HIPEC at University of Maryland

Q&A: Cytoreductive Surgery and HIPEC

Q: What are intraperitoneal surface malignancies?

A: The peritoneum is the largest serous membrane in the body, and consists, in the male, of a closed sac, while in female the free ends of the uterine tubes open directly into the peritoneal cavity. The peritoneum differs from the other serous membranes of the body in presenting a much more complex arrangement. It is formed of two layers, one applied against the abdominal wall cavity (parietes) and called parietal peritoneum while the second is reflected over the contained organs (viscera) and called the visceral peritoneum. These reflections are named according to their function as ligaments, mesentery, omentum, bursa.

The free surface of the peritoneal membrane is smooth and lubricated by a small quantity of serous fluid allowing the abdominal viscera to glide freely against the wall of the cavity or upon one another with the least possible amount of friction. The attached surface is rough, being connected to the viscera and inner surface of the abdominal wall.

Peritoneal surface malignancies, also called peritoneal carcinomatosis (PC), is the presence of cancer (malignant) cells on the surface of the peritoneum. The close relationship of the peritoneum to the abdominal organs can explain the frequency of direct extension of cancer originating from abdominal organs to the peritoneum. At the same time, its continuity and its serous fluid circulation can explain the frequency of the wide spread of the disease along its large surface area.

Q: Do these tumors originate in the peritoneum, or do they usually come from other cancer sites in the body?

A:Tumors that originate from the peritoneum are rare (1-2/million per year) and are called primary peritoneal tumors. This category includes mesothelioma and primary peritoneal serous carcinoma. Mesothelioma of the peritoneum related to asbestos exposure is less defined than that of pleural mesothelioma. It is a difficult pathological diagnosis that can be wrongly labeled adenocarcinoma of unknown primary and extensive pathological workup with immunomarkers is essential for the diagnosis.

Most of the peritoneal tumors originally arise in another organ and secondarily extend to the peritoneal membrane. In the vast majority of cases, the origin of these tumors are intra-abdominal organs including the appendix, colon, rectum, stomach and ovaries. In 20 percent of abdominal malignancies, the only site of tumor recurrence remains intra-abdominal.

Ten percent of patients with colorectal cancer will develop peritoneal carcinomatosis at the same time of their diagnosis and 25 percent of remaining patients will develop peritoneal carcinomatosis later on in the disease process.

Appendiceal cancer is usually diagnosed in the postoperative setting with peritoneal spread. The peritoneal involvement in this case is either in the form of mucinous ascites with low grade adenomatous tumor (Diffuse peritoneal adenomucinosis or DPAM), or peritoneal deposit of mucinous carcinoma (Peritoneal mucinous carcinomatosis or PMCA). The two conditions can present clinically in the form of abundant mucinous ascitis and are called pseudomyxoma peritonei (PMP). Though clinically similar, DPAM and PMCA are different in their histology and their potential to spread to other organs. DPAM is characterized by the presence of abundant mucinous ascites with scant cells with minimal atypia and rarely spread to lymph nodes or other organs. On the other hand, PMCA presents with mucinous ascites and abundant cancerous cells and has the potential to spread to lymph nodes and distant organs. Both types cause abundant mucinous ascites that results in abdominal distention and pain and is the source of fibrosis that can cause bowel obstruction.

Other extra-abdominal organs such as the breast can also extend to the peritoneum.

Q: How is this type of cancer different from other kinds of GI cancer? What makes these cancers so difficult to treat?

A: For a long time these tumors were classified as non-surgical because of the wide territory of the peritoneum membrane and the frequent extension of the disease to multiple intra-abdominal organs. Consequently, the possibility to achieve complete excision through a long, complex surgery involving resection of multiple abdominal organs was aborted due to the high risk and limited benefits of such an approach. At the same time, systemic intravenous chemotherapy had a little effect on the peritoneal tumors as the peritoneum membrane constitutes a compartment separate from the vascular compartment (the blood). Therefore, peritoneal tumors showed poor prognosis despite the best systemic therapy.

With the advance of the surgical techniques, equipment, and postoperative care, the peritoneum is now considered an intra-abdominal organ that is can respond to surgery, called cytoreductive surgery (CRS). The development of the intraperitoneal route of heated chemotherapy administration (HIPEC) allows a direct contact between the tumor cells and the chemotherapeutic agent to control all residual microscopic disease. The development of CRS-HIPEC revolutionized the natural history of peritoneal tumors.

Q: Can you explain what “cytoreductive” surgery means? What is involved in this procedure?

A: As previously mentioned, the peritoneum is viewed as an organ which, when affected with cancer, can respond to resection. However, surgical excision is complex and involves removal of some of its surface area and destruction of the tumor cells in other areas to achieve a complete cytoreduction (a decrease of the cancer cell load) and prepare the field for the intra-peritoneal heated chemotherapy.

