- Email: [email protected]
Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients
Available online at www.sciencedirect.com
ScienceDirect EJSO xx (2016) 1e8
www.ejso.com
Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients: Results of a prospective validation study in 91 patients F. Jeune a, A. Brouquet a,*, C. Caramella d, M. Gayet b, S. Abdalla a, A.-L. Verin b, A. Thirot Bidault c, C. Penna a, S. Benoist a a
Department of Digestive and Oncologic Surgery, Assistance Publique, H^opitaux de Paris, University ParisSud, Le Kremlin Bic^etre, France b Department of Radiology, Assistance Publique, H^opitaux de Paris, University Paris-Sud, Le Kremlin Bic^etre, France c Department of Medical Oncology, Assistance Publique, H^opitaux de Paris, University Paris-Sud, Le Kremlin Bic^etre, France d Department of Radiology, Institut Gustave Roussy, Assistance Publique, H^opitaux de Paris, University ParisSud, Villejuif, France Accepted 26 February 2016 Available online - - -
Abstract Background: The presence of cardiophrenic angle lymph node (CPALN) has been associated with the risk of peritoneal carcinomatosis (PC) in high risk colon cancer patients. Its accuracy to predict PC and its prognostic value in non-selected CRC patients has not been validated prospectively. Methods: From 2011 to 2013, all patients undergoing colectomy for colon cancer were included prospectively. Presence of CPALN was assessed on preoperative computed tomography scan by two radiologists. Surgical exploration was used as reference for the diagnosis of PC. Factors associated with presence of CPALN and progression-free survival were analyzed. Results: Ninety one patients fulfilled inclusion criteria. CPALN was detected in 36 patients (39.5%) on CT scan. At surgical exploration, PC was found in 6 patients (6.5%). Sensitivity, specificity, negative predictive value, positive predictive value and overall accuracy of CPALN on CT scan for predicting PC were 67%, 62%, 96%, 11% and 63% respectively. In multivariate analysis, the presence of distant metastases whatever the site was associated with the presence of CPALN (p ¼ 0.03; hazard ratio HR ¼ 3.8; confidence interval CI 95% ¼ 1.1e13.3). In the multivariate analysis, only vascular involvement (p ¼ 0.034, HR ¼ 3.574, CI 95% ¼ 1.10e11.60) was associated with progressionfree survival whereas CPALN was not found to predict outcome (p ¼ 0.893). Conclusion: CPALN is a common finding in non-selected colon cancer patients. Although in the absence of CPALN, PC can almost be excluded, its value for the diagnosis of PC is limited. Our findings support that CPALN is mainly an indicator of metastatic spread of the tumor. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Colorectal cancer; Cardiophrenic angle lymph node; Peritoneal carcinomatosis; Colorectal cancer metastasis
Introduction * Corresponding author. Department of Digestive Surgery and Surgical Oncology, Bic^etre Hospital, Assistance Publique H^opitaux de Paris, Universite PariseSud, 78, rue du General Leclerc 94275 Le Kremlin Bic^etre, France. Tel.: þ33 1 45 21 34 70; fax: þ33 1 45 21 34 74. E-mail address: [email protected] (A. Brouquet).
Approximately 25% of colorectal cancer (CRC) patients develop peritoneal carcinomatosis (PC) at some point during the course of their disease.1 PC is still considered as a crucial event in CRC2,3 because of its poor prognosis.4e7 In
http://dx.doi.org/10.1016/j.ejso.2016.02.256 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
2
F. Jeune et al. / EJSO xx (2016) 1e8
patients with limited PC, aggressive treatment approach including complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CCS þ HIPEC) can improve outcome with the possibility of cure.6,8 However, diagnosis of PC on imaging at an early stage remains difficult regardless of imaging modality that is used. Sensitivity of computed tomography (CT) scan in detecting small peritoneal implants widely ranges from 11% to 60%.9 Magnetic resonance imaging and PET-CT have also been tested for the diagnosis of PC but their performances remain poor for the detection of subcentimeter peritoneal lesions.10e12 Recently, the presence of visible cardiophrenic angle lymph nodes (CPALN) on CT has been shown to be strongly associated with intraoperative finding of PC in a single center series of CRC patients at high-risk of PC.13 In the same series, the presence of visible CPALN had no impact on CRC oncologic outcome.14 Those two studies evaluated the interest of CPALN in selected high-risk CRC patients which may not represent the whole population of patients with colorectal cancer. Prospective validation of the interest of the presence of CPALN for the detection of PC and its prognostic impact has never been evaluated in an independent non-selected CRC patient population. Early diagnosis of PC using the presence or absence of CPALN would considerably help to define treatment strategy to CRC patients. The aim of this prospective study was to evaluate the accuracy for the diagnosis of PC and the prognostic impact of the presence of CPALN on imaging in a consecutive cohort of nonselected patients undergoing surgery for CRC. Patient and methods Patients From February 2011 to March 2013, it was decided to detect prospectively the presence of CPALN in nonselected CRC patients in our institution who fulfilled the following inclusion criteria: biopsy-proven colon cancer, available preoperative imaging of chest and abdomen, complete abdominal exploration at surgery, follow-up of at least 24 months. Patients with concomitant cancer and patients with rectal cancer were excluded. This observational nontherapeutic study was conducted according to French ethics law and was approved by the French Institutional Ethics Board. Among the 217 patients who were treated for CRC at our institution, 91 fulfilled inclusion criteria (Fig. 1). Preoperative imaging All patients had a preoperative triple-phase helical CT scan (Siemens Ò definition ASþ) with 5-mm reconstructions within 1 month prior to surgical exploration. In patients with synchronous metastases treated by neoadjuvant chemotherapy, only imaging after the end of chemotherapy
PaƟents with colorectal cancer N = 217
PaƟents with rectal cancer N = 59 PaƟents with mulƟple neoplasia N = 23
PaƟents with inadequate preoperaƟve work-up N = 15 No surgical exploraƟon N = 29 Elligible paƟents N = 91 Figure 1. Flow chart of the study.
