LETTER TO THE EDITOR Considerations on the Selection Process for Cytoreductive Surgery and Hyperthermic IntraPeritoneal Chemotherapy for Colorectal Carcinomatosis To the Editor: e read the article by Cashin et al1 with great interest. As a tertiary referral center for the treatment of peritoneal diseases, we are constantly faced with the puzzling decision of whether to proceed with cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy). We strongly agree with the authors that, in the field of colorectal carcinomatosis, defining patient selection policy is the key to the appropriate cure. In the current context of shortage of resources, along with growing waiting lists in referral centers, we sought to obtain 2 main results—avoid “blank” laparotomies (ie, avoiding admittance of patients to the operating theater with a tumor load that precludes optimal cytoreduction) and selection of patients with a good prognosis (ie, patients who may really benefit from HIPEC with respect to modern chemotherapy associations). Cashin et al propose a scoring system—the Corep score—mainly based on preoperative hematologic factors and tumor marker determinations, with the aim of reaching both targets. We believe that these 2 clinical problems should be approached by separated strategies. Regarding the first issue—avoidance of “blank” laparotomies—we agree with the authors that imaging modalities are useful to exclude patients with overt contraindications to treatment but are unreliable for selection of patients for whom an optimal cytoreduction can be predicted. In our current clinical practice, we feel that explorative laparoscopy is the most accurate instrument to evaluate the feasibility of cytoreduction. As the main determinant of complete cytoreduction is the involvement of the small bowel and its mesentery, we perform an explorative laparoscopy in all patients with inconclusive imaging. Following this strategy, we have reduced our useless laparotomy rate to less than 5%.
W
Disclosure: The authors declare no conflicts of interest. C 2014 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/14/26202-e0048 DOI: 10.1097/SLA.0000000000001021
e48 | www.annalsofsurgery.com
The second issue—the selection of patients with a good prognosis—is more complicated. Given the lack of molecular biomarkers, we must rely on traditional prognostic factors. In most reported multivariate analyses, primary tumor histology, tumor load [Peritoneal Cancer Index (PCI) score] and completeness of cytoreduction (CC score) are the most important prognosticators of survival.2–4 The response to neoadjuvant chemotherapy, albeit debated, is another factor that is often taken into account.2 After the publication of the multicenter study by Glehen et al,2 coauthored by us, we changed our selection policy with the aim of primarily treating patients with less advanced or less aggressive disease, on the basis of primary tumor histology (for metachronous carcinomatosis), disease extension, and response to chemotherapy. In particular, we exclude patients with progressing disease during chemotherapy, or those presenting with a poor primary prognostic factor (ie, T4, N2, or G3), together with high tumor load (estimated PCI >16), from the treatment plan. Moreover, we do not proceed to HIPEC unless an optimal cytoreduction is obtained (ie, CC score = 0–1). Patients with suboptimal cytoreduction (CC score = 2–3) have a median expected survival of around 8 months.2 We believe that in this subset, explorative laparotomies should be minimized and HIPEC should be avoided. Following this policy, in our more recent experience (32 patients treated for colorectal carcinomatosis among 183 HIPEC cases performed since 2004), we have registered a median survival as high as 50 months, with a 5-year survival of around 40%. We currently do not consider hematologic status, as it may be influenced by many variables besides tumor aggressiveness, or tumor marker status, as we believe that preoperative marker level is only an indirect measure of tumor load whereas marker variation is only an indirect estimate of tumor response to preoperative therapy. Instead, we consider the more reliable diagnostic laparoscopy for tumor load estimation and preoperative imaging to estimate response to chemotherapy. With respect to this point, we have noted that the authors do register PCI and CC scores, as reported in the “Methods” section, but no information is given about these variables in the “Results” section. We would like to ask them if, in their experience, a correlation exists between tumor marker status (or Corep score) and intraoperative tumor load as expressed by PCI score. Moreover, we would like to know if the authors are also including patients in their series with a suboptimal cytoreduction (ie, CC score >1). If this is the case, do they exclude that the inclusion of these patients may compromise the reliability of their score?
We congratulate the authors for having raised such a crucial point toward the definitive acceptance of surgical treatment for patients with colorectal carcinomatosis. Marco Vaira, MD Manuela Robella, MD Paolo Massucco, MD Michele De Simone, MD Candiolo Cancer Institute – FPO, IRCCS Unit of Surgical Oncology Torino, Italy [email protected]
REFERENCES 1. Cashin PH, Graf W, Nygren P, et al. Patient selection for cytoreductive surgery in colorectal peritoneal carcinomatosis using serum tumor markers: an observational cohort study. Ann Surg. 2012; 256:1078–1083. 2. Glehen O, Sugarbaker PH, Elias D, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer. A multi-institutional study of 506 patients. J Clin Oncol. 2004;22:3284–3292. 3. Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010;28:63–68. 4. Cavaliere F, De Simone M, Virz`ı S, et al. Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O. Eur J Surg Oncol. 2011;37: 148–154.
