NEW TREATMENTS FOR PERITONEAL CARCINOMATOSIS: CYTOREDUCTIVE SURGERY AND HIPEC

Peritoneal carcinomatosis is a rare and aggressive cancer that spreads to the peritoneum. This disease is generally considered terminal, with a very challenging prognosis.

Previously, the only treatment for peritoneal carcinomatosis was cytoreductive surgery and systemic chemotherapy. Unfortunately, patients responded poorly to chemotherapy delivered through the bloodstream.

A more novel therapeutic approach for peritoneal carcinomatosis combines cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). HIPEC involves bathing the abdomen directly with warmed chemotherapy drugs to improve drug delivery and decrease toxicity.

The combination of precision cytoreductive surgery and intraperitoneal delivery of hyperthermic chemotherapy has been shown to improve long-term outcomes.

What is Peritoneal Carcinomatosis?

Peritoneal carcinomatosis is a rare condition where primary cancer spreads to the peritoneum, the thin membrane that lines the abdomen and covers most digestive organs.

This condition can occur with any type of cancer but is most common in people with primary cancers of the digestive tract (stomach, pancreas, appendix, rectum, colon) and ovaries. 

A diagnosis of peritoneal cancer usually means that the primary cancer is at an advanced stage and has spread.

In rare cases, primary peritoneal cancer can originate in the peritoneum itself instead of spreading from another organ.

In its early stages, the symptoms of peritoneal carcinomatosis are non-specific, so the patient may not notice a problem until the peritoneal cancer advances.

Most patients experience the following common peritoneal carcinomatosis symptoms:

• Abdominal bloating
• Abdominal pain or back pain
• Nausea
• Constipation
• Weight loss
• Fatigue

Nevertheless, these peritoneal cancer symptoms are also common in many other conditions, so it can be difficult for patients to identify the early signs of peritoneal carcinomatosis.

More specifically, peritoneal cancer that has spread from abdominal cancer can cause ascites, an abnormal fluid buildup in the peritoneum.

Ascites (an abnormal fluid buildup between the lining of the abdomen and abdominal organs) from peritoneal carcinomatosis can lead to the following symptoms:

• Uncomfortable swelling in the abdomen or ankles
• Unexplained weight gain
• A sense of fullness
• Feeling unusually heavy
• Indigestion or nausea

The Prognosis of Peritoneal Carcinomatosis

In most cases, peritoneal carcinomatosis is considered a terminal illness with a difficult prognosis. However, questions such as - how long can you live with stage 4 peritoneal cancer - depend on multiple factors.

So, what is the survival rate of peritoneal carcinomatosis?

Type	Survival Rate
Primary Peritoneal Carcinomatosis	Varies from 11 to 17 months
Secondary Peritoneal Carcinomatosis	Dependent on the stage of cancer Stages 0, 1, and 2: 5 to 10 months Stages 3 and 4: 2 to 3.9 months

The survival rates of peritoneal cancer also depend on the location of the primary tumor. Peritoneal carcinomatosis originating from pancreatic cancer has the worst prognosis, followed by those from gastric and colorectal origins. 

On the other hand, ovarian cancer peritoneal carcinomatosis has a better prognosis.

Treatment for Peritoneal Carcinomatosis

It can be challenging to treat peritoneal carcinomatosis since it is usually an advanced form of cancer that has spread from somewhere else.

The treatment strategy for peritoneal carcinomatosis depends on the stage and origin of peritoneal cancer.

Therefore, determining the optimal treatment for a peritoneal carcinomatosis patient requires a multidisciplinary approach.

In addition, access to the latest research, including genetic profiling and Epigenetics (study of the microenvironment which affects how the genes work), can help improve outcomes.

Traditional Treatment of Peritoneal Carcinomatosis

The standard treatment of peritoneal carcinomatosis includes cytoreductive surgery (also known as the Sugarbaker procedure) with chemotherapy.

Chemotherapy

Previously, the only available treatment for peritoneal carcinomatosis was chemotherapy delivered systemically through the blood.

Nonetheless, patients with peritoneal metastasis do not respond well to systemic chemotherapy. This led many doctors to focus on palliative care to manage patients' symptoms in the final stages of peritoneal cancer.

However, recent advancements in the delivery of chemotherapeutic drugs have provided a more effective treatment option for patients with peritoneal cancers.

Cytoreductive Surgery

Cytoreductive or debulking surgery is an operation that removes any visible cancerous tumors from the abdominal cavity.

Surgeons use highly precise surgical skills to remove as much disease as possible while preserving the surrounding organs.

After cytoreductive surgery, if all the tumor is removed and there’s no residual disease left, then the survival rate improves. 

In peritoneal carcinomatosis from ovarian cancer, patients with no residual disease after debulking surgery have a survival rate of over 100 months (over 8 years).

However, if some residual disease remains after debulking surgery, the ovarian cancer peritoneal metastasis prognosis becomes worse. For example, 1 cm of residual disease left behind after surgery can reduce the median ovarian peritoneal cancer survival to less than 50 months (around 4 years).