and before surgery were considered for the study. The presence of CPALN was defined as round or oval-shaped nodules located above the surface of the diaphragm, adjacent to the anterior part of the pericardium. Independent reading of imaging was made by two radiologists (MG and ALV) who fulfilled a standardized form dedicated to the study purpose including the following data: presence or absence of CPALN, number of CPALN, size of CPALN. In case of disagreement, CT scans were reviewed by the two radiologists for consensus. Diagnosis of PC on imaging was defined as peritoneal nodules or omental fat infiltration with or without ascites. Detection of distant lymph nodes metastases, liver and lung metastases was also systematically carried out. All CT images were reviewed at multidisciplinary meeting including radiologists, gastrointestinal oncologists, and surgeons to define treatment strategy. Surgical procedure At laparotomy, complete exploration of the peritoneal cavity was carried out. All peritoneal lesions potentially considered as PC were as usual sampled for pathological examination. In patients with biopsy-proven PC diagnosed at surgery, the extent of peritoneal disease was calculated according the peritoneal cancer index.15,16 In patients with localized, peritumoral PC, complete resection of the macroscopic lesions of PC was combined to resection of the primary tumor. In patients with disseminated PC, surgical resection limited to the primary cancer was decided according to preoperative symptoms: in asymptomatic patients, primary cancer and peritoneal disease was left in
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8
place in order to facilitate further complete CCS þ HIPEC whereas primary cancer was resected in symptomatic patients. Surgical resection and lymphadenectomy was performed according to the French digestive cancer guidelines.17 Briefly, en-bloc 5 cm surgical margins colonic tumor resection was performed combined with high ligation of mesenteric vessels. CPALN dissection was not routinely performed even in patients in whom CPALN was detected on preoperative imaging. Postoperative follow-up In non-metastatic patients, decision for postoperative chemotherapy was made at a multidisciplinary meeting including radiologists, gastrointestinal oncologists, and surgeons based on French digestive cancer guidelines. Briefly, stage IV, stage III and poor histologic features or high risk stage II colon cancer patients were eligible for 6 months postoperative oxaliplatin-based chemotherapy.18 All patients had regular follow-up including physical examination and CT scan every 3e4 months during the first 2 years and every 6 months thereafter. Peritoneal recurrence was defined as any new lesion or abnormalities detected on follow-up imaging. Statistics Quantitative data were expressed as mean standard deviation (SD) or median, and qualitative data as frequency and percent. For the evaluation of the accuracy of CPALN on imaging to detect PC, intraoperative findings with biopsyproven PC were used as the reference. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CPALN on preoperative imaging to predict intraoperative PC were analyzed. For the detection of factors associated with the presence of CPALN, univariate analysis was used to examine the relationship between CPALN and the following variables: age, gender (male vs female), primary tumor site (ascending vs descending colon), primary tumor T stage, lymph node metastasis (positive vs negative), vascular and perineural involvement (presence vs absence), postoperative chemotherapy, liver metastases (presence vs absence), and PC (presence vs absence). Variables associated with p value < 0.2 were subsequently analyzed in a multivariate logistic regression model. Overall survival (OS) and progression-free survival (PFS) were calculated by using the KaplaneMeier method and compared by using log rank test from the date of surgery. In patients with non metastatic colon cancer, progression was defined as first recurrence after surgical resection of primary cancer. In patients with stage IV disease progression was defined by first progression on clinical and imaging follow-up using RECIST criteria.19 Univariate analysis was used to examine the relationship between progression-free survival and the following variables: age, gender (male vs female), primary tumor site (ascending vs descending colon), primary tumor T stage,
3
lymph node metastasis (positive vs negative), vascular and perineural involvement (presence vs absence), postoperative chemotherapy, distant metastasis (presence vs absence), and CPALN (presence vs absence), mucinous component (presence vs absence), tumor grade (well differentiated vs poorly/moderately), postoperative morbidity. Variables associated with p value < 0.2 were subsequently analyzed in a Cox multivariate regression model. A p value < 0.05 was considered as significant. Comparisons between groups were analyzed with the chi-squared or Fisher’s exact test for proportions, the ManneWhitney U test for medians, and Student’s t test for means, as appropriate. Results Patients characteristics and surgical procedures Patients characteristics are summarized in Table 1. Patients had preoperative CT scan within a median of 2.9 weeks (0e10.4) prior to surgery. Overall 23 patients had stage IV disease. Seventeen patients (18.7%) had only extraperitoneal metastases including liver-only metastases in 9 (9.9%), lungonly metastases in 3 (3.3%), liver and lung metastases in 4 (4.4%), and liver and adrenal metastases in 1 patient (1%). Six other patients (6.6%) had PC, including 5 patients (5.5%) with concomitant extraperitoneal metastases and 1 patient (1%) with isolated PC. Ten patients (11%) received preoperative chemotherapy including 8 patients (8.8%) Table 1 Clinicopathological characteristics of 91 patients undergoing colectomy for colon cancer. (N ¼ 91) Median age (range) Gender (M/F) Median body mass index (range) Primary tumor sitea Ascending colon Descending colon Primary tumor T stage T1 T2 T3 T4 Median number of examined lymph nodes (range) Primary tumor N stage N0 N1 N2 Nx Metastatic disease (stage IV)b Liver Lung Peritoneal carcinomatosis Other Preoperative chemotherapy
71.3 (22.3e96.2) 51/40 23.3 (17.8e33.5) 42 (46) 55 (61) 7 (7.5) 7 (7.5) 45 (50) 32 (35) 22 (5e141) 50 (55) 22 (24) 16 (18) 3 (3) 23 (25) 17 (19) 9 (10) 6 (7) 2 (2) 10 (11)
Percentages are in parentheses. a 6 patients had synchronous tumors. b Several patients had multiple sites of metastatic disease.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
4
F. Jeune et al. / EJSO xx (2016) 1e8
with stage IV disease and 2 patients (2.2%) with nonmetastatic but locally advanced colon cancer. In these last two patients, preoperative chemotherapy was administered to facilitate tumor resection. Surgical procedure consisted in right hemicolectomy in 31 patients, left hemicolectomy in 47 patients and subtotal colectomy or visceral extended resection for 13 patients. In the 6 patients with PC, mean peritoneal index was 2.83. Among these 6 patients, 4 had complete resection of macroscopic PC lesions combined with resection of the primary tumor. The 2 remaining patients had colectomy for symptomatic cancer without resection of PC. These two patients were further offered a CCS þ HIPEC. Fourteen patients developed postoperative complications including anastomotic leakages in 4 (4.4%), intraabdominal abscess in 2 (2.2%), and medical complications in 8 (8.8%). After surgery, postoperative chemotherapy was initiated in 38 (42%) patients. Eighteen patients received postoperative FOLFOX or LV5FU for stage III or high-risk stage II colon cancer. Among the 8 stage IV patients who received preoperative chemotherapy, 7 restarted postoperative chemotherapy using the same regimen as preoperatively and 1 patient did not receive postoperative treatment because of prolonged preoperative chemotherapy. Thirteen additional stage IV colon cancer patients who underwent upfront colectomy received postoperative chemotherapy. The 2 stage IV remaining patients did not receive preoperative or postoperative chemotherapy for severe comorbidities. Postoperative chemotherapy regimens in stage IV colon cancer were as follows: FOLFIRI þ bevacizumab in 9 patients, FOLFOX þ bevacizumab in 5 patients, FOLFOX in 4 patients, and FOLFIRI in 2 patients. Accuracy of CPALN to detect PC and univariate and multivariate analysis of factors associated with the presence of CPALN On preoperative CT scan, CPALN was detected in 36 (39.5%) patients by the two radiologists. No consensus review was necessary as a perfect agreement was obtained between both radiologists on the detection of CPALN. Among 36 patients with CPLAN, 20 (55.6%) had only one node, whereas 16 (44.4%) had 2 or more nodes. Median maximum diameter of CPALN was 8.7 mm (range 4e19). On preoperative imaging work up, PC was suspected in 7 patients (7.7%). These 7 patients with preoperative suspicion of limited PC on imaging were not referred directly to a peritoneal malignancy centre because they required emergency surgery in 2 or presented contra-indications for CCS þ HIPEC including advanced age in 3 or medical comorbidities in 2. Among the 36 patients with CPALN detected on CT scan, 5 (13.9%) patients had concomitant signs of PC on imaging. In 36 patients presenting with CPALN on preoperative imaging, PC was found and confirmed at laparotomy in 4 (11%) patients (Table 2). In
Table 2 Accuracy of CPALN to predict PC in 91 patients who underwent colectomy for colon cancer. Pathology
Imaging Total
CPALN present CPALN absent
Total
PC
No PC
4 2 6 (6.6%)
32 53 85 (93.4%)
36 (39.6%) 55 (60.4%) 91 (100%)
55 patients who did not have CPALN on preoperative CT, no PC was found in 53 but PC was found and confirmed at laparotomy in 2 patients. These two patients had no sign of PC on preoperative CT. Among 6 patients who had intraoperative confirmation of PC, 4 had CPALN on preoperative CT. Sensitivity, specificity, negative predictive value, positive predictive value and overall accuracy of the presence of CPALN on imaging to predict intraoperative finding of PC was 67%, 62%; 96%; 11% and 63% respectively. Results of univariate analysis of factors associated with the presence of CPALN on preoperative imaging are summarized in Table 3. The presence of distant metastases (p ¼ 0.035; hazard ratio [HR] ¼ 3.824; confidence interval [CI] 95% ¼ 1.10e13.31) and the absence of mucinous component (p ¼ 0.035, HR ¼ 0.253, CI 95% ¼ 0.07e0.91) were significantly associated with the presence of CPALN in multivariate analysis.