Reply:
W
e are very thankful for the commentary by Vaira et al on our study.1 We agree that the issue of patient selection for treatment of colorectal cancer (CRC) peritoneal metastases is of great importance. The first issue raised was that of resectability. The suggestion to go to laparoscopy is a valid one and many institutions use this modality in patients with inconclusive computed tomographic scans. One purpose of the colorectal peritoneal metastases (COREP) score was to perhaps be able to avoid this extra surgical procedure.1 This is particularly important as surgical resources are limited, and if previous surgery has been performed it might be difficult to view all quadrants due to adhesions. More research is needed to determine if the COREP score can replace laparoscopy, but some promising results have been shown (see the points described later). The second issue was related to selecting patients who may truly benefit from the surgery. As Vaira and colleagues point out, Disclosure: The authors declare no conflicts of interest. 10.1097/SLA.0000000000001168
Annals of Surgery r Volume 262, Number 2, August 2015
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 2, August 2015
this is the important part and the most difficult. The rationale behind the COREP score is to identify patients who may not benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Such score should ideally be simple, objective and based on factors easily retrieved preoperatively. A follow-up study has been published pooling part of the developing set with the validation set to answer several of the questions raised by Vaira and colleagues.2 1. COREP correlates with PCI and, more importantly, seems to have greater prognostic ability than peritoneal cancer index (PCI) alone in a multiple Cox regression model.3 2. The completeness of cytoreduction (CC) score is referred to in the follow-up study, where an R1 resection was the same as CC 0 and R2 resection the same as CC 1-3. A COREP score of 6 or more predicts an inadequate CC 1-3 result very well (81% overall accuracy—as defined by the area under the receiver operating curve).3 3. The aspect of open-and-close laparotomies is addressed in both studies.1,3 In the primary study, the open-and-close rate was 15%.1 Had patients with COREP score 6 or more been excluded, the rate would have dropped to 7%. In the follow-up study, a COREP score of 6 or more predicts an open-and-close laparotomy with 88% overall accuracy. 4. Both studies include all patients with openand-close laparotomies and as well as all CC score results. The follow-up study did exclude a few patients due to inadequate data needed to apply the peritoneal surface disease severity score.3 Furthermore, the first study also gives the number of patients denied surgery after referral and the cause of denial.1
Letter to the Editor
5. Finally, the hemoglobin level was used mainly as a measure of general well-being in the patient (which of course is a crude factor for this) and the white cell count was used as a measure of possible inflammatory response. In the future, a C-reactive protein level might be more relevant for this.
of patients with peritoneal metastases from CRC. One such relevant subset is patients with high-volume peritoneal disease, that is, to randomize patients with resectable colorectal peritoneal disease and a PCI more than 20 to CRS/HIPEC or to systemic chemotherapy.
When many selection criteria for treatment are used, one may wonder if it is not just cherry-picking being done. If young patients with optimal performance status and good response to preoperative chemotherapy, a low PCI of 16 or less, and no prior surgery are selected, results will be excellent but many patients who might benefit will be denied surgery. Reports of the referral process are lacking, the current study notwithstanding.1 This is needed as this would help us to know how many are being denied CRS and HIPEC and for what reason. The COREP score can be used in this setting to provide some measure of objectivity in this process. The purpose of this treatment is not to prove good results in a super select minority. This runs the risk of leaving many patients out who could have benefited from the treatment. For example, a recent study from our institution has shown that patients with PCI more than 20 may still have potential for curative results.2 The main goal is a complete cytoreduction. This is where excellence in surgery cannot be replaced by narrow patient selection. Much more research needs to be performed in this area to develop some kind of objectivity and standardization to the selection process. This will also make the interpretation and comparison of outcome data easier. We hope to see more discussion about patient selection and further research in this area. However, multicenter randomized prospective clinical trials might be the only way to adequately define the role of CRS and HIPEC in various subsets
Peter Cashin, MD Wilhelm Graf, MD, PhD Department of Surgical Sciences Section of Surgery Uppsala University Uppsala, Sweden
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Peter Nygren, MD, PhD Department of Radiology, Oncology and Radiation Sciences Section of Oncology Uppsala University Uppsala, Sweden Haile Mahteme, MD, PhD Department of Surgical Sciences Section of Surgery Uppsala University Uppsala, Sweden [email protected]
REFERENCES 1. Cashin PH, Graf W, Nygren P, et al. Patient selection for cytoreductive surgery in colorectal peritoneal carcinomatosis using serum tumor markers: an observational cohort study. Ann Surg. 2012; 256:1078–1083. 2. Cashin PH, Dranichnikov F, Mahteme H. Cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy treatment of colorectal peritoneal metastases: cohort analysis of high volume disease and cure rate. J Surg Oncol. 2014;110:203–206. 3. Cashin PH, Graf W, Nygren P, et al. Comparison of prognostic scores for patients with colorectal cancer peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2013;20:4183– 4189.
