CRS and HIPEC for Colorectal Cancer Peritoneal Metastases

Transcript: edited for clarity

Next speaker is Dr. Nikhil Agrawal.

Good morning, everyone.

I'll be talking about the role of cytoreductive surgery and HIPEC in colorectal cancer. Let me ask you a question: How many of us will do a liver resection for colorectal cancer liver metastasis? Can I get a show of hands? Thank you. And how many of us will do a CRS-HIPEC for colorectal cancer peritoneal metastasis? Okay, so that's what I expected. The numbers are less for CRS-HIPEC! Why is that? This is the question that should come to our minds.

We can see that the survival outcomes of this procedure are almost equivalent to resection for colorectal cancer liver metastases. So, this should be in the armamentarium of all GI surgeons. When we see a colorectal cancer patient with resectable peritoneal metastasis, we should consider doing CRS-HIPEC. Colorectal cancer patients can have peritoneal metastasis as a synchronous or metachronous presentation. Five percent of them will have isolated peritoneal metastasis as a synchronous presentation. Twenty percent of them will develop this later and almost one-third of them will have isolated peritoneal metastases. Broadly, around 10 percent of colorectal cancer patients in synchronous or metachronous settings will have isolated peritoneal metastases and they are potential candidates for CRS-HIPEC.

The Problem with Peritoneal Metastasis

The problem with peritoneal metastasis is that systemic chemotherapy is not effective. Compared to pulmonary and liver metastasis, peritoneal metastasis has the worst outcome with systemic chemotherapy. The reasons are poor peritoneal vascularization and a plasma peritoneal barrier. The AJCC has specifically classified this as M1c. Even with modern systemic chemotherapy, targeted agents and everything, the survival that we can achieve with systemic treatment is around 18 to 20 months.

Intuitively, it appears that if systemic chemotherapy cannot reach the peritoneum, probably local therapies will help. Initially, people tried local chemotherapy, but the penetration was only around one to three millimetres. Later, heat was shown to increase the penetration to around five to seven millimetres.

History of CRS-HIPEC

Dr. Sugarbaker introduced the complete peritonectomy procedure in 1995. It was a highly invasive procedure that included six different procedures. Despite the morbidity, the procedure showed good outcomes. However, it was later discovered that by performing complete cytoreduction for macroscopic disease and HIPEC for microscopic disease; it was possible to eliminate all disease in the peritoneum and improve outcomes. HIPEC has the advantage of chemotherapy being absorbed through the portal system, which reduces the systemic side effects as the chemotherapy is detoxified directly in the liver.

Clinical Trials

The Netherlands trial was the first trial of CRS-HIPEC in colorectal cancer. The accrual was from 1998 to 2001. This trial showed that with CRS-HIPEC using mitomycin C for 90 minutes, the median overall survival (OS) improved from 12 months to 23 months. A later follow-up study with eight-year follow-up was published in 2008 and it showed that progression-free survival (PFS) and disease-specific survival were still positive. Specifically, the cohort that underwent complete cytoreduction had a five-year OS of 45 percent. There was some criticism of this trial, as single agent chemotherapy was used, and the mortality of CRS-HIPEC was 8 percent.

There were two more trials following this. They are not randomised controlled trials; they are cohort studies. The French trial showed oxaliplatin came in. Here, modern systemic chemotherapy was used in patients with a mean of around 2.3 lines in each patient. In this trial, the five-year overall survival improved from 13% to 51% with the addition of CRS-HIPEC. The median survival was 23 months versus 63 months. A similar type of outcome was shown in the American Pittsburgh study as well.

A meta-analysis which looked at all the trials, including randomised controlled trials and cohort studies, consistently showed improved survival with CRS-HIPEC. All the studies which have looked into CRS-HIPEC versus systemic chemotherapy have shown significant improvement in survival following this procedure.

PRODIGE 7 Trial

CRS-HIPEC is an established procedure, but the role of HIPEC is being called into question following the PRODIGE 7 trial, which was published last year. This was the French trial and, in this trial, patients were after complete cytoreduction divided into two arms. One arm received HIPEC and one arm didn't receive HIPEC. The agent used for HIPEC was oxaliplatin. In this trial, the overall survival, which was the primary endpoint, was equivalent in both the groups. It was excellent but equivalent. Both of the arms showed a median survival of around 43%, and the HIPEC arm had a delayed adverse events grade three or more 60 days and beyond. In a subset analysis, the patients who had PCI between 11 to 15 showed a better response with HIPEC.

There are many criticisms of the PRODIGE 7 trial. Some criticisms were that in the control group, 12 of the patients crossed over to receive subsequent CRS-HIPEC, these patients were heavily treated with oxaliplatin which induces oxaliplatin resistance, which was the drug used in this trial. There were also some questions on the fluid, some questions on the dosing, and some questions on the neoadjuvant therapy.

After that, the PSOGI (Peritoneal Surface Oncology Group International), which is a body that looks into peritoneal surface malignancy, did a survey and the practice has changed from oxaliplatin to mitomycin mostly all across the world.

HIPEC Delivery Techniques

After HIPEC, there are two ways to deliver HIPEC: open or closed technique. Most centres use a hybrid technique where you just cover the open abdomen with a sheet and then deliver the drug. As with all other tumours, tumour biology and patient selection are the most important factors.

