Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC

Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome... Ann Surg Oncol (2018) 25:2347–2356 https://doi.org/10.1245/s10434-018-6539-x OR IGINAL ARTIC L E – COLORECTAL CANCER Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC 1 2 1 1 Nina R. Sluiter, MD , Koen P. Rovers, MD , Youssra Salhi, BSc , Stijn L. Vlek, MD , Veerle M. H. Coupe´,MD, 3 4 1 2 PhD , Henk M. W. Verheul, MD, PhD , Geert Kazemier, MD, PhD , Ignace H. J. T. de Hingh, MD, PhD , and Jurriaan B. Tuynman, MD, PhD 1 2 Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery, Catharina Hospital Eindhoven, Eindhoven, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands ABSTRACT Catherina Hospital Eindhoven containing 345 CRC Introduction. Cytoreduction and hyperthermic intraperi- patients treated with the intent of HIPEC were utilized. toneal chemotherapy (HIPEC) improve the survival of Results. High Peritoneal Cancer Index (PCI) scores were colorectal cancer (CRC) patients with peritoneal metas- associated with worse DFS [hazard ratio (HR) 1.04, 95% tases. Patient selection is key since this treatment is confidence interval (CI) 1.00–1.08, p = 0.040] and OS (HR associated with high morbidity. Patients with peritoneal 1.11, 95% CI 1.07–1.15, p \ 0.001) in multivariate anal- recurrence within 1 year after previous adjuvant ysis. Furthermore, patients with peritoneal recurrence chemotherapy are thought to benefit less from HIPEC within 1 year following adjuvant chemotherapy had worse treatment; however, no published data are available to DFS (HR 2.13, 95% CI 1.26–3.61, p = 0.005) and OS (HR assist in clinical decision making. This study assessed 2.76, 95% CI 1.45–5.27, p = 0.002) than patients who did whether peritoneal recurrence within 1 year after adjuvant not receive adjuvant chemotherapy or patients with peri- chemotherapy was associated with survival after HIPEC toneal recurrence after 1 year. treatment. Conclusion. Peritoneal recurrence within 1 year after Methods. Peritoneal recurrence within 1 year after adju- previous adjuvant chemotherapy, as well as high PCI vant chemotherapy, as well as other potentially prognostic scores, are associated with poor survival after cytoreduc- clinical and pathological variables, were tested in univari- tion and HIPEC. These factors should be considered in ate and multivariate analysis for correlation with primary order to avoid high-morbidity treatment in patients who outcomes, i.e. overall survival (OS) and disease-free sur- might not benefit from such treatment. vival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Cytoreductive surgery (CRS) combined with hyper- thermic intraperitoneal chemotherapy (HIPEC) is currently the only potentially curative treatment for colorectal cancer 1,2 (CRC) patients with limited peritoneal metastases (PM). Electronic supplementary material The online version of this This approach increases median survival rates from 12 to article (https://doi.org/10.1245/s10434-018-6539-x) contains 16 months after treatment with systemic chemotherapy supplementary material, which is available to authorized users. 3–5 alone to 33–45 months, translating to a 5-year survival 4,6,7 rate of 35%. However, the combination of extensive The Author(s) 2018 surgery and HIPEC is associated with relatively high First Received: 27 February 2018; 8–10 morbidity and mortality rates of 16–64% and 1–5%, Published Online: 31 May 2018 respectively. Hence, it is of utmost importance to carefully N. R. Sluiter, MD select patients who will benefit most from this treatment. e-mail: n.sluiter@vumc.nl 2348 N. R. Sluiter et al. In recent years, there has been wide interest in the Patient Selection and Data Collection identification of prognostic factors in patients with PM, 11 12,13 both clinically and biologically. Nevertheless, the The present study was approved by the Medical Ethics lack of randomized controlled trials and the large hetero- Review Committee of the VU University Medical Center (2018.124). Patients with PM of colorectal adenocarcinoma geneity of published studies limit the use of these variables in clinical practice. The current body of prognostic char- who underwent surgery with the intent of CRS and HIPEC were considered for inclusion in this study, whereas acteristics include the Peritoneal Cancer Index (PCI; a score for peritoneal tumor burden) and biological tumor patients with synchronous metastases and low-grade characteristics such as primary tumor differentiation. appendiceal mucinous neoplasms (LAMN), as well as Some have combined variables to predict outcome after patients without histologically proven PM, were excluded. CRS and HIPEC using nomograms such as the Peritoneal The following clinicopathological and follow-up data were Surface Disease Severity Score (PSDSS) or the collected from the records of both institutions: age, sex, Colorectal Peritoneal Metastases Prognostic Surgical Score American Society of Anesthesiologists (ASA) score, 14,15 (COMPASS). These characteristics rely heavily on information on comorbidity and primary tumor character- intra- or postoperative findings, whereas selection of istics, prior treatment, and prior surgical scores (PSS). A PSS of 0 was recorded when there was no history of HIPEC patients should ideally take place before the start of treatment. Therefore, identification and validation of new abdominal surgery or only a biopsy; a PSS of 1 was recorded when abdominal surgery was performed in one of prognostic variables that can be assessed preoperatively is warranted. the abdominal regions; and a PSS of 2 was recorded for In clinical practice, patients developing PM despite surgery in two to five regions, and a PSS of 3 for surgery in treatment with adjuvant chemotherapy after primary tumor more than five regions. surgery seem to benefit less from CRS and HIPEC, espe- Intraoperatively, the extent of peritoneal disease was cially if PM are diagnosed within 1 year after primary quantified using the PCI, a numeric score that combines the tumor resection, or even during chemotherapeutic treat- lesion size (0–3) with the amount of affected abdomino- ment. Accordingly, several studies exclude patients with pelvic regions (to a maximum of 13) to a score from 0 to 21,22 PM development or progression despite systemic 39. After completion of CRS, resection outcome was 6,16,17 determined according to the maximal size of residual tumor chemotherapy from CRS and HIPEC. Moreover, certain guidelines encourage consideration of this factor in tissue: an R1 (complete) resection was scored when no 18,19 macroscopically visible tumor was left behind; an R2a the CRS and HIPEC selection process; however, no data are currently available to support this decision in resection was scored when the tumor was smaller than clinical practice. This study aimed to assess whether peri- 2.5 mm; and an R2b resection was scored when the toneal recurrence within 1 year after adjuvant residual tumor was larger than 2.5 mm. chemotherapy is associated with poor survival in CRC Postoperatively, hospital complications were docu- patients after CRS and HIPEC. mented and scored according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grading sys- METHODS tem. Follow-up data, including recurrences and death, were obtained from both hospitals. To examine whether patients who developed PM after Operative Treatment adjuvant chemotherapy had worse outcomes, patients were divided into four groups based on administration of adju- Patients from the VU University Medical Center and the Catharina Hospital Eindhoven, two tertiary referral centers, vant chemotherapy (yes vs. no) and time to diagnosis of PM after primary tumor resection (within 1 year vs. after were included in this study. Both hospitals performed CRS and HIPEC according to the same standardized protocol. more