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Intraoperative packed red blood cell transfusion (iPRBT) and PCI-normalised iPRBT rates (iPRBT/PCI ratio) negatively affect short- and long-term outcomes of patients undergoing cytoreductive surgery and intraperitoneal chemotherapy – An analysis of 880 patients
Abstract
Background:
Most studies on the effects of intraoperative packed red blood cell transfusions (iPRBT) on patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown deleterious outcomes. It is unclear if this is a result of the transfusion itself or because iPRBTs serve as a surrogate of more advanced disease.
Methods:
A retrospective analysis of 880 patients treated from 1996 to 2017. The effect of any exposure to iPRBT as well as the effect of peritoneal cancer index (PCI)-normalised iPRBT rates (ratio of iPRBT/PCI) on patients short- and long-term outcomes (recurrence-free (RFS) and overall survival (OS)) were assessed. Equally, the prognostic effect of postoperative PRBTs was analysed and adjusted for.
Results:
Of the 880 patients included, only 26.4% had no iPRBT whereas 59.2% of patients had no postoperative PRBT. Patients with no iPRBTs had significantly lower PCIs, less high-grade complications, shorter ICU and hospital length of stay, as well as improved RFS and OS. Furthermore, high PCI-normalised iPRBTs resulted in worse perioperative and long-term outcomes, with a median OS of 41 months vs. 103 months (5-year survival rate 36.6% vs. 66.1%; p < 0.001) and median RFS of 13 months vs. 30 months (5-year RFS rate 18.3% vs. 37.6% p < 0.001) compared to those with a low iPRBT/PCI ratio. This independent effect was confirmed upon multivariable Cox regression analysis which corrected for important confounders including complexity of procedures and postoperative PRBTs (adjusted HR [aHR]2.04, 95%CI 1.36-3.04, p = 0.001 for OS; aHR 1.38, 95%CI 1.06-1.81, p = 0.017 for RFS). However, subgroup analysis (stratified by histopathologic disease entities) revealed that this independent prognostic effect was seen in high-grade mucinous appendiceal neoplasms, whereas PCI-normalised IPRBTs were not significantly prognostic in other histopathologic subgroups.
Conclusion:
iPRBTs significantly and independently impact perioperative and long-term outcomes of patients undergoing CRS/HIPEC. However, this effect mainly seems to occur in patients with high-grade mucinous neoplasms, whereas it may only be of borderline prognostic significance in other patient groups. The development of blood-sparing protocols may help improve outcomes of patients undergoing this complex oncologic procedure.
... An important limitation in studies of transfusion and cancer progression is that cancer progression and blood transfusion share similar risk factors. Examples of these include tumor size, anatomical location, lymphovascular invasion, surgical time, anemia, and overall advanced locoregional stage (94)(95)(96)(97). To address these concerns, studies have implemented a variety of statistical methods to indicate an independent effect of transfusion, such as multivariable regression and propensity-score matching. ...
... In contrast, the prognostic value of blood transfusion on cancer progression has been shown for cancers of the esophagogastric function (100), liver (101), prostate (102), and pancreas (103,104). Finally, in oncologic nephrectomy for renal cell carcinoma or cytoreductive surgery with intraperitoneal chemotherapy for mucinous appendiceal neoplasms, intraoperative (but not postoperative) transfusion had an independent effect on progression-free survival (97). ...
Purpose of Review
To examine the most recent evidence about known controversies on the effect of perioperative transfusion on cancer progression.
Recent Findings
Laboratory evidence suggests that transfusion-related immunomodulation can be modified by blood management and storage practices, but it is likely of less intensity than the effect of the surgical stress response. Clinical evidence has questioned the independent effect of blood transfusion on cancer progression for some cancers but supported it for others. Despite major changes in surgery and anesthesia, cancer surgery remains a major player in perioperative blood product utilization. Prospective data is still required to strengthen or refute existing associations.
Summary
Transfusion-related immunomodulation in cancer surgery is well-documented, but the extent to which it affects cancer progression is unclear. Associations between transfusion and cancer progression are disease-specific. Increasing evidence shows autologous blood transfusion may be safe in cancer surgery.
... The lack of data on the number of blood transfusions is a major drawback of our study unfortunately. Since they may negatively impact perioperative and long-term outcomes of patients, sparing protocols are advisable [22,25,27,43,[58][59][60]. ...
Background:
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy may significantly improve survival for selected patients with peritoneal surface malignancies, but it has always been criticized due to the high incidence of postoperative morbidity and mortality.
Methods:
Data were collected from nine Italian centers with peritoneal surface malignancies expertise within a collaborative group of the Italian Society of Surgical Oncology. Complications and mortality rates were recorded, and multivariate Cox analysis was used to identify risk factors.
Results:
The study included 2576 patients. The procedure was mostly performed for ovarian (27.4%) and colon cancer (22.4%). The median peritoneal cancer index was 13. Overall postoperative morbidity and mortality rates were 34% and 1.6%. A total of 232 (9%) patients required surgical reoperation. Multivariate regression logistic analysis identified the type of perfusion (p ≤ 0.0001), body mass index (p ≤ 0.0001), number of resections (p ≤ 0.0001) and colorectal resections (p ≤ 0.0001) as the strongest predictors of complications, whereas the number of resections (p ≤ 0.0001) and age (p = 0.01) were the strongest predictors of mortality.
Conclusions:
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is a valuable option of treatment for selected patients with peritoneal carcinomatosis providing low postoperative morbidity and mortality rates, if performed in high-volume specialized centers.
... Studies have shown perioperative blood transfusions to be associated with poor oncologic outcomes for cancer in general as well as for colon, renal cell, gastric, and pancreatic cancers and hepatocellular carcinoma. [16][17][18][19][20][21][22] This ellicits the question whether recurrent RPS tends to be of a higher grade than primary RPS, which would be more in line with the biology of these more aggressive cancers. A majority of our patients (63%) who experienced recurrence had a grade 2 or 3 sarcoma. ...
Background
This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking.Methods
Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used.ResultsThe 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis.ConclusionsA surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.
Cytoreductive Surgery (CRS) ± Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is associated with a high incidence of postoperative morbidity. Our aim was to identify independent, potentially actionable perioperative predictors of major complications.
We reviewed patients who underwent CRS ± HIPEC from June 2020 to January 2022 at a high-volume center. Postoperative complications were categorized using the Comprehensive Complication Index, with the upper quartile defining major complications. Multivariate logistic analysis identified predictive and protective factors.
Of 168 patients, 119 (70.8%) underwent HIPEC. Mean Comprehensive Complication Index was 12.6 (12.7) and upper quartile cut-off was 22.6. Medical complications were more frequent but less severe than surgical (63% vs 18%). Forty-six patients (27.4%) comprised the “major complications” group (mean CCI 30.1 vs 6.3). Multivariate logistic regression showed that heart disease (RR 1.9; 95% CI: 1.1 to 3.3), number of anastomoses (RR 2.4; 95% CI:1.3 to 4.6) and first 24-h fluid balance (RR 1.1; 95% CI: 1.1 to 1.2), were independently associated as risk factors for major complications, while opioid-free anesthesia (RR 0.6; 95% CI: 0.3 to 0.9) and high preoperative hemoglobin (RR 0.9; CI 95%: 0.9 to 0.9) were independent-protective factors.
Preoperative heart diseases, number of anastomoses and first 24 h-fluid balance are independent risk factors for major postoperative complications, while high preoperative hemoglobin and opioid-free anesthesia are protective. Correction of anemia prior to surgery, avoiding positive fluid balance and incorporation of opioid-free anesthesia strategy are potential actionable measures to reduce postoperative morbidity.
