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 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.

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.

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. I will just highlight the two. One is the French trial, from which the 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, and it 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. To illustrate how it plays out, I'll give you an example of a patient who has peritoneal disease to start with. This patient had peritoneal disease which was mostly localised to the right side of the abdomen. The Peritoneal Cancer Index (PCI) was 10, and it was a mucin-secreting adenocarcinoma. We gave neoadjuvant chemotherapy to this patient, and there was a good response. This is the post neoadjuvant chemotherapy CT scan, and this is the disease during surgery. You can see the peritoneum is studded with nodules. Then, you achieve complete cytoreduction and then you perform HIPEC.

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. In fact, if you look at the literature that came in following this, there was a flurry of responses to this trial because intuitively it appears that HIPEC for microscopic disease should be done and this trial challenged that dogma. Still, people have not accepted the findings. 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. However, looking at the previous trial data, they are almost known to be equivalent.

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 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. However, we should know that these patients are likely to have poor outcomes.

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. There is a debate between CT, MRI, and PET-CT, with PET-CT being slightly better than CT and MRI still evolving. 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. Based on these measurements, the PCI is calculated. A PCI of 16 is generally taken as a cut-off for deciding to perform surgery.

To make patient selection even better, we have to look at certain criteria. The ECOG performance status is one of the important factors, as well as the extent of extra-abdominal disease. Limited extra-abdominal disease is not a contraindication. One of the consensus statements looked into this, and a nomogram was developed. Up to three or four liver metastases is okay, there shouldn't be any biliary obstruction, the hepatoduodenal ligament shouldn't have much disease and ureteral obstruction shouldn't be there. There shouldn't be gross small bowel and mesenteric involvement, which is a big no-no. One of the problems with this is that CT is not always reliable in finding small bowel and mesenteric involvement, so it is generally detected on staging laparoscopy and sometimes on laparotomy. The gastrohepatic ligament should be relatively free.

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) and CC3 (residual nodules greater than 2.5 cm).

The AJCC also gives R criteria, R0 (no residual microscopic disease), R1 (positive microscopic disease). R2a is described as residual tumours < 0.5 cm, R2b designates tumours between 0.5–2.0 cm, and R2c represents remaining nodules > 2 cm.

To clarify, CC0 and CC1 have been shown to be the best predictors of long-term cure rates. Initially, some data suggested that both were equivalent, but now it is understood that CC0 is better than CC1.

An example of this procedure is demonstrated in the images shown. The first image is of the right upper quadrant, where a complete peritonectomy and even a glissenectomy is performed to achieve a CC0 score. Similarly, the second image shows the CC0 in the left upper quadrant.

This image shows a high-volume disease; this is not from colorectal cancer. I have taken this image to show you an example and in this image you can see the pelvis. These are the ureters here and are completely exposed and you achieve CC0 here.

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%. with older studies showing higher mortality rates and more recent studies showing lower rates. 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.

To summarise, 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. However, 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.

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, but the conversation between the surgeon and patient about CRS-HIPEC generally has not occurred. We have to consider the expected morbidity, mortality, and cost. In an emergent setting, the same considerations apply. 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, as diagnostic laparoscopy can be difficult due to adhesions? And if confirmed, how do you offer CRS-HIPEC to these patients?

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 of peritoneal metastasis non-invasively, if possible, through radiological imaging and biopsy if possible 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. The decision will depend on the patient's overall condition, and the stage and volume of the peritoneal disease.

Audience comment: Great presentation, I have two comments. One, regarding the limited disease that was mentioned, I believe that 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. The second comment is that often in clinical practice, we end up not documenting the PCI score. It's a complex score, but the diagram is easily available on the internet. After surgery, it's important to take a printout and document the score. We often see that 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 of the patient.

I would like to add a couple of points to that comment. First, it is important to document the peritoneal carcinomatosis index (PCI) by taking photos and videos during the surgery. This is especially important for centres that do not routinely document PCI. Second, 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.

Additionally, it is important to note that the goal of surgery in these cases is primarily cyto-reduction. The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) is an added benefit, but it is not necessary for improving survival. For patients with low PCI, cyto-reduction alone may be sufficient. However, in patients with higher PCI, the addition of HIPEC may provide additional benefit.

Furthermore, it's important to note that selective peritonectomy is preferable after a patient has received adjuvant therapy. Total peritonectomy has not been shown to be beneficial in this setting. It's better to have a laparoscopy and assessment prior to starting neoadjuvant chemotherapy.

Thank you!

End of session.