Treating Peritoneal Metastases With Cytoreductive Surgery and Intraperitoneal Chemotherapy

August 28, 2020

Two Decades of Treatment and Research at UPMC

Peritoneal metastases, also termed peritoneal surface malignancies or peritoneal carcinomatosis, refer to cancers that have spread locoregionally within the peritoneal cavity. They include primary cancers that arise from the peritoneal lining (e.g., malignant peritoneal mesothelioma) and those that metastasize to the peritoneal cavity from other organs (e.g., secondary spread of appendix, colorectal, ovarian cancers). The utilization of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for the treatment of peritoneal metastases has increased worldwide over the last three decades.1

Medical oncologists may be unfamiliar with the rationale, optimal timing, and indications for CRS-IPC; technical advances in this combinatory locoregional treatment; oncologic outcomes associated with this treatment approach; and ongoing novel surgical trials for peritoneal metastases.

In this article for referring physicians, Haroon A. Choudry MD, FACS, associate professor of surgery and surgical oncology, and director of the David C. Koch Regional Perfusion Cancer Therapy Center at UPMC Hillman Cancer Center, discusses the use and benefits of CRS-IPC (specifically focusing on hyperthermic intraperitoneal chemoperfusion [HIPEC]), and UPMC’s experience and research with this treatment modality during the last two decades. 

What Are the Benefits of CRS-HIPEC for Peritoneal Metastases?

The addition of CRS-HIPEC as a component of multimodality therapy for well-selected patients with peritoneal metastases has the potential to provide long-term survival benefits. Taking the example of colorectal cancer, modern systemic chemotherapy regimens have significantly improved median survival (~ 25-37 months) of well-selected patients with colorectal systemic (nonperitoneal) metastases, but long-term survival rates have not improved (< 5%).2,3 Modern systemic chemotherapy regimens are less effective against PM from colorectal cancer (median survival ~ 12-16 months).4 This is mostly attributed to low rates of complete response (despite improvements in partial response rates), development of chemoresistance, and poor penetration into the peritoneal cavity. CRS-HIPEC provides an opportunity for complete resection (surgical “complete response”) and direct delivery of high-dose chemotherapy into the peritoneal cavity and, therefore, can impact long-term survival. In fact, preliminary data from a recently completely randomized trial of modern systemic chemotherapy and CRS, with or without HIPEC, demonstrated median survival of 41-42 months and five-year survival rates of 37-39%.5

What Misconceptions Persist Around the Use of CRS-HIPEC?

The first misconception is that there is a lack of robust data for the use of CRS-HIPEC in all instances. While it is true that there is a lack of level one data for some indications, the knowledge gap is shrinking. Randomized trials for cancers of the appendix or peritoneal mesothelioma are exceedingly difficult to conduct due to the diseases' rarity. However, CRS-HIPEC can be, and largely is, considered as a standard of care for appropriate patients with these cancers, based on multiple large institutional studies showing excellent results. There is increasing evidence concerning ovarian and colorectal cancer, including level one data, to support the use of CRS-HIPEC in well-selected patients. The key is to use CRS-HIPEC in well-selected patients for whom treatment can be effective.

Another misconception that seems to be prevalent is that CRS-HIPEC is an exceedingly dangerous procedure with high morbidity and mortality rates. In reality, the risk of serious complications is about 20-30%, and the mortality risk is approximately 2-5% when performed at experienced high-volume centers. These rates of adverse events are comparable to other major esophageal and pancreatic surgeries, so the perceptions of the danger of the procedure are not supported by the data. High-volume centers with experienced surgeons and programs, such as exist at UPMC, are well equipped to handle the challenges presented by these complex cases. At the risk of overstating it, patient selection is a driving factor to optimize surgical success and minimize complications.

What Is the Optimal Timing for CRS-HIPEC?

The timing for CRS-HIPEC is critical if it is to factor into a patient’s care pathway. Appropriate referral early in the course of the disease should be prioritized so that a multidisciplinary and collaborative assessment of the feasibility, efficacy, and timing of CRS-HIPEC can be determined for a specific patient with peritoneal metastases.

Often patients are referred for a CRS-HIPEC consult as a last resort after they have failed to improve with other treatment modalities. To effectively be considered for CRS-HIPEC, patients with peritoneal locoregional dissemination ought to be referred early for consultation and assessment of their disease.

How Important Is Patient Selection and What Factors Typically Influence the Efficacy of CRS-HIPEC?

Along with timing, optimal patient selection for CRS-HIPEC is crucial. Not every case of peritoneal metastases will be amenable to CRS-HIPEC. Given the variety of primary histologies for which CRS-HIPEC may be considered, and the many nuances associated with a decision for or against surgical intervention, a multidisciplinary tumor board approach is used at UPMC to optimize patient selection and care pathways. 

When reviewing patient cases, there are five main criteria or prognostic factors that UPMC surgeons and clinicians use to determine the suitability of CRS-HIPEC for a patient. 