Red Flags and Patient Selection

Red flags include aggressive tumours, young patients, and signet ring cell histology that have been shown to have poor outcomes. Patients with severe comorbid illnesses and advanced stages are often excluded. If we specifically look at signet ring cell histology, the long-term cure rates are poorer, but that doesn't exclude these patients from receiving CRS-HIPEC because the survival will still be better compared to chemotherapy.

Peritoneal Carcinomatosis Index (PCI)

One of the most important quantifiable factors in these patients is the Peritoneal Carcinomatosis Index (PCI), which is a crucial factor when considering surgery for these patients. Laparotomy is the best way to identify or quantify the PCI, but it can also be done through non-invasive methods such as radiological PCI using CT, MRI, or PET-CT. Some centres use a combination of cross-sectional imaging, mostly PET-CT, along with staging laparoscopy when deciding to perform surgery. Most centres use a cut-off of 16, some centres use a cut-off of 20, and in the PRODIGE 7 trial, the cut-off was 25.

To calculate the PCI, the abdomen is divided into nine quadrants and four more quadrants for the upper jejunal, lower jejunal, upper ileum, and lower ileum. Tumour is graded based on size, 0-3, where 0 indicates no tumour, 1 indicates a tumour up to 0.5 centimetres, 2 indicates a tumour up to 5 centimetres, and 3 indicates a tumour greater than 5 centimetres or a conglomerate mass greater than 5 centimetres.

Completeness of Cytoreduction (CC) Score

Once you have ascertained this and are going to perform surgery, the Completeness of Cytoreduction (CC) score is important. We should strive to achieve a CC0, which means that macroscopically we have removed all the disease. It is quantified as:

• CC0
— no residual disease
• CC1
— residual disease less than 2.5 mm
• CC2
— residual disease between 2.5mm and 2.5 cm
• CC3
— residual nodules greater than 2.5 cm

The AJCC also gives R criteria:

• R0
— no residual microscopic disease
• R1
— positive microscopic disease
• R2a
— residual tumours < 0.5 cm
• R2b
— tumours between 0.5–2.0 cm
• R2c
— remaining nodules > 2 cm

Morbidity and Mortality

CRS-HIPEC is a major procedure that is associated with a certain level of morbidity and mortality. The morbidity rate is around 30%, which is similar to that of a Whipple procedure. Mortality rates have been found to be dependent on the disease volume; around 0-4%. In order to improve outcomes, it is important for high-volume centres to perform a large number of cases and for surgeons to have experience performing at least 100-200 cases in order to develop the necessary proficiency.

Summary

• A significant proportion of colorectal cancer (CRC) patients will have isolated peritoneal metastasis, which is associated with poor survival rates when treated with modern systemic chemotherapeutic agents.
• The addition of Cytoreductive Surgery (CRS) with or without Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has the potential to extend survival in a significant and meaningful way.
• Patient selection is key to the success of this procedure, and the Peritoneal Carcinomatosis Index (PCI) is an important factor to consider.
• The goal should be to achieve a CC0 (completeness of cytoreduction) score and as the volume of cases increases, better outcomes can be expected.

Thank you.

End of the talk.

Q&A Session

Question 1:

In cases where the patient has a PCI of 6-7 or less than 15 and if the tumour is bleeding, the primary should be resected? What about the role of neo-adjuvant chemotherapy? What should be the management protocol?

Answer:

Neoadjuvant chemotherapy is not mandatory. While some studies have shown a benefit, it is not a requirement. For patients who are found to have peritoneal metastasis at laparotomy or laparoscopy, they can be divided into two groups. One group is patients taken up for elective surgery, who are asymptomatic and not bleeding or obstructed. In these cases, upfront CRS-HIPEC can be considered. If the disease volume is low and the patient's situation permits, CRS-HIPEC can be done, otherwise, the strategy used in elective cases can be applied, such as taking biopsies, giving neoadjuvant therapy, and proceeding with surgery at a later date.

Question 2:

My question is about the protocol for patients who have had a resection of the primary tumour and have returned with suspicious peritoneal nodules on follow-up. How do you confirm that these are peritoneal metastases? And if confirmed, how do you offer CRS-HIPEC to these patients?

Answer:

In summary, when a patient who has previously undergone primary resection for colorectal cancer returns with suspected peritoneal metastasis, the management protocol will depend on several factors such as the size of the peritoneal nodules, CEA, the patient's symptoms, and their disease-free interval. The first step would be to confirm the diagnosis non-invasively if possible through radiological imaging and biopsy, or staging laparoscopy. A laparotomy may be required. The management options include giving the patient neoadjuvant therapy before surgery, or proceeding with upfront CRS-HIPEC.

Audience Comments:

• Regarding limited disease, in cases where you see a small deposit of 0.5 cm in the adjacent peritoneum, it's not harmful to remove it. Limited cytoreduction without HIPEC has been shown to improve survival.
• It is important to document the PCI score after surgery. Even though there are deposits all over the peritoneal cavity, the size of the deposits is small, resulting in a low PCI score. This is important to understand as it changes the way that the medical oncologist and surgeon approach the treatment.
• It is important to document the peritoneal carcinomatosis index (PCI) by taking photos and videos during the surgery.
• When performing a staging laparoscopy for peritoneal metastasis, it is important to use multiple ports, carefully examine the pelvis, small bowel and lesser sac, and not just rely on the visual inspection of the peritoneal cavity.
• Selective peritonectomy is preferable after a patient has received adjuvant therapy. Total peritonectomy has not been shown to be beneficial in this setting.

Thank you!

End of session.