www.annalsofsurgery.com | e49
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
W
Disclosure: The authors declare no conflicts of interest. C 2014 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/14/26202-e0048 DOI: 10.1097/SLA.0000000000001021
e48 | www.annalsofsurgery.com
The second issue—the selection of patients with a good prognosis—is more complicated. Given the lack of molecular biomarkers, we must rely on traditional prognostic factors. In most reported multivariate analyses, primary tumor histology, tumor load [Peritoneal Cancer Index (PCI) score] and completeness of cytoreduction (CC score) are the most important prognosticators of survival.2–4 The response to neoadjuvant chemotherapy, albeit debated, is another factor that is often taken into account.2 After the publication of the multicenter study by Glehen et al,2 coauthored by us, we changed our selection policy with the aim of primarily treating patients with less advanced or less aggressive disease, on the basis of primary tumor histology (for metachronous carcinomatosis), disease extension, and response to chemotherapy. In particular, we exclude patients with progressing disease during chemotherapy, or those presenting with a poor primary prognostic factor (ie, T4, N2, or G3), together with high tumor load (estimated PCI >16), from the treatment plan. Moreover, we do not proceed to HIPEC unless an optimal cytoreduction is obtained (ie, CC score = 0–1). Patients with suboptimal cytoreduction (CC score = 2–3) have a median expected survival of around 8 months.2 We believe that in this subset, explorative laparotomies should be minimized and HIPEC should be avoided. Following this policy, in our more recent experience (32 patients treated for colorectal carcinomatosis among 183 HIPEC cases performed since 2004), we have registered a median survival as high as 50 months, with a 5-year survival of around 40%. We currently do not consider hematologic status, as it may be influenced by many variables besides tumor aggressiveness, or tumor marker status, as we believe that preoperative marker level is only an indirect measure of tumor load whereas marker variation is only an indirect estimate of tumor response to preoperative therapy. Instead, we consider the more reliable diagnostic laparoscopy for tumor load estimation and preoperative imaging to estimate response to chemotherapy. With respect to this point, we have noted that the authors do register PCI and CC scores, as reported in the “Methods” section, but no information is given about these variables in the “Results” section. We would like to ask them if, in their experience, a correlation exists between tumor marker status (or Corep score) and intraoperative tumor load as expressed by PCI score. Moreover, we would like to know if the authors are also including patients in their series with a suboptimal cytoreduction (ie, CC score >1). If this is the case, do they exclude that the inclusion of these patients may compromise the reliability of their score?
We congratulate the authors for having raised such a crucial point toward the definitive acceptance of surgical treatment for patients with colorectal carcinomatosis. Marco Vaira, MD Manuela Robella, MD Paolo Massucco, MD Michele De Simone, MD Candiolo Cancer Institute – FPO, IRCCS Unit of Surgical Oncology Torino, Italy [email protected]
REFERENCES 1. Cashin PH, Graf W, Nygren P, et al. Patient selection for cytoreductive surgery in colorectal peritoneal carcinomatosis using serum tumor markers: an observational cohort study. Ann Surg. 2012; 256:1078–1083. 2. Glehen O, Sugarbaker PH, Elias D, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer. A multi-institutional study of 506 patients. J Clin Oncol. 2004;22:3284–3292. 3. Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010;28:63–68. 4. Cavaliere F, De Simone M, Virz`ı S, et al. Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O. Eur J Surg Oncol. 2011;37: 148–154.
