Treatment of Incurable Cancer with Surgery and Heated Chemotherapy (HIPEC)
Aviram Nissan
Professor and Chief, Deprtment of General and Oncological Surgery-Surgery C
Sheba Medical Center, Affyliated with the Sackler School of Medicine, Tel Aviv University.
aviram.nissan @sheba.health.gov.il
Almog Ben-Yaacov
Attending Surgeon, Deprtment of General and Oncological Surgery-Surgery C
Sheba Medical Center, Affyliated with the Sackler School of Medicine, Tel Aviv University.
almog.benyaacov@sheba.health.gov.il
Some types of cancers are very difficult to treat and until recently, considered incurable. Cancers that spread to the lining surfaces of the peritoneal (abdominal) cavity are known as Peritoneal surface malignancies (PSM). The abdominal cavity is the space in the abdomen that contains the stomach, colon, liver, uterus, ovaries, and other abdominal organs. The peritoneum is a tissue that lines the abdominal wall and covers abdominal organs.
Cancer in each of the abdominal organs can spread to abdominal surfaces and the peritoneum. This kind of spread is called peritoneal carcinomatosis or Peritoneal metastsis and traditionally, considered an incurable disease. Most cancers involving the peritoneum, originate from abdominal organs and include metastasis of cancer of the appendix, cancer of the colon and rectum, cancer of the ovaries, and cancer of the stomach. While primary cancers of the peritoneum are rare, they include peritoneal mesotheleoma and primary peritoneal carcinoma.
The rationale for a new treatment approach
The evolution of surgical techniques has allowed the advancement of surgical therapy for peritoneal metastasis. We have moved from the old paradigm of palliation with chemotherapy or limited surgery aimed at relieving symptoms, and into a new era of radical surgery combined with heated chemotherapy providing this patient population with a new hope for cure.
The new approach for cancers that spread to the peritoneum combines surgery and heated chemotherapy to be performed at the time of surgery. This approach is a result of a lengthy and extensive research showing that certain chemotherapy drugs can reach very high concentrations in tumor tissues when applied directly into the peritoneal cavity. Some of the drugs used, can kill cancer cells more effectively when heated to a temperature of 42.0 C.
The HIPEC procedure
There has been much research done on the effect of heat (hyperthermia) on cancer cells. It has been proven that heat can inhibit the growth of cancer cells. In order to kill 100% of all cancer cells growing in a petri dish in the laboratory – we needed to heat them to 46 degrees Celsius for 20 minutes. If the same heat was applied to a patient it would cause irreparable damage to the patient’s healthy tissue. Researchers found that using heat in the range of 42-44 degrees Celsius (for 60-120 minutes) kills the cancer cells with little damage done to the healthy cells. Other research has shown that combining chemotherapy drugs with this heat increases the heat’s effect in killing the cancer cells. Applying chemotherapy at these temperatures through the veins of a conscious patient will cause irreparable brain damage. Another complication is that the chemotherapy cools as it penetrates farther into the peritoneum. Therefore, this method works best on metastases that are spread over a wide area.
A number of studies conducted in the US and Europe have shown that colon cancer patient treated with heat and chemotherapy increased their life expectancy by more than five years. The most important factor with this treatment was the ability of the surgeon to remove all growths. The most important factor for the success of this combined modality treatment was the ability of the surgeon to remove all growths. More recent studies show the efficacy of the HIPEC procedure in cancer of the ovary, mesothelioma and other, less common, tumors. Undoubtedly surgery with HIPEC is most effective in tumors of the appendix such as pseudomyxoma peritonei (PMP).
The term “Intraperitoneal” means that the treatment is delivered to the abdominal cavity. The term “Hyperthermic Chemotherapy” means that the solution containing chemotherapy is heated to a temperature greater than normal body temperature. The administration of intra-peritoneal hyperthermic chemotherapy is called HIPEC. Because heated chemotherapy can penetrate only at a very limited distance in the tumor tissue, it is imperative to remove all visible and palpable tumor deposits before HIPEC is delivered.
The surgery to remove peritoneum tumors is long, complex and incorporates heated chemotherapy for 90 minutes. Therefore, it is important for us to make sure that candidates for this type of surgery are up for the procedure. Only patients at a high functioning level, who do not have any serious heart or pulmonary disease will be considered for this treatment.
As the disease is spread across the abdomen, it is extremely important for the surgeons to map out the borders of the affected area. Together with the specific criteria, this step is imperative for surgeons in order to ensure that the candidates have the highest chance for a successful resection. It is difficult to estimate the size of the diseased area – even using the most advanced imaging devices. Most surgeons use CT scans in order to see the scope of the diseased area.
Doctors from all over the world have decided on a universal staging system for peritoneal cancer. This system is used today on patients all over the world and is called the peritoneal cancer index (PCI). Additionally, there have been universal criteria that patients must meet in order to be considered candidates for the surgery.
Patients who would be considered for surgery must have the following:
- Their cancer is limited to the peritoneum (several metastases in the liver are allowed)
- No obstruction of the small intestine
- The affected area of the small intestine must be limited to single areas and the superior mesenteric artery cannot be affected
Once the procedure is over, the patient is transferred to the ICU for 1-2 days observation. Some patients quireanadditional round of chemotherapy for five days following surgery. This chemotherapy is not heated, and is meant to increase the effectiveness of the surgery. In order to prevent infections the patient will be given antibiotics until surgery is finished.
The Surgery
The surgery is done under general anesthesia. Due to the length, complexity and high temperature of the chemotherapy, the anesthesiologists must be specially trained for this procedure. They must be able to handle complicated problems such as blood loss and maintaining body temperature for many hours. To avoid situations of hypertension or renal failure, the anesthesiologists must also be able to administer the appropriate anesthetics based on the different stages of required consciousness of the patient.
