In the Clinic

On Cancer: Heated Chemotherapy: Using Robust Science to Guide Clinical Decisions

By Esther Napolitano, BS, Science Writer/Editor  |  Friday, November 15, 2013
Pictured: Oliver Zivanovic, Garrett Nash & Dennis Chi Surgeons Oliver Zivanovic, Garrett Nash, and Dennis Chi are leading novel studies of a procedure called hyperthermic intraperitoneal chemotherapy, also known as HIPEC.

A procedure called hyperthermic (heated) intraperitoneal chemotherapy, or HIPEC, has shown some promise in early studies for certain types of cancer. Although a number of hospitals in the country are now offering HIPEC, the data to support its use is limited, and some experts argue that more research is needed to evaluate the risks and benefits of the approach, which patients are most likely to benefit, and whether it is better than standard therapies.

Now experts at Memorial Sloan Kettering have set out to attain conclusive scientific evidence to determine the effectiveness of HIPEC in patients with colorectal or appendix cancer, and in women with certain gynecologic cancers.

HIPEC is based on a related approach that involves the delivery of unheated chemotherapy directly into the lining of the abdominal area, known as the peritoneal cavity, through a surgically implanted catheter. This technique allows a high concentration of medication to reach the area where the cancer was surgically removed in order to treat residual cancer cells. Pioneered at Memorial Sloan Kettering, the technique — known as intraperitoneal chemotherapy (IPC) — has been shown in several trials to extend survival among patients with certain cancers when delivered in the days or weeks following surgery.

Heating Chemotherapy to Boost Effect

Laboratory evidence suggests that heat makes cancer cells more sensitive to certain chemotherapy agents and may improve the ability of those drugs to penetrate and kill cancer cells more efficiently. During HIPEC, surgeons heat chemotherapy to around 107 degrees Fahrenheit and infuse it into the peritoneal cavity immediately after surgery is completed.

“This approach allows surgeons to give higher doses of anticancer drugs than they can intravenously, directly exposing any remaining cancer cells to a ‘bath’ of chemotherapy,” says gynecologic surgeon Oliver Zivanovic. “However, it is not an insignificant procedure, adding another two hours of time in the operating room while the patient is under anesthesia.”

Risks and Benefits of HIPEC

HIPEC has been studied in patients with appendix cancer, peritoneal mesothelioma, colorectal cancer, uterine cancer, and ovarian cancer — solid tumors with a similar propensity to spread to the peritoneal lining. Some studies have reported complications such as decreased white blood cell count, anemia, low platelets, gastrointestinal issues, and neuropathy, a nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness.

On the other hand, because HIPEC delivers cancer drugs directly to the area where microscopic cancer cells may persist, and only a small portion of a given drug is absorbed into the blood stream, side effects such as nausea are minimal compared to those that can occur with multiple cycles of traditional, intravenous chemotherapy. In addition, a number of early studies have shown HIPEC to be safe. One trial conducted in Europe demonstrated a survival advantage of surgery with HIPEC compared to systemic chemotherapy alone among patients with colorectal cancer.

At Memorial Sloan Kettering, HIPEC is offered to patients only within the context of clinical studies. A specially trained team of experienced surgeons, nurses, and anesthesiologists works together to safely administer the treatment, operate the equipment, and monitor the patient. Radiologists are also involved to ensure the careful review of radiologic images taken before and after surgery.

“A number of US hospitals have begun offering HIPEC as a treatment option outside of the clinical trial setting based on positive data from small studies evaluating a single group of patients without a control group for comparison,” says Dr. Zivanovic, who is Director of Innovative Surgical Technology at Memorial Sloan Kettering. “Rather than extrapolating from those results, we have chosen to carefully study this approach in randomized clinical trials.”

Studying HIPEC for Gynecologic Cancers

Memorial Sloan Kettering is the first cancer center in the United States to offer a randomized clinical trial to study HIPEC in women who are having surgery for a recurrence of ovarian, fallopian tube, or peritoneal cancer. The study — in which patients are arbitrarily assigned to one of two treatment groups and followed prospectively over time — is helping researchers learn which approach provides the best balance of safety and effectiveness.

