Colorectal Cancer With Peritoneal Metastases: A Plea for Cooperation Between Medical and Surgical Oncologists

Drs. Loggie and Thomas have put together an excellent and comprehensive review of the development, rationale for, and evolution of hyperthermic intraperitoneal chemotherapy (HIPEC) in gastrointestinal cancers with peritoneal carcinomatosis.[1] They address very important lessons that have been learned with regard to patient selection, the steep learning curve required to perform a safe cytoreductive operation, and what the key components of a reasonable operation should be (ie, limited morbidity, minimal or no mortality, preserved physiology, and rapid return to good performance status). They conclude their review by stating that cytoreductive surgery (CS) plus HIPEC should be the standard of care for appendiceal and colorectal cancers with peritoneal disease.

I agree 100% with their comments. Here I offer my opinion regarding the current status and future directions in the care of patients with colorectal cancer and peritoneal metastases, in particular with regard to the role that CS + HIPEC might play as part of a multidisciplinary treatment plan. I also explain why, even though I agree that CS + HIPEC should be part of the standard of care for patients with colorectal cancer and peritoneal metastases, it is not at the present time and, in my view, will not be any time soon.

There is no question that for patients with colorectal cancer and peritoneal metastases, the best outcomes data result from the incorporation of CS + HIPEC into the treatment algorithm. This is a fact that cannot be denied. However, let us talk some numbers so we can put things in perspective.

There are about 150,000 new cases of colorectal cancer per year in the United States. In about 8% of these, there is evidence of peritoneal dissemination at the time of diagnosis, and in up to 25% of cases, such evidence is present at the time of tumor recurrence.[2] Some of these patients will also have liver and/or lung metastases and thus will not be candidates for CS + HIPEC. If we estimate that 5%-a very conservative number-of colorectal cancer patients (those with peritoneal dissemination and no evidence of other metastases) would be candidates for complete surgical eradication of their isolated peritoneal metastatic disease and would also be candidates for HIPEC, this would make about 7,500 patients per year needing CS + HIPEC in the United States.

My estimation-arrived at by talking to those who sell the commercially available machines that deliver HIPEC-is that about 1,400 HIPEC procedures were performed in the United States last year. The most common diagnosis in these patients was appendiceal cancer, and probably less than 25% of the procedures were performed in patients with colorectal cancer. That would be 350 cases, or about 5% of the potential candidates. These numbers reflect the fact that the vast majority of patients with colorectal cancer and peritoneal metastases are being treated by medical oncologists-with a combination of cytotoxic chemotherapy and biologic agents-and are not being referred to be evaluated for a peritoneal surface malignancy program. Colorectal cancer patients with peritoneal metastases are staged as stage IVB and are seen as patients with unresectable metastatic disease. Few of them are entered into clinical trials, and the usual treatment strategy is to continue systemic therapies until disease progression, intolerable side effects, or death.[3] This is the current status of the vast majority of patients with colorectal cancer and peritoneal metastases, even if there are no data that can support such mono-disciplinary practice.

In Verwaal’s study, the outcome of patients treated with CS + HIPEC was 22 months, which was almost double the survival of the patients who received only systemic chemotherapy.[4] Perhaps the selection of patients for CS + HIPEC has improved over the years, but there have been very few changes (if any) when it comes to the surgery or the way in which HIPEC is delivered. As Drs. Thomas and Loggie point out, numerous studies are currently showing median survivals for CS + HIPEC that exceed 40 to 60 months. I think improvements in systemic therapy are responsible for a significant component of that increase in survival.

The French trial PRODIGE 7 was designed to evaluate what the added benefit is of including HIPEC along with complete CS.[5] The participation of multiple institutions with varying degrees of experience, and the fact that the timing of incorporation of systemic therapies and the agents used were not mandated for those who participated in the trial, will make this trial, in my estimate, a negative study that will fail to demonstrate the role of HIPEC. However, PRODIGE 7 will make one very important contribution: It will demonstrate the value of having surgery to remove the peritoneal metastases and receiving systemic chemotherapy. Therefore, this will be a landmark study highlighting the importance of a multidisciplinary management approach in patients with colorectal cancer and peritoneal metastases.

We have learned and continue to learn a lot about colorectal cancer and peritoneal metastases. Our ongoing challenge is to determine the optimal sequence of all currently available therapies. We need to stratify patients based on the biological aggressiveness of their tumor, as well as on the basis of the tumor burden; not all patients with peritoneal metastases are the same. At the present time, genomic profile analysis can only help us identify patients with tumors that are “bad actors,” but hopefully in the near future it will help us treat patients with more targeted therapies. Our future goal should be to increase the resectability of patients with colorectal cancer and peritoneal metastases by improving selection criteria and by referring early, but also by using systemic therapies in the neoadjuvant setting. Better outcomes will be tied to therapies that help to maintain the complete surgical response; whether that includes HIPEC and/or more systemic therapies remains to be determined.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Loggie BW, Thomas P. Gastrointestinal cancers with peritoneal carcinomatosis: surgery and hyperthermic intraperitoneal chemotherapy. Oncology (Williston Park). 2015;29:515-21.

2. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies. Results from the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88:358-63.

3. Klaver YLB, Simkens LHJ, Lemmens VEPP, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol. 2012;38:617-23.

4. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737-43.

5. Elias D, Goéré D, Dumont F, et al. Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer. 2014;50:332-40.