doi:10.1111/codi.12924
Original article
Elevated tumour markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumour removal F. Di Fabio, W. Aston, F. Mohamed, K. Chandrakumaran, T. Cecil and B. Moran Peritoneal Malignancy Institute and Colorectal Surgery, Basingstoke and North Hampshire Hospitals, Basingstoke, UK Received 15 November 2014; accepted 31 December 2014;
Abstract Aim Elevation of the preoperative tumour markers in pseudomyxoma peritonei (PMP) is common and is a risk factor for recurrence. There has, however, been no documentation of the effect of complete tumour removal on tumour markers levels after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of the study was to compare the tumour markers 7 days after surgery in patients with elevated preoperative levels. Method This was an observational prospective study of patients with PMP of appendiceal origin treated in one of the UK National Referral Centres for this condition. Thirty patients [median age = 61 (range: 31–74) years; six men] with an elevated preoperative level of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and/or carbohydrate antigen 19-9 (CA19-9) underwent repeated estimation, 7 days after CRS and HIPEC for PMP. Results The median preoperative CEA level of 12 lg/l fell to 0.75 lg/l postoperatively (P < 0.0001), CA-125 fell from 45 to 31 kU/l (P = 0.183) and CA19-9 fell from 134 to 37 kU/l (P = 0.003). The CEA was raised
Introduction Pseudomyxoma peritonei (PMP) is an uncommon disease characterized by mucinous ascites usually originating from a perforated mucinous tumour of the appendix. In the Netherlands it has an estimated annual incidence of two to three per million population[1]. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are the current optimal Correspondence to: Brendan Moran and Francesco Di Fabio, Peritoneal Malignancy Institute and Colorectal Surgery, Basingstoke and North Hampshire Hospitals, Aldermaston Road, Basingstoke, Hampshire RG24 9NA, UK. E-mail: [email protected]; [email protected]
698
in 22 (73%) of 30 patients preoperatively and in two (7%) of 30 patients 7 days after surgery (P < 0.0001). The corresponding data for CA-125 were 18 (60%) and 13 (43%) (P = 0.196) and for CA19-9 they were 24 (80%) and 16 (53%) (P = 0.028). Conclusion This is the first documentation of a reduction or normalization of CEA 7 days after CRS, but not for CA19-9 or CA-125. This may indicate completeness of surgical resection and could aid selection for adjuvant therapy and predict prognosis. Long-term follow-up is, however, necessary to determine the significance of this observation. Keywords Tumour markers, appendix tumour, pseudomyxoma peritonei, carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 19-9 What does this paper add to the literature? This is the first study showing a reduction or normalization of CEA after cytoreductive surgery for pseudomyxoma of appendiceal origin. This may indicate surgical radicality, aid selection for adjuvant therapy and help determine frequency of follow up, but validation by long-term follow-up is required.
treatments for PMP [2,3]. When complete cytoreduction is achieved, 5-year disease-free survival rates above 80% have been reported [4]. Owing to the rarity of PMP there is uncertainty concerning the prediction of prognosis, the role, if any, for postoperative systemic chemotherapy and the frequency of follow up. Currently, histological categorization into low- or high-grade appendiceal tumours broadly differentiates patients with good or poor prognosis [5], but this does not explain the biological behaviour, with some low-grade tumours recurring early, and sometimes very aggressively. In addition to histological grading, tumour-marker measurements have been shown to pre-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 698–703
F. Di Fabio et al.
dict prognosis [4,6–10]. When tumour markers, particularly carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and carbohydrate antigen 19-9 (CA19-9), are elevated, there is an increased risk of recurrence and a reduction in survival [4,6–10]. A recent report of 519 patients with PMP of appendiceal origin, who underwent complete tumour removal, demonstrated that disease-free survival was inversely proportional to the number of tumour markers elevated before surgery [4]. Disease-free and overall survival rates in patients with normal levels of tumour markers were significantly different from those in patients with abnormality of one, two or all three of the markers CEA, CA-125 and CA19-9 [4]. Patients with high-grade tumours are more likely to have elevated tumour markers, and we and others have demonstrated that patients with elevated markers may have a pathologically lowgrade tumour [11]. It is likely that secretion of excessive tumour markers detected by elevated serum levels may indicate more aggressive biology than indicated by the histopathology. This is important when considering postoperative chemotherapy and both the frequency and intensity of follow up. To our knowledge, there has been no documentation on the effect of complete tumour removal on the level of tumour markers in the early postoperative period, when these tumour markers had been elevated preoperatively. The present study compared tumour marker concentrations before, and 7 days after, CRS and HIPEC, in a group of patients with raised preoperative levels of these markers.