Survival, recurrence and prognostic significance of CPALN After 28 months median follow-up (IC95% ¼ 24e33.2 months), 1-year and 3-year overall survival rates for the entire cohort were 92 and 87% respectively, 1-year and 3year progression free survival rates were 81 and 67% respectively. Twenty patients developed disease recurrence (n ¼ 8) or progression of metastatic colon cancer (n ¼ 12) and 7 patients died from disease progression during follow up. Overall survival rate was not different in patients with or without CPALN (Fig. 2). In contrast, patients with CPALN had a decreased progression-free survival compared to patients without CPALN (Fig. 3). One year and 3-year progressionfree survival rates were 98% and 80.5% in patients without CPALN and 74.3% and 46.4% in patients presenting with CPALN (p ¼ 0.035). Among patients presenting with CPALN, number of nodes did not affect outcome (p ¼ 0.443). Results of univariate and multivariate analyses of factors associated with progression-free survival are reported in Table 4. In univariate analysis, presence of nodes involvement, perineural and vascular involvement, metastatic disease and presence of CPALN were associated with progression-free survival. In multivariate analysis, presence of CPALN was not significantly associated with progression-free survival and only the presence of vascular involvement (p ¼ 0.034, HR ¼ 3.574, CI
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8 Table 3 Univariate analysis of factors associated with the presence of CPALN in 91 patients who underwent colectomy for colon cancer. N (%)
Univariate Multivariate analysis analysis P OR Confidence interval 95%
Age <70 years 43 (47) 0.196 0.138 >70 years 48 (53) Gender Female 40 (44) 0.939 Male 51 (56) Primary tumor sitea Ascending colon 37 (41) 0.781 Descending colon 54 (59) Primary tumor T stage T1/T2 14 (15) 0.554 T3/T4 77 (86) Median number of examined lymph nodes 12 nodes or more 8 (9) 0.706 < 12 nodes 80 (88) ND 3 (3) Perineural invasion Presence 34 (37) 0.602 Absence 52 (57) ND 5 (5) Venous invasion Presence 33 (36) 0.437 Absence 53 (58) ND 5 (5) Lymphatic invasion Presence 26 (31) 0.516 Absence 57 (69) ND 8 (9) Mucinous component Presence 20 (22) 0.035 0.035 0.253 0.07e0.91 Absence 59 (65) ND 12 (13) Tumor differentiation Well 25 (27) 0.712 Moderate/poorly 58 (64) ND 8 (9) Primary tumor node involvement N0 50 (55) 0.560 N1/N2 38 (42) Nx 3 (3) Peritoneal carcinomatosis Presence 6 (7) 0.209 Absence 85 (93) Distant metastatic disease Present 23 (25) 0.152 0.035 3.824 1.10e13.31 Absent 68 (75) a
Only the most advanced tumor was taken into account.
95% ¼ 1.101e11.601) was associated with progression-free survival. Discussion This study shows that CPALN is a common finding in non-selected colon cancer patients. Although in the absence of CPALN, PC can almost be excluded, its value for the
5
diagnosis of PC is limited. Our findings support that CPALN is associated with metastatic disease and not specifically PC, and therefore more likely reflects metastatic spread of colon cancer. To our knowledge, this study is the first to prospectively evaluate the interest of CPALN for the diagnosis of PC in non-selected population-based cohort of CRC patients. We report a 39.5% incidence of CPALN finding on CT in non-selected colon cancer patients. In contrast, PC was diagnosed in only 6.5% of patients. The interest of CPALN for the diagnosis of PC has been reported by Caramella et al. in a series of patients with CRC at high-risk of PC.13 The accuracy of CPALN in this context was good, with a very high negative predictive value and adequate sensitivity suggesting that it could be of valuable interest for the diagnosis of PC in patients with CRC. In the current series, we confirm that negative predictive value of CPALN for the diagnosis of PC in colon cancer is good (96%) and therefore, in the absence of CPALN, the probability of unexpected finding of PC at surgical exploration is extremely low. Although sensitivity and specificity of CPALN in the current series are similar to those already reported,13 we observed decreased positive predictive value of CPALN that considerably limits its interest for the diagnosis of PC in non-selected colon cancer patients. In the initial publication reporting on the interest of CPALN for the diagnosis of PC,13 59% of the patients presented with metastatic CRC and 30% of patients had PC. The high incidence of PC in this latter series might explain improved positive predictive value of CPALN for the diagnosis of PC. In our series, CPALN was associated with the presence of metastatic disease and not specifically with PC. In previous reports, CPALN was found to be associated with liver involvement in abdominal cancer including CRC.20,21 Although our findings suggest that CPALN can not be used alone as a diagnostic tool for PC, it might represent a good indirect indicator of metastatic spread of CRC regardless the location of metastasis. This result is of importance especially in CRC patients without obvious metastatic disease on preoperative imaging work-up. This finding raises the question of the interest of additional investigations including FDG-PET to eliminate metastatic spread of the cancer prior to define treatment strategy to these patients. An alternative, in patients presenting with CPALN without other sign of obvious metastatic disease on preoperative imaging work up, is probably a careful postoperative follow-up in order to detect early recurrence. A number of authors have proposed a systematic CPALN dissection to eliminate tumor involvement. In the current study, we did not perform CPALN dissection. A number of authors argue that CPALN might be reactive to systemic dissemination of cancer. In a recent study including 11 patients with ovarian carcinoma and PC undergoing cytoreductive surgery and systematic CPALN dissection when the node was present and greater than 5 mm in short axis diameter in CT scan, CPALN was
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
6
F. Jeune et al. / EJSO xx (2016) 1e8 1,0
Overall survival
0,8
0,6
0,4
0,2
p = 0.878 0,0 0
12
24
36
Months Figure 2. Overall survival in 91 colon cancer patients with (continuous line) or without (dotted line) cardiophrenic angle lymph node.