than 1 year). These categories will be referred to as follows: (1) PM within 1 year without adjuvant Cytoreductive surgery consisted of complete debulking, stripping of the affected peritoneum, and removal of the chemotherapy; (2) PM after more than 1 year without adjuvant chemotherapy; (3) PM within 1 year after adju- omentum. When deemed necessary, multiorgan resec- tions were carried out. Subsequently, if a macroscopic vant chemotherapy; and (4) PM more than 1 year after complete resection was achieved, either oxaliplatin adjuvant chemotherapy. A diagnosis of PM was based on 2 2 regular follow-up after resection of the primary tumor, (460 mg/m body surface) or mitomycin C (35 mg/m body surface) was installed in the peritoneal cavity, with a consisting of carcinoembryonic antigen (CEA) measure- ments, and ultrasound and computed tomography (CT) target temperature of 39–41 C for 30 or 90 min, respectively. scans, according to the Dutch guidelines. Clinical Prognosticators for HIPEC Surgery 2349 TABLE 1 Baseline characteristics of all patients TABLE 1 continued Characteristic n (%) Characteristic n (%) General characteristics 2 140 (81.9) All 175 3 10 (5.8) Female sex 93 (53.1) HIPEC characteristics Age, years Operative procedure Mean (SD) 61.7 (10.3) Open CRS and HIPEC 138 (78.9) ASA classification Laparoscopic CRS and HIPEC 3 (1.7) I–II 150 (85.7) Open–close 34 (19.4) III 25 (14.3) PCI Primary tumor characteristics Mean (SD) 12 (8) Location HIPEC chemotherapy Colon 159 (90.9) Mitomycin C 128 (90.8) Rectum 16 (9.1) Oxaliplatin 13 (9.2) Tumor differentiation Resection score Good/moderate 127 (84.1) R1 135 (77.1) Poor 20 (13.3) R2a 6 (3.5) Signet cell 4 (2.6) R2b 34 (19.4) Tumor histology SAE Adenocarcinoma 138 (81.7) Total 94 (53.7) Mucinous adenocarcinoma 31 (18.3) Grade I: mild 12 (6.9) T stage Grade II: moderate 35 (20.0) T1–3 107 (61.8) Grade III: severe 32 (18.3) T4 66 (38.2) Grade IV: life-threatening 13 (7.4) N stage Grade V: death 2 (1.1) N0 66 (37.9) Reoperation 32 (18.3) N1–2 108 (62.1) ASA American Society of Anesthesiologists, CAPOX Distant metastases 13 (7.4) capecitabine ? oxaliplatin, CRS cytoreductive surgery, FOLFOX leucovorin ? 5-FU ? oxaliplatin, HIPEC hyperthermic intraperi- Stage toneal therapy, PCI Peritoneal Cancer Index, PM peritoneal 1–2 62 (35.8) metastases, SAE serious adverse event, SD standard deviation, 5-FU 3–4 111 (64.2) 5-fluorouracil Perioperative treatment Primary tumor: adjuvant chemotherapy 111 (64.2) Statistical Analysis Primary tumor: adjuvant chemotherapy type Oxaliplatin 2 (1.8) Associations between clinicopathological variables were Capecitabine 4 (3.6) tested using the Fisher’s exact test or Chi square test for CAPOX 71 (64.0) two categorical/dichotomous variables, or the independent FOLFOX 14 (12.6) t test or one-way analysis of variance (ANOVA) for a 5-FU 1 (0.9) continuous, normally distributed variable with a dichoto- Unknown 19 (17.1) mous or categorical variable, respectively. A significant Development of PM difference was assumed for a p value \ 0.05 (two-sided B 1, no chemotherapy 30 (17.1) test). If necessary, variables were dichotomized to provide [ 1 year, no chemotherapy 34 (19.4) a minimum of ten events per category in the survival B 1 year after chemotherapy 36 (20.6) analysis. Dichotomization was performed on the basis of [ 1 year after chemotherapy 75 (42.9) mean values for continuous variables. Overall survival HIPEC: neoadjuvant chemotherapy 21 (12.1) (OS) and disease-free survival (DFS) were defined as the HIPEC: adjuvant chemotherapy 72 (41.4) time (in months) from the date of CRS and HIPEC to the Prior surgical score date of death from any cause or date of recurrence, 0 13 (7.6) respectively. Univariate associations between OS or DFS 1 8 (4.7) and clinicopathological variables that could be determined preoperatively were tested using the Kaplan–Meier method 2350 N. R. Sluiter et al. TABLE 2 Overview of univariate survival analysis a a Characteristic DFS p value OS p value n Median DFS (95% CI) n Median OS (95% CI) General characteristics All patients 138 12.0 (8.8–13.2) 175 27.0 (20.6–33.4) Sex Male 58 11.0 (9.4–12.6) 0.367 82 26.0 (9.7–42.3) 0.768 Female 80 12.0 (8.1–15.9) 93 28.0 (21.6–34.3) Age, years B 60 56 12.0 (8.2–15.8) 0.657 69 28.0 (18.5–37.5) 0.487 [ 60 82 11.0 (8.7–13.3) 106 27.0 (17.9–36.1) ASA classification I–II 121 12.0 (9.7–14.3) 0.309 150 27.0 (20.1–33.8) 0.171 III 17 9.0 (3.8–14.2) 25 16.0 (8.8–23.2) Primary tumor characteristics Location Colon 126 12.0 (10.0–14.0) 0.072 159 28.0 (21.7–34.3) 0.237 Rectum 12 6.0 (4.7–7.3) 16 19.0 (2.9–35.1) Differentiation Good/moderate 110 12.0 (9.8–14.2) 0.918 127 35.0 (21.6–48.4) 0.003 Poor/signet cell 16 9.0 (7.2–10.8) 24 9.0 (2.0–16.0) Histology Adenocarcinoma 117 12.0 (9.8–14.2) 0.301 138 29.0 (19.3–38.7) 0.392 Mucinous 19 9.0 (6.2–11.8) 31 23.0 (16.0–30.1) T stage T1–3 85 11.0 (8.8–13.2) 0.387 107 24.0 (15.0–33.0) 0.918 T4 51 14.0 (9.7–18.3) 66 29.0 (16.7–41.3) N stage N0 53 14.0 (6.7–21.3) 0.181 66 35.0 (20.6–49.4) 0.790 N1–2 84 11.0 (8.9–13.1) 108 24.0 (19.5–28.5) Distant metastases No 128 11.0 (8.7–13.3) 0.896 162 28.0 (21.0–35.0) 0.610 Yes 10 11.0 (2.0–20.0) 13 24.0 (18.4–29.6) Stage Stage 1–2 49 14.0 (6.1–21.9) 0.169 62 35.0 (18.4–51.6) 0.982 Stage 3–4 88 11.0 (9.0–13.0) 112 24.0 (19.8–28.2) Perioperative treatment Primary tumor: adjuvant chemotherapy No 52 12.0 (8.0–16.0) 0.194 64 35.0 (22.8–47.2) 0.658 Yes 86 11.0 (9.3–12.7) 111 24.0 (18.4–29.6) Development of PM after primary tumor resection B 1 year, no chemotherapy 25 20.0 (7.1–32.9) \ 0.001 30 42.0 (17.7–66.4) \ 0.001 [ 1 year, no chemotherapy 27 9.0 (4.5–13.5) 34 24.0 (15.9–32.1) B 1 year after chemotherapy 27 6.0 (4.1–7.9) 36 18.0 (11.7–24.3) [ 1 year after chemotherapy 59 13.0 (10.2–15.8) 75 56.0 (28.9–83.2) HIPEC: neoadjuvant chemotherapy No 124 12.0 (10.0–14.0) 0.781 154 27.0 (19.9–34.1) 0.565 Yes 14 9.0 (5.6–12.4) 21 24.0 (8.6–39.4) Clinical Prognosticators for HIPEC Surgery 2351 TABLE 2 continued a a Characteristic DFS p value OS p value n Median DFS (95% CI) n Median OS (95% CI) HIPEC: adjuvant chemotherapy No 77 11.0 (9.0–13.0) 0.496 102 24.0 (12.7–35.3) 0.167 Yes 61 12.0 (9.6–14.4) 72 28.0 (12.4–43.6) Prior surgical score 0–2 129 11.0 (8.8–13.2) 0.577 161 24.0 (16.8–31.2) 0.075 3 9 21.0 (8.2–33.8) 10 Not reached HIPEC/PM characteristics PCI B 11 91 13.0 (9.6–16.4) 0.002 94 56.0 (–) \ 0.001 [ 11 46 8.0 (4.9–11.1) 77 15.0 (9.4–20.6) HIPEC chemotherapy type Mitomycin C 126 11.0 (9.0–13.0) 0.649 128 37.0 (26.3–47.7) 0.922 Oxaliplatin 12 22.0 (0–51.5) 13 29.0 (–) ASA American Society of Anesthesiologists, CI confidence interval, DFS disease-free survival, HIPEC hyperthermic intraperitoneal therapy, OS overall survival, PCI Peritoneal Cancer Index, PM peritoneal metastases Log-rank test Oncologic Outcomes (log-rank test). Variables with a p value B 0.1 in univariate survival analysis were included in a multivariate Cox A complete overview of univariate survival analysis is regression analysis. Variable selection in the Cox model was performed using backward selection, with a threshold presented in Table 2. Figure 1 depicts the survival curves p value of 0.1 for exclusion from the model. Statistical of the statistically significant variables in univariate analyses were performed using the Statistical Package for analysis. Social Sciences (SPSS) version 23 for Windows (IBM Corporation, Armonk, NY, USA). Disease-Free Survival The median DFS of the whole cohort was 12.0 months RESULTS (95% CI 8.8–13.2). Patients with a diagnosis of PM within 1 year after adjuvant chemotherapy had a median DFS of Baseline Characteristics 6.0 months (95% CI 4.1–7.9), compared with 20.0 months (95% CI 7.1–32.9) in patients with PM within 1 year In the VU University Medical Center and Catharina Hospital Eindhoven, 345 patients with peritoneally without adjuvant chemotherapy, 9.0 months (95% CI 