Systemic Therapy vs. Cytoreductive Surgery and IP Chemotherapy for Peritoneal Metastases From CRC

Jun 29, 2016


By Paul H. Sugarbaker, MD, FACS, FRCS
MedStar Washington Hospital Center

In the 1990s, before modern systemic chemotherapy for colorectal cancer was available, three groups reported an approximately 25% long-term survival rate when patients with peritoneal metastases were treated using cytoreductive surgery (CRS) and perioperative hyperthermic intraperitoneal chemotherapy (HIPEC).1-3 Of course, there were treatment failures with this approach. Therefore, as modern systemic chemotherapy and molecular treatments became available for patients with colorectal cancer, these treatment modalities were added to CRS/HIPEC in an attempt to cure peritoneal metastases from colorectal cancer.4 Now that response rates to systemic chemotherapy have increased and the median survival of patients with metastatic colorectal cancer has improved to nearly 30 months, questions have arisen regarding the aggressive surgical treatments required by complete CRS with HIPEC. Does modern systemic chemotherapy improve the results of treatment using CRS/ HIPEC? Or are CRS and HIPEC now unnecessary as a result of the more robust responses with modern systemic chemotherapy?

In my opinion, this debate goes beyond this assigned topic of peritoneal metastases from colorectal cancer. It seeks to answer the question regarding the validity of a third treatment modality for prevention and treatment of disseminated gastrointestinal cancer: Are the management strategies limited to surgery and systemic chemotherapy or is there a third important modality— regional chemotherapy? In this debate, the regional chemotherapy being considered is perioperative chemotherapy with HIPEC. In other clinical settings, it is hepatic artery infusions.5


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The Argument for CRS/HIPEC in Metastatic Colorectal Cancer

By David P. Ryan, MD
Massachusetts General Hospital

Over the last 15 years, the management of colorectal cancer has changed profoundly. With the addition of FOLFOX (fluorouracil/leucovorin/oxaliplatin), FOLFIRI (leucovorin/fluorouracil/ irinotecan), anti-VEGF therapy, antiepidermal growth factor antibodies for patients with wild-type KRAS tumors, and now TAS-102, more than 20% of patients will live on and off chemotherapy for 5 or more years.1 Yet, the treatment of patients with isolated peritoneal carcinomatosis remains controversial as some clinicians continue to pursue CRS/HIPEC.

Peritoneal carcinomatosis is one of the most dreaded presentations of metastatic colorectal cancer due to the high likelihood of profound symptom burden that is very difficult to control. Most patients, at a minimum, will experience abdominal distention and bloating. But, at its worst, peritoneal carcinomatosis causes multifocal gastrointestinal (GI) obstructions leading to complete shutdown of the GI tract and is often associated with profound pain and nausea that can be very difficult to control with medications. It is not unusual to hear our medical oncology colleagues at Massachusetts General Hospital who are not accustomed to dealing with patients with peritoneal carcinomatosis remark after an inpatient rotation on how difficult it was to manage patients on the GI Oncology service.

Thankfully, isolated peritoneal carcinomatosis is an uncommon event, occurring in less than 5% of patients with metastatic colorectal cancer.2 However, peritoneal carcinomatosis as a component of widespread metastatic disease occurs in 20% of patients with stage IV colorectal cancer. There is broad agreement that the use of CRS/HIPEC should be restricted to those patients with isolated peritoneal carcinomatosis due to the controversy surrounding it, as well as the morbidity and mortality associated with it.3 However, there is broad disagreement among clinicians about the appropriate use of CRS/ HIPEC in those patients with isolated peritoneal carcinomatosis. The procedure was developed in the 1970s, at a time when the only effective chemotherapy for metastatic colorectal cancer was 5-fluorouracil (5-FU). Multiple studies documented that peritoneal carcinomatosis was associated with a shorter overall survival on the order of 6 months. CRS was introduced with the goal of removing all gross disease and thus prolonging survival.4 CRS involves the attempt to surgically resect all visible tumors within the abdomen and pelvis, as well as visceral organs if they are involved with disease. Due to the initially poor survival associated with surgery, intraperitoneal chemotherapy was soon adopted as a means of further cytoreducing the amount of tumor left behind at the time of surgery.