involved by tumor in 45% of patients.22 Other authors have evaluated the interest of PDG-PET-CT to better define tumor involvement within CPALN in a small series of ovarian cancer patients.23 However, based on these data, systematic
CPALN dissection or FDG-PET-CT can not be recommended. In the current series, CPALN was associated with progression-free survival in patients undergoing colectomy
1,0
Progression-free survival
0,8
0,6
0,4
0,2
p = 0.035 0,0 0
12
24
36
Months Figure 3. Progression-free survival in 91 colon cancer patients with (continuous line) or without (dotted line) cardiophrenic angle lymph node.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8 Table 4 Univariate and multivariate analysis of factors associated with progressionfree survival in 91 patients who underwent colectomy for colon cancer. Univariate analysis
Multivariate analysis P
Age <70 years 0.348 >70 years Gender Female 0.702 Male Primary tumor site Ascending colon 0.963 Descending colon Primary tumor T stage T1/T2 0.066 0.976 T3/T4 Median number of examined lymph nodes 12 nodes or more 0.599 <12 nodes Perineural invasion Present 0.014 0.498 Absent Vascular invasion Present <0.0001 0.034 Absent Lymphatic invasion Present 0.224 Absent Mucinous component Present 0.240 Absent Tumor differentiation Well 0.259 Moderate/poorly Primary tumor node involvement N0 <0.0001 0.081 N1/N2 Distant metastatic disease Present <0.0001 0.188 Absent Postoperative morbidity 0.557 CPALN Present 0.032 0.837 Absent
HR
Confidence interval 95%
7
In conclusion, this prospective study shows that CPALN is a common finding in non-selected colon cancer patients. Our results support that CPALN might be considered as an indicator of metastatic spread of the tumor rather than a predictor of PC. Therefore, CPALN should not be used to predict for PC even if in its absence, PC can almost be excluded. Overall, although CPALN increases the possibility of metastatic or peritoneal disease, it does not necessarily represent metastatic disease in itself. In this perspective, the presence of CPALN in patients without other sign of metastasis would be particularly useful to tailor treatment strategy with the increasing use of multimodality treatment in colon cancer. Further large and prospective studies should investigate whether CPALN could be used to predict tumor stage in colon cancer patients. Conflict of interest The authors have no conflict of interest to disclose.
3.574
1.101e11.601
for colon cancer. The prognostic value of CPALN in colon cancer has been evaluated in several studies and remains debated. In patients with PC, Elias et al.14 showed in a series of 114 patients undergoing cytoreductive surgery þ hyperthermic intraperitoneal chemotherapy that CPALN had no impact on cancer outcome. In another series of 85 patients undergoing liver resection for metastatic CRC, CPALN was not associated with survival and recurrence.24 In our series, CPALN was not an independent factor associated with recurrence in multivariate analysis. Our results suggest that CPALN may not be a prognostic factor by itself but rather more likely reflects metastatic spread of cancer.
Acknowledgments This work was supported PREDI (Association pour la Recherche en Chirurgie digestive).
References 1. Koppe MJ, Boerman OC, Oyen WJ, et al. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006;243:212–22. 2. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol 2012;30:263–7. 3. Lemmens VE, Klaver YL, Verwaal VJ, et al. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer 2011;128:2717–25. 4. Jayne DG, Fook S, Loi C, et al. Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002;89:1545–50. 5. 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;28:63–8. 6. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681–5. 7. Quenet F, Goere D, Mehta SS, et al. Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann Surg 2011;254:294–301. 8. Sadahiro S, Suzuki T, Maeda Y, et al. Prognostic factors in patients with synchronous peritoneal carcinomatosis (PC) caused by a primary cancer of the colon. J Gastrointest Surg 2009;13:1593–8. 9. Koh JL, Yan TD, Glenn D, et al. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol 2009;16:327–33. 10. De Bree E, Koops W, Kroger R, et al. Peritoneal carcinomatosis from colorectal or appendiceal origin: correlation of preoperative CT with
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
8
F. Jeune et al. / EJSO xx (2016) 1e8
11. 12.
13.
14.
15. 16.
17.
18.
intraoperative findings and evaluation of interobserver agreement. J Surg Oncol 2004;86:64–73. Dromain C, Leboulleux S, Auperin A, et al. Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT. Abdom Imaging 2008;33:87–93. Soussan M, Des Guetz G, Barrau V, et al. Comparison of FDG-PET/CT and MR with diffusion-weighted imaging for assessing peritoneal carcinomatosis from gastrointestinal malignancy. Eur Radiol 2012;22:1479–87. Caramella C, Pottier E, Borget I, et al. Value of cardiophrenic angle lymph node for the diagnosis of colorectal peritoneal carcinomatosis. Eur J Cancer 2013;49:3798–805. Elias D, Borget I, Farron M, et al. Prognostic significance of visible cardiophrenic angle lymph nodes in the presence of peritoneal metastases from colorectal cancers. Eur J Surg Oncol 2013;39:1214–8. Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995;221:29–42. Yan TD, Black D, Savady R, et al. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxomaperitonei. Ann Surg Oncol 2007;14:484–92. Phelip JM, Bouche O, Conroy T, et al. Cancer colorectal metastatique. Thesaurus National de Cancerologie Digestive February 2014. http:// www.snfge.org/tncd. Andre T, Boni C, Mounedji-Boudiaf L, et al. Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. NEJM 2004;350:2341–51.
19. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. 20. Graham NJ, Libshitz HI. Cascade of metastatic colorectal carcinoma from the liver to the anterior diaphragmatic lymph nodes. Acad Radiol 1995;2:282–5. 21. Wechsler RJ, Nazarian LN, Grady CK, et al. The association of paracardial adenopathy with hepatic metastasis found on CT arterial portography. Abdom Imaging 1995;20:201–5. 22. Yoo HJ, Lim MC, Song YJ, et al. Transabdominal cardiophrenic lymph node dissection via incised diaphragm replace conventional video-assisted thoracic surgery for cytoreductive surgery in advanced ovarian cancer. Gynecol Oncol 2013;129:341–5. 23. Hynninen J, Auranen A, Carpen O, et al. FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread. Gynecol Oncol 2012;126:64–8. 24. Aslam R, Coakley FV, Williams G, et al. Pronostic importance of superior diaphragmatic adenopathy at computed tomography in patients with resectable hepatic metastases from colorectal carcinoma. J Comput Assist Tomogr 2008;32:173–7.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
ScienceDirect EJSO xx (2016) 1e8
www.ejso.com
Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients: Results of a prospective validation study in 91 patients F. Jeune a, A. Brouquet a,*, C. Caramella d, M. Gayet b, S. Abdalla a, A.-L. Verin b, A. Thirot Bidault c, C. Penna a, S. Benoist a a
Department of Digestive and Oncologic Surgery, Assistance Publique, H^opitaux de Paris, University ParisSud, Le Kremlin Bic^etre, France b Department of Radiology, Assistance Publique, H^opitaux de Paris, University Paris-Sud, Le Kremlin Bic^etre, France c Department of Medical Oncology, Assistance Publique, H^opitaux de Paris, University Paris-Sud, Le Kremlin Bic^etre, France d Department of Radiology, Institut Gustave Roussy, Assistance Publique, H^opitaux de Paris, University ParisSud, Villejuif, France Accepted 26 February 2016 Available online - - -
Abstract Background: The presence of cardiophrenic angle lymph node (CPALN) has been associated with the risk of peritoneal carcinomatosis (PC) in high risk colon cancer patients. Its accuracy to predict PC and its prognostic value in non-selected CRC patients has not been validated prospectively. Methods: From 2011 to 2013, all patients undergoing colectomy for colon cancer were included prospectively. Presence of CPALN was assessed on preoperative computed tomography scan by two radiologists. Surgical exploration was used as reference for the diagnosis of PC. Factors associated with presence of CPALN and progression-free survival were analyzed. Results: Ninety one patients fulfilled inclusion criteria. CPALN was detected in 36 patients (39.5%) on CT scan. At surgical exploration, PC was found in 6 patients (6.5%). Sensitivity, specificity, negative predictive value, positive predictive value and overall accuracy of CPALN on CT scan for predicting PC were 67%, 62%, 96%, 11% and 63% respectively. In multivariate analysis, the presence of distant metastases whatever the site was associated with the presence of CPALN (p ¼ 0.03; hazard ratio HR ¼ 3.8; confidence interval CI 95% ¼ 1.1e13.3). In the multivariate analysis, only vascular involvement (p ¼ 0.034, HR ¼ 3.574, CI 95% ¼ 1.10e11.60) was associated with progressionfree survival whereas CPALN was not found to predict outcome (p ¼ 0.893). Conclusion: CPALN is a common finding in non-selected colon cancer patients. Although in the absence of CPALN, PC can almost be excluded, its value for the diagnosis of PC is limited. Our findings support that CPALN is mainly an indicator of metastatic spread of the tumor. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Colorectal cancer; Cardiophrenic angle lymph node; Peritoneal carcinomatosis; Colorectal cancer metastasis
Introduction * Corresponding author. Department of Digestive Surgery and Surgical Oncology, Bic^etre Hospital, Assistance Publique H^opitaux de Paris, Universite PariseSud, 78, rue du General Leclerc 94275 Le Kremlin Bic^etre, France. Tel.: þ33 1 45 21 34 70; fax: þ33 1 45 21 34 74. E-mail address: [email protected] (A. Brouquet).
Approximately 25% of colorectal cancer (CRC) patients develop peritoneal carcinomatosis (PC) at some point during the course of their disease.1 PC is still considered as a crucial event in CRC2,3 because of its poor prognosis.4e7 In
http://dx.doi.org/10.1016/j.ejso.2016.02.256 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
2
F. Jeune et al. / EJSO xx (2016) 1e8
patients with limited PC, aggressive treatment approach including complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CCS þ HIPEC) can improve outcome with the possibility of cure.6,8 However, diagnosis of PC on imaging at an early stage remains difficult regardless of imaging modality that is used. Sensitivity of computed tomography (CT) scan in detecting small peritoneal implants widely ranges from 11% to 60%.9 Magnetic resonance imaging and PET-CT have also been tested for the diagnosis of PC but their performances remain poor for the detection of subcentimeter peritoneal lesions.10e12 Recently, the presence of visible cardiophrenic angle lymph nodes (CPALN) on CT has been shown to be strongly associated with intraoperative finding of PC in a single center series of CRC patients at high-risk of PC.13 In the same series, the presence of visible CPALN had no impact on CRC oncologic outcome.14 Those two studies evaluated the interest of CPALN in selected high-risk CRC patients which may not represent the whole population of patients with colorectal cancer. Prospective validation of the interest of the presence of CPALN for the detection of PC and its prognostic impact has never been evaluated in an independent non-selected CRC patient population. Early diagnosis of PC using the presence or absence of CPALN would considerably help to define treatment strategy to CRC patients. The aim of this prospective study was to evaluate the accuracy for the diagnosis of PC and the prognostic impact of the presence of CPALN on imaging in a consecutive cohort of nonselected patients undergoing surgery for CRC. Patient and methods Patients From February 2011 to March 2013, it was decided to detect prospectively the presence of CPALN in nonselected CRC patients in our institution who fulfilled the following inclusion criteria: biopsy-proven colon cancer, available preoperative imaging of chest and abdomen, complete abdominal exploration at surgery, follow-up of at least 24 months. Patients with concomitant cancer and patients with rectal cancer were excluded. This observational nontherapeutic study was conducted according to French ethics law and was approved by the French Institutional Ethics Board. Among the 217 patients who were treated for CRC at our institution, 91 fulfilled inclusion criteria (Fig. 1). Preoperative imaging All patients had a preoperative triple-phase helical CT scan (Siemens Ò definition ASþ) with 5-mm reconstructions within 1 month prior to surgical exploration. In patients with synchronous metastases treated by neoadjuvant chemotherapy, only imaging after the end of chemotherapy
PaƟents with colorectal cancer N = 217
PaƟents with rectal cancer N = 59 PaƟents with mulƟple neoplasia N = 23
PaƟents with inadequate preoperaƟve work-up N = 15 No surgical exploraƟon N = 29 Elligible paƟents N = 91 Figure 1. Flow chart of the study.
