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Impacts of low peritoneal cancer index on the survival outcomes of patient with peritoneal carcinomatosis of colorectal origin
Abstract
Introduction:
The combination of cytoreductive surgery (CRS) and perioperative chemotherapy (PIC) have been proposed as an innovative technique for peritoneal carcinomatosis and is currently considered as a standard treatment for colorectal peritoneal carcinomatosis (CRPC) in selected patients. Peritoneal cancer index (PCI) has been suggested to be the most important prognostic factors for the outcomes of patients with CRPC. In this paper, we have studied patients with CRPC and a very low PCI of 5 or less and their survival outcomes.
Methods:
This is a retrospective study of prospectively collected data of 60 consecutive patients with CRPC and PCI ≤5, who underwent CRS and PIC by the same surgical team at St George hospital in Sydney, Australia between January 1996 and April 2015. Clinical outcomes of these patients were analysed.
Results:
Hospital mortality was 0%. 14 patients (23.4%) had grade III/IV morbidity. The median follow-up was 22.2 months (range=0.1-104.2). The median survival was 80.6 months (95% confidence interval (CI)=35.1-126.1), with an overall 1-year, 3-year, and 5-year survival rate of 96.1%, 72.6% and 54.7% respectively. Among 60 patients, 31 patients experienced the recurrence of the disease (51.7%). The median disease-free survival was 10.8 months (95%CI=7.2-14.4).
Conclusion:
This innovative approach combining CRS and PIC has shown encouraging outcomes and offers hope for patients with CRPC. Our results suggest that CRS and PIC can be performed safely to provide significant survival benefits for patients with low volume of disease. Early referral to specialist centre for evaluation is warranted for better survival outcomes.
... An additional treatment protocol each was described for the combination of MMC with 5-fluorouracil (5-FU) [125], the active irinotecan (IRI) metabolite hydroxycamptothecin (HCPT) [126] and etoposide (ETO) [119] (Table S7). Using single-agent oxaliplatin (L-OHP), at least twelve different manners of drug dosing were described in 44 articles (Table S4) [28,31-35, 54,55,60,65,66,69,72,75,76,81,82,91,108,111,116,121,. Between 2004 and 2016 seven articles were published, outlining four diverse ways of dosing a combination of L-OHP and IRI (Table S5) [32, 83,134,140,144,149,150]. ...
... As a monotherapy CDDP was insignificant in CRC (1%) (Table S6) [108,147]. The second most frequently used drug was L-OHP mainly employed as a single-agent therapy (26%; Figure 2a,c, Table S4) [28,[31][32][33][34][35]54,55,60,65,66,69,72,75,76,81,82,91,108,111,116,121, or combined with IRI (Table S5) [32, 83,134,140,144,149,150]. Rarely, monotherapies with other drugs were mentioned (Table S8) [139,[151][152][153]. ...
... The second most frequently used HIPEC drug was L-OHP, which was used according to 26% of reports ( Figure 2c) [28,31-35, 54,55,60,65,66,69,72,75,76,[81][82][83]91,108,111,116,121,. With L-OHP a remarkable homogeneity concerning drug dosing was observed and all but four articles used mg/m 2 for benchmarking ( Figure 6, Table S4). ...
Cytoreductive surgery (CRS), followed by hyperthermic intraperitoneal chemotherapy (HIPEC), combines radical surgery with abdominal heated chemotherapy, constituting a multimodal treatment approach. Since clear standards for HIPEC conduct in colorectal carcinoma (CRC) are lacking, we aimed to provide a comprehensive structured survey. Data sources and study eligibility criteria: A systematic literature search was performed in PubMed, with keywords “HIPEC” and “colorectal cancer”, according to established guidelines. Articles were systematically screened, selecting 87 publications complemented by 48 publications identified through extended search for subsequent synthesis and evaluation, extracting inter alia details on used drugs, dosage, temperature, exposure times, and carrier solutions. Results: Compiled publications contained 171 reports on HIPEC conduct foremost with mitomycin C and oxaliplatin, but also other drugs and drug combinations, comprising at least 60 different procedures. We hence provide an overview of interconnections between HIPEC protocols, used drugs and carrier solutions as well as their volumes. In addition, HIPEC temperatures and dosing benchmarks, as well as an estimate of in vivo resulting drug concentrations are demonstrated. Conclusions and implications: Owing to recent developments, HIPEC conduct and practices need to be reassessed. Unfortunately, imprecise and lacking reporting is frequent, which is why minimal information requirements should be established for HIPEC and the introduction of final drug concentrations for comparability reasons seems sensible.