Aims:
To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context.
Methods:
Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity.
Results:
Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity.
Conclusion:
While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.
Objective
To investigate the clinical value of laparoscopic cytoreductive surgery (CRS) in treating of appendiceal pseudomyxoma peritonei with limited disease and low tumor burden.
Methods
The clinical data of patients with appendiceal pseudomyxoma peritonei treated by surgery with CRS at the Aerospace Center Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into laparoscopic or open CRS groups according to the operation method. A propensity score-matched (PSM) analysis (1:1) was performed, the related clinical variables were compared between the two groups, and the effect on progression-free survival (PFS) was also analyzed.
Results
One hundred and eight patients were included in this study. After PSM, 33 patients were selected from each group and the age and peritoneal cancer index were matched between the two groups. There were significant differences in operation time (P < 0.001), intraoperative bleeding (P < 0.001), intraoperative blood transfusion (P = 0.007), hospital stay (P < 0.001). The analysis of PFS showed that there was no significant difference between the two operation methods. After multivariate analysis, the pathologic subtype (P = 0.012) was identified as an independent prognostic factor for PFS.
Conclusion
The curative effect of laparoscopic CRS is like that of open operation, which can significantly shorten the operation time and hospital stay and reduce intraoperative bleeding and blood transfusion event. The laparoscopic CRS is safe and feasible in strictly selected patients. The pathologic subtype is an independent factor affecting the prognosis for PFS.
Background
Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes.
Methods
Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively.
Results
The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8–67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0–107.6) and 66.0 months (95% CI: 48.3–83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32–2.29) and RFS (HR: 1.55, 95%CI: 1.20–2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days.
Conclusions
Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.
Standarization of surgical outcomes throughout minor and major surgical procedures is mandatory. Complex surgical procedures such as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) should provide proficient oncological and surgical outcomes. Healthcare pathways should promote efficiency, safety and timely equitable delivery of patient centered platforms.
Health quality indicators (QI) represent a surrogate of health care outcomes. Donabedian identified three areas of interest to assess healthcare QI: structure indicators (healthcare locations where programs/services are delivered), process indicators (provider tasks performed on patient’s behalf-based on guidelines) and outcome indicators (effect or result of health care in the patient).
Statistical analysis is of primary relevance in the quality of health care outcomes assessment using the statistical process control techniques propossed by She wart and its graphical representation by Spiegelhalter. Statistical process control provides an estimation over time of every health care activity directly on published data, and has been previously applied in hospital audits. With this methodology we could control the stability of a process and detect variations in its results. Nevertheless, the results of surgical activity have an important variability between patients, centers and institutions. Part of this variability is considered within normal limits and non-avoidable, however, an avoidable portion exists and it should be detected and quantified. The aim of the statistical process control is to quantify that avoidable variabilility in order to provide reproducibility of surgical outcomes and provide a benchmark standard for comparative purpose.
Cytoreductive surgery have shown to have an important variability in its indications and chemotherapy treatments, variability between institutions and surgeons and a variability of results due to its prolonged learning curve. In orther to objectively classify results as desirable, is necessary to identify quality indicators and calculate their standard value for each process. In recent years, quality indicators and acceptable quality limits for several surgical oncologic procedures have been reported, but there is still a lack of this information regarding CRS+HIPEC for peritoneal metastases of colorrectal origin. The aim of this study is to identify clinically relevant QI, their quality standard and determine acceptable quality limits for each indicator in CRS+HIPEC of peritoneal metastasis for colorectal origin.
El mayor conocimiento de la historia natural de la carcinomatosis peritoneal ha permitido su valoración como una progresión locorregional. Tras los trabajos publicados por Sugarbaker tanto a nivel quirúrgico, con la descripción de las técnicas de peritonectomía como a nivel farmacológico experimental para la aplicación de la quimioterapia intraperitoneal hipertérmica (HIPEC), se considera un tratamiento locorregional de la enfermedad confinada al abdomen. Así, una cirugía radical de citorreducción con extirpación de la enfermedad macroscópica y la aplicación posterior de HIPEC para control de la enfermedad microscópica residual, ha obtenido resultados muy superiores a la quimioterapia aislada.
En todo tratamiento quirúrgico, y más en aquellos de mayor complejidad como la cirugía de citorreducción y HIPEC (CRS+HIPEC), se debe garantizar una atención sanitaria óptima que ofrezca una adecuada calidad en la asistencia y disminuya la variabilidad en los tratamientos y en los resultados. Esta gestión de la calidad viene determinada por una serie de indicadores y estándares, medibles, reproducibles y que garantizan los cambios y mejoras en la asistencia si fuera necesario.
En los últimos años se han evaluado estándares de calidad en varios procesos asistenciales relacionados con el cáncer, sin embargo, Carecemos de estándares de ca en el ámbito del tratamiento multidisciplinar de la cirugía oncológica peritoneal.
Hipótesis
Mediante la aplicación de los métodos de análisis y la utilización de las gráficas de control de procesos, es posible determinar los estándares de calidad en los resultados de la cirugía de carcinomatosis peritoneal de origen colorrectal, a partir de datos objetivos y estadísticamente robustos publicados en la literatura.
Objetivos
1. Determinar cuáles son los indicadores de calidad y su valor correspondiente, clínicamente relevantes
2. Establecer escalas o intervalos con los límites de variabilidad o límites de calidad aceptables para cada indicador, de fácil medición, que sirvan de herramienta a las unidades de cirugía oncológica peritoneal y permitan auditar los resultados de forma sencilla y objetiva Resultados y conclusiones
1. Se han determinado 20 indicadores de calidad: media de supervivencia global, media de supervivencia global a 1 año y a 5 años, media de supervivencia libre de enfermedad global, a 1 año y a 5 años, supervivencia libre de enfermedad global, a 1 año y a 5 años, tasa de resecciones completas, duración media de la cirugía, estancia media hospitalaria, tasa de mortalidad global, tasa de morbilidad global, tasa de morbilidad mayor, tasa de reintervenciones, tasa de hemorragias postoperatorias, tasa de fístulas intestinales, tasa de dehiscencia de anastomosis, tasa de infecciones de herida, tasa de complicaciones médicas, tasa de recurrencia global y tasa de fallo de rescate.
Background
A number of studies have investigated the effect of perioperative blood transfusion (PBT) for patients after radical prostatectomy (RP), with some reporting conflicting results. A systematic review of the literature and a meta-analysis were conducted to explore the association between PBT (autologous or allogeneic) and biochemical recurrence-free survival (BRFS), overall survival (OS) and cancer-specific survival (CSS) in patients undergoing RP.
Methods
The PubMed, Medline, Cochrane Library, and Embase databases were searched for published controlled clinical studies on perioperative allogeneic or autologous blood transfusion (BT) and patient survival after RP. STATA software version 12.0 was used for data analysis. We used hazard ratios (HRs) and 95% confidence intervals (CIs) to test the correlation between BT and patient survival after RP.
Results
Data from a total of 26,698 patients in ten published studies were included in the meta-analysis. The meta-analysis results showed that autologous BT was not associated with BRFS (HR: 1.06; 95% CI: 0.96–1.18; Z = 1.17; P = 0.24), OS (HR: 0.86; 95% CI: 0.71–1.04; Z = 1.58; P = 0.11), or CSS (HR: 0.98; 95% CI: 0.49–1.96; Z = 0.05; P = 0.96). Allogeneic BT exhibited a significant association with worse BRFS (HR: 1.09; 95% CI: 1.01–1.16; Z = 2.37; P = 0.02), OS (HR: 1.43; 95% CI: 1.24–1.64; Z = 4.95; P<0.01) and CSS (HR: 1.74; 95% CI: 1.18–2.56; Z = 2.81; P = 0.005).