Method This was a prospective study from a high-volume UK national referral centre for PMP of appendiceal origin. It was deemed as an exercise in service development by the Research and Development Committee and therefore did not require formal ethical approval. The aim was to assess the serum tumour marker levels of patients undergoing complete CRS and HIPEC, before, and 7 days after, surgery. A secondary endpoint was to compare changes, after surgery, in the levels of tumour markers in low-grade and high-grade tumours. carcinoembryonic antigen (lg/l), CA-125 (kU/l; kilo unit per litre) and CA19-9 (kU/l) levels were measured 2 days before surgery and 7 days postoperatively. The normal range for CEA was < 0.5– 5 lg/l, for CA-125 was 0–35 kU/l and for CA19-9 was 0–33 kU/l. Patients demonstrating an incomplete CRS, normal tumour markers preoperatively and/or failure to comply with the study protocol were excluded from the study.
Tumour markers in pseudomyxoma peritonei
All patients admitted for CRS and HIPEC between 29 October 2013 and 16 April 2014 were eligible. Fifty-three patients were treated, of whom 46 underwent complete CRS and seven had maximal tumour debulking. Of the 46 patients, preoperative measurement of CEA, CA-125 and CA19-9 demonstrated that 10 (22%) had markers in the normal ranges and 36 (78%) had at least one elevated marker. Six patients were excluded because they were not compliant with the protocol and failed to have the tumour markers checked 7 days after surgery. This left 30 patients [median age = 61 (range: 31–74) years; 24 women and six men]. Of these 30 patients, one marker was elevated in six (CEA in one, CA-125 in one and CA19-9 in four), two markers were elevated in 14 (CEA and CA125 in four, CEA and CA 19-9 in seven, and CA-125 and CA19-9 in three) and all three markers were elevated in 10. The preoperative assessment, surgical management and follow-up protocol for patients with PMP have been described previously [4]. The resected surgical specimen was classified as either low-grade mucinous carcinoma peritonei or high-grade mucinous carcinoma peritonei on pathological evaluation by an experienced peritoneal malignancy pathologist [5]. Statistical analysis
Statistical analysis was performed using the statistical software STATA for Windows (Stata Corporation, College Station, TX, USA). Median values and interquartile range were given for continuous variables as their values distribution was skewed. The nonparametric Wilcoxon rank-sum test was used to compare continuous variables. Fisher’s exact test was applied for the analysis of categorical variables. The level of statistical significance was set at P < 0.05.
Results Nineteen (63%) of the 30 patients had a low-grade tumour. The median preoperative CEA level decreased from 12 to 0.75 lg/l postoperatively (P < 0.0001), the CA-125 from 45 to 31 kU/l (P = 0.183) and the CA19-9 from 134 to 37 kU/L (P = 0.003). An elevated CEA was noted in 22 (73%) patients preoperatively and in two (7%) at 7 days postoperatively (P < 0.0001). Carbohydrate antigen 125 was elevated in 18 (60%) patients preoperatively and in 13 (43%) patients postoperatively (P = 0.196), and CA19-9 was elevated in 24 (80%) of patients preoperatively and in 16 (53%) patients postoperatively (P = 0.028; Table 1). The trends of tumour markers in low-grade and high-grade tumours are shown in Table 2. There