4.5–13.5) in patients with PM after more than 1 year metastasized CRC were treated with the intent of CRS and HIPEC from January 2008 until May 2016. After exclusion without adjuvant chemotherapy, and 13.0 months (95% CI 10.2–15.8) in patients with PM more than 1 year after of patients with synchronous metastases, other pathology subtypes, and patients without histologically proven PM, adjuvant chemotherapy (p \ 0.001) (Fig. 1a). Further- 175 patients were selected for further analysis. Table 1 more, patients with a PCI [ 11 had a DFS of 8.0 months (95% CI 4.9–11.1), compared with 13.0 months (95% CI represents the baseline characteristics of all patients. The majority of baseline characteristics did not differ 9.6–16.4) in patients with lower PCI scores (p = 0.002) (Fig. 1b). Other factors that were considered in univariate significantly between the group of patients with PM within 1 year after adjuvant chemotherapy and the groups of survival analysis included gender, sex, age, ASA classifi- cation, poor or signet cell tumor differentiation, mucinous patients who did not receive adjuvant chemotherapy or were diagnosed with PM after more than 1 year (electronic tumor type, primary tumor location, primary tumor stage, perioperative treatment, and type of chemotherapy, and supplementary Table 1). As expected, lymph node involvement at the time of primary tumor resection was were therefore not associated with DFS (Table 2). more frequently diagnosed in patients who received adju- vant chemotherapy (p \ 0.001). 2352 N. R. Sluiter et al. a Disease-free survival - Development of PM c Overall survival - Development of PM 1,0 1,0 0,8 0,8 0,6 0,6 56.0 months 0,4 0,4 42.0 months 18.0 months 20.0 months 27.0 months 12.0 months 0,2 0,2 13.0 months 9.0 months 24.0 months 0,0 0,0 6.0 months p<0.001 p<0.001 020 40 60 80 020 40 60 80 Overall survival (months) Disease-free survival (months) PM ≤ 1 year, no chemotherapy (n=30) PM ≤ 1 year, no chemotherapy (n=25) PM > 1 year, no chemotherapy (n=34) PM > 1 year, no chemotherapy (n=27) PM ≤ 1 year after chemotherapy (n=36) PM ≤ 1 year after chemotherapy (n=27) PM > 1 year after chemotherapy (n=75) PM > 1 year after chemotherapy (n=59) All patients (n=175) All patients (n=138) d Overall survival - PCI b Disease-free survival - PCI 1,0 1,0 0,8 0,8 56.0 months 0,6 0,6 0,4 0,4 13.0 months 27.0 months 0,2 0,2 15.0 months 12.0 months 8.0 months p=0.002 0,0 0,0 p<0.001 020 40 60 80 020 40 60 80 Disease-free survival (months) Overall survival (months) PCI ≤11 (n=91) PCI ≤11 (n=94) PCI >11 (n=46) PCI >11 (n=77) All patients (n=138) All patients (n=175) e Overall survival - Differentiation 1,0 0,8 0,6 0,4 35.0 months 9.0 months 0,2 27.0 months 0,0 p=0.003 020 40 60 80 Overall survival (months) Good/moderate differenaon (n=127) Poor/signet cell differenaon (n=24) All paents (n=175) Clinical Prognosticators for HIPEC Surgery 2353 b FIG. 1 Kaplan–Meier curves of all patients. Graphs (a) and 95% CI 9.4–20.6) compared with patients with a PCI B 11 (b) depict the disease-free survival curves: (a) patients with PM (56.0 months, 95% CI –) (p \ 0.001; Fig. 1d). Third, a within 1 year without chemotherapy, versus PM after more than poor or signet cell tumor differentiation was associated 1 year without chemotherapy, versus PM within 1 year after with a worse median OS of 9.0 months (95% CI 2.0–16.0), chemotherapy, versus PM more than 1 year after chemotherapy; (b) patients with a PCI B 11 versus patients with a PCI [ 11. Graphs compared with 35.0 months (95% CI 21.6–48.4) in patients c–e depict the overall survival curves: (c) patients with PM within with well to moderately differentiated primary tumors 1 year without chemotherapy, versus PM after more than 1 year (p = 0.003) (Fig. 1e). without chemotherapy, versus PM within 1 year after chemotherapy, versus PM more than 1 year after chemotherapy; (d) patients with a PCI B 11 versus patients with a PCI [ 11; (e) patients with poor/ Multivariate Analysis signet cell differentiation versus patients with good/moderate differentiation. PM peritoneal metastases, PCI Peritoneal Cancer Both high PCI (HR 1.04 for each PCI point, 95% CI Index 1.00–1.08, p = 0.040) and peritoneal recurrence within 1 year after adjuvant chemotherapy (HR 2.13, 95% CI 1.26–3.61, p = 0.005) remained significant in the multi- Overall Survival variate DFS model (reference category: PM more than 1 year after chemotherapy) (Table 3). In the multivariate The median OS of the entire cohort was 27.0 months OS model, only peritoneal recurrence within 1 year after (95% CI 20.6–33.4). Patients with a diagnosis of PM adjuvant chemotherapy (HR 2.76, 95% CI 1.45–5.27, within 1 year after adjuvant chemotherapy had worse p \ 0.002) and high PCI scores (HR 1.11 for each PCI median OS (18.0 months, 95% CI 11.7–24.3) than patients point, 95% CI 1.07–1.15, p \ 0.001) were associated with with PM within 1 year without adjuvant chemotherapy worse OS (reference category: PM more than 1 year after (42.0 months, 95% CI 17.7–66.4), patients with PM after chemotherapy) (Table 3). Variables that had a p value more than 1 year without adjuvant chemotherapy B 0.1 in univariate survival analysis, but were excluded (24.0 months, 95% CI 15.9–32.1), and patients with PM from the final model after multivariate Cox regression more than 1 year after adjuvant chemotherapy analysis, were primary tumor location (p = 0.130) for DFS (56.0 months, 95% CI 28.9–83.2) (p \ 0.001). PCI scores and primary tumor differentiation (p = 0.118) and PSS [ 11 were associated with worse median OS (15 months, (p = 0.376) for OS. DISCUSSION TABLE 3 Final model resulting from multivariate survival analysis Variable Hazard rate (95% CI) p value This prospective cohort study shows that peritoneal recurrence within 1 year after previous adjuvant Disease-free survival chemotherapy and a high initial PCI index are the most PCI 1.04 (1.00–1.08) 0.040 important risk factors for poor DFS and OS in patients with Development of PM peritoneally metastasized CRC. This effect was indepen- [ 1 year after chemotherapy Reference 0.001 dent of primary tumor stage or tumor differentiation. In B 1 year, no chemotherapy 0.57 (0.31–1.06) 0.075 175 patients treated with the intent of CRS and HIPEC in [ 1 year, no chemotherapy 1.20 (0.67–2.19) 0.535 two tertiary referral centers, patients with PM diagnosed B 1 year after chemotherapy 2.13 (1.26–3.61) 0.005 within 1 year after adjuvant chemotherapy had worse Overall survival median DFS (HR 2.13, p = 0.005) and OS (HR 2.76, PCI 1.11 (1.07–1.15) \ 0.001 p \ 0.001) than patients not treated with adjuvant Development of PM chemotherapy or patients who were diagnosed with PM [ 1 year after chemotherapy Reference 0.019 after more than 1 year in both univariate and multivariate B 1 year, no chemotherapy 1.34 (0.62–2.92) 0.454 analysis. A high PCI was the only other variable associated [ 1 year, no chemotherapy 1.89 (0.95–3.76) 0.071 with DFS and OS in the multivariate models (HR 1.04, B 1 year after chemotherapy 2.76 (1.45–5.27) 0.002 p = 0.040; and HR 1.11, p \ 0.001, respectively). Variables with a p value B 0.1 in univariate survival analysis were Cytoreduction and HIPEC is currently the preferred included in a multivariate Cox regression analysis: (1) primary tumor 1 2 treatment option for patients with PM of CRC, , but due location, development of PM, and PCI for DFS; (2) primary tumor to the relatively high morbidity rates associated with this differentiation, development of PM, PSS, and PCI for OS procedure, the need for careful patient selection should be CI confidence interval, DFS disease-free survival, OS overall sur- 8–10 vival, PCI Peritoneal Cancer Index, PM peritoneal metastases, PSS emphasized. Preoperative decision making is crucial, prior surgical score warranting practical clinical and pathological prognostic 2354 N. R. Sluiter et