“This phase II study will provide the most reliable, unbiased information about whether HIPEC really does make a difference in the outcomes of patients with these cancers,” says gynecologic surgeon Dennis S. Chi.

Half of the patients will receive HIPEC followed by five cycles of intravenous chemotherapy after the surgery. The other half will receive six cycles of postoperative intravenous chemotherapy. Investigators will follow patients for two years after the treatment to compare the incidence of recurrence and side effects between the two groups.

“It is important to understand which patients are most likely to benefit from HIPEC and whether it is as good or better than standard therapy based on how long they remain free of disease progression. If the results support it, we will be able to confidently recommend HIPEC as a treatment option for these patients,” adds Dr. Chi, who is the principal investigator of the study.

Exploring Effectiveness in Colorectal and Appendix Cancers

Memorial Sloan Kettering is also offering a randomized, phase II clinical trial comparing HIPEC to EPIC in patients with metastatic colorectal cancer or appendix cancer. It will be the first-ever prospective trial of any treatment for patients with appendix cancer worldwide, and the first randomized trial of IP chemotherapy for patients with colorectal cancer in the United States.

Patients will be randomly assigned to one of two groups to receive either HIPEC at the time of surgery or early postoperative intraperitoneal chemotherapy (EPIC), which is delivered for three days immediately following surgery. Researchers will compare the number of patients in each group who remain free of disease recurrence after three years and compare complication rates and changes in the quality of life of the patients undergoing each treatment. They will also collect tumor tissue to identify unique genetic markers that may make the cancers more sensitive to certain treatments, including the chemotherapies used in the trial and other types of drugs.

“Our goal is to have a balanced trial that will determine which of these treatments is superior and provide information we need to guide future patient management,” says oncologic surgeon Garrett M. Nash, who is leading the trial.

“If our findings show that HIPEC is safe and effective, we may have an opportunity to explore whether the effectiveness of other types of treatments such as targeted drugs and immune therapies can also be enhanced using this approach,” adds Dr. Zivanovic.

Comments

Hi at Mskkcc, nice to hear that you are exploring other therapies to combat this deadly disease.. I was randomized to receive radiation therapy as part of the CHOP treatment for NHL, before undergoing an Autologous Transplant in 2002, rather than additional CHOP therapy... This decision saved my life... One size doesn't fit all ..... Thank You for the wonderful life saving work you do at this World Class Facility...

I had cancer from my Appendix Sept. 2011 and went through HIPEC- I also had many organs removed. I am a 52 year old women, I am feeling great and back to normal. It was a tough time, but I survived…It does work

Terri at what point was HIPEC done on you? Did you have surgery or chemo first? What side effects did you encounter from HIPEC? This procedure has been discussed as an option for me, just not sure i want to unergo it.

I was diagnosed with appendix cancer with PMP in 2007. I was treated at MSK using EPIC soon after my surgery followed by 12 cycles of chemo. The entire treatment was just under 1 year due to few delays from low WBC, & platlets.
There were a few rough spots in the beginning with my hands & feet from the systemic chemo but once the right dose of neurontin was found things improved. HIPEC & the extensive surgery wasn't for me. It would have been a last resort. I have no regrets. I am very healthy today with no recurrence.

Hilary, thank you for sharing your story. We're glad to hear you're doing well.

In February 2014 my wife was diagnosed and treated (CRS, C1) for appendiceal cancer (primary), metastasized throughout the peritoneum (St. IV-B). Cytopathology revealed exclusively low-grade cells. I have been unable to find a single paper in the literature describing a prospective, randomized, multi-center trial comparing CRS +/- HIPEC (or EPIC). In February 2005, Miner et al. at your institution expressed skepticism about the procedure. Anecdote is not data. The plural of anecdotes is not data. Has there been any data since then?