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 698–703
699
F. Di Fabio et al.
Tumour markers in pseudomyxoma peritonei
Table 1 Impact of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on elevated tumour markers. Variable CEA Elevated (>5 lg/l) Median value (lg/l) CA-125 Elevated (> 35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l)
Postoperative (7 days)
P
22 (73) 12 (4.8–22)
2 (7) 0.75 (0–1.3)
35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l) High-grade tumours (n = 11) CEA Elevated (> 5 lg/l) Median value (lg/l) CA-125 Elevated (> 35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l)
Postoperative (7 days)
P
14 (74) 12 (4.8–23)
1 (5) 0.6 (0–2.3)
Original article
Elevated tumour markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumour removal F. Di Fabio, W. Aston, F. Mohamed, K. Chandrakumaran, T. Cecil and B. Moran Peritoneal Malignancy Institute and Colorectal Surgery, Basingstoke and North Hampshire Hospitals, Basingstoke, UK Received 15 November 2014; accepted 31 December 2014;
Abstract Aim Elevation of the preoperative tumour markers in pseudomyxoma peritonei (PMP) is common and is a risk factor for recurrence. There has, however, been no documentation of the effect of complete tumour removal on tumour markers levels after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of the study was to compare the tumour markers 7 days after surgery in patients with elevated preoperative levels. Method This was an observational prospective study of patients with PMP of appendiceal origin treated in one of the UK National Referral Centres for this condition. Thirty patients [median age = 61 (range: 31–74) years; six men] with an elevated preoperative level of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and/or carbohydrate antigen 19-9 (CA19-9) underwent repeated estimation, 7 days after CRS and HIPEC for PMP. Results The median preoperative CEA level of 12 lg/l fell to 0.75 lg/l postoperatively (P < 0.0001), CA-125 fell from 45 to 31 kU/l (P = 0.183) and CA19-9 fell from 134 to 37 kU/l (P = 0.003). The CEA was raised
Introduction Pseudomyxoma peritonei (PMP) is an uncommon disease characterized by mucinous ascites usually originating from a perforated mucinous tumour of the appendix. In the Netherlands it has an estimated annual incidence of two to three per million population[1]. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are the current optimal Correspondence to: Brendan Moran and Francesco Di Fabio, Peritoneal Malignancy Institute and Colorectal Surgery, Basingstoke and North Hampshire Hospitals, Aldermaston Road, Basingstoke, Hampshire RG24 9NA, UK. E-mail: [email protected]; [email protected]
698
in 22 (73%) of 30 patients preoperatively and in two (7%) of 30 patients 7 days after surgery (P < 0.0001). The corresponding data for CA-125 were 18 (60%) and 13 (43%) (P = 0.196) and for CA19-9 they were 24 (80%) and 16 (53%) (P = 0.028). Conclusion This is the first documentation of a reduction or normalization of CEA 7 days after CRS, but not for CA19-9 or CA-125. This may indicate completeness of surgical resection and could aid selection for adjuvant therapy and predict prognosis. Long-term follow-up is, however, necessary to determine the significance of this observation. Keywords Tumour markers, appendix tumour, pseudomyxoma peritonei, carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 19-9 What does this paper add to the literature? This is the first study showing a reduction or normalization of CEA after cytoreductive surgery for pseudomyxoma of appendiceal origin. This may indicate surgical radicality, aid selection for adjuvant therapy and help determine frequency of follow up, but validation by long-term follow-up is required.
treatments for PMP [2,3]. When complete cytoreduction is achieved, 5-year disease-free survival rates above 80% have been reported [4]. Owing to the rarity of PMP there is uncertainty concerning the prediction of prognosis, the role, if any, for postoperative systemic chemotherapy and the frequency of follow up. Currently, histological categorization into low- or high-grade appendiceal tumours broadly differentiates patients with good or poor prognosis [5], but this does not explain the biological behaviour, with some low-grade tumours recurring early, and sometimes very aggressively. In addition to histological grading, tumour-marker measurements have been shown to pre-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 698–703
F. Di Fabio et al.
dict prognosis [4,6–10]. When tumour markers, particularly carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and carbohydrate antigen 19-9 (CA19-9), are elevated, there is an increased risk of recurrence and a reduction in survival [4,6–10]. A recent report of 519 patients with PMP of appendiceal origin, who underwent complete tumour removal, demonstrated that disease-free survival was inversely proportional to the number of tumour markers elevated before surgery [4]. Disease-free and overall survival rates in patients with normal levels of tumour markers were significantly different from those in patients with abnormality of one, two or all three of the markers CEA, CA-125 and CA19-9 [4]. Patients with high-grade tumours are more likely to have elevated tumour markers, and we and others have demonstrated that patients with elevated markers may have a pathologically lowgrade tumour [11]. It is likely that secretion of excessive tumour markers detected by elevated serum levels may indicate more aggressive biology than indicated by the histopathology. This is important when considering postoperative chemotherapy and both the frequency and intensity of follow up. To our knowledge, there has been no documentation on the effect of complete tumour removal on the level of tumour markers in the early postoperative period, when these tumour markers had been elevated preoperatively. The present study compared tumour marker concentrations before, and 7 days after, CRS and HIPEC, in a group of patients with raised preoperative levels of these markers.