al. factors. The diagnosis of PM relatively shortly after prior taken into account. First, our data are possibly subjected to chemotherapy can be assessed preoperatively in contrast to selection bias that is associated with cohort studies. Sec- well-established prognostic factors that are obtained after ond, based on our results, we can conclude that patients or during the operation, such as PCI, resection scores and with early peritoneal recurrence after adjuvant combined prognostic scores, including the PSDSS and chemotherapy have decreased survival; however, there is 14,15 the relatively novel COMPASS. Hence, the selection no solid evidence for an alternative treatment. The effect of of patients with early peritoneal recurrence after prior second-line chemotherapy in this subgroup of patients, chemotherapy might help identify patients who benefit less with a poor response to prior chemotherapy, has yet to be from HIPEC, in this way preventing unnecessary exposure proven. Palliative treatment regimens are heterogeneous in to an invasive procedure that may even harm the patient. this patient group, which makes it hard to gather valid The association between early peritoneal recurrences after retrospective data from a control cohort. Thereby, new adjuvant chemotherapy and poor outcome could be options arise for patients not suitable for HIPEC treatment, explained by a more aggressive biological tumor behavior, including Pressurized IntraPeritoneal Aerosol Chemother- leading to a poor response to chemotherapy and, subse- apy (PIPAC). This innovative therapy consists of repetitive quently, a poor response to HIPEC treatment. intraperitoneal administration of aerosolized chemotherapy Several other study groups have already excluded and has already been shown to be feasible and safe in end- patients with rapid PM development or progression under stage PM originating from several primaries. For CRC 6,16,17 systemic chemotherapy from CRS and HIPEC. In patients, PIPAC with oxaliplatin, whether in combination addition, various guidelines recommend the use of this with systemic chemotherapy or not, showed encouraging selection criterion in the workup of potential HIPEC can- results. Future studies in well-defined populations should 18,19 didates. In contrast, two relatively small retrospective demonstrate the potential role of PIPAC in patients with studies argued that there is no reason for excluding patients irresectable PM of CRC since the current evidence for with quick peritoneal relapses after prior chemotherapy PIPAC in this population is scarce. from HIPEC. A single-center study including 21 cases To provide the answers necessary to take our results found a median OS of 28 months in patients who did not into the clinical practice, a prospective study should com- respond to adjuvant chemotherapy, which led the authors to pare HIPEC with systemic chemotherapy in patients with conclude that the survival of this group was comparable PM within 1 year after chemotherapy. Until then, CRS and with survival rates in other HIPEC patients ; however, this HIPEC may be considered a valid option in this group of study did not include a control group. Another retrospec- patients if the peritoneal tumor burden is limited (PCI tive study compared 19 patients with tumor progression B 11). Therefore, whether the limited DFS observed in this despite neoadjuvant chemotherapy with the same number cohort of patients with early PM development justifies the of patients with stable disease under neoadjuvant high morbidity and mortality rates of the CRS and HIPEC chemotherapy, resulting in an insignificant survival dif- procedure should be carefully considered. Next to identi- ference between these groups. The relatively small fication of clinical prognosticators, future research should groups in both studies might hamper these outcomes and focus on identifying molecular tissue and blood-borne conclusions. characteristics to select patients with biologically favorable High PCI emerged as a second characteristic that was tumor characteristics responding best to further aggressive associated with poor outcome in the present cohort. This therapies such as CRS and HIPEC. Additionally, identifi- variable is an established prognostic factor and is widely cation of biomarkers and clinical prognostic factors could used for the identification of patients with curable peri- potentially help us optimize the HIPEC procedure, aiming toneal disease, defined as a PCI B 20. The present for a personalized treatment rather than the current one- results, supported by the available literature, emphasize the size-fits-all approach. This can be illustrated by selection of importance of performing a diagnostic laparoscopy to the most effective chemotherapeutic drug based on the determine PCI indices prior to HIPEC surgery, especially prediction of individual chemotherapeutic responses, since current imaging techniques lack sensitivity for which may eventually result in a tailored and more robust 28,29 detection of PM. No other variables were associated HIPEC treatment, leading to improved oncologic outcomes with DFS and OS in the multivariate models. Importantly, in subgroups with relatively poor prognosis. the primary tumor stage was not a significant risk factor for poor DFS and OS. To our knowledge, this is currently the largest study showing that the development of PM following adjuvant therapy is a poor prognostic factor after treatment with CRS and HIPEC. However, some limitations should be Clinical Prognosticators for HIPEC Surgery 2355 perioperative intraperitoneal chemotherapy for colorectal peri- CONCLUSIONS toneal carcinomatosis. World J Surg. 2010;34(1):70–78. 10. Ihemelandu CU, McQuellon R, Shen P, Stewart JH, Votano- The present study found support for considering both poulos K, Levine EA. Predicting postoperative morbidity PCI and early peritoneal recurrence after adjuvant therapy following cytoreductive surgery with hyperthermic intraperi- toneal chemotherapy (CS ? HIPEC) with preoperative FACT-C in patient selection prior to CRS and HIPEC. Prospective (Functional Assessment of Cancer Therapy) and patient-rated trials might help us move forward by confirming or performance status. Ann Surg Oncol. 2013;20(11):3519–3526. rejecting factors associated with outcome in retrospective 11. Kwakman R, Schrama AM, van Olmen JP, et al. Clinicopatho- studies, ultimately providing clear guidelines to identify logical parameters in patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal the right patients for the right treatment. cancer metastases: a meta-analysis. Ann Surg. 2016;263(6):1102–1111. DISCLOSURES Nina R. Sluiter, Koen P. Rovers, Youssra Salhi, 12. Sluiter NR, de Cuba EM, Kwakman R, et al. Versican and vas- Stijn L. Vlek, Veerle M. H. Coupe ´, Henk M. W. Verheul, Geert cular endothelial growth factor expression levels in peritoneal Kazemier, Ignace H. J. T. de Hingh, and Jurriaan B. Tuynman declare metastases from colorectal cancer are associated with survival no conflicts of interest. after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Clin Exp Metastasis. 2016;33(4):297–307. 13. de Cuba EM, de Hingh IH, Sluiter NR, et al. Angiogenesis-re- OPEN ACCESS This article is distributed under the terms of the lated markers and prognosis after cytoreductive surgery and Creative Commons Attribution 4.0 International License (http://crea hyperthermic intraperitoneal chemotherapy for metastatic col- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, orectal cancer. Ann Surg Oncol. 2016;23(5):1601–1608. distribution, and reproduction in any medium, provided you give 14. Simkens GA, van Oudheusden TR, Nieboer D, et al. 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Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC

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Medicine & Public Health; Surgical Oncology; Oncology; Surgery
