Surgeon Highlights Regional Therapy Approaches for mCRC

Byrne Lee, MD

In past years, management of metastatic colorectal cancer (mCRC) has required a more palliative approach, but recent therapeutic advances have improved patient outcomes. Despite this progress, there is still much work left to be done, said Byrne Lee, MD.

Investigators had hoped that data from recent studies evaluating the use of hyperthemic intraperitoneal chemotherapy (HIPEC)—particularly PRODIGE 7 and COLOPEC—would help lead to a more refined treatment approach for patients with peritoneal metastases. However, both trials failed to demonstrate the benefit of HIPEC in this patient subset.

In PRODIGE 7, patients were randomized to receive an addition of HIPEC oxaliplatin heated to 43 degrees Celsius in an attempt to increase efficacy, said Lee, who is the chief of the Upper GI and Mixed Tumor Surgery Service and an associate professor of surgical oncology at City of Hope. Investigators found that there was no survival benefit to heated chemotherapy delivered straight to the abdomen in patients with peritoneal metastasis. Median overall survival in the non—HIPEC arm was 41.2 months compared with 41.7 months for the patients treated with HIPEC.¹ Relapse-free survival was 11.1 months for patients treated without HIPEC versus 13.1 months for those treated with heated chemotherapy.

The COLOPEC study, results of which were presented at the 2019 Gastrointestinal Cancers Symposium, showed benefit for surgical debulking, but did not succeed in bolstering the need for HIPEC in these patients. Regarding the primary endpoint of 18-month peritoneal metastasis-free survival rate, researchers observed no statistically significant difference: 76% for patients in the control arm versus 81% for patients treated with surgery followed by HIPEC (HR, 0.86; 95% CI, 0.51-1.54).²

Although some of these patients may benefit from this modality, Lee said that more evidence is needed before this approach can become standard practice. He added that this is not the only regional therapy under investigation for patients with peritoneal metastasis. A newer delivery treatment, referred to as pressurized intraperitoneal aerosol chemotherapy (PIPAC), is of interest and is already being used in Europe and Asia.

OncLive: What is the use of intraperitoneal chemotherapy and surgery for the treatment of peritoneal metastases for CRC?

Could you elaborate on some of these studies that were presented at the 2019 Gastrointestinal Cancers Symposium?

In an interview with OncLive at the 2019 State of the Science Summit™ on Gastrointestinal Cancers, Lee further discussed regional treatment strategies for patients with mCRC.Lee: In the past, this has been a deadly disease with a very poor prognosis. Over the years, however, we have been utilizing aggressive cytoreductive and debulking surgeries to rid the peritoneum of disease. We have also included intraperitoneal chemotherapies, which have been shown to improve survival in recent randomized trials. I shared some of the updates that were presented at the 2019 Gastrointestinal Cancers Symposium. There does appear to be an improvement with cytoreductive surgery, but the use of intraperitoneal chemotherapy may or may not improve survival. We definitely need more studies to improve our knowledge on this.There was a study presented in 2018 by a large French group, the long-awaited PRODIGE 7 trial, which looked at the use of cytoreductive surgery with or without HIPEC for the treatment of CRC with peritoneal metastasis. In this trial, patients were randomized to receive either surgery or surgery with HIPEC; this utilized a more European regimen comprised of oxaliplatin perfused for 30 minutes at 43 degrees Celsius. In that trial, there was no improvement in overall survival or progression-free survival (PFS) when HIPEC was used. It did, however, show that cytoreductive surgery works—there was a median PFS of approximately 40 months in both arms, and we have used this study to show that aggressive surgical debulking can help certain patients with peritoneal metastasis.

With the conflicting results with HIPEC, how do optimally select patients for this approach?

Is regional therapy used in conjunction with systemic therapy?

Where do you see future research headed?

How do the 2 approaches, HIPEC and PIPAC, differ from one another?

[At the State of the Science Summit^TM] I also [discussed] a study presented this year called the COLOPEC trial. This looked at using HIPEC as an adjuvant treatment for patients with high-risk CRC; these are patients with perforated colon cancers or T4 colon cancers. Again, the [goal] was to find out whether or not the use of intraperitoneal chemotherapy and cytoreductive surgery would improve survival in these patients. Data from this study also showed that the use of HIPEC may not have helped in this subset of patients.Currently, as American surgeons, we often use HIPEC regimens that are different than the recent trials. For instance, both trials, PRODIGE 7 and COLOPEC, utilized oxaliplatin for an infusion time of 30 minutes. In the United States, the majority of our centers actually use mitomycin C, and we perfuse for 90 to 120 minutes. We do feel that in a subset of patients the extra perfusion time may help with the results. At this time, HIPEC for CRC will need more evidence [to become part of routine practice]. More trials are on the way.Intraperitoneal chemotherapy has been utilized in other cancers, not just CRC. It is the combination of treatments—whether cytoreductive surgery, systemic therapy, or intraperitoneal chemotherapy—but we do think this is improving survival for patients with peritoneal metastasis. This approach is used in conjunction with other modalities.Intraperitoneal chemotherapy or other intraperitoneal therapies will evolve. I don't think HIPEC will be the last endeavor for regional therapy for patients with peritoneal metastasis. I discussed a newer delivery of treatment called PIPAC); it is currently utilized in Europe and Asia, but there are several centers in the United States that are interested in bringing it here as well. This may be an interesting way to deliver effective therapy for [patients with] peritoneal metastasis.HIPEC is utilizing heated intraperitoneal chemotherapy; it is essentially a bath. We utilize a machine to perfuse the abdomen at a constant rate and temperature. We generally use this modality after cytoreductive surgery because we have to reduce all the peritoneal metastasis to microscopic disease.

What is your take-home message for community oncologists who are treating patients with CRC?

PIPAC is a new way of delivering chemotherapy into the abdomen. We do not perform surgery at the time of PIPAC, so it can be used in conjunction with systemic chemotherapy. There are benefits of both. With PIPAC, it allows me to better visualize treatment. With each session, the surgeons can gauge how the cancer is responding to treatments. Additionally, by the way it is delivered, it is safe, and patients are able to continue on therapy. We don't have the big surgery to worry about; this modality will become more prevalent [in the future].The biggest thing to emphasize is that metastatic disease, in the past, had been looked at in a nihilistic approach—mainly palliative and quality-of-life measures. As newer therapies [come into practice], whether chemotherapy is delivered systemically or via intraperitoneal injection, patients are living longer. They are surviving longer without their cancer. In terms of stage IV disease, we definitely are pushing the boundaries and achieving improved survival, especially in patients who respond to chemotherapy and regional therapy.

Many of the newer therapies are associated with some morbidity. These approaches we mentioned do bring a new spectrum of symptoms and potential complications that need to be [monitored for]. Understanding these are important, not just for the comfort of the patient but for the comfort of the nurses in the frontlines, too. Education on these newer drugs and surgeries is important for healthcare professionals.

References

1. Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. 2018;36 (suppl; abstr LBA 3503). doi: 10.1200/JCO.2018.36.18_suppl.LBA3503
2. Klaver C, Wisselink D, Punt C, et al. Adjuvant HIPEC in patients with colon cancer in patients with high risk of peritoneal metastases: outcome of the COLOPEC multicenter randomized trial. J Clin Oncol. 2019;37 (suppl 4; abstr 482). doi: 10.1200/JCO.2019.37.4_suppl.482.