and before surgery were considered for the study. The presence of CPALN was defined as round or oval-shaped nodules located above the surface of the diaphragm, adjacent to the anterior part of the pericardium. Independent reading of imaging was made by two radiologists (MG and ALV) who fulfilled a standardized form dedicated to the study purpose including the following data: presence or absence of CPALN, number of CPALN, size of CPALN. In case of disagreement, CT scans were reviewed by the two radiologists for consensus. Diagnosis of PC on imaging was defined as peritoneal nodules or omental fat infiltration with or without ascites. Detection of distant lymph nodes metastases, liver and lung metastases was also systematically carried out. All CT images were reviewed at multidisciplinary meeting including radiologists, gastrointestinal oncologists, and surgeons to define treatment strategy. Surgical procedure At laparotomy, complete exploration of the peritoneal cavity was carried out. All peritoneal lesions potentially considered as PC were as usual sampled for pathological examination. In patients with biopsy-proven PC diagnosed at surgery, the extent of peritoneal disease was calculated according the peritoneal cancer index.15,16 In patients with localized, peritumoral PC, complete resection of the macroscopic lesions of PC was combined to resection of the primary tumor. In patients with disseminated PC, surgical resection limited to the primary cancer was decided according to preoperative symptoms: in asymptomatic patients, primary cancer and peritoneal disease was left in
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8
place in order to facilitate further complete CCS þ HIPEC whereas primary cancer was resected in symptomatic patients. Surgical resection and lymphadenectomy was performed according to the French digestive cancer guidelines.17 Briefly, en-bloc 5 cm surgical margins colonic tumor resection was performed combined with high ligation of mesenteric vessels. CPALN dissection was not routinely performed even in patients in whom CPALN was detected on preoperative imaging. Postoperative follow-up In non-metastatic patients, decision for postoperative chemotherapy was made at a multidisciplinary meeting including radiologists, gastrointestinal oncologists, and surgeons based on French digestive cancer guidelines. Briefly, stage IV, stage III and poor histologic features or high risk stage II colon cancer patients were eligible for 6 months postoperative oxaliplatin-based chemotherapy.18 All patients had regular follow-up including physical examination and CT scan every 3e4 months during the first 2 years and every 6 months thereafter. Peritoneal recurrence was defined as any new lesion or abnormalities detected on follow-up imaging. Statistics Quantitative data were expressed as mean standard deviation (SD) or median, and qualitative data as frequency and percent. For the evaluation of the accuracy of CPALN on imaging to detect PC, intraoperative findings with biopsyproven PC were used as the reference. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CPALN on preoperative imaging to predict intraoperative PC were analyzed. For the detection of factors associated with the presence of CPALN, univariate analysis was used to examine the relationship between CPALN and the following variables: age, gender (male vs female), primary tumor site (ascending vs descending colon), primary tumor T stage, lymph node metastasis (positive vs negative), vascular and perineural involvement (presence vs absence), postoperative chemotherapy, liver metastases (presence vs absence), and PC (presence vs absence). Variables associated with p value < 0.2 were subsequently analyzed in a multivariate logistic regression model. Overall survival (OS) and progression-free survival (PFS) were calculated by using the KaplaneMeier method and compared by using log rank test from the date of surgery. In patients with non metastatic colon cancer, progression was defined as first recurrence after surgical resection of primary cancer. In patients with stage IV disease progression was defined by first progression on clinical and imaging follow-up using RECIST criteria.19 Univariate analysis was used to examine the relationship between progression-free survival and the following variables: age, gender (male vs female), primary tumor site (ascending vs descending colon), primary tumor T stage,
3
lymph node metastasis (positive vs negative), vascular and perineural involvement (presence vs absence), postoperative chemotherapy, distant metastasis (presence vs absence), and CPALN (presence vs absence), mucinous component (presence vs absence), tumor grade (well differentiated vs poorly/moderately), postoperative morbidity. Variables associated with p value < 0.2 were subsequently analyzed in a Cox multivariate regression model. A p value < 0.05 was considered as significant. Comparisons between groups were analyzed with the chi-squared or Fisher’s exact test for proportions, the ManneWhitney U test for medians, and Student’s t test for means, as appropriate. Results Patients characteristics and surgical procedures Patients characteristics are summarized in Table 1. Patients had preoperative CT scan within a median of 2.9 weeks (0e10.4) prior to surgery. Overall 23 patients had stage IV disease. Seventeen patients (18.7%) had only extraperitoneal metastases including liver-only metastases in 9 (9.9%), lungonly metastases in 3 (3.3%), liver and lung metastases in 4 (4.4%), and liver and adrenal metastases in 1 patient (1%). Six other patients (6.6%) had PC, including 5 patients (5.5%) with concomitant extraperitoneal metastases and 1 patient (1%) with isolated PC. Ten patients (11%) received preoperative chemotherapy including 8 patients (8.8%) Table 1 Clinicopathological characteristics of 91 patients undergoing colectomy for colon cancer. (N ¼ 91) Median age (range) Gender (M/F) Median body mass index (range) Primary tumor sitea Ascending colon Descending colon Primary tumor T stage T1 T2 T3 T4 Median number of examined lymph nodes (range) Primary tumor N stage N0 N1 N2 Nx Metastatic disease (stage IV)b Liver Lung Peritoneal carcinomatosis Other Preoperative chemotherapy
71.3 (22.3e96.2) 51/40 23.3 (17.8e33.5) 42 (46) 55 (61) 7 (7.5) 7 (7.5) 45 (50) 32 (35) 22 (5e141) 50 (55) 22 (24) 16 (18) 3 (3) 23 (25) 17 (19) 9 (10) 6 (7) 2 (2) 10 (11)
Percentages are in parentheses. a 6 patients had synchronous tumors. b Several patients had multiple sites of metastatic disease.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
4
F. Jeune et al. / EJSO xx (2016) 1e8
with stage IV disease and 2 patients (2.2%) with nonmetastatic but locally advanced colon cancer. In these last two patients, preoperative chemotherapy was administered to facilitate tumor resection. Surgical procedure consisted in right hemicolectomy in 31 patients, left hemicolectomy in 47 patients and subtotal colectomy or visceral extended resection for 13 patients. In the 6 patients with PC, mean peritoneal index was 2.83. Among these 6 patients, 4 had complete resection of macroscopic PC lesions combined with resection of the primary tumor. The 2 remaining patients had colectomy for symptomatic cancer without resection of PC. These two patients were further offered a CCS þ HIPEC. Fourteen patients developed postoperative complications including anastomotic leakages in 4 (4.4%), intraabdominal abscess in 2 (2.2%), and medical complications in 8 (8.8%). After surgery, postoperative chemotherapy was initiated in 38 (42%) patients. Eighteen patients received postoperative FOLFOX or LV5FU for stage III or high-risk stage II colon cancer. Among the 8 stage IV patients who received preoperative chemotherapy, 7 restarted postoperative chemotherapy using the same regimen as preoperatively and 1 patient did not receive postoperative treatment because of prolonged preoperative chemotherapy. Thirteen additional stage IV colon cancer patients who underwent upfront colectomy received postoperative chemotherapy. The 2 stage IV remaining patients did not receive preoperative or postoperative chemotherapy for severe comorbidities. Postoperative chemotherapy regimens in stage IV colon cancer were as follows: FOLFIRI þ bevacizumab in 9 patients, FOLFOX þ bevacizumab in 5 patients, FOLFOX in 4 patients, and FOLFIRI in 2 patients. Accuracy of CPALN to detect PC and univariate and multivariate analysis of factors associated with the presence of CPALN On preoperative CT scan, CPALN was detected in 36 (39.5%) patients by the two radiologists. No consensus review was necessary as a perfect agreement was obtained between both radiologists on the detection of CPALN. Among 36 patients with CPLAN, 20 (55.6%) had only one node, whereas 16 (44.4%) had 2 or more nodes. Median maximum diameter of CPALN was 8.7 mm (range 4e19). On preoperative imaging work up, PC was suspected in 7 patients (7.7%). These 7 patients with preoperative suspicion of limited PC on imaging were not referred directly to a peritoneal malignancy centre because they required emergency surgery in 2 or presented contra-indications for CCS þ HIPEC including advanced age in 3 or medical comorbidities in 2. Among the 36 patients with CPALN detected on CT scan, 5 (13.9%) patients had concomitant signs of PC on imaging. In 36 patients presenting with CPALN on preoperative imaging, PC was found and confirmed at laparotomy in 4 (11%) patients (Table 2). In
Table 2 Accuracy of CPALN to predict PC in 91 patients who underwent colectomy for colon cancer. Pathology
Imaging Total
CPALN present CPALN absent
Total
PC
No PC
4 2 6 (6.6%)
32 53 85 (93.4%)
36 (39.6%) 55 (60.4%) 91 (100%)
55 patients who did not have CPALN on preoperative CT, no PC was found in 53 but PC was found and confirmed at laparotomy in 2 patients. These two patients had no sign of PC on preoperative CT. Among 6 patients who had intraoperative confirmation of PC, 4 had CPALN on preoperative CT. Sensitivity, specificity, negative predictive value, positive predictive value and overall accuracy of the presence of CPALN on imaging to predict intraoperative finding of PC was 67%, 62%; 96%; 11% and 63% respectively. Results of univariate analysis of factors associated with the presence of CPALN on preoperative imaging are summarized in Table 3. The presence of distant metastases (p ¼ 0.035; hazard ratio [HR] ¼ 3.824; confidence interval [CI] 95% ¼ 1.10e13.31) and the absence of mucinous component (p ¼ 0.035, HR ¼ 0.253, CI 95% ¼ 0.07e0.91) were significantly associated with the presence of CPALN in multivariate analysis.