Surgery for peritoneal carcinomatosis was first performed in 1980 in Japan and then gained popularity in Europe in late 1980s. It began to be performed in USA in 1995. Currently there are less than 15 centers in United States performing HIPEC. The University of Maryland Greenebaum Comprehensive Cancer Center team was among the pioneers of applying this treatment modality and was actively involved in defining its proper indication.

Generally, the procedure is performed through a median laparotomy (long abdominal midline incision) and a complete and meticulous exploration looking for peritoneal deposits. Next, peritoneal and organ resection takes place, and finally the hyperthermic chemotherapy is administered.

Complete cytoreduction is achieved when the largest residual deposit is less than 2.5 mm in size.

Complete lysis of adhesions from prior surgeries is necessary for full exploration and frequently complete liver mobilization is also needed to evaluate the disease extension behind the liver with excision of its ligaments. The peritoneum with wide visible disease is resected while limited disease can be destroyed by electrical fulguration. The apparently normal peritoneum is left and treated only with HIPEC. The omentum is systematically removed due to the frequency of the presence of cancer cells on its surface even if it looks healthy. Segments of the visceral peritoneum that show disease extending to an underlying viscera need to be resected completely, along with the underlying viscera. Other segments with superficial disease can be treated with electrofulguration, followed by immediate cooling of the underlying viscera to avoid its injury.

Q: Heated chemotherapy is used in combination with this type of surgery. How is this chemotherapy given to the patient?

A: The peritoneal route of chemotherapy allows a high concentration of the chemotherapy to be in direct contact with cancerous cells with minimal systemic absorption and side effects. The most common used chemotherapeutic agents are mitomycin, oxaliplatin, irinotecan and cisplatin. The addition of heat to the chemotherapy intensifies the activity of some chemotherapeutic agents and increases diffusion of the chemotherapeutic agents between the cells. Immediate application of intra-peritoneal chemotherapy after the CRS controls the submillimetric disease and diffuses to two or three layers of cells exposed before the formation of early physiologic (normal) postoperative adhesions, where these cells can be trapped away from the reach of the chemotherapy.

This heated chemotherapy can be administered using an open or closed technique. In open technique, the abdominal wall is left open and elevated to accommodate the heated chemotherapy that circulates through in- and out-flow lines attached to a pump and heating unit. In the closed method, the skin is closed after passing the tubes through the separated incision and the abdominal cavity is filled with the HIPEC solution that circulates using a pump with heating unit. The HIPEC part of the procedure usually lasts for about 90 minutes, with the cycled chemotherapeutic agent kept at around 42 °C through a heated pump.

Q: What are the benefits of HIPEC for patients with abdominal cancer?

A: The application of CRS-HIPEC therapy has revolutionized the management of the peritoneal carcinomatosis. For primary peritoneal tumors, malignant mesothelioma had a very poor prognosis in the past with median survival of 9-14 months. Now more than two-thirds of patients (69 percent) survive after five years from receiving CRS-HIPEC.

In the case of peritoneal carcinomatosis from colorectal cancer, similar poor results were obtained with the best systemic chemotherapy (less than one year median survival). Since 2003, multiple European and North American studies have reported that about one third of patients have no evidence of any disease recurrence (disease-free survival) after five years from receiving complete CRS-HIPEC therapy.

Regarding mucinous tumors and pseudomyxoma peritonei (PMP) the five-year survival for patients with grade 3 disease was only 6 percent with systemic chemotherapy. Now, studies report a 50-80 percent five-year survival in grade 3 patients after receiving complete CRS-HIPEC therapy. It should be emphasized also that regardless of the survival benefit, a net improvement of the quality of life is obtained from the surgical management of these patients with dramatic improvement of abdominal distention, pain and bowel obstruction.

For patients with diffuse peritoneal carcinomatosis from ovarian cancer, studies showed improved survival, with five-year survival rate of 16.7 percent, compared favorably with the best non-surgical care with no patients surviving to five years.

To summarize, current data show a clear benefit of CRS-HIPEC for patients with primary peritoneal cancer and peritoneal carcinomatosis of appendicular, colorectal and ovarian cancers. The results of these studies are dependent on the team experience and complete cytoreduction.

An international conference took place in 2006 to define the role and indications of HIPEC in colorectal cancer. UMGCC experts participated in this conference, as well as in its final consensus statement. According to these guidelines, CRS-HIPEC was recognized as the standard of care of PC dissemination from colorectal cancer providing that the disease is limited to the abdomen and that a complete CRS can be achieved. PubMed

Regarding peritoneal carcinomatosis from gastric cancer, the results of CRS-HIPEC are immature. Incomplete CRS does not provide any advantage for these patients and even complete CRS did not show the dramatic results compared to those obtained in the case of mesothelioma or peritoneal carcinomatosis for colorectal cancer.