... Notably, the T3 stage was the most common tumor stage among patients without PM, whereas the T4 stage was most prevalent in patients with PM, which is consistent with the invasive nature of T4 tumors that involve adjacent organs or the visceral peritoneum [9,10]. A prior study similarly reported that the T4 stage was a significant predictor of metastasis in CRC patients with metachronous disease [11]. ...
... Additionally, a French study in 2011 observed no signs of recurrence after second-look surgeries despite visible peritoneal carcinomatosis in 62% of patients with ovarian involvement [17]. A study published in 2015 suggested that patients with high-risk features for PM, such as T4 stage, mucinous tumors, Krukenberg tumors, or elevated CEA levels, could benefit from secondlook laparoscopic surgery for early detection [11]. ...
Background
The incidence of colorectal cancer (CRC) is increasing nationally, emphasizing the importance of early detection. Late-stage diagnosis, particularly with peritoneal metastasis (PM), is associated with poor outcomes despite advancements in treatment. PM poses a challenge owing to the lack of standardized treatment, although cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) shows promise in improving survival rates. This study aimed to document the incidence and risk factors for patients presenting with PM following CRC.
Materials and methods
This retrospective chart review study was conducted at King Abdulaziz Medical City in Saudi Arabia. Patients of all ages and genders who underwent surgical resection for CRC from January 2016 to December 2021 were included. Patients with PM at primary index surgery, distant organ metastasis to the lung or liver, or other types of cancer were excluded. The data was analyzed via SPSS Statistics version 27.0 (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.), t-test, Wilcoxon rank-sum test, chi-square test, and Fisher’s exact tests.
Results
Among 565 patients with CRC, 65 patients (11.5%) developed PM. Tumor characteristics such as T4 stage, mucinous tumors, elevated CEA, and the presence of ovarian metastasis at primary resection were independent factors for peritoneal recurrence. However, in univariate and multivariate associations, the presence of ovarian metastasis, mucinous tumors, postoperative CEA levels exceeding 5 ng/ml, and perforation are significant risk factors for PM development post-surgery, with hazard ratios of 6.457 (CI 2.481-16.801) and 4.057 (2.029-8.115), respectively.
Conclusion
Mucinous tumors and ovarian metastasis are significant risk factors for PM development, emphasizing the importance of early identification for tailored treatment strategies such as CRS and HIPEC.
... However, CT has a wide sensitivity range of 24.5%-79% for detecting peritoneal metastases, potentially underestimating the PCI by 24%-33% [4,[8][9][10][11][12]. Although patients with very low PCIs are ideal candidates for CRS þ HIPEC, small peritoneal lesions are difficult to detect by CT [13][14][15]. Furthermore, if tumor loads are found to be excessive at operation, underestimation can lead to unnecessary "open-and-close" procedures and avoidably prolonged recovery times and complications. Accurate patient identification can therefore ensure optimal use of surgical and financial resources. ...
... To date, we could find no studies comparing diagnostic laparoscopy with CT in patient selection for CRS þ HIPEC based on the estimated PCI. Although some studies have been performed comparing the accuracies of CT and laparotomy [4,[10][11][12], these showed that the median PCI score estimated by CT (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) was significantly lower than that estimated by laparotomy (13-39) (p-value, <0.001 to 0.003) [4,[10][11][12]. One study illustrated that, despite CT scans underestimating the PCI, only 12% of patients would require an open-and-close procedure [4]. ...
Background
Despite its widespread use, computed tomography (CT) is not perfect for evaluating peritoneal metastases of colorectal origin before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). We therefore evaluated the value of adding diagnostic laparoscopy to CT when assessing patient eligibility for CRS + HIPEC.
Methods
This was a retrospective study of a consecutive series of 112 patients evaluated systematically by diagnostic laparoscopy and CT between January 2012 and January 2018. Patient eligibility for CRS + HIPEC was assessed by the peritoneal cancer index (PCI) both at the time of initial diagnostic laparoscopy and during the retrospective review of CT images. Two experienced radiologists who were blinded to the PCI result at laparoscopy then independently estimated the PCI based on CT imaging. The primary outcome was the number of patients eligible for CRS + HIPEC by each method.