Survival, recurrence and prognostic significance of CPALN After 28 months median follow-up (IC95% ¼ 24e33.2 months), 1-year and 3-year overall survival rates for the entire cohort were 92 and 87% respectively, 1-year and 3year progression free survival rates were 81 and 67% respectively. Twenty patients developed disease recurrence (n ¼ 8) or progression of metastatic colon cancer (n ¼ 12) and 7 patients died from disease progression during follow up. Overall survival rate was not different in patients with or without CPALN (Fig. 2). In contrast, patients with CPALN had a decreased progression-free survival compared to patients without CPALN (Fig. 3). One year and 3-year progressionfree survival rates were 98% and 80.5% in patients without CPALN and 74.3% and 46.4% in patients presenting with CPALN (p ¼ 0.035). Among patients presenting with CPALN, number of nodes did not affect outcome (p ¼ 0.443). Results of univariate and multivariate analyses of factors associated with progression-free survival are reported in Table 4. In univariate analysis, presence of nodes involvement, perineural and vascular involvement, metastatic disease and presence of CPALN were associated with progression-free survival. In multivariate analysis, presence of CPALN was not significantly associated with progression-free survival and only the presence of vascular involvement (p ¼ 0.034, HR ¼ 3.574, CI
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8 Table 3 Univariate analysis of factors associated with the presence of CPALN in 91 patients who underwent colectomy for colon cancer. N (%)
Univariate Multivariate analysis analysis P OR Confidence interval 95%
Age <70 years 43 (47) 0.196 0.138 >70 years 48 (53) Gender Female 40 (44) 0.939 Male 51 (56) Primary tumor sitea Ascending colon 37 (41) 0.781 Descending colon 54 (59) Primary tumor T stage T1/T2 14 (15) 0.554 T3/T4 77 (86) Median number of examined lymph nodes 12 nodes or more 8 (9) 0.706 < 12 nodes 80 (88) ND 3 (3) Perineural invasion Presence 34 (37) 0.602 Absence 52 (57) ND 5 (5) Venous invasion Presence 33 (36) 0.437 Absence 53 (58) ND 5 (5) Lymphatic invasion Presence 26 (31) 0.516 Absence 57 (69) ND 8 (9) Mucinous component Presence 20 (22) 0.035 0.035 0.253 0.07e0.91 Absence 59 (65) ND 12 (13) Tumor differentiation Well 25 (27) 0.712 Moderate/poorly 58 (64) ND 8 (9) Primary tumor node involvement N0 50 (55) 0.560 N1/N2 38 (42) Nx 3 (3) Peritoneal carcinomatosis Presence 6 (7) 0.209 Absence 85 (93) Distant metastatic disease Present 23 (25) 0.152 0.035 3.824 1.10e13.31 Absent 68 (75) a
Only the most advanced tumor was taken into account.
95% ¼ 1.101e11.601) was associated with progression-free survival. Discussion This study shows that CPALN is a common finding in non-selected colon cancer patients. Although in the absence of CPALN, PC can almost be excluded, its value for the
5
diagnosis of PC is limited. Our findings support that CPALN is associated with metastatic disease and not specifically PC, and therefore more likely reflects metastatic spread of colon cancer. To our knowledge, this study is the first to prospectively evaluate the interest of CPALN for the diagnosis of PC in non-selected population-based cohort of CRC patients. We report a 39.5% incidence of CPALN finding on CT in non-selected colon cancer patients. In contrast, PC was diagnosed in only 6.5% of patients. The interest of CPALN for the diagnosis of PC has been reported by Caramella et al. in a series of patients with CRC at high-risk of PC.13 The accuracy of CPALN in this context was good, with a very high negative predictive value and adequate sensitivity suggesting that it could be of valuable interest for the diagnosis of PC in patients with CRC. In the current series, we confirm that negative predictive value of CPALN for the diagnosis of PC in colon cancer is good (96%) and therefore, in the absence of CPALN, the probability of unexpected finding of PC at surgical exploration is extremely low. Although sensitivity and specificity of CPALN in the current series are similar to those already reported,13 we observed decreased positive predictive value of CPALN that considerably limits its interest for the diagnosis of PC in non-selected colon cancer patients. In the initial publication reporting on the interest of CPALN for the diagnosis of PC,13 59% of the patients presented with metastatic CRC and 30% of patients had PC. The high incidence of PC in this latter series might explain improved positive predictive value of CPALN for the diagnosis of PC. In our series, CPALN was associated with the presence of metastatic disease and not specifically with PC. In previous reports, CPALN was found to be associated with liver involvement in abdominal cancer including CRC.20,21 Although our findings suggest that CPALN can not be used alone as a diagnostic tool for PC, it might represent a good indirect indicator of metastatic spread of CRC regardless the location of metastasis. This result is of importance especially in CRC patients without obvious metastatic disease on preoperative imaging work-up. This finding raises the question of the interest of additional investigations including FDG-PET to eliminate metastatic spread of the cancer prior to define treatment strategy to these patients. An alternative, in patients presenting with CPALN without other sign of obvious metastatic disease on preoperative imaging work up, is probably a careful postoperative follow-up in order to detect early recurrence. A number of authors have proposed a systematic CPALN dissection to eliminate tumor involvement. In the current study, we did not perform CPALN dissection. A number of authors argue that CPALN might be reactive to systemic dissemination of cancer. In a recent study including 11 patients with ovarian carcinoma and PC undergoing cytoreductive surgery and systematic CPALN dissection when the node was present and greater than 5 mm in short axis diameter in CT scan, CPALN was
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
6
F. Jeune et al. / EJSO xx (2016) 1e8 1,0
Overall survival
0,8
0,6
0,4
0,2
p = 0.878 0,0 0
12
24
36
Months Figure 2. Overall survival in 91 colon cancer patients with (continuous line) or without (dotted line) cardiophrenic angle lymph node.