Method This was a prospective study from a high-volume UK national referral centre for PMP of appendiceal origin. It was deemed as an exercise in service development by the Research and Development Committee and therefore did not require formal ethical approval. The aim was to assess the serum tumour marker levels of patients undergoing complete CRS and HIPEC, before, and 7 days after, surgery. A secondary endpoint was to compare changes, after surgery, in the levels of tumour markers in low-grade and high-grade tumours. carcinoembryonic antigen (lg/l), CA-125 (kU/l; kilo unit per litre) and CA19-9 (kU/l) levels were measured 2 days before surgery and 7 days postoperatively. The normal range for CEA was < 0.5– 5 lg/l, for CA-125 was 0–35 kU/l and for CA19-9 was 0–33 kU/l. Patients demonstrating an incomplete CRS, normal tumour markers preoperatively and/or failure to comply with the study protocol were excluded from the study.
Tumour markers in pseudomyxoma peritonei
All patients admitted for CRS and HIPEC between 29 October 2013 and 16 April 2014 were eligible. Fifty-three patients were treated, of whom 46 underwent complete CRS and seven had maximal tumour debulking. Of the 46 patients, preoperative measurement of CEA, CA-125 and CA19-9 demonstrated that 10 (22%) had markers in the normal ranges and 36 (78%) had at least one elevated marker. Six patients were excluded because they were not compliant with the protocol and failed to have the tumour markers checked 7 days after surgery. This left 30 patients [median age = 61 (range: 31–74) years; 24 women and six men]. Of these 30 patients, one marker was elevated in six (CEA in one, CA-125 in one and CA19-9 in four), two markers were elevated in 14 (CEA and CA125 in four, CEA and CA 19-9 in seven, and CA-125 and CA19-9 in three) and all three markers were elevated in 10. The preoperative assessment, surgical management and follow-up protocol for patients with PMP have been described previously [4]. The resected surgical specimen was classified as either low-grade mucinous carcinoma peritonei or high-grade mucinous carcinoma peritonei on pathological evaluation by an experienced peritoneal malignancy pathologist [5]. Statistical analysis
Statistical analysis was performed using the statistical software STATA for Windows (Stata Corporation, College Station, TX, USA). Median values and interquartile range were given for continuous variables as their values distribution was skewed. The nonparametric Wilcoxon rank-sum test was used to compare continuous variables. Fisher’s exact test was applied for the analysis of categorical variables. The level of statistical significance was set at P < 0.05.
Results Nineteen (63%) of the 30 patients had a low-grade tumour. The median preoperative CEA level decreased from 12 to 0.75 lg/l postoperatively (P < 0.0001), the CA-125 from 45 to 31 kU/l (P = 0.183) and the CA19-9 from 134 to 37 kU/L (P = 0.003). An elevated CEA was noted in 22 (73%) patients preoperatively and in two (7%) at 7 days postoperatively (P < 0.0001). Carbohydrate antigen 125 was elevated in 18 (60%) patients preoperatively and in 13 (43%) patients postoperatively (P = 0.196), and CA19-9 was elevated in 24 (80%) of patients preoperatively and in 16 (53%) patients postoperatively (P = 0.028; Table 1). The trends of tumour markers in low-grade and high-grade tumours are shown in Table 2. There
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 698–703
699
F. Di Fabio et al.
Tumour markers in pseudomyxoma peritonei
Table 1 Impact of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on elevated tumour markers. Variable CEA Elevated (>5 lg/l) Median value (lg/l) CA-125 Elevated (> 35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l)
Postoperative (7 days)
P
22 (73) 12 (4.8–22)
2 (7) 0.75 (0–1.3)
35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l) High-grade tumours (n = 11) CEA Elevated (> 5 lg/l) Median value (lg/l) CA-125 Elevated (> 35 kU/l) Median value (kU/l) CA19-9 Elevated (> 33 kU/l) Median value (kU/l)
Postoperative (7 days)
P
14 (74) 12 (4.8–23)
1 (5) 0.6 (0–2.3)