The administration of intraperitoneal chemotherapy allows for higher concentration of cytotoxic chemotherapy in the peritoneal cavity when compared with intravenous chemotherapy.5 The early and then subsequent success of intraperitoneal chemotherapy in patients with ovarian cancer supported this concept and provided rationale for continued trials in patients with colorectal cancer. The initial use of intraperitoneal chemotherapy was via early postoperative intraperitoneal chemotherapy (EPIC).6 Although initial reports were promising, there were theoretical concerns regarding administration of EPIC, since the ability of chemotherapy to perfuse all peritoneal surfaces was often limited due to the onset of fibrosis and adhesions.7

In an attempt to improve upon the delivery of intraperitoneal chemotherapy and avoid the complications of EPIC, hyperthermia was introduced as a means of enhancing the cytotoxicity of chemotherapy; the use of hyperthermia was based on early studies.8-10 A recent study using a rat model did not find any benefit to heating intraperitoneal chemotherapy.11 Nevertheless, the combination of CRS and HIPEC became adopted at several centers both in the United States and Europe. In retrospective reviews, the range of postoperative mortality has been reported from 0% to as high as 12%, but currently, in most high-volume centers, has been reported to be in the 1% to 2% range.12 Grade 3 and 4 toxicities have been reported at 23% to 55%. Hematologic toxicity, including hemorrhage, fistulae, peritonitis, cerebral stroke, and renal insufficiency, were the most common complications, but other severe complications, including sepsis and pulmonary embolus, can also occur.12-14

There are two randomized studies of HIPEC versus systemic chemotherapy. In the first, Verwall and colleagues randomly assigned 105 patients (age 71 or younger) with metastatic colorectal cancer and isolated peritoneal carcinomatosis to receive CRS/ HIPEC (using mitomycin C) or systemic therapy (using 5-FU/leucovorin) alone. The patients treated with CRS/HIPEC had a statistically significant improved median survival of 22.4 months versus 12.6 months (p = 0.032).15 The study had several flaws. First, 18 of the 105 patients (17%) actually had appendiceal tumors, which can have variable histologies and can, at times, be more indolent than typical colorectal adenocarcinomas. Second, subsequent chemotherapy with oxaliplatin or irinotecan, which were just coming into use, was not recorded. Third, patients were not stratified by the most important prognostic factor: the extent of peritoneal disease and the ability to render the patient free of all disease surgically. Of note, in the surgical group, 8% of patients died from postoperative complications. In a follow-up publication by Verwall et al., with a median follow-up of 8 years, four out of 51 patients were alive in the systemic group and five out of 54 in the CRS/HIPEC group.13

Elias and colleagues in France attempted the second randomized study in this patient population. Unfortunately, it was terminated early before reaching the target accrual of 90 patients due to recruitment difficulties. In this study, 35 patients were randomly assigned to CRS plus EPIC or CRS alone. EPIC did not appear to improve outcomes, but patients with a complete cytoreduction had a 60% 2-year survival rate.16

So, what are we to make of CRS, HIPEC, or any intraperitoneal chemotherapy for patients with isolated peritoneal carcinomatosis from colorectal cancer? The main issue is that we are actually dealing with two separate questions. Since CRS and HIPEC are almost always given together, it is difficult to separate the independent effects of each one. It is very possible that CRS is curing a subset of patients with isolated peritoneal carcinomatosis in much the same way that patients with isolated liver metastases can be cured with surgical resection of their disease. The 5-year survival rate for patients with isolated peritoneal carcinomatosis who can be rendered free of all disease at the time of surgery is approximately 30% to 40% in multiple surgical experiences.12,14 Interestingly, a meta-analysis of all CRS/HIPEC cases performed from 1995 to 2009 demonstrated a median survival of 33 months in 722 patients with complete cytoreduction and a 5-year survival rate of 43% (range: 20% to 51%).17 In contrast, patients with incomplete cytoreduction had a much poorer outcome, with a median overall survival of only 8 months and a 5-year survival rate of 0%. These findings strongly suggest that surgical removal of all gross disease can achieve cure in a substantial subset of patients.

Thankfully, we may soon have an answer to the question of whether HIPEC is a required component of CRS. A French multicenter randomized controlled trial, Prodige 7, assigned 280 patients with peritoneal carcinomatosis from colorectal cancer with complete cytoreduction into two arms: HIPEC with oxaliplatin over 30 minutes at a minimum of 42°C and preceding intravenous 5-FU/leucovorin bolus or no HIPEC. The primary endpoint is 3- and 5-year overall survival. The study completed accrual and we are awaiting results.

CRS/HIPEC is a controversial treatment for patients with isolated peritoneal carcinomatosis from colorectal cancer. Long-term survival and cures have been consistently documented in patients who achieve a complete cytoreduction. It is reasonable to consider CRS in patients who can be rendered free of all disease. Whether HIPEC is beneficial at the time of CRS is unknown.