Peritoneal Ovarian Cancer Treatment

Ovarian cancer is the second most common gynecological malignancy in Europe and the USA, with approximately 200,000 new cases reported annually worldwide. It is also the leading cause of mortality due to gynecological cancer, accounting for 100,000 deaths yearly. A challenging aspect of ovarian cancer is that 75% of cases are detected late at stage 3 or 4.

The standard treatment protocol involved complete cytoreductive surgery, chemotherapy, and biological therapy. In cases of patients with BRCA mutations (genetic mutations linked to hereditary breast and ovarian cancer risk), data from trials on the use of PARP inhibition therapy (PARPi) for maintenance in frontline therapy have shown excellent results. PARPi is a type of targeted therapy that stops the poly(adenosine diphosphate-ribose) polymerase (PARP) enzyme found in cells from repairing cancer cells so that they die. PARPi is also approved for recurrent ovarian cancer for therapy and maintenance. Incidences of recurrence were most commonly observed in the peritoneum. Despite aggressive treatment and surgery, many women succumb to this disease each year.

New strategies in treatment include intraperitoneal chemotherapy (HIPEC, PIPAC), neoadjuvant chemotherapy, and new drugs for targeted therapy or immunotherapy.

HIPEC: Novel Treatment for Peritoneal Carcinomatosis

Hyperthermic intraperitoneal chemotherapy (HIPEC) is an innovative approach to treating peritoneal carcinomatosis.

It is an alternative, innovative method for administering chemotherapy. It involves delivering high doses of heated chemotherapy drugs directly into the abdomen.

HIPEC surgery is a two-step procedure. First, all visible cancerous tumors are surgically removed from the abdominal cavity by cytoreductive surgery. Then, the abdominal cavity is bathed directly with hot chemotherapeutic drugs (heated to 42 degrees Celsius) to kill any remaining microscopic cancer cells.

The hyperthermia (increased temperature) of the chemotherapy increases its toxicity. And the intraperitoneal delivery (directly into the abdomen) allows us to deliver much higher doses than possible with systemic chemotherapy. It also minimizes the toxicity of chemotherapy.

HIPEC Treatment Outcomes

Several studies investigated the effectiveness of HIPEC surgery in treating patients with different types of peritoneal cancers.

In the studies, patients received cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

The results of the studies indicated:

Pseudomyxoma Peritonei Management

In patients with Pseudomyxoma Peritonei (also termed appendix peritoneal carcinoma, where cancer spreads to the peritoneum from the appendix), cytoreductive surgery (CRS) combined with HIPEC was able to:

• Increase the median survival rate to 16.3 years (196 months)
• Increase the progression-free survival (PFS) to 8.2 years (98 months)
• Improve the overall survival rates at 5, 10, and 15 years

This approach also has very low mortality (2%-4%) and morbidity (30%-47%) rates

Mesothelioma Peritonei Management

Malignant peritoneal mesothelioma refers to cancer occurring in the mesothelial cells that line the peritoneal cavity. Harmful exposure to industrial toxins, asbestos in many cases, is the primary causative factor. According to studies, a combination of CRS with HIPEC in patients with Mesothelioma Peritonei was able to:

• Improve the overall median survival to 53 months
• Increase the 1, 3, and 5-year survival rates to 81%, 60%, and 47%, respectively

Small Bowel Adenocarcinoma Management

Studies showed that in cases of cancer of the small intestines spreading to the peritoneum, HIPEC and CRS increased the overall survival at five years to 33%.

Gastric Adenocarcinoma Management

The median survival rate of gastric cancer is 3 months, and around 60% of gastric cancer deaths are from peritoneal carcinomatosis.

Moreover, the median survival rate of metastatic gastric cancer is less than a year.

A study in China revealed that patients with gastric adenocarcinoma who received a combination of HIPEC and debulking surgery had better clinical outcomes than those who only received HIPEC.

Another study in France investigated the efficiency of combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) compared to CRS alone.

Adding HIPEC to cytoreductive surgery improved the overall survival and progression-free survival rates and did not increase morbidity.

Colorectal Carcinomatosis Management

The median survival rate of colorectal carcinomatosis with every therapeutic approach (chemotherapy, targeted therapy, immunotherapy) is not more than 16 months.

A previous study showed that adding HIPEC to cytoreductive surgery increases the overall survival to 30-41 months in patients with colorectal carcinomatosis. However, another study showed that the addition of HIPEC to CRS did not have a significant impact on overall survival.

The disparity between these two studies leads us to a positive conclusion that a specialized surgical team conducting precise treatment (only CRS) can improve the median overall survival of patients with peritoneal carcinomatosis.

Summary

HIPEC is now the standard care for metastatic appendiceal cancer and peritoneal mesothelioma. These diseases, previously considered terminal conditions, can now be possibly treated with cytoreductive surgery and HIPEC at experienced centers to improve long-term survival. Furthermore, based on evidence from multiple studies cited above, HIPEC treatment with cytoreductive surgery offers the possibility of long-term survival and even a cure for patients with this aggressive disease.

Sources:

• Peritoneal Cancer - StatPearls - NCBI Bookshelf
• The Treatment of Peritoneal Carcinomatosis in Advanced Gastric Cancer: State of the Art - PMC
• Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial - PMC
• Approach to pseudomyxoma peritonei - PMC

 

Disclaimer