Results
We identified 112 patients, of whom 95 (85%) were eligible for CRS + HIPEC based on diagnostic laparoscopy and 84 underwent CRS + HIPEC. Overall, 14 patients (17%) experienced an “open-and-close” procedure. In contrast to diagnostic laparoscopy, 100 patients (89%) were identified as being eligible for CRS + HIPEC by CT (p = 0.13), which would have resulted in an additional five open-and-close procedures.
Conclusions
Adding diagnostic laparoscopy to CT produced a clinically relevant, but statistically non-significant, reduction in the number of patients eligible for CRS + HIPEC. We conclude that diagnostic laparoscopy may be of use in preoperative assessments when systematic analysis by CT scores the PCI as greater than ten. Future research should focus on the cost-effectiveness of this approach.
... The efficacy of CRS/HIPEC highly depends on the extent of peritoneal involvement, which is often assessed with the peritoneal cancer index (PCI) as proposed by Jacquet and Sugarbaker [3,[15][16][17][18][19][20][21][22]. Patients with a low PCI (1)(2)(3)(4)(5) have reported median survival of up to 81 months and 5-year survival rates exceeding 70%, whereas only about 10% of patients with extensive PM (PCI ≥16) are alive at 5 years postoperative [23,24]. Besides a survival benefit, limited extent of peritoneal disease is also correlated with lower postoperative morbidity following CRS [15,17,19,25]. ...
... Patients visit the outpatient clinic twice a year during the first two to three years and annually thereafter, until five years postoperative. CEA-levels are determined at 12,15,18,21,24,30,36,48 and 60 months after primary resection. Imaging of the liver using ultrasound or CT is performed at 12, 24, 36, 48 and 60 months postoperative. ...
Background
Approximately 20–30% of patients with pT4 colon cancer develop metachronous peritoneal metastases (PM). Due to restricted accuracy of imaging modalities and absence of early symptoms, PM are often detected at a stage in which only a quarter of patients are eligible for curative intent treatment. Preliminary findings of the COLOPEC trial (NCT02231086) revealed that PM were already detected during surgical re-exploration within two months after primary resection in 9% of patients with pT4 colon cancer. Therefore, second look diagnostic laparoscopy (DLS) to detect PM at a subclinical stage may be considered an essential component of early follow-up in these patients, although this needs confirmation in a larger patient cohort. Furthermore, a third look DLS after a negative second look DLS might be beneficial for detection of PM occurring at a later stage.
Methods
The aim of this study is to determine the yield of second look DLS and added value of third look DLS after negative second look DLS in detecting occult PM in pT4N0-2 M0 colon cancer patients after completion of primary treatment. Patients will undergo an abdominal CT at 6 months postoperative, followed by a second look DLS within 1 month if no PM or other metastases not amenable for local treatment are detected. Patients without PM will subsequently be randomized between routine follow-up including 18 months abdominal CT, or an experimental arm with a third look DLS provided that PM or incurable metastases are absent at the 18 months abdominal CT. Primary endpoint is the proportion of PM detected after a negative second look DLS and will be determined at 20 months postoperative.
Discussion
Second look DLS is supposed to result in 10% occult PM, and third look DLS after negative second look DLS is expected to detect an additional 10% of PM compared to routine follow-up alone in patients with pT4 colon cancer. Detection of PM at an early stage will likely increase the proportion of patients eligible for curative intent treatment and subsequently improve survival, given the uniformly reported direct association between the extent of peritoneal disease and survival.
Trial registration
ClinicalTrials.gov: NCT03413254, January 2018.
Electronic supplementary material
The online version of this article (10.1186/s12885-019-5408-8) contains supplementary material, which is available to authorized users.
... Approximately 5-10% of patients diagnosed with CRC are additionally diagnosed with PM, and in recurrent disease, the incidence increases to 20-60% [3,4]. PM of CRC origin is associated with poor prognosis, averaging only 5-24 months [5,6]. ...
... For CRC patients, the average median OS was observed to be 32.3 months, ranging between 13 and 76.9 months, and with an average 5-year survival of 44.5%, ranging from 19 to 83.3 months for the studies included in this analysis. Systemic chemotherapy has also improved over recent years with a median OS of 13 months, ranging between 5 and 24 months, and a 5-year survival rate between 0 and 22% [6]. When ovarian cancer was the primary cause of PM, we observed an average median OS of 39.2 months, ranging between 5.8 and 65.6 months, and an average 5-year survival rate of 43.9%, ranging between 12 and 63.4%. ...