For peritoneal carcinomatosis from the liver, bile duct and pancreas, the role of CRS-HIPEC is yet to be studied and currently there is not a formal indication for this approach.

Q: How long does the surgery take?

A: As previously described, the procedure can be subdivided in three main parts: exploration, cytoreductive surgery and HIPEC. Only the HIPEC period has a fixed time limit from (60-120 minutes). The other two parts of the procedure are variable according to the presence of prior adhesions and their extension and the extent of the disease involving multiple abdominal organs requiring multiple resections. Generally speaking, the whole procedure time varies from 4-10 hours.

Q: What side effects can patients expect from this form of treatment?

A: CRS-HIPC is a major operation that may involve resection of abdominal organs. As expected, it carries a considerable post-operative (within 30 days from the surgery) morbidity of 12-56 percent and a mortality of 0-12 percent.

These complications can be grouped in three categories:

Intra-abdominal complications: Intra-abdominal gastrointestinal leak, abscess and fistula complicate about 15% of cases of CRS-HIPEC. This is increased with the number of bowel resection and anastomosis.
Abdominal wall morbidity: This category includes wound infection, abscess and dehiscence/evisceration of about 15%. This is a consequence of impaired wound healing from the application of the HIPEC and potential CRS involving resection of abdominal wall deposits.
Systemic complications: These are related to the systemic effect of the absorbed peritoneal chemotherapy and include bone marrow suppression, sepsis and pulmonary complications.
At the UMGCCC, we have adopted specific techniques to minimize the rate of these complications. First, we limit the number of bowel segment resections favoring complete fulguration of minor deposits in bowel segments when applicable, rather than resection. We also complete our cytoreduction, including resection of all intestinal segments, before the chemotherapy but perform the anastomosis (re-connection) after to minimize the negative wound healing effect of the HIPEC on the anastomotic edges.

In cases with multiple prior abdominal surgeries, preoperative abdominal wall hernias or CRS involving the abdominal wall, we place a biomaterial mesh as adjuvant to abdominal wall closure to enhance the abdominal wall healing and minimize the abdominal wall complications. At the same time, we work closely with the medical oncology physicians to calculate the appropriate dose of the chemotherapy in the HIPEC protocol for every patient to minimize the systemic effect of the absorbed chemotherapy

Q: How long is the recovery period for a patient having surgery and HIPEC?

A: The time frame varies according to the extent of resection, the patient’s age and preoperative general condition. Generally speaking, the average length of stay in the hospital is 5-7 days. By the time the patient is discharged from the hospital, all patients should be able to tolerate an oral diet, ambulate and have their postoperative pain controlled with regular oral pain medication. Most patients return to their work activity one month after the procedure, provided that lifting of heavy objects is avoided for a total of at least six weeks after the procedure.

Q: Is there a role of prophylactic HIPEC?

A: The diagnosis of peritoneal carcinomatosis by current methods is limited and usually the patients present with a radiological evidence of large deposits or, more often, with clinical complaints related to the peritoneal carcinomatosis and abdominal organ involvement (abdominal distension, pain, and bowel obstruction). No current data or guidelines exist today demonstrating the role of prophylactic CRS HIPEC in colorectal cancer. However, we know that the results of CRS-HIPE are better when applied early in the disease process. Studies are underway in Europe and the U.S. to discover whether early /prophylactic HIPEC for patients identified as high risk for developing peritoneal carcinomatosis is effective. Therefore, the prophylactic treatment can not be currently generalized but rather discussed with the patient in a multidisciplinary environment explaining potential risk and benefits of this approach.

Q: What is the role of laparoscopic approach?

A: In general, CRS-HIPEC requires complete exploration of the abdominal cavity and potentially multiple resections of abdominal viscera, rendering the laparoscopic approach of limited value besides initial exploration. However, in selected group of patients with minimal CRS or for second-look surgery and prophylactic HIPEC, laparoscopic HIPEC can be performed.

The benefit of such approach is based on avoiding the big abdominal incision and complications (about 15 percent). In addition, laparoscopy is traditionally associated with less postoperative pain, shorter hospital stay and earlier return to work activity. (See image)

It should be emphasized that, though feasible for selected group of patients, its role and application are not yet reported. Therefore, at UMGCCC we offer the laparoscopic approach for a selected subgroup of patients, while open CRS-HIPEC remains our standard technique.

Originally posted by University of Maryland Medical Center