Conclusion
Our data showed an association between allogeneic BT and reduced BRFS, OS and CSS in patients after RP. These findings indicate that perioperative blood conservation strategies are important for decreasing the allogeneic BT rate.
Premalignant lesions for many cancers have been identified, and efforts are currently directed toward identification of antigens expressed on these lesions that would provide suitable targets for vaccines for cancer prevention. Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts of which a subset has the potential to progress to cancer. Currently, there are no validated predictive markers for progression to malignancy. We hypothesized that the presence or absence of immune surveillance of these lesions would be one such factor. Here we show that the tumor antigen MUC1, which is abnormally expressed on pancreatic cancer and is a target for cancer immunosurveillance, is also abnormally expressed on premalignant IPMN. We show that some IPMN patients make MUC1-specific IgG. Moreover, we show evidence of CD4 and CD8 T cell infiltration into IPMN areas of high dysplasia suggesting an ongoing immune response within the lesions. We also found, however, increased levels of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in some IPMN patients as well as evidence of T cell exhaustion. Further studies correlating immunosurveillance or immunosuppression with IPMN progression to malignancy will help define the immune response as a biomarker of risk, leading potentially to a vaccine to boost spontaneous immunity and prevent progression to cancer.
Perioperative blood transfusion (PBT) is common in pancreatic surgery. Recent studies have suggested that PBT may be associated with worse long-term outcomes.
A systematic review and meta-analysis of studies comparing long-term clinical outcomes of cancer patients undergoing curative-intent pancreatic surgery with regard to occurrence of PBT was performed.
A total of 23 studies (4339 patients) were included in the systematic review, and 19 studies (3646 patients) were included in the meta-analysis. Nearly half (45.8 %) of all patients were female (range 25-60 %), and median age ranged from 59 to 72 years. About half (46.5 %, range 19-72 %) of the patients were transfused. Most had pancreatic ductal adenocarcinoma (69.5 %), while others had ampullary carcinoma (15.0 %), cholangiocarcinoma (7.4 %), or exocrine tumors of pancreas (8.1 %). Most (91.1 %) underwent pancreaticoduodenectomy, while the remaining patients underwent a total or distal pancreatectomy. The 5-year overall survival for all patients ranged from 0 to 65 %. Thirteen and nine of 19 studies reported a detrimental effect of PBT on survival on univariable and multivariable analysis, respectively. Overall, PBT was associated with shorter overall survival (pooled odds ratio 2.43, 95 % confidence interval 1.90-3.10); this finding was reproduced in sensitivity analysis.
Patients receiving PBT had significantly lower 5-year survival after curative-intent pancreatic surgery. Further research should focus on implementing guidelines for and discerning factors associated with the poor outcomes after PBT.
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.
Copyright © 2014 Elsevier Inc. All rights reserved.
The impact of perioperative allogenenic blood transfusion (ABT) on clinical outcomes for hepatocellular carcinoma (HCC) is conflicting and unclear. The aim of this meta-analysis is to evaluate the association between ABT and HCC clinical outcomes. Outcomes evaluated were all-cause death, tumor recurrence and postoperative complications.
Relevant articles were identified through MEDLINE search (up to November 2012). Meta-analyses were performed by using the fixed or random effect models. Study heterogeneity was assessed by Q-test and I(2) test. Publication bias was evaluated by funnel plots, Egger's and Begg's test.
A total of 5635 cases from 22 studies finally met our inclusion criteria. Meta-analysis indicated HCC patients with ABT had an increased risk of all-cause death at 3 and 5 years after surgery (respectively: OR = 1.92, 95% CI, 1.61-2.29,P<0.001; OR = 1.60, 95% CI, 1.47-1.73,P<0.001 ) compared with those without ABT. The risk of tumor recurrence was significantly higher for ABT cases at 1, 3 and 5 years (respectively: OR = 1.70, 95% CI, 1.38-2.10, P<0.001; OR = 1.22, 95% CI, 1.08-1.38, P<0.001; OR = 1.16, 95% CI, 1.08-1.24, P<0.001). The HCC cases with ABT significantly increased postoperative complications occurrence compared with non-ABT cases (OR = 1.78,95% CI, 1.34-2.37, P<0.001).
The findings from the current meta-analysis demonstrated that ABT was associated with adverse clinical outcomes for HCC patients undergoing surgery, including increased death, recurrence and complications. Therefore, ABT should not be performed if possible.
Debate on appropriate triggers for transfusion of allogeneic blood products and their effects on short- and long-term survival in surgical and critically ill patients continue with no definitive evidence or decisive resolution. Although transfusion-related immune modulation (TRIM) is well established, its influence on immune competence in the recipient and its effects on cancer recurrence after a curative resection remains controversial. An association between perioperative transfusion of allogeneic blood products and risk for recurrence has been shown in colorectal cancer in randomized trials; whether the same is true for other types of cancer remains to be determined. This article focuses on the laboratory, animal, and clinical evidence to date on the mechanistic understanding of inflammatory and immune-modulatory effects of blood products and their significance for recurrence in the cancer surgical patient.
Background:
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) are frequently used to treat appendiceal carcinomatosis. Some patients require multivisceral resection because of the volume of disease. It is unclear whether extent of CRS impacts survival in appendiceal carcinomatosis.
Methods:
We analyzed 282 patients undergoing attempted CRS/HIPEC for appendiceal carcinomatosis. Patients were defined as having undergone Extensive CRS (n = 60) if they had >3 organ resections or >2 anastomoses; a subgroup of Extreme CRS patients (n = 10) had ≥5 organ resections and ≥3 anastomoses. Kaplan-Meier survival curves and multivariate Cox-regression models were used to identify prognostic factors affecting outcomes.
Results:
Relative to the comparison group, patients undergoing Extensive CRS had a higher median peritoneal carcinomatosis index, operative duration, blood loss, and length of stay. No difference in completeness of cytoreduction, severe morbidity, or 60-day mortality was evident. Subgroup analysis of 10 patients undergoing extreme CRS likewise revealed no increase in severe morbidity or mortality. Median progression-free (PFS) and overall survival (OS) were 23.5 and 74 months in the comparison group; 18.5 (p = 0.086) and 51 (p = 0.85) months in the Extensive CRS group; and 40 months and not reached in the Extreme CRS subgroup. In a multivariable analysis, extent of CRS was not independently associated with PFS or OS.
Conclusions:
Extensive CRS is associated with greater OR time, blood loss, and length of stay, but is not associated with higher morbidity, mortality, or inferior oncologic outcomes in patients with appendiceal carcinomatosis.
Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
Cytoreductive surgery (CRS) with hyperthermic perioperative chemotherapy (HIPEC) has become a treatment option for selected patients with peritoneal metastases (PMs) from gastrointestinal malignancies. The purpose of this study is to evaluate our most recent data regarding pulmonary complications (respiratory distress, pleural effusion, and pneumonia) and attempt to identify risk factors associated with this management plan. This study includes the most recent 4-year experience with appendiceal and colorectal carcinomatosis patients treated in a uniform manner between January 1, 2006 and December 31, 2009. A prospective morbidity and mortality database was maintained and pulmonary adverse events were analyzed with special attention to subphrenic peritonectomy. There were 147 consecutive patients with a mean age of 49.9 years. Fourteen patients (10%) presented grades I-IV pulmonary complications for a total of 26 events. The peritonectomy of right upper quadrant was performed in 74% and right plus left in 49% of the patients. Statistically, there were no more pulmonary complications among patients submitted to peritoneal stripping of right or right and left hemidiaphragm as compared to no subdiaphragmatic peritonectomy (P = 1.00 and P = 0.58, resp.). In an analysis of 18 quantitative indicators and clinical variables with pulmonary adverse events, only blood replacement greater than six units showed a significant correlation (P = 0.0062). Pulmonary adverse events were observed in 10% of patients having CRS and HIPEC. Subphrenic peritonectomy was not a specific risk factor for developing these adverse events.
Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study.
A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International.
Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival.
The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.
Up to 25% of patients with metastatic colorectal cancer (CRC) present with peritoneal carcinomatosis (PC) as the only site of metastases. Complete cytoreductive surgery (CCRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) aims for locoregional disease control and long-term survival. Oxaliplatin is effective for treating advanced CRC. This study assesses the safety and efficacy of CCRS with HIPEC with oxaliplatin for patients with PC of CRC.
A Belgian prospective multicenter registry was performed to monitor perioperative morbidity and assess mortality, disease-free survival (DFS), and overall survival (OS).
Forty-eight consecutive patients underwent CCRS (R0/1) with HIPEC (male/female ratio 17/31, median age 60 years, range 24-76 years). Median PC index was 11 (range 1-22). Median operation time was 460 (range 125-840) min, with a median blood loss of 475 (range 2-6,000) ml. Thirty-day mortality was 0%. Complication rate (any grade) was 52.1%. Anastomotic leakage occurred in 10.4% of patients, bleeding in 6.3%, and bowel perforation in 2.1%. Median hospital stay was 20 (range 5-65) days. At median follow-up of 22.7 (range 3.2-55.7) months, OS was 97.9% [95% confidence interval (CI) 86.1-99.7] at 1 year and 88.7% (95% CI 73.6-95.4) at 2 years. DFS at 1 year was 65.8% (95% CI 52.3-76.2) and 45.5% (95% CI 34.3-55.9) at 2 years. Median time until recurrence was 19.8 months (95% CI 12-upper limit not defined). Only after dichotomizing PC index was a significant difference in OS found between low and high PC index.
CCRS followed by HIPEC with oxaliplatin for PC from CRC can be implemented with acceptable morbidity. Long-term DFS and OS can be achieved in selected patients.
This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM).
A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival.
Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002).
The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.
Background:
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with increased red blood cell transfusion (RBT) demand. Although the deleterious effects of RBT are documented in various settings, its effect in this setting is obscure. In this study, we evaluated the effects of different-grade RBT on the short- and long-term outcomes of CRS and HIPEC.
Methods:
We analyzed 231 patients with diffuse malignant peritoneal mesothelioma (DMPM) and 273 patients with pseudomyxoma peritonei (PMP) operated in our unit. RBT was categorized according to the amount of packed red blood cell units (PRBCs) administered (0, 1-2, 3-5, > 6). The effects of RBT on long-term oncological outcomes [progression-free survival (PFS) and overall survival (OS)] were assessed by using multivariate analysis.
Results:
Overall, 74% of the patients were transfused with a median of 2 PRBCs (range 0-37). Transfusion level correlated with operative time, surgical extent (as measured by the peritoneal carcinomatosis index), and age. Postoperatively, patients with major transfusion (> 6 PRBCs) had increased mortality rate (11.1%, p = 0.01) and length of hospital stay (31.2 ± 16.8 days, p = 0.01) compared with other levels of RBT. RBT was dose-dependently associated with oncological outcomes in both DMPM and PMP for both PFS [hazard ratio (HR) = 1.40, 95% confidence interval (CI) 1.12-1.74, p = 0.003; HR = 1.44, 95% CI 1.15-1.81, p = 0.001, respectively] and OS (HR = 1.57, 95% CI 1.21-2.03, p = 0.001; HR = 1.43, 95% CI 1.15-1.90, p = 0.01, respectively).
Conclusions:
Our data show a dose-dependent relationship between RBT and oncological outcomes. Further research to develop transfusion sparing protocols is needed in this extensive surgical procedure.
Objective:
The aim of this study was to elucidate the impact of intraoperative blood loss on outcomes following pancreatoduodenectomy (PD).
Background:
The negative impact of intraoperative blood loss on outcomes in PD has long been suspected but not well characterized, particularly those factors that may be within surgeons' control.
Methods:
From 2001 to 2015, 5323 PDs were performed by 62 surgeons from 17 institutions. Estimated blood loss (EBL) was discretized (0 to 300, 301 to 750, 751 to 1300, and >1300 mL) using optimal scaling methodology. Multivariable regression, adjusted for patient, surgeon, and institutional variables, was used to identify associations between EBL and perioperative outcomes. Factors associated with both increased and decreased EBL were elucidated. The relative impact of surgeon-modifiable contributors was estimated through beta coefficient standardization.
Results:
The median EBL of the series was 400 mL [interquartile range (IQR) 250 to 600]. Intra-, post-, and perioperative transfusion rates were 15.8%, 24.8%, and 37.2%, respectively. Progressive EBL zones correlated with intra- but not postoperative transfusion in a dose-dependent fashion (P < 0.001), with a key threshold of 750 mL EBL (8.14% vs 40.9%; P < 0.001). Increasing blood loss significantly correlated with poor perioperative outcomes. Factors associated with increased EBL were trans-anastomotic stent placement, neoadjuvant chemotherapy, pancreaticogastrostomy reconstruction, multiorgan or vascular resection, and elevated operative time, of which 38.7% of the relative impact was "potentially modifiable" by the surgeon. Conversely, female sex, small duct, soft gland, minimally invasive approach, pylorus-preservation, biological sealant use, and institutional volume (≥67/year) were associated with decreased EBL, of which 13.6% was potentially under the surgeon's influence.
Conclusion:
Minimizing blood loss contributes to fewer intraoperative transfusions and better perioperative outcomes for PD. Improvements might be achieved by targeting modifiable factors that influence EBL.
Background and objectives:
Serum tumor markers are prognostic in patients with colorectal cancer peritoneal carcinomatosis (CRPC) undergoing cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). Assessment of the ratio of tumor marker to volume, as depicted by peritoneal carcinomatosis index (PCI), and how this may affect overall (OS) and recurrence free survival (RFS) has not been reported.
Methods:
Survival effect of this ratio was analyzed in patients with CRPC managed from 1996 to 2016 with CRS and IPC.
Results:
Of 260 patients included, those with low CEA/PCI ratio (<2.3) had longer median OS (56 vs 24 months, P = 0.001) and RFS (13 vs 9 months, P = 0.02). The prognostic impact of CEA/PCI ratio was most pronounced in patients with PCI ≤ 10 (OS of 72 vs 30 months, P < 0.001; RFS of 21 vs 10 months, P = 0.002). In multivariable analysis, elevated CEA/PCI ratio was independently associated with poorer OS (adjusted HR 1.85, 95%CI 1.11-3.10, P = 0.02) and RFS (adjusted HR 1.58, 95%CI 1.04-2.41, P = 0.03).
Conclusion:
CEA/PCI ratio is an independent prognostic factor for OS and RFS in CRPC. This novel approach allows both tumor activity and volume to be accounted for in one index, thus potentially providing a more accurate indication of tumor biological behavior.
Background:
Serum tumour levels have been shown to be prognostic in patients with epithelial appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei (PMP)). A singular index which incorporates both tumour activity (as depicted by serum tumour marker levels) and tumour volume (as depicted by peritoneal carcinomatosis index (PCI)), may give a more precise surrogate of tumour biological behaviour. The prognostic implication of this index has not yet been reported.