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Abstract

Ann Surg Oncol (2018) 25:2347–2356 https://doi.org/10.1245/s10434-018-6539-x OR IGINAL ARTIC L E – COLORECTAL CANCER Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC 1 2 1 1 Nina R. Sluiter, MD , Koen P. Rovers, MD , Youssra Salhi, BSc , Stijn L. Vlek, MD , Veerle M. H. Coupe´,MD, 3 4 1 2 PhD , Henk M. W. Verheul, MD, PhD , Geert Kazemier, MD, PhD , Ignace H. J. T. de Hingh, MD, PhD , and Jurriaan B. Tuynman, MD, PhD 1 2 Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery, Catharina Hospital Eindhoven, Eindhoven, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands ABSTRACT Catherina Hospital Eindhoven containing 345 CRC Introduction. Cytoreduction and hyperthermic intraperi- patients treated with the intent of HIPEC were utilized. toneal chemotherapy (HIPEC) improve the survival of Results. High Peritoneal Cancer Index (PCI) scores were colorectal cancer (CRC) patients with peritoneal metas- associated with worse DFS [hazard ratio (HR) 1.04, 95% tases. Patient selection is key since this treatment is confidence interval (CI) 1.00–1.08, p = 0.040] and OS (HR associated with high morbidity. Patients with peritoneal 1.11, 95% CI 1.07–1.15, p \ 0.001) in multivariate anal- recurrence within 1 year after previous adjuvant ysis. Furthermore, patients with peritoneal recurrence chemotherapy are thought to benefit less from HIPEC within 1 year following adjuvant chemotherapy had worse treatment; however, no published data are available to DFS (HR 2.13, 95% CI 1.26–3.61, p = 0.005) and OS (HR assist in clinical decision making. This study assessed 2.76, 95% CI 1.45–5.27, p = 0.002) than patients who did whether peritoneal recurrence within 1 year after adjuvant not receive adjuvant chemotherapy or patients with peri- chemotherapy was associated with survival after HIPEC toneal recurrence after 1 year. treatment. Conclusion. Peritoneal recurrence within 1 year after Methods. Peritoneal recurrence within 1 year after adju- previous adjuvant chemotherapy, as well as high PCI vant chemotherapy, as well as other potentially prognostic scores, are associated with poor survival after cytoreduc- clinical and pathological variables, were tested in univari- tion and HIPEC. These factors should be considered in ate and multivariate analysis for correlation with primary order to avoid high-morbidity treatment in patients who outcomes, i.e. overall survival (OS) and disease-free sur- might not benefit from such treatment. vival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Cytoreductive surgery (CRS) combined with hyper- thermic intraperitoneal chemotherapy (HIPEC) is currently the only potentially curative treatment for colorectal cancer 1,2 (CRC) patients with limited peritoneal metastases (PM). Electronic supplementary material The online version of this This approach increases median survival rates from 12 to article (https://doi.org/10.1245/s10434-018-6539-x) contains 16 months after treatment with systemic chemotherapy supplementary material, which is available to authorized users. 3–5 alone to 33–45 months, translating to a 5-year survival 4,6,7 rate of 35%. However, the combination of extensive The Author(s) 2018 surgery and HIPEC is associated with relatively high First Received: 27 February 2018; 8–10 morbidity and mortality rates of 16–64% and 1–5%, Published Online: 31 May 2018 respectively. Hence, it is of utmost importance to carefully N. R. Sluiter, MD select patients who will benefit most from this treatment. e-mail: n.sluiter@vumc.nl 2348 N. R. Sluiter et al. In recent years, there has been wide interest in the Patient Selection and Data Collection identification of prognostic factors in patients with PM, 11 12,13 both clinically and biologically. Nevertheless, the The present study was approved by the Medical Ethics lack of randomized controlled trials and the large hetero- Review Committee of the VU University Medical Center (2018.124). Patients with PM of colorectal adenocarcinoma geneity of published studies limit the use of these variables in clinical practice. The current body of prognostic char- who underwent surgery with the intent of CRS and HIPEC were considered for inclusion in this study, whereas acteristics include the Peritoneal Cancer Index (PCI; a score for peritoneal tumor burden) and biological tumor patients with synchronous metastases and low-grade characteristics such as primary tumor differentiation. appendiceal mucinous neoplasms (LAMN), as well as Some have combined variables to predict outcome after patients without histologically proven PM, were excluded. CRS and HIPEC using nomograms such as the Peritoneal The following clinicopathological and follow-up data were Surface Disease Severity Score (PSDSS) or the collected from the records of both institutions: age, sex, Colorectal Peritoneal Metastases Prognostic Surgical Score American Society of Anesthesiologists (ASA) score, 14,15 (COMPASS). These characteristics rely heavily on information on comorbidity and primary tumor character- intra- or postoperative findings, whereas selection of istics, prior treatment, and prior surgical scores (PSS). A PSS of 0 was recorded when there was no history of HIPEC patients should ideally take place before the start of treatment. Therefore, identification and validation of new abdominal surgery or only a biopsy; a PSS of 1 was recorded when abdominal surgery was performed in one of prognostic variables that can be assessed preoperatively is warranted. the abdominal regions; and a PSS of 2 was recorded for In clinical practice, patients developing PM despite surgery in two to five regions, and a PSS of 3 for surgery in treatment with adjuvant chemotherapy after primary tumor more than five regions. surgery seem to benefit less from CRS and HIPEC, espe- Intraoperatively, the extent of peritoneal disease was cially if PM are diagnosed within 1 year after primary quantified using the PCI, a numeric score that combines the tumor resection, or even during chemotherapeutic treat- lesion size (0–3) with the amount of affected abdomino- ment. Accordingly, several studies exclude patients with pelvic regions (to a maximum of 13) to a score from 0 to 21,22 PM development or progression despite systemic 39. After completion of CRS, resection outcome was 6,16,17 determined according to the maximal size of residual tumor chemotherapy from CRS and HIPEC. Moreover, certain guidelines encourage consideration of this factor in tissue: an R1 (complete) resection was scored when no 18,19 macroscopically visible tumor was left behind; an R2a the CRS and HIPEC selection process; however, no data are currently available to support this decision in resection was scored when the tumor was smaller than clinical practice. This study aimed to assess whether peri- 2.5 mm; and an R2b resection was scored when the toneal recurrence within 1 year after adjuvant residual tumor was larger than 2.5 mm. chemotherapy is associated with poor survival in CRC Postoperatively, hospital complications were docu- patients after CRS and HIPEC. mented and scored according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grading sys- METHODS tem. Follow-up data, including recurrences and death, were obtained from both hospitals. To examine whether patients who developed PM after Operative Treatment adjuvant chemotherapy had worse outcomes, patients were divided into four groups based on administration of adju- Patients from the VU University Medical Center and the Catharina Hospital Eindhoven, two tertiary referral centers, vant chemotherapy (yes vs. no) and time to diagnosis of PM after primary tumor resection (within 1 year vs. after were included in this study. Both hospitals performed CRS and HIPEC according to the same standardized protocol. more than 1 