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CRS/HIPEC Should Be Given Alongside Systemic Therapy for Patients With Isolated Peritoneal Disease

By Edward A. Levine, MD
Wake Forest University

Peritoneal metastases complicate the initial diagnosis of colorectal cancer in approximately 10% of cases. The peritoneum is the second most common site of metastases (after the liver), found in nearly 50% of recurrent cases, and is the only site of recurrence in nearly one-third of colorectal carcinoma cases.1-4 Untreated, patients with peritoneal metastases have an anticipated survival of well under 1 year. Historically, such patients have been treated exclusively with systemic chemotherapy, in a palliative fashion, and approached with therapeutic nihilism. Unfortunately, the efficacy of systemic chemotherapy for peritoneal metastasis lags behind that found with metastatic tumors at other sites.5 The 5-year survival rate for patients with peritoneal metastases with “modern” systemic chemotherapy is in the 5% range, with median survival of approximately 20 months. This clearly represents a significant step forward from before the turn of the century.

While aggressive resection of isolated hepatic metastases from colorectal carcinoma has become widely accepted practice, the approach to patients with isolated peritoneal metastasis has been more controversial. For patients with isolated peritoneal metastases, which is a regional problem, treatment with an aggressive regional approach such as CRS/HIPEC has been a promising modality.6 Patients with peritoneal metastases from colon carcinoma undergoing CRS/HIPEC have 5-year survival rates in the 30% range, with a median survival of 32 months after complete resection.1,6 It is important to bear in mind that most studies of CRS/ HIPEC were performed on patients who had previously been treated with systemic chemotherapy; thus, median survival after surgery compares even more favorably with systemic chemotherapy. Further, most of the patients who are long-term survivors after CRS/ HIPEC are disease-free at 5 years.6-9

Similar to surgical therapy for metastatic disease to the liver or lung, complete cytoreduction is required for a significant survival benefit. Obtaining complete cytoreduction in the peritoneum can be a substantial surgical challenge, associated with a long learning curve for the surgical teams. However, there are several centers with considerable experience that have surmounted that obstacle. This has resulted in a significant minority of patients who have become long-term survivors with a good quality of life, whereas with previous therapies there were essentially no such survivors. Despite survival benefits in appropriately selected patients, the procedure can be associated with significant morbidity, particularly for patients with higher volumes of peritoneal metastases who are treated at inexperienced centers.

There has been but a single prospective randomized trial comparing CRS/ HIPEC and systemic chemotherapy to systemic chemotherapy alone. Reported initially in 2003, the findings from this trial of 105 randomly assigned patients demonstrated a significantly improved median overall survival benefit with CRS/HIPEC of 22.3 months, versus 12.6 months in the systemic chemotherapy–alone group, after a median follow-up of 21.6 months. This benefit was found despite the fact that perioperative mortality was two to three times greater than rates currently reported at leading centers (8%). Overall survival was significantly associated with the completeness of resection status (p < 0.0001) and the initial volume of disease (PCI) score.7 More recently, the authors published findings from a longer-term follow-up (median, 8 years) and showed that 5-year disease-free survival was 45% for patients with optimal cytoreduction and HIPEC, compared to less than 10% for those with incomplete cytoreduction or in the systemic therapy–alone arm.8 Although this study showed impressive and durable results, the findings were tempered by low participation rate, high mortality, and a now obsolete 5-FU/leucovorin regimen.7,8 Two other colorectal randomized controlled trials were opened in order to compare CRS followed by EPIC (Europe) or HIPEC (United States) versus cytoreduction with systemic therapy. Unfortunately, both trials were closed due to failure to accrue patients. The utility of intraperitoneal chemotherapy after CRS is currently being tested in the Prodige 7 trial in France, which has completed accrual of 280 patients.9

Although there are some who have suggested that CRS plus intraperitoneal chemotherapy is an alternative to systemic chemotherapy, I would suggest that peritoneal metastasis from colon cancer is best approached with systemic chemotherapy and not in lieu of it. Approaching all patients with peritoneal metastasis with therapeutic nihilism is clearly no longer appropriate. As with hepatic metastases, complete resection provides optimal results. Further, close collaboration between medical oncologists and surgical oncologists experienced in the evaluation of, and operative therapy for, peritoneal disease is important to optimize the survival of patients with metastases from colorectal carcinoma. Based upon currently available data, and unless the results of the Prodige 7 trial show otherwise, surgery with intraperitoneal chemotherapy should be considered for patients with isolated peritoneal disease who are otherwise fit.10 


The views and opinions expressed in Current Controversies in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.


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