Peritoneal metastasis (PM) originating from gastrointestinal and gynecological malignancies are associated with a poor prognosis and rapid disease progression. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment option with curative intent. Hyperthermia enhances the cytotoxicity of chemotherapeutic drugs, thereby killing microscopic tumors and reducing the risk of tumor recurrence. Eight parameters potentially have an impact on the efficacy of HIPEC: the type of drug, drug concentrations, carrier solution, volume of the perfusate, temperature of the perfusate, duration of the treatment, the technique of delivery, and patient selection. In this review, a literature search was performed on PubMed, and a total of 564 articles were screened of which 168 articles were included. Although HIPEC is a successful treatment, there is no standardized method for delivering HIPEC: the choice of parameters is presently largely determined by institutional preferences. We discuss the current choice of the parameters and hypothesize about improvements toward uniform standardization. Quantifying the effect of each parameter separately is necessary to determine the optimal way to perform HIPEC procedures. In vivo, in vitro, in silico, and other experimental studies should shed light on the role of each of the eight parameters.
... Peritoneal carcinomatosis (PC), also known as peritoneal dissemination, refers to the spread of malignancy along the lining surface of the peritoneal (abdominal) cavity [3]. PC stands as a grave consequence that menaces these patients, resulting in diminished quality of life and an unfavorable prognosis, attributed to issues like bowel obstructions and ascites [4][5][6]. While intravenous (IV) chemotherapy serves as a palliative measure for these cases, intraperitoneal (IP) chemotherapy, coupled with cytoreductive surgery (CRS), holds promise for treating these patients [7][8][9][10][11]. ...
Simple Summary
Intraperitoneal (IP) chemotherapy is a treatment for cancers in the abdomen, delivering anti-cancer drugs directly into the peritoneal cavity. While this method has shown promising outcomes, limited drug penetration into tumors remains a challenge due to their unique pathophysiology. Our study aims to investigate drug delivery during IP chemotherapy using a mathematical model. We incorporated a real tumor image into our model to understand how tumor vessels and their distribution affect drug delivery. Our model allowed us to analyze the spatiotemporal distribution of drug concentration in the tumor. We also quantitatively evaluated treatment efficacy by examining drug availability in the tumor, drug penetration depth, and the fraction of killed cells during the treatment. Our findings revealed that each tumor’s specific vascular network can impact drug delivery during IP chemotherapy. Our model provides valuable insights into the challenges of IP chemotherapy and holds promise for applications in personalized medicine.
Abstract
Intraperitoneal (IP) chemotherapy is a promising treatment approach for patients diagnosed with peritoneal carcinomatosis, allowing the direct delivery of therapeutic agents to the tumor site within the abdominal cavity. Nevertheless, limited drug penetration into the tumor remains a primary drawback of this method. The process of delivering drugs to the tumor entails numerous complications, primarily stemming from the specific pathophysiology of the tumor. Investigating drug delivery during IP chemotherapy and studying the parameters affecting it are challenging due to the limitations of experimental studies. In contrast, mathematical modeling, with its capabilities such as enabling single-parameter studies, and cost and time efficiency, emerges as a potent tool for this purpose. In this study, we developed a numerical model to investigate IP chemotherapy by incorporating an actual image of a tumor with heterogeneous vasculature. The tumor’s geometry is reconstructed using image processing techniques. The model also incorporates drug binding and uptake by cancer cells. After 60 min of IP treatment with Doxorubicin, the area under the curve (AUC) of the average free drug concentration versus time curve, serving as an indicator of drug availability to the tumor, reached 295.18 mol·m⁻³·s⁻¹. Additionally, the half-width parameter W1/2, which reflects drug penetration into the tumor, ranged from 0.11 to 0.14 mm. Furthermore, the treatment resulted in a fraction of killed cells reaching 20.4% by the end of the procedure. Analyzing the spatial distribution of interstitial fluid velocity, pressure, and drug concentration in the tumor revealed that the heterogeneous distribution of tumor vasculature influences the drug delivery process. Our findings underscore the significance of considering the specific vascular network of a tumor when modeling intraperitoneal chemotherapy. The proposed methodology holds promise for application in patient-specific studies.