year). These categories will be referred to as follows: (1) PM within 1 year without adjuvant Cytoreductive surgery consisted of complete debulking, stripping of the affected peritoneum, and removal of the chemotherapy; (2) PM after more than 1 year without adjuvant chemotherapy; (3) PM within 1 year after adju- omentum. When deemed necessary, multiorgan resec- tions were carried out. Subsequently, if a macroscopic vant chemotherapy; and (4) PM more than 1 year after complete resection was achieved, either oxaliplatin adjuvant chemotherapy. A diagnosis of PM was based on 2 2 regular follow-up after resection of the primary tumor, (460 mg/m body surface) or mitomycin C (35 mg/m body surface) was installed in the peritoneal cavity, with a consisting of carcinoembryonic antigen (CEA) measure- ments, and ultrasound and computed tomography (CT) target temperature of 39–41 C for 30 or 90 min, respectively. scans, according to the Dutch guidelines. Clinical Prognosticators for HIPEC Surgery 2349 TABLE 1 Baseline characteristics of all patients TABLE 1 continued Characteristic n (%) Characteristic n (%) General characteristics 2 140 (81.9) All 175 3 10 (5.8) Female sex 93 (53.1) HIPEC characteristics Age, years Operative procedure Mean (SD) 61.7 (10.3) Open CRS and HIPEC 138 (78.9) ASA classification Laparoscopic CRS and HIPEC 3 (1.7) I–II 150 (85.7) Open–close 34 (19.4) III 25 (14.3) PCI Primary tumor characteristics Mean (SD) 12 (8) Location HIPEC chemotherapy Colon 159 (90.9) Mitomycin C 128 (90.8) Rectum 16 (9.1) Oxaliplatin 13 (9.2) Tumor differentiation Resection score Good/moderate 127 (84.1) R1 135 (77.1) Poor 20 (13.3) R2a 6 (3.5) Signet cell 4 (2.6) R2b 34 (19.4) Tumor histology SAE Adenocarcinoma 138 (81.7) Total 94 (53.7) Mucinous adenocarcinoma 31 (18.3) Grade I: mild 12 (6.9) T stage Grade II: moderate 35 (20.0) T1–3 107 (61.8) Grade III: severe 32 (18.3) T4 66 (38.2) Grade IV: life-threatening 13 (7.4) N stage Grade V: death 2 (1.1) N0 66 (37.9) Reoperation 32 (18.3) N1–2 108 (62.1) ASA American Society of Anesthesiologists, CAPOX Distant metastases 13 (7.4) capecitabine ? oxaliplatin, CRS cytoreductive surgery, FOLFOX leucovorin ? 5-FU ? oxaliplatin, HIPEC hyperthermic intraperi- Stage toneal therapy, PCI Peritoneal Cancer Index, PM peritoneal 1–2 62 (35.8) metastases, SAE serious adverse event, SD standard deviation, 5-FU 3–4 111 (64.2) 5-fluorouracil Perioperative treatment Primary tumor: adjuvant chemotherapy 111 (64.2) Statistical Analysis Primary tumor: adjuvant chemotherapy type Oxaliplatin 2 (1.8) Associations between clinicopathological variables were Capecitabine 4 (3.6) tested using the Fisher’s exact test or Chi square test for CAPOX 71 (64.0) two categorical/dichotomous variables, or the independent FOLFOX 14 (12.6) t test or one-way analysis of variance (ANOVA) for a 5-FU 1 (0.9) continuous, normally distributed variable with a dichoto- Unknown 19 (17.1) mous or categorical variable, respectively. A significant Development of PM difference was assumed for a p value \ 0.05 (two-sided B 1, no chemotherapy 30 (17.1) test). If necessary, variables were dichotomized to provide [ 1 year, no chemotherapy 34 (19.4) a minimum of ten events per category in the survival B 1 year after chemotherapy 36 (20.6) analysis. Dichotomization was performed on the basis of [ 1 year after chemotherapy 75 (42.9) mean values for continuous variables. Overall survival HIPEC: neoadjuvant chemotherapy 21 (12.1) (OS) and disease-free survival (DFS) were defined as the HIPEC: adjuvant chemotherapy 72 (41.4) time (in months) from the date of CRS and HIPEC to the Prior surgical score date of death from any cause or date of recurrence, 0 13 (7.6) respectively. Univariate associations between OS or DFS 1 8 (4.7) and clinicopathological variables that could be determined preoperatively were tested using the Kaplan–Meier method 2350 N. R. Sluiter et al. TABLE 2 Overview of univariate survival analysis a a Characteristic DFS p value OS p value n Median DFS (95% CI) n Median OS (95% CI) General characteristics All patients 138 12.0 (8.8–13.2) 175 27.0 (20.6–33.4) Sex Male 58 11.0 (9.4–12.6) 0.367 82 26.0 (9.7–42.3) 0.768 Female 80 12.0 (8.1–15.9) 93 28.0 (21.6–34.3) Age, years B 60 56 12.0 (8.2–15.8) 0.657 69 28.0 (18.5–37.5) 0.487 [ 60 82 11.0 (8.7–13.3) 106 27.0 (17.9–36.1) ASA classification I–II 121 12.0 (9.7–14.3) 0.309 150 27.0 (20.1–33.8) 0.171 III 17 9.0 (3.8–14.2) 25 16.0 (8.8–23.2) Primary tumor characteristics Location Colon 126 12.0 (10.0–14.0) 0.072 159 28.0 (21.7–34.3) 0.237 Rectum 12 6.0 (4.7–7.3) 16 19.0 (2.9–35.1) Differentiation Good/moderate 110 12.0 (9.8–14.2) 0.918 127 35.0 (21.6–48.4) 0.003 Poor/signet cell 16 9.0 (7.2–10.8) 24 9.0 (2.0–16.0) Histology Adenocarcinoma 117 12.0 (9.8–14.2) 0.301 138 29.0 (19.3–38.7) 0.392 Mucinous 19 9.0 (6.2–11.8) 31 23.0 (16.0–30.1) T stage T1–3 85 11.0 (8.8–13.2) 0.387 107 24.0 (15.0–33.0) 0.918 T4 51 14.0 (9.7–18.3) 66 29.0 (16.7–41.3) N stage N0 53 14.0 (6.7–21.3) 0.181 66 35.0 (20.6–49.4) 0.790 N1–2 84 11.0 (8.9–13.1) 108 24.0 (19.5–28.5) Distant metastases No 128 11.0 (8.7–13.3) 0.896 162 28.0 (21.0–35.0) 0.610 Yes 10 11.0 (2.0–20.0) 13 24.0 (18.4–29.6) Stage Stage 1–2 49 14.0 (6.1–21.9) 0.169 62 35.0 (18.4–51.6) 0.982 Stage 3–4 88 11.0 (9.0–13.0) 112 24.0 (19.8–28.2) Perioperative treatment Primary tumor: adjuvant chemotherapy No 52 12.0 (8.0–16.0) 0.194 64 35.0 (22.8–47.2) 0.658 Yes 86 11.0 (9.3–12.7) 111 24.0 (18.4–29.6) Development of PM after primary tumor resection B 1 year, no chemotherapy 25 20.0 (7.1–32.9) \ 0.001 30 42.0 (17.7–66.4) \ 0.001 [ 1 year, no chemotherapy 27 9.0 (4.5–13.5) 34 24.0 (15.9–32.1) B 1 year after chemotherapy 27 6.0 (4.1–7.9) 36 18.0 (11.7–24.3) [ 1 year after chemotherapy 59 13.0 (10.2–15.8) 75 56.0 (28.9–83.2) HIPEC: neoadjuvant chemotherapy No 124 12.0 (10.0–14.0) 0.781 154 27.0 (19.9–34.1) 0.565 Yes 14 9.0 (5.6–12.4) 21 24.0 (8.6–39.4) Clinical Prognosticators for HIPEC Surgery 2351 TABLE 2 continued a a Characteristic DFS p value OS p value n Median DFS (95% CI) n Median OS (95% CI) HIPEC: adjuvant chemotherapy No 77 11.0 (9.0–13.0) 0.496 102 24.0 (12.7–35.3) 0.167 Yes 61 12.0 (9.6–14.4) 72 28.0 (12.4–43.6) Prior surgical score 0–2 129 11.0 (8.8–13.2) 0.577 161 24.0 (16.8–31.2) 0.075 3 9 21.0 (8.2–33.8) 10 Not reached HIPEC/PM characteristics PCI B 11 91 13.0 (9.6–16.4) 0.002 94 56.0 (–) \ 0.001 [ 11 46 8.0 (4.9–11.1) 77 15.0 (9.4–20.6) HIPEC chemotherapy type Mitomycin C 126 11.0 (9.0–13.0) 0.649 128 37.0 (26.3–47.7) 0.922 Oxaliplatin 12 22.0 (0–51.5) 13 29.0 (–) ASA American Society of Anesthesiologists, CI confidence interval, DFS disease-free survival, HIPEC hyperthermic intraperitoneal therapy, OS overall survival, PCI Peritoneal Cancer Index, PM peritoneal metastases Log-rank test Oncologic Outcomes (log-rank test). Variables with a p value B 0.1 in univariate survival analysis were included in a multivariate Cox A complete overview of univariate survival analysis is regression analysis. Variable selection in the Cox model was performed using backward selection, with a threshold presented in Table 2. Figure 1 depicts the survival curves p value of 0.1 for exclusion from the model. Statistical of the statistically significant variables in univariate analyses were performed using the Statistical Package for analysis. Social Sciences (SPSS) version 23 for Windows (IBM Corporation, Armonk, NY, USA). Disease-Free Survival The median DFS of the whole cohort was 12.0 months RESULTS (95% CI 8.8–13.2). Patients with a diagnosis of PM within 1 year after adjuvant chemotherapy had a median DFS of Baseline Characteristics 6.0 months (95% CI 4.1–7.9), compared with 20.0 months (95% CI 7.1–32.9) in patients with PM within 1 year In the VU University Medical Center and Catharina Hospital Eindhoven, 345 patients with peritoneally without adjuvant chemotherapy, 9.0 months (95% CI 