  1. The metastatic disease must be isolated to the peritoneal cavity. Concurrent metastatic disease elsewhere – the liver, lungs, or bone – is generally a contraindication to the use of CRS-HIPEC for patients with peritoneal metastases.
  2. Patients most amenable for CRS-HIPEC typically have low-grade, less aggressive tumors in whom surgeons can obtain a complete resection of the macroscopic disease. Incomplete cytoreductive surgery is less likely to be effective, making these individuals poorer candidates for CRS-HIPEC, except in some situations.
  3. For individuals with higher-grade tumors, systemic chemotherapy is often given for a short duration to assess tumor response (disease biology). Patients whose tumors progress on chemotherapy are less likely to benefit from CRS-HIPEC.
  4. Because CRS-HIPEC is an intense surgical procedure, patients with excessive comorbidities are poorer candidates since they are less likely to tolerate the treatment.
  5. The histology of the patient’s disease is an important factor when considering CRS-HIPEC. For peritoneal disease attributable to appendix cancer or malignant mesothelioma, CRS-HIPEC is often considered a standard of care. The data suggest that well-selected patients with ovarian and colon peritoneal metastases can be good candidates for CRS-HIPEC. For gastric and hepatobiliary peritoneal metastases, CRS-HIPEC is rarely utilized and considered experimental since there is a lack of data to support its use. 

How Extensive Is the UPMC Program for CRS-HIPEC?

Our program has performed more than 1900 CRS-HIPEC procedures in patients with peritoneal metastases over the last 20 years. Most of these procedures have been performed for peritoneal metastases from appendix cancer (43%), colorectal cancer (28%), malignant peritoneal mesothelioma (10%), and ovarian cancer (7%). 

Clinical Research and Trials at UPMC Hillman Cancer Center Involving CRS-HIPEC

Researchers and clinicians at UPMC Hillman Cancer Center have been studying and publishing our history with CRS-IPC  for nearly two decades.

More than 150 demographic, clinicopathologic, surgical, perioperative, and oncologic variables for each patient undergoing CRS-HIPEC have been entered into a prospectively maintained database, approved by the institutional internal review board. Based on the data collected from patients with peritoneal metastases undergoing CRS-HIPEC, more than 60 manuscripts have been published in peer-reviewed journals. This database has been vitally important for understanding the disease biology of peritoneal metastases, optimizing patient selection criteria, and improving patient outcomes. The role of CRS-HIPEC for the treatment of peritoneal metastases will continue to evolve but currently remains an important part of multimodal therapy.

Clinical trials are an essential component of the UPMC Hillman Cancer Center peritoneal metastases program. A novel dendritic cell vaccine trial was completed a few years ago and is currently under consideration for publication. Two new early phase clinical trials, including a cytokine-expressing oncolytic viral therapy trial and mucolytic therapy trial, will likely open for enrollment toward the end of this year.   

Patient Referrals and Additional Information

Patient selection is critical to the viability of CRS-HIPEC, and so too is the timing of surgery. High-volume centers with a history of treating peritoneal metastases are suited to assessing the viability of CRS-HIPEC in these complex cancer cases.

CRS-HIPEC is now widely performed to treat peritoneal metastases from appendix cancer, colorectal cancer, and malignant peritoneal mesothelioma, and this combination has demonstrated survival benefit. 

For patient referrals and for additional information about the peritoneal metastases program and CRS-HIPEC at UPMC, please contact the Division of Gastrointestinal Surgical Oncology at 412-623-5958.

References

1.  Spiliotis J, Halkia E, de Bree E. Treatment of Peritoneal Surface Malignancies With Hyperthermic Intraperitoneal Chemotherapy - Current Perspectives. Curr Oncol. 2016; 23(3): e266-75. doi: 10.3747/co.23.2831. PubMed PMID: 27330364; PMCID: PMC4900847.

2. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D’Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI Plus Bevacizumab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment of Patients With Metastatic Colorectal Cancer: Updated Overall Survival and Molecular Subgroup Analyses of the Open-Label, Phase 3 TRIBE Study. Lancet Oncol. 2015; 16(13): 1306-15. doi: 10.1016/S1470-2045(15)00122-9. PubMed PMID: 26338525.

3. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Muller S, Link H, Niederle N, Rost A, Hoffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-line Treatment for Patients With Metastatic Colorectal Cancer (FIRE-3): A Randomised, Open-Label, Phase 3 Trial. Lancet Oncol. 2014; 15(10): 1065-75. doi: 10.1016/S1470- 2045(14)70330-4. PubMed PMID: 25088940.

4. Franko J, Shi Q, Meyers JP, Maughan TS, Adams RA, Seymour MT, Saltz L, Punt CJA, Koopman M, Tournigand C, Tebbutt NC, Diaz-Rubio E, Souglakos J, Falcone A, Chibaudel B, Heinemann V, Moen J, De Gramont A, Sargent DJ, Grothey A, Analysis, Research in Cancers of the Digestive System G. Prognosis Of Patients With Peritoneal Metastatic Colorectal Cancer Given Systemic Therapy: An Analysis of Individual Patient Data From Prospective Randomised Trials From the Analysis and Research in Cancers of the Digestive System (ARCAD) Database. Lancet Oncol. 2016; 17(12): 1709-19. doi: 10.1016/S1470-2045(16)30500-9. PubMed PMID: 27743922.

5. Quenet F. Colorectal Peritoneal Carcinomatosis: What Is the Future of HIPEC? Eur J Surg Oncol. 2018; 44(12): 1847-8. doi: 10.1016/j.ejso.2018.08.009. PubMed PMID: 30224247.


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