Journal of Surgical Oncology 2014;109:225–226
EDITORIAL Prevention and Early Treatment of Peritoneal Metastases from Colorectal Cancer: Second-Look Laparotomy or Prophylactic HIPEC? DARIO BARATTI,
MD,*
SHIGEKI KUSAMURA, PhD, AND MARCELLO DERACO,
MD
Peritoneal Surface Malignancy Program, Colorectal Cancer Service, Department of Surgery, National Cancer Institute, Milan, Italy
Peritoneal metastases (PM) represent the second most common site of disease progression for colorectal cancer (CRC), after liver metastases [1]. In two recent population‐based studies, synchronous PM occurred in 4.3–7.1% of patients, and metachronous PM in 4.2– 4.5% [1,2]. CRC‐PM are associated with poor prognosis. Median survival was about 6 months in unselected case‐series treated with supportive/palliative therapies or outdated 5‐fluorouracil‐based systemic chemotherapy (s‐CT) [2,3]. More effective drugs, such as oxaliplatin, irinotecan, bevacizumab, and cetuximab in K‐RAS wild‐ type tumors have greatly improved response rates and survival in patients with advanced CRC, but recent reports suggest less survival benefit in PM, as compared with non‐PM metastatic CRC [1,3]. Given the absence of symptoms and current limitations of imaging in detecting small‐volume PM, early diagnosis, and treatment are difficult. Theoretically, there are two windows of opportunity to overcome these limitations. Some authors have advocated second‐look laparotomy after a reasonable time interval from resection of primary tumor for asymptomatic patients at high risk of developing colorectal PM. Other authors have tested adjuvant (or “prophylactic”) intraperitoneal chemotherapy (ip‐CT) at the time of primary surgery. Nevertheless, both options cannot be proposed to all the patients systematically, and primary tumor‐related features predicting metachronous PM are still poorly understood. Researchers from the Institut Gustave Roussy (Villejuif, France) have reviewed the medical literature up to 2011 [4]. Only three sub‐set populations were associated with a substantial risk of recurrent CRC‐PM after curative surgery. Metachronous PM are reported in 54–75% of patients with synchronous PM completely resected during primary surgery, 56–62% of those with synchronous ovarian metastases, and 14– 54% of those with perforated primary tumors. Inconclusive data were found on the predictive role of lymph‐node invasion, tumor location, laparoscopy, occlusive or bleeding presentation, mucinous or signet ring cell histology, positive peritoneal cytology, serosal, and adjacent organ invasion. Based on these findings, the authors have pursued a systematic second‐look approach after curative resection and adjuvant s‐CT. Forty‐ one patients were selected according to the three above‐mentioned criteria. PM were found and treated with complete surgery plus HIPEC in 23 patients (56%) without any sign of recurrence on imaging. The remaining patients (n ¼ 18) underwent complete abdominal exploration plus systematic HIPEC. Five‐year overall survival was 90%, which is a remarkable result in such a high‐risk subset of patients, with a favorable associated morbidity (only one operative death and barely 10% complication rate) [5]. After this preliminary study, a multicentric randomized trial was started in France in 2011 (Prodige 15) to compare standard follow‐up
ß 2014 Wiley Periodicals, Inc.