4.5–13.5) in patients with PM after more than 1 year metastasized CRC were treated with the intent of CRS and HIPEC from January 2008 until May 2016. After exclusion without adjuvant chemotherapy, and 13.0 months (95% CI 10.2–15.8) in patients with PM more than 1 year after of patients with synchronous metastases, other pathology subtypes, and patients without histologically proven PM, adjuvant chemotherapy (p \ 0.001) (Fig. 1a). Further- 175 patients were selected for further analysis. Table 1 more, patients with a PCI [ 11 had a DFS of 8.0 months (95% CI 4.9–11.1), compared with 13.0 months (95% CI represents the baseline characteristics of all patients. The majority of baseline characteristics did not differ 9.6–16.4) in patients with lower PCI scores (p = 0.002) (Fig. 1b). Other factors that were considered in univariate significantly between the group of patients with PM within 1 year after adjuvant chemotherapy and the groups of survival analysis included gender, sex, age, ASA classifi- cation, poor or signet cell tumor differentiation, mucinous patients who did not receive adjuvant chemotherapy or were diagnosed with PM after more than 1 year (electronic tumor type, primary tumor location, primary tumor stage, perioperative treatment, and type of chemotherapy, and supplementary Table 1). As expected, lymph node involvement at the time of primary tumor resection was were therefore not associated with DFS (Table 2). more frequently diagnosed in patients who received adju- vant chemotherapy (p \ 0.001). 2352 N. R. Sluiter et al. a Disease-free survival - Development of PM c Overall survival - Development of PM 1,0 1,0 0,8 0,8 0,6 0,6 56.0 months 0,4 0,4 42.0 months 18.0 months 20.0 months 27.0 months 12.0 months 0,2 0,2 13.0 months 9.0 months 24.0 months 0,0 0,0 6.0 months p<0.001 p<0.001 020 40 60 80 020 40 60 80 Overall survival (months) Disease-free survival (months) PM ≤ 1 year, no chemotherapy (n=30) PM ≤ 1 year, no chemotherapy (n=25) PM > 1 year, no chemotherapy (n=34) PM > 1 year, no chemotherapy (n=27) PM ≤ 1 year after chemotherapy (n=36) PM ≤ 1 year after chemotherapy (n=27) PM > 1 year after chemotherapy (n=75) PM > 1 year after chemotherapy (n=59) All patients (n=175) All patients (n=138) d Overall survival - PCI b Disease-free survival - PCI 1,0 1,0 0,8 0,8 56.0 months 0,6 0,6 0,4 0,4 13.0 months 27.0 months 0,2 0,2 15.0 months 12.0 months 8.0 months p=0.002 0,0 0,0 p<0.001 020 40 60 80 020 40 60 80 Disease-free survival (months) Overall survival (months) PCI ≤11 (n=91) PCI ≤11 (n=94) PCI >11 (n=46) PCI >11 (n=77) All patients (n=138) All patients (n=175) e Overall survival - Differentiation 1,0 0,8 0,6 0,4 35.0 months 9.0 months 0,2 27.0 months 0,0 p=0.003 020 40 60 80 Overall survival (months) Good/moderate differenaon (n=127) Poor/signet cell differenaon (n=24) All paents (n=175) Clinical Prognosticators for HIPEC Surgery 2353 b FIG. 1 Kaplan–Meier curves of all patients. Graphs (a) and 95% CI 9.4–20.6) compared with patients with a PCI B 11 (b) depict the disease-free survival curves: (a) patients with PM (56.0 months, 95% CI –) (p \ 0.001; Fig. 1d). Third, a within 1 year without chemotherapy, versus PM after more than poor or signet cell tumor differentiation was associated 1 year without chemotherapy, versus PM within 1 year after with a worse median OS of 9.0 months (95% CI 2.0–16.0), chemotherapy, versus PM more than 1 year after chemotherapy; (b) patients with a PCI B 11 versus patients with a PCI [ 11. Graphs compared with 35.0 months (95% CI 21.6–48.4) in patients c–e depict the overall survival curves: (c) patients with PM within with well to moderately differentiated primary tumors 1 year without chemotherapy, versus PM after more than 1 year (p = 0.003) (Fig. 1e). without chemotherapy, versus PM within 1 year after chemotherapy, versus PM more than 1 year after chemotherapy; (d) patients with a PCI B 11 versus patients with a PCI [ 11; (e) patients with poor/ Multivariate Analysis signet cell differentiation versus patients with good/moderate differentiation. PM peritoneal metastases, PCI Peritoneal Cancer Both high PCI (HR 1.04 for each PCI point, 95% CI Index 1.00–1.08, p = 0.040) and peritoneal recurrence within 1 year after adjuvant chemotherapy (HR 2.13, 95% CI 1.26–3.61, p = 0.005) remained significant in the multi- Overall Survival variate DFS model (reference category: PM more than 1 year after chemotherapy) (Table 3). In the multivariate The median OS of the entire cohort was 27.0 months OS model, only peritoneal recurrence within 1 year after (95% CI 20.6–33.4). Patients with a diagnosis of PM adjuvant chemotherapy (HR 2.76, 95% CI 1.45–5.27, within 1 year after adjuvant chemotherapy had worse p \ 0.002) and high PCI scores (HR 1.11 for each PCI median OS (18.0 months, 95% CI 11.7–24.3) than patients point, 95% CI 1.07–1.15, p \ 0.001) were associated with with PM within 1 year without adjuvant chemotherapy worse OS (reference category: PM more than 1 year after (42.0 months, 95% CI 17.7–66.4), patients with PM after chemotherapy) (Table 3). Variables that had a p value more than 1 year without adjuvant chemotherapy B 0.1 in univariate survival analysis, but were excluded (24.0 months, 95% CI 15.9–32.1), and patients with PM from the final model after multivariate Cox regression more than 1 year after adjuvant chemotherapy analysis, were primary tumor location (p = 0.130) for DFS (56.0 months, 95% CI 28.9–83.2) (p \ 0.001). PCI scores and primary tumor differentiation (p = 0.118) and PSS [ 11 were associated with worse median OS (15 months, (p = 0.376) for OS. DISCUSSION TABLE 3 Final model resulting from multivariate survival analysis Variable Hazard rate (95% CI) p value This prospective cohort study shows that peritoneal recurrence within 1 year after previous adjuvant Disease-free survival chemotherapy and a high initial PCI index are the most PCI 1.04 (1.00–1.08) 0.040 important risk factors for poor DFS and OS in patients with Development of PM peritoneally metastasized CRC. This effect was indepen- [ 1 year after chemotherapy Reference 0.001 dent of primary tumor stage or tumor differentiation. In B 1 year, no chemotherapy 0.57 (0.31–1.06) 0.075 175 patients treated with the intent of CRS and HIPEC in [ 1 year, no chemotherapy 1.20 (0.67–2.19) 0.535 two tertiary referral centers, patients with PM diagnosed B 1 year after chemotherapy 2.13 (1.26–3.61) 0.005 within 1 year after adjuvant chemotherapy had worse Overall survival median DFS (HR 2.13, p = 0.005) and OS (HR 2.76, PCI 1.11 (1.07–1.15) \ 0.001 p \ 0.001) than patients not treated with adjuvant Development of PM chemotherapy or patients who were diagnosed with PM [ 1 year after chemotherapy Reference 0.019 after more than 1 year in both univariate and multivariate B 1 year, no chemotherapy 1.34 (0.62–2.92) 0.454 analysis. A high PCI was the only other variable associated [ 1 year, no chemotherapy 1.89 (0.95–3.76) 0.071 with DFS and OS in the multivariate models (HR 1.04, B 1 year after chemotherapy 2.76 (1.45–5.27) 0.002 p = 0.040; and HR 1.11, p \ 0.001, respectively). Variables with a p value B 0.1 in univariate survival analysis were Cytoreduction and HIPEC is currently the preferred included in a multivariate Cox regression analysis: (1) primary tumor 1 2 treatment option for patients with PM of CRC, , but due location, development of PM, and PCI for DFS; (2) primary tumor to the relatively high morbidity rates associated with this differentiation, development of PM, PSS, and PCI for OS procedure, the need for careful patient selection should be CI confidence interval, DFS disease-free survival, OS overall sur- 8–10 vival, PCI Peritoneal Cancer Index, PM peritoneal metastases, PSS emphasized. Preoperative decision making is crucial, prior surgical score warranting practical clinical and pathological prognostic 2354 N. R. Sluiter et al. factors. The