The study followed 44 patients who underwent 47 HIPEC procedures from 2003 to 2010.

Results of the study show that nearly 63 percent of patients treated with carboplatin survived five years after receiving HIPEC, compared to about 27 percent of patients treated with mitomycin. Patients in the carboplatin group also had shorter stays in the hospital and intensive care, and required fewer blood transfusions.

Survival after HIPEC with Carboplatin or Mitomycin
	One-year Survival	Five-year Survival
Caroplatin	89.7 percent	62.5 percent
Mitomycin	72.3 percent	27.3 percent

According to Dr. Brian Loggie, lead surgeon in the study and a pioneer in HIPEC surgery, carboplatin is clearly the better option. However, the study’s sample size of 44 patients is limiting.

With only about 1,000 U.S. patients diagnosed with peritoneal mesothelioma each year, it may be some time before researchers complete a larger, more reliable investigation. Debate over the best option will likely continue as experts search for HIPEC drugs that provide the longest survival with minimal complications.

Treatment Centers That Perform HIPEC

Despite the rarity of peritoneal mesothelioma, leading treatment centers across the nation are equipped to perform HIPEC.

Centers with a mesothelioma specialist trained in HIPEC include:

• Arizona Cancer Center
  Tucson, AZ
• UC San Diego Moores Cancer Center
  La Jolla, CA
• Sylvester Comprehensive Cancer Center
  Miami, FL
• H. Lee Moffitt Cancer Center
  Tampa, FL
• Midwestern Regional Medical Center
  Zion, IL
• Ochsner Cancer Institute
  New Orleans, LA
• Brigham and Women’s Hospital
  Boston, MA
• University of Maryland Greenebaum Cancer Center
  Baltimore, MD
• Wake Forest University
  Winston Salem, NC
• Alegent Creighton Health
  Omaha, NE
• Mount Sinai Hospital
  New York, NY
• The Cleveland Clinic Cancer Institute
  Cleveland, OH
• Southwestern Regional Medical Center
  Tulsa, OK
• UPMC Cancer Center
  Pittsburgh, PA
• MD Anderson Texas
  Houston, TX

The main reason this procedure is not offered as a standard treatment option at all mesothelioma cancer centers is because of the complexity of the cytoreductive surgery and lack of familiarity with the HIPEC procedure and equipment. In addition, there is some skepticism in the medical community because there currently are no studies showing a comparison of patients who have undergone this procedure vs. patients who have not in a randomized trial.

Controversial Role in Pleural Mesothelioma

Although several leading medical centers now offer heated chemotherapy to pleural mesothelioma patients, the procedure was once an option only for patients with the peritoneal form of the cancer.

According to one study against the procedure, the chest cavity absorbs the chemotherapy drugs too efficiently after surgery. Because so much blood flows through the lungs and surrounding structures of the chest, the body quickly absorbs the drugs and spreads them via the blood stream. This leads to similar levels of chemotherapy drugs in the blood as with traditional chemotherapy treatment, which is associated with more severe side effects.

Despite this problem, heated chemotherapy seems to be gaining traction among some pleural mesothelioma specialists. Under the guidance of mesothelioma pioneer Dr. David Sugarbaker, formerly of the International Mesothelioma Program in Boston, Dr. Marcelo DaSilva developed a HIPEC regimen that improved survival by an average of three to four years. Other specialists have seen positive results with the technique over the years.

Heated Chemotherapy Studies for Pleural Mesothelioma

Study	Number of Patients	Surgery	Heated Chemotherapy Drug(s)	Overall Median Survival (Months)
Tilleman, 2008	92	Extrapleural Pneumonectomy	Cisplatin	13.1
Zellos, 2009	29	Extrapleural Pneumonectomy	Cisplatin	20
Richards, 2006	44	Pleurectomy/ Decortication	Cisplatin	18
van Ruth, 2003	8	Extrapleural Pneumonectomy	Doxorubicin	11
Monneuse, 2003	16	Pleurectomy/ Decortication	Mitomycin C and Cisplatin	18
Colleoni, 1996	20	Pleurectomy/ Decortication	Cisplatin and Cytarabine	11.5
Sauter, 1995	13	Pleurectomy/ Decortication	Cisplatin	9
Lee, 1995	15	Pleurectomy/ Decortication	Cisplatin	11.5
Rice, 1995	19	Pneumonectomy/ Decortication	Cisplatin	13
Rusch, 1994	27	Extrapleural Pneumonectomy	Cisplatin	18.3

Future Studies Will Aim to Improve Technique

For the right patients, heated chemotherapy can extend survival and provide a better quality of life. Studies have described impressive survival benefits for patients with pleural and peritoneal mesothelioma.

However, the medical community has yet to reach an agreement on the best drug combination, chemotherapy temperature and exposure time for mesothelioma patients. As researchers uncover more about the technique, it is likely that survival outcomes will continue to improve.