Methods:
A retrospective cohort study of all patients with PMP managed from 1996 to 2016 with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) was performed by analysing the survival effect of the ratio of preoperative serum CEA, CA19.9 and CA125 to PCI.
Results:
Three hundred and eighty-six patients were included. In patients with low-grade PMP, elevated CA19-9/PCI ratio resulted in poorer median overall survival times (104 months vs NR, 95%CI 83 - NR, log-rank p < 0.001) and was an independent predictor of reduced overall survival on multivariable analysis (adjusted HR 5.60, 95%CI 1.60-19.68, p = 0.007). In patients with high-grade PMP, no statistically significant difference in survival was recognised.
Conclusion:
CA19-9/PCI ratio is an independent prognostic factor for overall survival in patients with low-grade PMP undergoing CRS and IPC. By accounting for both tumour activity and tumour volume simultaneously, this novel index behaves as a surrogate of tumour biology and provides a useful adjunct for decisions regarding treatment allocation in this patient group.
Purpose of review:
This review summarizes current and prior observations regarding transfusion-related immunomodulation (TRIM) and puts these ideas into a modern immunological context, incorporating concepts from innate, adaptive, and nutritional immunity. We propose that TRIM research focus on determining whether there are specific, well-defined immunosuppressive effects from transfusing 'pure' red blood cells (RBCs) themselves, along with the by-products produced by the stored RBCs as a result of the 'storage lesion.' Macrophages are a key cell type involved in physiological and pathological RBC clearance and iron recycling. The plasticity and diversity of macrophages makes these cells potential mediators of immune suppression that could constitute TRIM.
Recent findings:
Recent reports identified the capacity of macrophages and monocytes to exhibit 'memory.' Exposure to various stimuli, such as engulfment of apoptotic cells and interactions with ß-glucan and lipopolysaccharide, were found to induce epigenetic, metabolic, and functional changes in certain myeloid cells, particularly macrophages and monocytes.
Summary:
Macrophages may mediate the immunosuppressive aspects of TRIM that arise as a result of transfused RBCs and their storage lesion induced by-products.
Background and objectives:
Perioperative red blood cell transfusions (PBT) may be associated with worse survival. In this study of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), we investigated whether there was an association between PBT and survival.
Materials and methods:
A retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis was conducted. Univariate and multivariate analyses were used to identify factors associated with survival.
Results:
Of the 270 patients analysed, 170 (63%) received PBT. A PBT was not significantly associated with recurrence-free survival (RFS) (HR = 1·03; 95% CI: 0·7-1·51; P = 0·879) or overall survival (OS) (HR = 0·65; 95% CI: 0·38-1·11; P = 0·116). Higher number of PBT units (≥5) was not associated with worse RFS (P = 0·077) or OS (P = 0·079). Independent predictors of poor survival included as follows: estimated blood loss and high tumour grade for RFS (both P < 0·001), and male gender (P = 0·029) and high tumour grade (P < 0·001) for OS. Higher preoperative haemoglobin was independently associated with better RFS (P = 0·011) and OS (P = 0·006).
Conclusions:
In this retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis, PBT was not significantly associated with survival.
Introduction:
There is a paucity of data on the impact of allogenic blood transfusion (ABT) on morbidity and survival outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).
Methods:
Nine hundred and thirty-five consecutive CRS/HIPEC procedures were performed between 1996 and 2016 at a high-volume institution in Sydney, Australia. Of these, 337(36%) patients required massive ABT (MABT) (≥5 units). Peri-operative complications were graded according to the Clavien-Dindo classification. The association of concomitant MABT with 21 peri-operative outcomes and overall survival (OS) was assessed using univariate and multivariate analyses.
Results:
In-hospital mortality was 1.8%. Patients requiring MABT had more extensive disease as reflected by a higher peritoneal cancer index (≥17) (70 vs. 29%, p < 0.001) and longer operative times (≥9 h) (82 vs. 35%, p < 0.001). After accounting for confounding factors, MABT was associated with in-hospital mortality (relative risk (RR), 7.72; 95% confidence interval (CI), 1.35-10.11; p = 0.021) and grade III/IV morbidity (RR, 2.05; 95% CI, 1.42-2.95; p < 0.001). MABT was associated with an increased incidence of prolonged hospital stay (≥28 days) (RR, 1.86; 95% CI, 1.26-2.74; p = 0.002) and intensive care unit stay (≥4 days) (RR, 1.83; 95% CI, 1.24-2.70, p = 0.002). It was also associated with a significant OS in patients with colorectal cancer peritoneal carcinomatosis (RR 4.49; p < 0.001) and pseudomyxoma peritonei (RR, 4.37; p = 0.026), but not appendiceal cancer (p = 0.160).
Conclusion:
MABT is an independent predictor for poorer peri-operative outcomes including in-hospital mortality and grade III/IV morbidity. It may also compromise long-term survival, particularly in patients with colorectal cancer peritoneal carcinomatosis.
Background
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined treatment option for well-selected patients with peritoneal carcinomatosis (PC). The study aimed to identify factors influencing cancer-specific survival (CSS) and disease-free survival (DFS). Methods
Data of 113 patients with colorectal or appendicular carcinomatosis from a single center operated between 2009 and 2014 were retrospectively collected and analyzed. Patients with high-grade tumors received standard perioperative chemotherapy, and patients with low-grade appendix tumors were directly operated. HIPEC was performed after radical CRS. ResultsPatients had carcinomatosis from appendix neoplasms in 63% (71/113), including low-grade and high-grade tumors, and colorectal cancer in 37% (42/113). Complete cytoreduction and HIPEC were possible in 67% of patients. Major morbidity occurred in 10.6% of patients, and mean follow-up was 28 months. For colorectal PC, median CSS and DFS were 40 and 12 months, respectively. Median DFS was 19 months for high-grade appendix tumors, while median CSS has not been reached. All patients with diffuse peritoneal adenomucinosis were still alive at time of analysis; rate of DFS was 96% for these patients after 3 years. Major postoperative complications (Clavien-Dindo IIIB or higher) and positive nodal state were associated with impaired CSS and DFS, while a peritoneal cancer index score of >10 was independently associated with impaired CSS. ConclusionsCRS/HIPEC offers a survival benefit in well-selected patients with PC. Major postoperative complications affect long-term oncologic outcome of these patients.
Background and aims:
The treatment of peritoneal malignancies with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be associated with massive surgical blood loss. Maintaining high fibrinogen levels throughout surgery may reduce blood loss in these patients. The primary aim of the study was to see if Tranexamic Acid (TXA) and cryoprecipitate reduced surgical blood loss and hence red cell transfusions. A comparison was made with a cohort of patients treated with fresh frozen plasma (FFP) alone. The secondary aim was to measure the effect of both protocols on coagulation parameters and the incidence of arterial or venous thrombosis.
Method:
We used prospectively collected data from 201 patients who had complete CRS with HIPEC for peritoneal malignancy using different protocols during two discrete 12-month time periods.
Results:
The new transfusion protocol led to a higher average fibrinogen level intra-operatively and post-operatively, with a significant reduction in average RBC, FFP and platelet transfusion intra-operatively per patient from 4·2 to 1·8 units, 6·2 to 0·2 units and 0·1 to 0 units, respectively. No significant difference in PT or APTT was seen between patients treated with the standard and new protocols. Venous thrombosis occurred in seven patients treated with the standard protocol and five with the new protocol. A single case of arterial thrombosis was seen in both groups.