Reply:
W
e are very thankful for the commentary by Vaira et al on our study.1 We agree that the issue of patient selection for treatment of colorectal cancer (CRC) peritoneal metastases is of great importance. The first issue raised was that of resectability. The suggestion to go to laparoscopy is a valid one and many institutions use this modality in patients with inconclusive computed tomographic scans. One purpose of the colorectal peritoneal metastases (COREP) score was to perhaps be able to avoid this extra surgical procedure.1 This is particularly important as surgical resources are limited, and if previous surgery has been performed it might be difficult to view all quadrants due to adhesions. More research is needed to determine if the COREP score can replace laparoscopy, but some promising results have been shown (see the points described later). The second issue was related to selecting patients who may truly benefit from the surgery. As Vaira and colleagues point out, Disclosure: The authors declare no conflicts of interest. 10.1097/SLA.0000000000001168
Annals of Surgery r Volume 262, Number 2, August 2015
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 2, August 2015
this is the important part and the most difficult. The rationale behind the COREP score is to identify patients who may not benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Such score should ideally be simple, objective and based on factors easily retrieved preoperatively. A follow-up study has been published pooling part of the developing set with the validation set to answer several of the questions raised by Vaira and colleagues.2 1. COREP correlates with PCI and, more importantly, seems to have greater prognostic ability than peritoneal cancer index (PCI) alone in a multiple Cox regression model.3 2. The completeness of cytoreduction (CC) score is referred to in the follow-up study, where an R1 resection was the same as CC 0 and R2 resection the same as CC 1-3. A COREP score of 6 or more predicts an inadequate CC 1-3 result very well (81% overall accuracy—as defined by the area under the receiver operating curve).3 3. The aspect of open-and-close laparotomies is addressed in both studies.1,3 In the primary study, the open-and-close rate was 15%.1 Had patients with COREP score 6 or more been excluded, the rate would have dropped to 7%. In the follow-up study, a COREP score of 6 or more predicts an open-and-close laparotomy with 88% overall accuracy. 4. Both studies include all patients with openand-close laparotomies and as well as all CC score results. The follow-up study did exclude a few patients due to inadequate data needed to apply the peritoneal surface disease severity score.3 Furthermore, the first study also gives the number of patients denied surgery after referral and the cause of denial.1
Letter to the Editor
5. Finally, the hemoglobin level was used mainly as a measure of general well-being in the patient (which of course is a crude factor for this) and the white cell count was used as a measure of possible inflammatory response. In the future, a C-reactive protein level might be more relevant for this.
of patients with peritoneal metastases from CRC. One such relevant subset is patients with high-volume peritoneal disease, that is, to randomize patients with resectable colorectal peritoneal disease and a PCI more than 20 to CRS/HIPEC or to systemic chemotherapy.
When many selection criteria for treatment are used, one may wonder if it is not just cherry-picking being done. If young patients with optimal performance status and good response to preoperative chemotherapy, a low PCI of 16 or less, and no prior surgery are selected, results will be excellent but many patients who might benefit will be denied surgery. Reports of the referral process are lacking, the current study notwithstanding.1 This is needed as this would help us to know how many are being denied CRS and HIPEC and for what reason. The COREP score can be used in this setting to provide some measure of objectivity in this process. The purpose of this treatment is not to prove good results in a super select minority. This runs the risk of leaving many patients out who could have benefited from the treatment. For example, a recent study from our institution has shown that patients with PCI more than 20 may still have potential for curative results.2 The main goal is a complete cytoreduction. This is where excellence in surgery cannot be replaced by narrow patient selection. Much more research needs to be performed in this area to develop some kind of objectivity and standardization to the selection process. This will also make the interpretation and comparison of outcome data easier. We hope to see more discussion about patient selection and further research in this area. However, multicenter randomized prospective clinical trials might be the only way to adequately define the role of CRS and HIPEC in various subsets
Peter Cashin, MD Wilhelm Graf, MD, PhD Department of Surgical Sciences Section of Surgery Uppsala University Uppsala, Sweden
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Peter Nygren, MD, PhD Department of Radiology, Oncology and Radiation Sciences Section of Oncology Uppsala University Uppsala, Sweden Haile Mahteme, MD, PhD Department of Surgical Sciences Section of Surgery Uppsala University Uppsala, Sweden [email protected]
REFERENCES 1. Cashin PH, Graf W, Nygren P, et al. Patient selection for cytoreductive surgery in colorectal peritoneal carcinomatosis using serum tumor markers: an observational cohort study. Ann Surg. 2012; 256:1078–1083. 2. Cashin PH, Dranichnikov F, Mahteme H. Cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy treatment of colorectal peritoneal metastases: cohort analysis of high volume disease and cure rate. J Surg Oncol. 2014;110:203–206. 3. Cashin PH, Graf W, Nygren P, et al. Comparison of prognostic scores for patients with colorectal cancer peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2013;20:4183– 4189.
www.annalsofsurgery.com | e49
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