... Peritoneal cancer index (PCI) has been a strong indicator of prognosis for patients receiving cytoreductive surgery. However, radiological determination of PCI before surgery has often not correlated with the surgical PCI due to the limitations in visualisation of the tumour (4,(6)(7)(8). In addition, several clinicopathological variables impact the prognosis of colorectal carcinoma. ...
Background/aim:
Peritoneal cancer index (PCI) has been a strong indicator of prognosis for patients receiving cytoreductive surgery. The aim of this single institution study was to compare the survival of peritoneal carcinoma cases treated with cytoreduction surgery arising from colorectal cancer grouped by PCI scores.
Patients and methods:
A retrospective study of a prospective dataset maintained from 2000 till September 2022, for peritoneal metastases from colorectal cancers was carried out. Of the total of 1,625 peritoneal metastases cases, 415 were identified with colorectal cancer and considered for analysis. Survival was followed for 60 months since the index-peritonectomy for cases in this study.
Results:
Hazard ratio for 5-year survival using the Cox regression analysis over time (t) with a Log-rank (Mantel-Cox) test for significance between the groups indicated, <15 vs. 15 (HR=2.121, p=0.0338), <15 vs. 16-20 (HR=2.748, p<0.0001), <15 vs. >20 (HR=3.158, p<0.0001), 15 vs. 16-20 (HR=1.262, p=0.5658), 15 vs. >20 (HR=1.566, p=0.2771) and for PCI category 16-20 vs. >20 (HR=1.204, p=0.5355) for survival. Median survival for the categories of PCI <15, PCI-15, PCI-16-20, and PCI >15 was 43.967 (95%CI=28.31-59.63), 20.67 (95%CI=5.01-36.33), 19.50 (95%CI=3.84-35.16), and 14.30 (95%CI=1.36-29.96), respectively.
Conclusion:
A correlation of PCI with survival was confirmed in this study reinforcing the need for assessment of PCI at surgery to help prognostication. Detecting synchronous peritoneal metastases early and prompt treatment can help prevent recurrence and increase survival.
... Peritoneal metastasis (PM) originating from primary gastric, ovarian or colorectal cancer are often associated with poor survival (1)(2)(3). In general, we can identify three treatment strategies: systemic chemotherapy, surgery and cytoreductive surgery followed by Hyperthermic IntraPeritoneal Chemotherapy (HIPEC). ...
Introduction
CytoReductive Surgery (CRS) followed by Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is an often used strategy in treating patients diagnosed with peritoneal metastasis (PM) originating from various origins such as gastric, colorectal and ovarian. During HIPEC treatments, a heated chemotherapeutic solution is circulated through the abdomen using several inflow and outflow catheters. Due to the complex geometry and large peritoneal volume, thermal heterogeneities can occur resulting in an unequal treatment of the peritoneal surface. This can increase the risk of recurrent disease after treatment. The OpenFoam-based treatment planning software that we developed can help understand and map these heterogeneities.
Methods
In this study, we validated the thermal module of the treatment planning software with an anatomically correct 3D-printed phantom of a female peritoneum. This phantom is used in an experimental HIPEC setup in which we varied catheter positions, flow rate and inflow temperatures. In total, we considered 7 different cases. We measured the thermal distribution in 9 different regions with a total of 63 measurement points. The duration of the experiment was 30 minutes, with measurement intervals of 5 seconds.
Results
Experimental data were compared to simulated thermal distributions to determine the accuracy of the software. The thermal distribution per region compared well with the simulated temperature ranges. For all cases, the absolute error was well below 0.5°C near steady-state situations and around 0.5°C, for the entire duration of the experiment.
Discussion
Considering clinical data, an accuracy below 0.5°C is adequate to provide estimates of variations in local treatment temperatures and to help optimize HIPEC treatments.
... However, in the subgroup analysis, additional HIPEC improved the OS rate of patients with a moderate peritoneal cancer index (PCI) of 11-15. A series of 60 patients with mild PCI of 5 or less treated with CS and perioperative chemotherapy, including HIPEC, revealed that the 5-year OS rate was 54.7% and the median DFS interval was 10.8 months (17), which is equivalent to our results obtained from 31 patients with peritoneal dissemination. Most of our patients (87%) had extremely mild PCI (1/2); therefore, (18)(19)(20)(21)(22). Choi et al. reported that the 5-year OS rate in patients after PALN dissection was 53.4%, which was significantly better than the 12.0% in patients without resection (P = 0.045), and three or more metastatic LNs were an independent negative prognostic factor (18). ...