and second‐look laparotomy with systematic HIPEC. This trial will clarify if the exceptional survival results mentioned above are due to treatment effect or they simply reflect an earlier diagnosis of PM. If the latter hypothesis should be true, a lead time bias might have occurred in this setting. A similar randomized trial has been designed in Italy by peritoneal malignancy management centers within the Lombardy region (EudraCT number 2012‐002739‐27). More recently, the issue of risk factors for metachronous PM has been addressed in a population‐based study of 11.124 patients treated for CRC in Stockholm County (Sweden) during the period 1995–2007 [2]. Independent predictors for metachronous PC were right‐sided colon cancer (P ¼ 0.002), pT4 tumor stage (P < 0.001), pN2 nodal stage with
EDITORIAL Prevention and Early Treatment of Peritoneal Metastases from Colorectal Cancer: Second-Look Laparotomy or Prophylactic HIPEC? DARIO BARATTI,
MD,*
SHIGEKI KUSAMURA, PhD, AND MARCELLO DERACO,
MD
Peritoneal Surface Malignancy Program, Colorectal Cancer Service, Department of Surgery, National Cancer Institute, Milan, Italy
Peritoneal metastases (PM) represent the second most common site of disease progression for colorectal cancer (CRC), after liver metastases [1]. In two recent population‐based studies, synchronous PM occurred in 4.3–7.1% of patients, and metachronous PM in 4.2– 4.5% [1,2]. CRC‐PM are associated with poor prognosis. Median survival was about 6 months in unselected case‐series treated with supportive/palliative therapies or outdated 5‐fluorouracil‐based systemic chemotherapy (s‐CT) [2,3]. More effective drugs, such as oxaliplatin, irinotecan, bevacizumab, and cetuximab in K‐RAS wild‐ type tumors have greatly improved response rates and survival in patients with advanced CRC, but recent reports suggest less survival benefit in PM, as compared with non‐PM metastatic CRC [1,3]. Given the absence of symptoms and current limitations of imaging in detecting small‐volume PM, early diagnosis, and treatment are difficult. Theoretically, there are two windows of opportunity to overcome these limitations. Some authors have advocated second‐look laparotomy after a reasonable time interval from resection of primary tumor for asymptomatic patients at high risk of developing colorectal PM. Other authors have tested adjuvant (or “prophylactic”) intraperitoneal chemotherapy (ip‐CT) at the time of primary surgery. Nevertheless, both options cannot be proposed to all the patients systematically, and primary tumor‐related features predicting metachronous PM are still poorly understood. Researchers from the Institut Gustave Roussy (Villejuif, France) have reviewed the medical literature up to 2011 [4]. Only three sub‐set populations were associated with a substantial risk of recurrent CRC‐PM after curative surgery. Metachronous PM are reported in 54–75% of patients with synchronous PM completely resected during primary surgery, 56–62% of those with synchronous ovarian metastases, and 14– 54% of those with perforated primary tumors. Inconclusive data were found on the predictive role of lymph‐node invasion, tumor location, laparoscopy, occlusive or bleeding presentation, mucinous or signet ring cell histology, positive peritoneal cytology, serosal, and adjacent organ invasion. Based on these findings, the authors have pursued a systematic second‐look approach after curative resection and adjuvant s‐CT. Forty‐ one patients were selected according to the three above‐mentioned criteria. PM were found and treated with complete surgery plus HIPEC in 23 patients (56%) without any sign of recurrence on imaging. The remaining patients (n ¼ 18) underwent complete abdominal exploration plus systematic HIPEC. Five‐year overall survival was 90%, which is a remarkable result in such a high‐risk subset of patients, with a favorable associated morbidity (only one operative death and barely 10% complication rate) [5]. After this preliminary study, a multicentric randomized trial was started in France in 2011 (Prodige 15) to compare standard follow‐up
ß 2014 Wiley Periodicals, Inc.
and second‐look laparotomy with systematic HIPEC. This trial will clarify if the exceptional survival results mentioned above are due to treatment effect or they simply reflect an earlier diagnosis of PM. If the latter hypothesis should be true, a lead time bias might have occurred in this setting. A similar randomized trial has been designed in Italy by peritoneal malignancy management centers within the Lombardy region (EudraCT number 2012‐002739‐27). More recently, the issue of risk factors for metachronous PM has been addressed in a population‐based study of 11.124 patients treated for CRC in Stockholm County (Sweden) during the period 1995–2007 [2]. Independent predictors for metachronous PC were right‐sided colon cancer (P ¼ 0.002), pT4 tumor stage (P < 0.001), pN2 nodal stage with