Conclusion:
Patients treated with upfront TXA and cryoprecipitate during CRS required less RBC transfusion than those treated with the standard protocol of early FFP.
We investigated the effects of perioperative blood transfusion in the prognosis of hereditary and sporadic colon cancer. There are 1075 colon cancer patients, including 936 sporadic colon cancer and 139 with hereditary colon cancer undergoing surgery at our hospital. All patients underwent 10 years of follow-up. In the sporadic group, mortality, local recurrence rate and distant metastases rate of transfused patients were significantly higher than non-transfused patients. The 10-year survival rates were significantly lower in patients receiving blood transfusions compared to non-transfused patients. In the hereditary group, mortality was higher in transfused patients compared to non-transfused patients.
Background:
High-grade (HG) mucinous appendiceal neoplasms (MAN) have a worse prognosis than low-grade histology. Our objective was to assess the safety and efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) in patients with high-grade, high-volume (HG-HV) peritoneal metastases in whom the utility of this aggressive approach is controversial.
Methods:
Prospectively collected perioperative data were compared between patients with peritoneal metastases from HG-HV MAN, defined as simplified peritoneal cancer index (SPCI) ≥12, and those with high-grade, low-volume (HG-LV; SPCI <12) disease. Kaplan-Meier curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes.
Results:
Overall, 54 patients with HG-HV and 43 with HG-LV peritoneal metastases underwent CRS/HIPEC. The HG-HV group had longer operative time, increased blood loss/transfusion, and increased intensive care unit length of stay (p < 0.05). Incomplete macroscopic cytoreduction (CC-1/2/3) was higher in the HG-HV group compared with the HG-LV group (68.5 vs. 32.6 %; p = 0.005). Patients with HG-HV disease demonstrated worse survival than those with HG-LV disease (overall survival [OS] 17 vs. 42 m, p = 0.009; time to progression (TTP) 10 vs. 14 m, p = 0.024). However, when complete macroscopic resection (CC-0) was achieved, the OS and progression-free survival of patients with HG-HV disease were comparable with HG-LV disease (OS 56 vs. 52 m, p = 0.728; TTP 20 vs. 19 m, p = 0.393). In a multivariate Cox proportional hazard regression model, CC-0 resection was the only significant predictor of improved survival for patients with HG-HV disease.
Conclusions:
Although patients with HG-HV peritoneal metastases from MAN have worse prognosis compared with patients with HG-LV disease, their survival is comparable when complete macroscopic cytoreduction is achieved.
The prognostic effect of perioperative blood transfusion on recurrence and survival in patients undergoing resection of gastric adenocarcinoma (GAC) remains controversial.
All patients who underwent resection for GAC from 2000 to 2012 at the 7 institutions of the US Gastric Cancer Collaborative were identified. The effect of transfusion on recurrence-free (RFS) and overall survival (OS) in the context of adverse clinicopathologic variables was examined by univariate and multivariate regression analyses.
Of 965 patients, 765 underwent curative intent R0 resection. Median follow-up was 44 months; 30-day mortalities were excluded. Median estimated blood loss (EBL) was 200 mL, and 168 patients (22%) received perioperative allogeneic blood transfusions. Transfused patients were less likely to receive adjuvant therapy (44% vs 56%; p = 0.01). Transfusion was associated with significantly decreased median RFS (13.5 vs 37.2 months, p < 0.001). Median OS was similarly decreased in patients receiving transfusions (18.6 vs 49.8 months, p < 0.001). On multivariate analysis, transfusion remained an independent risk factor for decreased RFS (hazard ratio [HR] 1.63; 95% CI 1.13 to 2.37; p = 0.010) and decreased OS (HR 1.79; 95% CI 1.21 to 2.67; p = 0.004), regardless of EBL or need for splenectomy. Timing (intraoperative vs postoperative) and volume of transfusion did not alter the negative prognostic effect of transfusion on survival.
Perioperative allogeneic blood transfusion is associated with decreased RFS and OS after resection of gastric cancer, independent of adverse clinicopathologic factors. This supports the judicious use of perioperative transfusion during resection of gastric cancer.
Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
Peritoneal carcinomatosis (PC) results from the secondary spread of many intraabdominal tumour types, such as colorectal malignancy (colorectal cancer, CRC), disseminated peritoneal adenomucinosis (DPAM), appendiceal cancer, ovarian carcinoma, sarcoma or from the occurrence of primary peritoneal disease such as peritoneal mesothelioma. The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has seen improvements in survival in selected cases of these cancers.
Between 1996 and 2014, a prospective database of 675 patients was created for the peritonectomy unit at our hospital. In total, 827 peritonectomy procedures (including redo CRS) were performed for the major subgroups of PC: DPAM 220; appendiceal cancer (peritoneal mucinous adenocarcinoma (PMCA)) 191; CRC 234; diffuse malignant peritoneal mesothelioma (DMPM) 73 and others 109. There were 152 redo-peritonectomy procedures within the total mentioned earlier (CRC 26; DPAM 58; DMPM 18; appendix 40; other 10).
The 5-year survivals for DPAM and PMCA were 80% and 42% respectively. The 5-year survivals for appendiceal cancer with peritoneal cancer index (PCI) <10, 10-20 and >20 were 60, 57 and 37% respectively (P = 0.09). The 2- and 5-year survivals for CRC were 56 and 24% respectively. The 5-year survivals for PCI 0-5, 6-10, 11-15 and >15 were 59, 15, 7 and 0% respectively (P = 0.000). The 5-year survival for DMPM with PCI < 10, 10-20 and >20 were 100, 55 and 39% respectively (P = 0.01).
CRS in combination with HIPEC provides a chance of long-term survival in selected cases of PC when compared with systemic therapy alone.
© 2015 Royal Australasian College of Surgeons.
Peritoneal carcinomatosis is a common evolution of gastrointestinal cancers. The prognosis of patients with such disease is dependent upon pre-operative and post-operative variables. CT scan of the abdomen and the pelvis represents the adequate standardized radiologic exam for pre-operative evaluation of tumor volume and location in the peritoneal cavity. It may provide informations regarding the selection of patients for complete cytoreductive surgery. Clinical factors like the extent of prior surgical procedures, the grade of the primary tumor, and the mucin content of peritoneal implants may also help to select patients for an adequate treatment approach. Several intra-operative factors including the cancer distribution into the peritoneal cavity and the completeness of surgery need to be prospectively recorded by the surgeon in order to assess quantitatively their impact on the prognosis of patients with peritoneal carcinomatosis. This review provides standardized methodologies in the assessment of these clinical variables.
Red blood cell transfusions (RBCTs) are associated with cancer recurrence following resection of colorectal cancer. Their impact after colorectal liver metastases (CRLM) resection remains debated. We sought to explore the association between perioperative RBCT and oncologic outcomes following resection of CRLM.
We reviewed patients undergoing partial hepatectomy for CRLM from 2003 to 2012 at a single institution. Date of death was abstracted from a validated population-based cancer registry. Primary outcome was overall survival (OS). Secondary outcome was recurrence-free survival (RFS). Survivals were estimated using Kaplan-Meier methods and compared with log-rank test based on transfusion status. Cox regression analysis examined the association of RBCT with OS and RFS, while adjusting for age, preoperative chemotherapy, Clinical Risk Score, and period of treatment (2003-2007 vs. 2008-2012).