Background
Although surgical resection for liver or lung metastases of colorectal cancer has been widely accepted, the use of this approach for extrahepatopulmonary metastases remains debatable due to the systemic nature of the disease. The aim of this study was to clarify the utility of resection along with perioperative chemotherapy for patients with extrahepatopulmonary metastases of colon cancer.
Methods
This is a retrospective single-arm study at a single institution. Forty-two patients with resectable extrahepatopulmonary metastases who underwent metastasectomy with curative intent between 2009 and 2018 at Nagoya University Hospital were retrospectively analyzed. The primary outcomes measured were overall and relapse-free survival.
Results
The most common metastatic site was the peritoneum (n = 31), followed by the distant lymph nodes (n = 10), ovary (n = 1) and spleen (n = 1), with overlaps. Preoperative and postoperative chemotherapies were administered to 22 and 8 patients, respectively; the remaining 14 patients received surgery alone. R0 resection was achieved in 36 patients (85.7%). The 5-year overall survival and 3-year relapse-free survival rates were 58.6% and 33.8%, respectively. In the univariate analysis, R1 resection was associated with a poor relapse-free survival rate (P = 0.02). In the multivariate analysis, the absence of perioperative chemotherapy was an independent risk factor for poor overall survival rates (P = 0.02).
Conclusions
Surgical resection benefited selected patients with extrahepatopulmonary metastases with favorable long-term survival outcomes. Surgery alone without systemic chemotherapy is likely to bring poor outcome; therefore, preoperative induction might be promising to keep up with chemotherapy.
... PCI is widely accepted as one of the most important prognostic factors for patients with PC, especially of colorectal origin, with one paper by Faron (16). PCI is not only useful as a prognostic indicator, but can potentially help predict volume of PC over time, estimating the likelihood of a complete cytoreduction at second-look surgery (17). ...
Background/aim:
Formation of stoma during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) is often performed to reduce the risk of anastomotic leak. Subsequent stoma reversal provides a unique opportunity for second-look surgery to detect early peritoneal recurrence. Current surveillance methods often fail to detect disease early, including imaging and biochemical markers. In our study, we examined the safety and efficacy of second-look surgery for detection and treatment of disease recurrence.
Patients and methods:
We performed a retrospective analysis of prospectively collected data from 35 patients undergoing stoma reversal from 2015 to 2019 with negative pre-operative imaging.
Results:
A total of 37% of cases had disease recurrence, with a median peritoneal cancer index of 4. Complete cytoreduction was achieved in all patients. The majority of patients (77%) suffered minor complications only. Median length of hospital stay was 12 days.
Conclusion:
Second-look surgery detects early disease recurrence and is a safe alternative to conventional screening methods post primary CRS/HIPEC for PC. Long-term, routine second-look surgery can improve survival.
... PM can result from several gastrointestinal or gynecological origins such as colorectal cancer, ovarian cancer and gastric cancer. Patients with PM from colorectal or gastric origin are observed to have an average overall survival of 5-24 months and 4-8 months, respectively (Pelz et al., 2010;Thomassen et al., 2014;Huang et al., 2015;Tan et al., 2017). For ovarian cancer patients, the metastatic involvement of the peritoneum reduces the 5-year survival rate from over 90% to just 25-29% (Testa et al., 2018). ...
Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after debulking cytoreductive surgery. During HIPEC, a limited number of catheters are used to administer and drain fluid containing chemotherapy (41–43 °C), yielding heterogeneities in the peritoneum. Large heterogeneities may lead to undertreated areas, increasing the risk of recurrences. Aiming at intra-abdominal homogeneity is therefore essential to fully exploit the potential of HIPEC. More insight is needed into the extent of the heterogeneities during treatments and assess their effects on the efficacy of HIPEC. To that end we developed a computational model containing embedded tumor nodules in an environment mimicking peritoneal conditions. Tumor- and treatment-specific parameters affecting drug delivery like tumor size, tumor shape, velocity, temperature and dose were assessed using three-dimensional computational fluid dynamics (CFD) to demonstrate their effect on the drug distribution and accumulation in nodules. Clonogenic assays performed on RKO colorectal cell lines yielded the temperature-dependent IC50 values of cisplatin (19.5–6.8 micromolar for 37–43 °C), used to compare drug distributions in our computational models. Our models underlined that large nodules are more difficult to treat and that temperature and velocity are the most important factors to control the drug delivery. Moderate flow velocities, between 0.01 and 1 m/s, are optimal for the delivery of cisplatin. Furthermore, higher temperatures and higher doses increased the effective penetration depth with 69% and 54%, respectively. We plan to extend the software developed for this study toward patient-specific treatment planning software, capable of mapping and assist in reducing heterogeneous flow patterns.