involved by tumor in 45% of patients.22 Other authors have evaluated the interest of PDG-PET-CT to better define tumor involvement within CPALN in a small series of ovarian cancer patients.23 However, based on these data, systematic
CPALN dissection or FDG-PET-CT can not be recommended. In the current series, CPALN was associated with progression-free survival in patients undergoing colectomy
1,0
Progression-free survival
0,8
0,6
0,4
0,2
p = 0.035 0,0 0
12
24
36
Months Figure 3. Progression-free survival in 91 colon cancer patients with (continuous line) or without (dotted line) cardiophrenic angle lymph node.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
F. Jeune et al. / EJSO xx (2016) 1e8 Table 4 Univariate and multivariate analysis of factors associated with progressionfree survival in 91 patients who underwent colectomy for colon cancer. Univariate analysis
Multivariate analysis P
Age <70 years 0.348 >70 years Gender Female 0.702 Male Primary tumor site Ascending colon 0.963 Descending colon Primary tumor T stage T1/T2 0.066 0.976 T3/T4 Median number of examined lymph nodes 12 nodes or more 0.599 <12 nodes Perineural invasion Present 0.014 0.498 Absent Vascular invasion Present <0.0001 0.034 Absent Lymphatic invasion Present 0.224 Absent Mucinous component Present 0.240 Absent Tumor differentiation Well 0.259 Moderate/poorly Primary tumor node involvement N0 <0.0001 0.081 N1/N2 Distant metastatic disease Present <0.0001 0.188 Absent Postoperative morbidity 0.557 CPALN Present 0.032 0.837 Absent
HR
Confidence interval 95%
7
In conclusion, this prospective study shows that CPALN is a common finding in non-selected colon cancer patients. Our results support that CPALN might be considered as an indicator of metastatic spread of the tumor rather than a predictor of PC. Therefore, CPALN should not be used to predict for PC even if in its absence, PC can almost be excluded. Overall, although CPALN increases the possibility of metastatic or peritoneal disease, it does not necessarily represent metastatic disease in itself. In this perspective, the presence of CPALN in patients without other sign of metastasis would be particularly useful to tailor treatment strategy with the increasing use of multimodality treatment in colon cancer. Further large and prospective studies should investigate whether CPALN could be used to predict tumor stage in colon cancer patients. Conflict of interest The authors have no conflict of interest to disclose.
3.574
1.101e11.601
for colon cancer. The prognostic value of CPALN in colon cancer has been evaluated in several studies and remains debated. In patients with PC, Elias et al.14 showed in a series of 114 patients undergoing cytoreductive surgery þ hyperthermic intraperitoneal chemotherapy that CPALN had no impact on cancer outcome. In another series of 85 patients undergoing liver resection for metastatic CRC, CPALN was not associated with survival and recurrence.24 In our series, CPALN was not an independent factor associated with recurrence in multivariate analysis. Our results suggest that CPALN may not be a prognostic factor by itself but rather more likely reflects metastatic spread of cancer.
Acknowledgments This work was supported PREDI (Association pour la Recherche en Chirurgie digestive).
References 1. Koppe MJ, Boerman OC, Oyen WJ, et al. Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006;243:212–22. 2. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol 2012;30:263–7. 3. Lemmens VE, Klaver YL, Verwaal VJ, et al. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer 2011;128:2717–25. 4. Jayne DG, Fook S, Loi C, et al. Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002;89:1545–50. 5. 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;28:63–8. 6. Elias D, Lefevre JH, Chevalier J, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681–5. 7. Quenet F, Goere D, Mehta SS, et al. Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC after cytoreductive surgery for colorectal carcinomatosis. Ann Surg 2011;254:294–301. 8. Sadahiro S, Suzuki T, Maeda Y, et al. Prognostic factors in patients with synchronous peritoneal carcinomatosis (PC) caused by a primary cancer of the colon. J Gastrointest Surg 2009;13:1593–8. 9. Koh JL, Yan TD, Glenn D, et al. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol 2009;16:327–33. 10. De Bree E, Koops W, Kroger R, et al. Peritoneal carcinomatosis from colorectal or appendiceal origin: correlation of preoperative CT with
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256
8
F. Jeune et al. / EJSO xx (2016) 1e8
11. 12.
13.
14.
15. 16.
17.
18.
intraoperative findings and evaluation of interobserver agreement. J Surg Oncol 2004;86:64–73. Dromain C, Leboulleux S, Auperin A, et al. Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT. Abdom Imaging 2008;33:87–93. Soussan M, Des Guetz G, Barrau V, et al. Comparison of FDG-PET/CT and MR with diffusion-weighted imaging for assessing peritoneal carcinomatosis from gastrointestinal malignancy. Eur Radiol 2012;22:1479–87. Caramella C, Pottier E, Borget I, et al. Value of cardiophrenic angle lymph node for the diagnosis of colorectal peritoneal carcinomatosis. Eur J Cancer 2013;49:3798–805. Elias D, Borget I, Farron M, et al. Prognostic significance of visible cardiophrenic angle lymph nodes in the presence of peritoneal metastases from colorectal cancers. Eur J Surg Oncol 2013;39:1214–8. Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995;221:29–42. Yan TD, Black D, Savady R, et al. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxomaperitonei. Ann Surg Oncol 2007;14:484–92. Phelip JM, Bouche O, Conroy T, et al. Cancer colorectal metastatique. Thesaurus National de Cancerologie Digestive February 2014. http:// www.snfge.org/tncd. Andre T, Boni C, Mounedji-Boudiaf L, et al. Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. NEJM 2004;350:2341–51.
19. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. 20. Graham NJ, Libshitz HI. Cascade of metastatic colorectal carcinoma from the liver to the anterior diaphragmatic lymph nodes. Acad Radiol 1995;2:282–5. 21. Wechsler RJ, Nazarian LN, Grady CK, et al. The association of paracardial adenopathy with hepatic metastasis found on CT arterial portography. Abdom Imaging 1995;20:201–5. 22. Yoo HJ, Lim MC, Song YJ, et al. Transabdominal cardiophrenic lymph node dissection via incised diaphragm replace conventional video-assisted thoracic surgery for cytoreductive surgery in advanced ovarian cancer. Gynecol Oncol 2013;129:341–5. 23. Hynninen J, Auranen A, Carpen O, et al. FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread. Gynecol Oncol 2012;126:64–8. 24. Aslam R, Coakley FV, Williams G, et al. Pronostic importance of superior diaphragmatic adenopathy at computed tomography in patients with resectable hepatic metastases from colorectal carcinoma. J Comput Assist Tomogr 2008;32:173–7.
Please cite this article in press as: Jeune F, et al., Cardiophrenic angle lymph node is an indicator of metastatic spread but not specifically peritoneal carcinomatosis in colorectal cancer patients, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.02.256