Among 483 patients, 27.5 % received RBCT. Ninety-day postoperative mortality was 4.8 %. At median follow-up of 33 (interquartile range 20.1-54.8) months, 5-year OS was inferior in transfused patients (45.9 vs. 61.0 %; p < 0.0001). Five-year RFS was decreased with RBCT (15.5 vs. 31.6 %; p < 0.0001). The difference persisted when considering only 90-day survivors for 5-year OS (53.1 vs. 61.9 %, p = 0.023) and RFS (15.6 vs. 31.6 %; p < 0.0001). After adjustment for prognostic factors, RBCT was independently associated with decreased OS (hazard ratio 2.24; 95 % confidence interval 1.60-3.15) and RFS (hazard ratio 1.71; 95 % confidence interval 1.28-2.28).
Perioperative RBCT is independently associated with decreased OS and RFS following hepatectomy for CRLM. Interventions to minimize and rationalize the use of RBCT for hepatectomy are warranted to mitigate this detrimental effect on long-term outcomes.
The deleterious effect of perioperative allogeneic blood transfusion in patients with resected lung cancer has been controversial. We conducted this meta-analysis to answer the question of whether perioperative allogeneic blood transfusion adversely affects recurrence and survival in patients with resected lung cancer. Included were 23 studies with 6,474 patients. The result showed allogeneic blood transfusion was significantly associated with earlier recurrence and worse survival in patients with surgically resected lung cancer. We suggest transfusion policy should be stricter in lung cancer patients undergoing resection, especially with early-stage disease. Prospective large-scale studies are still warranted.
To determine the effect of allogeneic blood transfusion (ABT) on clinical outcomes in patients with colorectal cancer undergoing surgery.
Perioperative ABTs may be associated with adverse clinical outcomes.
Systematic review of the literature with odds ratio (OR) and incidence rate ratio (IRR) meta-analyses of predefined clinical outcomes based on a MEDLINE search.
In total, 20,795 colorectal cancer (CRC) patients observed for more than 59.2 ± 26.1 months (108,838 patient years) were included, of which 58.8% were transfused. ABT was associated with increased all-cause mortality OR = 1.72 (95% confidence interval [CI] 1.55-1.91, P < 0.001); I(2) = 23.3% (0-51.1) and IRR = 1.31 (1.23-1.39, P < 0.001), I(2) = 0.0% (0-37.0). ABT was also associated with increased ORs (95% CI, P) for cancer-related mortality of 1.71 (1.43-2.05, P <0.001), combined recurrence-metastasis-death 1.66 (1.41-1.97, P < 0.001), postoperative infection 3.27 (2.05-5.20, P < 0.001), and surgical reintervention 4.08 (2.18-7.62, <0.001). IRR (95% CI, P) was 1.45 (1.26-1.66, <0.001) for cancer-related mortality and 1.32 (1.19-1.46, <0.001) for recurrence-metastasis-death. Mean length of hospital stay was significantly longer in transfused compared with nontransfused patients (17.8 ± 4.8 vs 13.9 ± 4.7 days, P = 0.005).
In patients with colorectal cancer (CRC) undergoing surgery, ABTs are associated with adverse clinical outcomes, including increased mortality. Measures aimed at limiting the use of ABTs should be investigated further.
Background:
Because of scarce data from larger series and nonhomogeneous selection criteria, further information is needed on peritonectomy with hyperthermic intraperitoneal chemotherapy (HIPEC) in managing patients with ovarian peritoneal carcinomatosis.
Methods:
In an open, prospective, single-center nonrandomized phase 2 study conducted from November 2000 to April 2007, 47 patients with primary advanced or recurrent ovarian cancer and diffuse peritoneal carcinomatosis were enrolled; 22 underwent primary and 25 secondary cytoreduction plus immediate HIPEC followed by systemic chemotherapy.
Results:
The overall mean Sugarbaker peritoneal cancer index was 14.9 (range, 6-28). A mean of 6 surgical procedures were required per patient (range, 4-10). In 87.3% of the patients debulking achieved optimal cytoreduction (Sugarbaker completeness of cytoreduction [CC] score 0-1), whereas in 12.7% it left macroscopic residual disease (CC-2 or CC-3). Major complications developed in 21.3% of the patients and the in-hospital mortality rate was 4.2%. The mean overall survival was 30.4 months, median survival was 24 months, and mean disease-free survival was 27.4 months. Five-year survival was 16.7%. Univariate (log-rank test and analysis of variance) and multivariate analyses (Cox proportional-hazard model) identified the CC score as the main factor capable of independently influencing survival.
Conclusions:
Peritonectomy procedures combined with HIPEC offer promising long-term survival in patients with diffuse peritoneal ovarian carcinomatosis. They achieve high adequate primary and secondary surgical cytoreduction rates with acceptable morbidity and mortality.
Background:
Perioperative intraperitoneal chemotherapy (PIC) is delivered by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). The relative survival benefits of each or both regimens are explored in this large series of patients undergoing cytoreduction at a single institution.
Methods:
Patients with a complete (CCR0) or optimal (CCR1) cytoreduction who received intraperitoneal chemotherapy for appendiceal and colorectal peritoneal carcinomatosis were included for analysis. PIC regimens were delivered according to the treatment protocol. Standardized statistical analyses were performed.
Results:
Of 262 patients, 98 patients (37%) had colorectal peritoneal carcinomatosis, 108 patients (41%) had low-grade pseudomyxoma peritonei and 56 patients (21%) had appendiceal peritoneal carcinomatosis. For pseudomyxoma peritonei, recurrence-free survival (RFS) did not vary with PIC regimen, 5-year survival was 86% in the HIPEC and EPIC group and 64% in the HIPEC or EPIC group (P = 0.070). For appendiceal peritoneal carcinomatosis, RFS and overall survival (OS) did not vary with PIC regimen. For colorectal peritoneal carcinomatosis, the median RFS was 33 months in the HIPEC and EPIC group, 19 months in the HIPEC alone group and 20 months in the EPIC alone group (P = 0.046). OS did not vary with PIC regimen.
Conclusion:
From our experience, without compromising the perioperative morbidity and mortality, PIC consisting of HIPEC and EPIC appears to be associated with potential survival benefits of improved OS in pseudomyxoma peritonei and RFS in colorectal peritoneal carcinomatosis.
To evaluate the association between perioperative blood transfusion on the recurrence and survival of patient with advanced ovarian cancer.
Cytoreductive surgery for ovarian cancer can be an extensive procedure often requiring allogeneic blood transfusions. Blood transfusions can have detrimental effects on immune function which can lead to a decrease in the organism ability to detect and destroy metastasis.
The study was a retrospective cohort investigation. Patients with advanced ovarian cancer (stage III) undergoing cytoreductive surgery were stratified by the need for perioperative blood transfusion. Allogeneic transfusions were non-leucodepleted. Primary outcome included time to recurrence and survival. Data were extracted from the gynaecology oncology database at Northwestern University. Times to event outcomes were evaluated by constructing Kaplan-Meyer curves and Cox regression.
The charts of 136 subjects were evaluated. Seventy-six received blood transfusion. Median [95% confidence interval (CI)] time to recurrence for the non-transfusion group was longer, i.e. 17 (6-27) months, compared to 11 (8-14) months for the transfused group (P = 0.03). Median (95% CI) survival following surgery was longer in the non-transfused group, i.e. 58 (43-73) months, compared to 36 (28-44) months for the transfused group (P = 0.04). Cox regression showed that transfused subjects had shorter median times to recurrence and mortality after adjusting for age and tumour grade.
There is an association between ovarian cancer recurrence and allogeneic perioperative blood transfusion in patients with advanced ovarian cancer undergoing cytoreductive surgery. These findings may have important implications in the perioperative management of those patients.