... PM originated from CRC is associated with poor prognosis, with an average survival of only 5-24 months. 4,5 Maximum cytoreductive surgery (CRS) to remove macroscopic tumors from the abdominal cavity, and then intraperitoneal chemotherapy to eradicate all residual microscopic diseases are currently the standard treatment for advanced CRC. [6][7][8] Hyperthermic intraperitoneal chemotherapy (HIPEC) followed by CRS is the most proactive way of dealing with PC, 9 showing significant survival rate increase. 10 ...
Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. In vitro, we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. In vivo, we established xenograft models of CRC-PC and assessed the antitumor effect by in vivo imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly in vitro, and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited in vivo. Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application.
Impact statement
Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both in vitro and vivo. The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.
... Hence, most researches have reported that CC-0 and CC-1 were the standard for cytoreductive surgery. In contrast, the recommendation of CC-2 and CC-3 surgery is not currently advisable (36). ...
Colorectal cancer (CRC) is stated as the third most frequent cancer in people around the world. In patients, its recurrence occurs most commonly in the peritoneum, accounting for 25% to 35% of all recurrences, making it the second most common site for CRC. Although new and more effective chemotherapeutic agents and combinations were developed, the results of systemic chemotherapy showed only a limited impact on survival, which is disappointing. It is known that cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) lead to survival improvement in comparison to the sole treatment consisting in intravenous chemotherapy. This combined procedure showed encouraging results in terms of overall survival, lower complication rates and better patient outcomes in many reported findings. The objective of this article was to review published data for evaluating the outcome of CRS and HIPEC versus standard of care.
... If early detection achieved, PM patients with low peritoneal carcinomatosis index (PCI) (≤5) can be treated properly (by CRS + HIPEC) with a markedly high survival rate and even could have better prognosis than those with liver metastasis with a 3-year survival of 89% [27]. Huang et al. [28] supported these data by reviewing 60 low PCI PM patients and observed a 5-year survival rate of 54.7% with no mortality. Sugarbaker established survivorship using the PCI. ...
Introduction
Abdominal wall invasion by cancerous cells arising from the colon with an overlying secondary infection that presents as an abdominal wall abscess has been encountered previously, but such a symptom is rarely the first presentation of colon cancer. There are very few cases reported in the literature.
Case Presentation
In this case report, we present a case of a 66-year-old male presenting with abdominal wall abscess that was refractory to treatment. The patient later was found to have an abdominal wall invasion by an underlying colonic carcinoma.
Conclusion
The purpose of this review is to set forth the proper approach when encountering such cases and emphasize on the significance of keeping a high index of suspicion. We also highlight the need for utilizing proper diagnostic imaging modalities prior to invasive intervention.
... A French multicentre trial included 523 patients who had undergone operation from 23 centers in four Frenchspeaking countries between 1990 and 2007, the results of which showed remarkably better survival in patients with complete CRS than in those with incomplete CRS [10]. Huang et al. [29] found that CRS plus perioperative intraperitoneal chemotherapy can be safely performed to provide encouraging survival benefits for patients with CPM. Hence, CC-0 and CC-1 have been recommended to be the standard for CRS by most researches. ...
Peritoneum is one of the common sites of metastasis in advanced stage colorectal cancer patients. Colorectal cancer patients with peritoneal metastases (PM) are traditionally believed to have poor prognosis, which indicates it is of no value to adopt surgical treatment. With the advancement of surgical techniques, hyperthermic intraperitoneal chemotherapy (HIPEC), and multidisciplinary treatment in recent years, the cognition and treatment strategies of colorectal peritoneal metastases (CPM) have changed dramatically. In terms of prognosis, CPM under the palliative systemic treatment shows an inferior outcome compared with nonperitoneal metastasis. