A Q&A with Michael Foote, MD, MSK Gastrointestinal Medical Oncologist and member of the Peritoneal Surface Malignancies Consortium Group
The Peritoneal Surface Malignancies Consortium Group (PSM Consortium Group) is a national, multidisciplinary collaboration of surgical and medical gastrointestinal oncology specialists from top cancer centers. The group recently published a series of updated consensus guidelines for the clinical management of peritoneal metastases related to a variety of gastrointestinal malignancies.
We spoke with Dr. Foote to discuss the major updates for the management of colorectal cancer (1) and appendiceal cancer (2) (3)peritoneal metastases and how the changes will improve patient outcomes and streamline patient care.
Colorectal cancer is the third-leading cause of cancer-related deaths in the United States. How common are colorectal cancer peritoneal metastases, and how do they affect outcomes?
Peritoneal metastases occur in about 5% to 15% of patients with colorectal cancer. About half of these cases present at the same time as the primary tumor, and the other half present on relapse. Colorectal cancer peritoneal metastases (CRC-PM) have a worse prognosis compared to other metastatic sites, with a median overall survival (OS) of about 16 months and are associated with malnutrition and bowel obstruction.
What was the most notable update in the CRC-PM consensus guidelines?
The traditional approach was to treat patients with CRC-PM indefinitely with chemotherapy; the role of surgery in this situation was controversial. The new guidelines recommend cytoreductive surgery for patients with disease confined to the peritoneal cavity, with the use of neoadjuvant chemotherapy for three to six months to potentially downstage tumor burden and target micrometastases. (1)
Patients who meet the eligibility criteria, even those with stage 4 disease, can have good outcomes with surgery. Testing the biology of the cancer in advance of surgery is essential: aggressive cancer that does not shrink is more likely to recur after surgery. (1)
What form of chemotherapy is recommended for CRC-PM?
The guidelines include a summary of recommended initial and subsequent systemic chemotherapy regimens for various types of metastatic colorectal malignancy with peritoneal involvement. Some examples of first-line treatment options include FOLFOX or FOLFOXIRI doublet chemotherapy with or without anti-EGFR or anti-VEGF agents for patients with initially unresectable proficient mismatch-repair/microsatellite stable metastatic CRC, and immunotherapy for those with deficient mismatch repair/microsatellite instability-high disease. (1)
Is hyperthermic intraperitoneal chemotherapy (HIPEC) recommended for CRC-PM?
The use of HIPEC was a controversial topic among PSM Consortium Group members. The guidelines netted out recommending consideration for upfront cytoreductive surgery with or without intraperitoneal chemotherapy with either EPIC (early postoperative intraperitoneal chemotherapy) or HIPEC, and only for select patients with a high performance status, low to moderate peritoneal carcinomatosis index (PCI), low anticipated surgical morbidity, and a prediction of complete cytoreduction.
At MSK, though, we no longer use HIPEC to treat CRC-PM for two reasons. First, we find that the chemotherapy only stays in the abdomen for a short period of time, so questions remain about whether it penetrates cancer cells.
Second, evidence from large trials has shown it doesn’t improve survival. Results from the large, phase 3 PRODIGE 7 trial conducted at 17 cancer centers in France (NCT00769405) showed no overall survival benefit from adding HIPEC to cytoreductive surgery compared with surgery alone. ([4]) The PRODIGE 7 results prompted us to stop accruing patients to the CRC-PM cohort of the MSK-led ICARuS trial (NCT01815359), a phase 2 multicenter study that was evaluating the relative efficacy of HIPEC versus EPIC after surgery. Our analysis, as presented at the 2023 ASCO Gastrointestinal Cancers Symposium, showed consistent results with PRODIGE 7 with no difference in three-year progression-free survival (PFS) between treatment arms. (5)
Current imaging methods are not very sensitive in detecting CRC-PM. How do you manage this uncertainty when assessing patients and determining the best treatment plans?
PMs don’t show on scans for about 50% to 65% of patients, underscoring the importance of the physical exam and patient history. When a patient is losing weight, experiencing pain and bloating, and having difficulties with bowel movements, I’ll revise their treatment plan based on how they feel, rather than relying on scan results alone.
Does evaluating genetic markers inform treatment decisions for PM?
Identifying genetic markers in PM can help us more precisely identify patients who will do well with surgery or chemotherapy. For example, we know that patients with TP53 mutations likely have more aggressive cancer and may not do as well with surgery as those without.
Recently, we evaluated over 58,000 patient tumors to find genetic mutations that might allow the cancer to live better in the peritoneal cavity. We found that patients with activation of one gene – GNAS – had especially high rates of peritoneal metastases across many types of cancer, including colorectal, pancreatic, hepatobiliary, and cervical cancers. Patients with GNAS-mutated tumors also exhibited reduced response to first-line systemic therapy, shorter time on treatment before progression, and worse OS. Our report was published in the Journal of Clinical Oncology in August 2024. (6) We received federal funding to help develop new strategies to target GNAS and treat peritoneal metastases.
Were there any updates for the surveillance of CRC-PM?
The new guidelines are not dramatically different from the standard of care, but they serve as a helpful reminder of what to look for. However, they do point out that some patients may benefit from multiple surgeries if they’ve had a prolonged remission after the first surgery.
Let’s shift gears and discuss appendiceal cancer-PM. How common are they, and how do they affect outcomes?
Appendiceal cancers are rare, heterogeneous tumors that are present in 1 out of about 200,000 people. Appendiceal cancer is unique in that when it spreads in the body outside of the appendix, it almost always travels to the peritoneal cavity.
Median OS estimates vary depending on tumor biology, from as low as 12 months for poorly differentiated disease to as long as 78 months for well-differentiated disease. About 25% of patients with appendiceal cancer develop recurrence within the first three years after surgery, with higher rates as peritoneal involvement and grade increase.
There is limited data available to guide treatment decisions for appendiceal cancer, especially as they have been traditionally treated as CRC. Did any recent research from MSK provide input to the new consensus guidelines?
It is difficult for oncologists to know what the best treatments are for appendiceal cancer because tumors that look similar under the microscope can behave very differently. We published landmark research to classify appendiceal cancers based on their genomic profile in the Journal of Clinical Oncology in 2022. Our findings were integrated into the new guidelines.
We identified distinct molecular patterns that identify subtypes of appendiceal adenocarcinomas: a clinically indolent RAS-mutated/GNAS-wild type/TP53 subtype; a chemotherapy-resistant GNAS-mutated predominant subtype; and an aggressive, highly aneuploid TP53-mutated predominant subtype. The findings underscored the value of profiling tumors to guide treatment decision-making on whether to offer cytoreductive surgery and/or systemic therapy. (7)
What were the most notable updates in the appendiceal-PM guidelines?
There are two parts to the new consensus guidelines for appendiceal cancer: Part 1 covers tumors without peritoneal involvement (2) and Part 2 covers tumors with peritoneal involvement. (3)
Within the latter, key updates included recommending cytoreductive surgery to most patients with low-grade peritoneal disease who are surgical candidates and to many patients with high-grade disease. The guidelines also provide protocols for the timing of systemic chemotherapy and surveillance, with a discussion of common pitfalls in pathologic classification.
In summary, what impact will the new consensus guidelines for CRC-PM and appendiceal-PM have?
The guidelines represent the collective recommendations of the PSM Consortium Group, based on the available research and our clinical expertise treating patients at tertiary cancer centers. They should go a long way toward streamlining care and improving patient outcomes.
At the same time, the new consensus guidelines highlight the need for more research into gastrointestinal malignancies with peritoneal metastasis.