The treatment of peritoneal carcinomatosis is based on cytoreduction followed by hyperthermic intraperitoneal chemotherapy and combined with adjuvant chemotherapy. In 2003, a randomized trial was finished comparing systemic chemotherapy alone with cytoreduction followed by hyperthermic intraperitoneal chemotherapy and systemic chemotherapy. This trial showed a positive result favoring the studied treatment. This trial has now been updated to a minimal follow-up of 6 years to show long-term results.
For all patients still alive, the follow-up was updated until 2007. In the original study, four patients were excluded-two because of no eligible histology/pathology and two because of major protocol violations. After randomization, four patients in the HIPEC arm and six in the control arm were not treated using the intended therapy, one patient because of withdrawal, one because of a life-threatening other malignant disease and the others because of progressive disease before initiation of the treatment. During the follow-up, one patient was crossed over from the control arm and underwent cytoreduction and HIPEC for recurrent disease, after the assigned treatment was completed. The data from these patients were censored at the moment of the cross-over. Progression-free and disease-specific survival were analyzed using the Kaplan Meyer test and compared using the log rank method. The long-term results were studied in more detail to evaluate efficacy and toxicity.
At the time of this update, the median follow-up was almost 8 years (range 72-115 months). In the standard arm, 4 patients were still alive, 2 with and 2 without disease; in the "HIPEC' arm, 5 patients were still alive, 2 with and 3 without disease. The median progression-free survival was 7.7 months in the control arm and 12.6 months in the HIPEC arm (P = 0.020). The median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm (P = 0.028). The 5-year survival was 45% for those patients in whom a R1 resection was achieved.
With 90% of all events having taken place up to this time, this randomized trial shows that cytoreduction followed by HIPEC does significantly add survival time to patients affected by peritoneal carcinomatosis of colorectal origin. For a selected group, there is a possibility of long-term survival.
Transfusion of packed red blood cells (PRBCs) increases morbidity and mortality in select surgical specialty patients. The impact of low-volume, leukoreduced RBC transfusion on general surgery patients is less well understood.
The American College of Surgeons National Surgical Quality Improvement Program participant use file was queried for general surgery patients recorded in 2005 to 2006 (n = 125,223). Thirty-day morbidity (21 uniformly defined complications) and mortality, demographic, preoperative, and intraoperative risk variables were obtained. Infectious complications and composite morbidity and mortality were stratified across intraoperative PRBCs units received. Multivariable logistic regression was used to assess influence of transfusion on outcomes, while adjusting for transfusion propensity, procedure type, wound class, operative duration, and 30+ patient risk factors.
After adjustment for transfusion propensity, procedure group, wound class, operative duration, and all other important risk variables, 1 U PRBCs significantly (p < 0.05) increased risk of 30-day mortality (odds ratio [OR] = 1.32), composite morbidity (OR = 1.23), pneumonia (OR = 1.24), and sepsis/shock (OR = 1.29). Transfusion of 2 U additionally increased risk for these outcomes (OR = 1.38, 1.40, 1.25, 1.53, respectively; p <or= 0.05) plus surgical-site infection (OR = 1.25; p < 0.05). A risk index for calculating transfusion likelihood demonstrated very good discrimination (c-index = 0.844).
Intraoperative transfusion of PRBCs increases risk for mortality and several morbidities in general surgery patients. These risks, substantial for even 1 U, remain after adjustment for transfusion propensity and numerous risk factors available in the American College of Surgeons National Surgical Quality Improvement Program. Transfusion for mildly hypovolemic or anemic patients should be discouraged in light of these risks.
Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has demonstrated improved survival in selected patients with peritoneal carcinomatosis (PC). This treatment modality is associated with high blood loss and often requires massive allogenic red blood cell transfusion (MABT). Our study is the first of its kind to evaluate the risk factors for intraoperative MABT in peritonectomy procedures.
Two hundred and forty-three consecutive CRS and PIC procedures were evaluated. The associations between 17 preoperative and intraoperative risk factors and intraoperative MABT (>or=6 units) were assessed by univariate and multivariate analysis.
One hundred and eighty-six (77%) procedures required intraoperative transfusion of packed red blood cells. Ninety-one procedures required MABT (37%). Multivariate analysis showed six significant risk factors for intraoperative MABT: operative length > 9 h (p < 0.001), preoperative hemoglobin < 125 g/l (p < 0.001), operation date prior to 2004 (p = 0.002), peritoneal cancer index >or= 16 (p = 0.006), preoperative international normalized ratio (INR) >or= 1.2 (p = 0.008), and number of peritonectomy procedures >or= 4 (p = 0.021). Statistical analysis also revealed that MABT was associated with increased intensive care unit (ICU) (p < 0.001), high-dependency unit (HDU) (p = 0.020), and total hospital stay (p < 0.001) and with severe morbidity (p < 0.001).
Patients with preoperative anemia, impaired coagulation profile or extensive tumor burden are at high risk of MABT. Appropriate blood conservation strategies should be adopted in these patients on the basis of their risk factors.
To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin.
Between February 1998 and August 2001, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime. The primary end point was survival.
After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P =.032). The treatment-related mortality in the aggressive therapy group was 8%. Most complications from HIPEC were related to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P <.0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P <.0001).
Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.
Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time.
A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide.
The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons.
The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
Decisions regarding the treatment of cancer depend on the anatomic location of the malignancy and the biologic aggressiveness of the disease. Some patients may have isolated intraabdominal seeding of malignancy of limited extent or of low biologic grade. In the past these clinical situations have been regarded as lethal. We have used the cytoreductive approach to achieve long-term disease-free survival in some patients with peritoneal carcinomatosis, peritoneal sarcomatosis, or mesothelioma. The cytoreductive approach may require six peritonectomy procedures to resect or strip cancer from all intraabdominal surfaces. These are (1) greater omentectomy-splenectomy, (2) left upper quadrant peritonectomy, (3) right upper quadrant peritonectomy, (4) lesser omentectomy-cholecystectomy with stripping of the omental bursa, (5) pelvic peritonectomy with sleeve resection of the sigmoid colon, and (6) antrectomy. These peritonectomy procedures and preparation of the abdomen for early postoperative intraperitoneal chemotherapy are described.
Allogeneic blood transfusion (ABT)-related immunomodulation (TRIM) encompasses the laboratory immune aberrations that occur after ABT and their established or purported clinical effects. TRIM is a real biologic phenomenon resulting in at least one established beneficial clinical effect in humans, but the existence of deleterious clinical TRIM effects has not yet been confirmed. Initially, TRIM encompassed effects attributable to ABT by immunomodulatory mechanisms (e.g., cancer recurrence, postoperative infection, or virus activation). More recently, TRIM has also included effects attributable to ABT by pro-inflammatory mechanisms (e.g., multiple-organ failure or mortality). TRIM effects may be mediated by: (1) allogeneic mononuclear cells; (2) white-blood-cell (WBC)-derived soluble mediators; and/or (3) soluble HLA peptides circulating in allogeneic plasma. This review categorizes the available randomized controlled trials based on the inference(s) that they permit about possible mediator(s) of TRIM, and examines the strength of the evidence available for relying on WBC reduction or autologous transfusion to prevent TRIM effects.
The Beneficial Effects of Minimizing Blood Loss in Pancreatoduodenectomy
- Seykora T.F.
- Ecker B.L.
- McMillan M.T.
- Maggino L.
- Beane J.D.
- Fong Z.V.
- Hollis R.H.
- Dickson E.J.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience.
- Yan T.D.
- Deraco M.
- Baratti D.
- Kusamura S.
- Elias D.
- Glehen O.