Administering HIPEC requires special preparations. The patient’s body temperature must be low during the initial stages of HIPEC administration. The body temperature cannot go above 39 degrees centigrade (102.2' F).
The surgery begins by separating the peritoneal layer from the front side abdominal areas, until reaching the back muscles. After determining that no additional metastasis in critical locations can prevent a complete resection, the surgeons will begin the process of separating the liver and peeling the metastases from the capsule surrounding it. After peeling the peritoneum from the diaphragm (sometimes, requiring a partial resection of the diaphragm or spleen), the stomach is released and the surrounding area is checked for metastases. The small intestine and the colon are also scanned. The final part of the resection is done in the pelvic area, which, in most cases, also has metastases. Resections of the uterus, ovaries (among women) and upper rectum, if needed, complete the resection stage of the operation.
The reconstruction stage is complex and includes the reconstruction and reattachment of parts of the colon and digestive tract. Based on the evaluation of the surgeon, this stage is done either before or after the administration of HIPEC. In some cases, the surgeon must create a stoma.
The most complex stage is the administration of HIPEC. The surgeon inserts tubes into the peritoneum, together with a thermometer (to maintain the optimal temperature). Surgeons begin by administering 3 liters of solution until the flow mechanism is regulated. At this stage, a special machine heats up the chemotherapy liquid. The temperatures are regulated by a machine as they enter the patient’s body. To prevent tissue damage, the machines beep and stop administration if the temperature rises above the temperature set by the surgeon. After reaching optimal temperature, the surgeon adds chemotherapy liquid to a special container with a pump that uniformly spreads the liquid over the area. This entire process takes 2 hours.
Resection of Peritoneal Tumor Metastases
Despite the fact that colon cancer is a systemic disease which affects the entire body, surgical treatment to remove the primary tumor is the most important type of treatment. When the nearby lymph nodes are affected and surgically removed, doctors will add chemotherapy as part of the patient’s treatment regimen. This lowers the chances of a recurrence. Even if metastases are found in the liver or lungs, some patients are able to undergo resections to remove them. Together with chemotherapy, there is a chance this patient will fully recover (30-40% chance). Among colon cancer patients with metastases, a metastasis in the peritoneum occurs among 15% of patients. If the metastases can be removed, the patient has the same chances as one who metastasized in the liver.
Unlike metastases in the liver or other solid organs, peritoneal metastases are smaller and spread out all over the peritoneum cavity. Therefore, it is harder to determine whether or not these metastases are operable with a CT or PET scan. To fully remove the tumor, the surgeon will have to perform a resection on a larger area and possibly other organs in the area. This complicates the surgery and increases the risk of complications.
In recent years, there have been great strides made in the development of effective drugs for colon cancer patients. New cytotoxic and biological drugs have been developed which doubles a colon cancer patient’s life expectancy and significantly lowers recurrences among patients who’ve undergone full resections.
Metastases that develop in solid organs also create new blood vessels (angiogenesis), which is why they are able to grow into one solid mass. It also means that chemotherapy drugs that get to them are more concentrated. These blood vessels can be destroyed with drugs that stop the production process of blood vessels (like Avastin). Metastases that develop in the peritoneum cannot create blood vessels and therefore the metastases cannot develop into large, solid masses. The concentration of chemotherapy in the veins is lower and its effectiveness decreases. However, drugs that directly injected into the peritoneum can penetrate its membrane and are absorbed directly into the blood stream. Theoretically, patients can receive a higher concentration of chemotherapy directly in the peritoneum with fewer side effects.
There are two types of primary malignant tumors:
- Primary Peritoneal Carcinoma
- Mesothelioma
Metastases can come from a number of different primary cancer sites:
- Colon cancer
- Ovarian cancer
- Cancer of the appendix including Pseudomyoxoma peritoneii (PMP)
- Stomach cancer
- Uncommon tumors
The survival rates for patients suffering from metastases depend on a number of factors, the most important factor being the primary cancer source. The patients with the highest chances of survival are those whose primary cancer is pseudomyxoma peritonei (PMP), while those suffering from pancreatic cancer have the lowest chances of survival.
Chemotherapy has limited value for these patients. Researchers have spent years searching for alternative therapeutic treatments. Pioneers in this field of research include American researchers Paul Sugarbaker and French researcher Francois Gillis. Each of these researchers developed a surgical technique for cancer removal. Later on, a supplementary treatment method was developed where chemotherapy is administered during surgery with the help of a special pump, usually used for bypass surgery (HIPEC). A large number of medical centers around the world have adopted this treatment method. In recent years, following development of more efficient pumps, this method has become the accepted treatment method for peritoneal cavity metastases.
The most effective way to treat colon cancer is to remove the tumor. Chemotherapy is also administered in order to prevent a recurrence. If the tumor metastasizes, and the tumor is able to be completely removed, there is a good chance of survival
Results of cytoreductive surgery and HIPEC
This new treatment approach is currently practiced in more than 200 medical centers worldwide. Sheba Medical Center was among the early adaptors to this paradigm shift with more than 350 patients treated by Prof. Nissan's team. Our results have positioned us among the leading centers in the world. We have been able to maintain relatively low morbidity and mortality rates. We have been able to offer long term survival (cure) or prolong disease-free survival in two thirds of our patients. One third of our patients, experienced early disease recurrence following the HIPEC procedure.
We have the CRS_HIPEC School where we train surigcal teams from differnt countries. Surgeons interested in stratinmg a HIPEc center can bring their teams for one week workshop and then upon their return to their native countries, our team asisst them with the first cases.