Eric, we are looking into this and will let you know when we're able to get some information for you. Thank you for your comment.

Dear Dr. Sharps, we sent your inquiry to Dr. Nash and he responded: "There have been no randomized trials of treatment for low grade appendix cancer. All data is retrospective and/or not controlled. We are doing the first trial in the world which will assess the efficacy of IP chemo for appendix cancer (ICARuS)."

If your wife would like to make an appointment for a consultation with one of our specialists, please call our Physician Referral Service at 800-525-2225. Thank you for your comment.

Thank you Dr. Nash. ICARuS will not address whether chemotherapy is beneficial or not, since every patient enrolled will receive HIPEC or EPIC. In any case, my wife would be excluded from the trial based on the first and third exclusionary criteria. The natural history of appendiceal neoplasm (low- or high-grade) with PMP, post CRS, absent antiproliferative chemotherapy (systemic or HIPEC/EPIC) will remain unknown. Perhaps the French study (Prodige-7?) will be informative.

My husband was operated on in March at a hospital in NJ for removal of a polyp near his appendix. When they opened him up they found appendix cancer. The surgeon did the debulking procedure but the HIPEC treatment was not available at that facility. I made an appointment with one your the doctors at Sloan, who is currently treating him. At time of surgery 18 lymph nodes were removed and found to be negative. CAT scan taken a few weeks ago at Sloan showed the cancer had spread to his liver and 1 lymph node and they weren't sure weather a spot in his pelvis was a problem or from surgery. He had a port implanted and is receiving Chemo for two days every other week. The doctor said that because the cancer had spread he was not a candidate for HIPEC and the best course of action was his current chemo treatment. I want to be proactive with regard to his treatment, so I am questioning if he is getting the BEST treatment available at Sloan for his condition and to extend his life. Are the physicians at Sloan knowledgable about the treatment options offered by Drs Fournier and Mansfield at M.D. Anderson in Houston and would my husband be a candidate for such treatment.
Respectfully submitted,
Carol Smith

Dear Carol, we are sorry to hear that your husband's cancer has spread. Rest assured, he is in good hands. Your husband's physician and the disease management team that is managing his care would be knowledgeable about which treatment would be most helpful for your husband's specific situation.

Memorial Sloan Kettering has taken a leadership role in the development of HIPEC. It is still the subject of investigation here and at other hospitals, so it may be unclear which patients will benefit. HIPEC is currently being compared to another treatment called EPIC in patients with metastatic appendix cancer in the context of a clinical trial. We won't know which is more effective until the results are published. Here is the link to the study for more information: http://www.mskcc.org/cancer-care/trial/12-289.

There are strict criteria for participation in any clinical trial, so we would recommend that you and your husband discuss whether he is a candidate for this trial with his physician at Memorial Sloan Kettering.

Thank you for your comment.

You have been doing EPIC for a long time now, what kind of success has it achieved? If someone had to choose between EPIC and HIPEC now, before trial results, which would be the better course? Would a doctor at msk ever refer to another hospital because msk does not offer HIPEC at this time?

Dear Fred, we sent your inquiry to Dr. Nash and he responded:

"The reported results of HIPEC and EPIC for colon and appendix cancer, in the best hands, are equivalent. In order to conduct a trial, such as ICARuS, the investigators must demonstrate to the Institutional Review Board that there is no evidence that one treatment is better than the other. If EPIC or HIPEC were already found to be superior, the trial would not approved as it would be unethical. To date, about 80% of patients who are deemed eligible and are offered participation in the ICARuS trial at MSK decide to enroll in the trial, 10% have chosen to have treatment with EPIC at MSK but outside of the trial, and 10% have gone elsewhere for HIPEC. I have suggested other hospitals who do intraperitoneal therapy when patients who consult with me wish to have a 2nd opinion or have treatment closer to home."

If you are interested in making an appointment at Memorial Sloan Kettering and have additional questions about this trial, please call our Physician Referral Service at 800-525-2225. Thank you for your comment.

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