diagnosis of PM relatively shortly after prior taken into account. First, our data are possibly subjected to chemotherapy can be assessed preoperatively in contrast to selection bias that is associated with cohort studies. Sec- well-established prognostic factors that are obtained after ond, based on our results, we can conclude that patients or during the operation, such as PCI, resection scores and with early peritoneal recurrence after adjuvant combined prognostic scores, including the PSDSS and chemotherapy have decreased survival; however, there is 14,15 the relatively novel COMPASS. Hence, the selection no solid evidence for an alternative treatment. The effect of of patients with early peritoneal recurrence after prior second-line chemotherapy in this subgroup of patients, chemotherapy might help identify patients who benefit less with a poor response to prior chemotherapy, has yet to be from HIPEC, in this way preventing unnecessary exposure proven. Palliative treatment regimens are heterogeneous in to an invasive procedure that may even harm the patient. this patient group, which makes it hard to gather valid The association between early peritoneal recurrences after retrospective data from a control cohort. Thereby, new adjuvant chemotherapy and poor outcome could be options arise for patients not suitable for HIPEC treatment, explained by a more aggressive biological tumor behavior, including Pressurized IntraPeritoneal Aerosol Chemother- leading to a poor response to chemotherapy and, subse- apy (PIPAC). This innovative therapy consists of repetitive quently, a poor response to HIPEC treatment. intraperitoneal administration of aerosolized chemotherapy Several other study groups have already excluded and has already been shown to be feasible and safe in end- patients with rapid PM development or progression under stage PM originating from several primaries. For CRC 6,16,17 systemic chemotherapy from CRS and HIPEC. In patients, PIPAC with oxaliplatin, whether in combination addition, various guidelines recommend the use of this with systemic chemotherapy or not, showed encouraging selection criterion in the workup of potential HIPEC can- results. Future studies in well-defined populations should 18,19 didates. In contrast, two relatively small retrospective demonstrate the potential role of PIPAC in patients with studies argued that there is no reason for excluding patients irresectable PM of CRC since the current evidence for with quick peritoneal relapses after prior chemotherapy PIPAC in this population is scarce. from HIPEC. A single-center study including 21 cases To provide the answers necessary to take our results found a median OS of 28 months in patients who did not into the clinical practice, a prospective study should com- respond to adjuvant chemotherapy, which led the authors to pare HIPEC with systemic chemotherapy in patients with conclude that the survival of this group was comparable PM within 1 year after chemotherapy. Until then, CRS and with survival rates in other HIPEC patients ; however, this HIPEC may be considered a valid option in this group of study did not include a control group. Another retrospec- patients if the peritoneal tumor burden is limited (PCI tive study compared 19 patients with tumor progression B 11). Therefore, whether the limited DFS observed in this despite neoadjuvant chemotherapy with the same number cohort of patients with early PM development justifies the of patients with stable disease under neoadjuvant high morbidity and mortality rates of the CRS and HIPEC chemotherapy, resulting in an insignificant survival dif- procedure should be carefully considered. Next to identi- ference between these groups. The relatively small fication of clinical prognosticators, future research should groups in both studies might hamper these outcomes and focus on identifying molecular tissue and blood-borne conclusions. characteristics to select patients with biologically favorable High PCI emerged as a second characteristic that was tumor characteristics responding best to further aggressive associated with poor outcome in the present cohort. This therapies such as CRS and HIPEC. Additionally, identifi- variable is an established prognostic factor and is widely cation of biomarkers and clinical prognostic factors could used for the identification of patients with curable peri- potentially help us optimize the HIPEC procedure, aiming toneal disease, defined as a PCI B 20. The present for a personalized treatment rather than the current one- results, supported by the available literature, emphasize the size-fits-all approach. This can be illustrated by selection of importance of performing a diagnostic laparoscopy to the most effective chemotherapeutic drug based on the determine PCI indices prior to HIPEC surgery, especially prediction of individual chemotherapeutic responses, since current imaging techniques lack sensitivity for which may eventually result in a tailored and more robust 28,29 detection of PM. No other variables were associated HIPEC treatment, leading to improved oncologic outcomes with DFS and OS in the multivariate models. Importantly, in subgroups with relatively poor prognosis. the primary tumor stage was not a significant risk factor for poor DFS and OS. To our knowledge, this is currently the largest study showing that the development of PM following adjuvant therapy is a poor prognostic factor after treatment with CRS and HIPEC. However, some limitations should be Clinical Prognosticators for HIPEC Surgery 2355 perioperative intraperitoneal chemotherapy for colorectal peri- CONCLUSIONS toneal carcinomatosis. World J Surg. 2010;34(1):70–78. 10. Ihemelandu CU, McQuellon R, Shen P, Stewart JH, Votano- The present study found support for considering both poulos K, Levine EA. Predicting postoperative morbidity PCI and early peritoneal recurrence after adjuvant therapy following cytoreductive surgery with hyperthermic intraperi- toneal chemotherapy (CS ? HIPEC) with preoperative FACT-C in patient selection prior to CRS and HIPEC. Prospective (Functional Assessment of Cancer Therapy) and patient-rated trials might help us move forward by confirming or performance status. Ann Surg Oncol. 2013;20(11):3519–3526. rejecting factors associated with outcome in retrospective 11. Kwakman R, Schrama AM, van Olmen JP, et al. Clinicopatho- studies, ultimately providing clear guidelines to identify logical parameters in patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal the right patients for the right treatment. cancer metastases: a meta-analysis. Ann Surg. 2016;263(6):1102–1111. DISCLOSURES Nina R. Sluiter, Koen P. Rovers, Youssra Salhi, 12. Sluiter NR, de Cuba EM, Kwakman R, et al. Versican and vas- Stijn L. Vlek, Veerle M. H. Coupe ´, Henk M. W. Verheul, Geert cular endothelial growth factor expression levels in peritoneal Kazemier, Ignace H. J. T. de Hingh, and Jurriaan B. Tuynman declare metastases from colorectal cancer are associated with survival no conflicts of interest. after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Clin Exp Metastasis. 2016;33(4):297–307. 13. de Cuba EM, de Hingh IH, Sluiter NR, et al. Angiogenesis-re- OPEN ACCESS This article is distributed under the terms of the lated markers and prognosis after cytoreductive surgery and Creative Commons Attribution 4.0 International License (http://crea hyperthermic intraperitoneal chemotherapy for metastatic col- tivecommons.org/licenses/by/4.0/), which permits unrestricted use, orectal cancer. Ann Surg Oncol. 2016;23(5):1601–1608. distribution, and reproduction in any medium, provided you give 14. Simkens GA, van Oudheusden TR, Nieboer D, et al. 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Annals of Surgical OncologySpringer Journals

Published: May 31, 2018

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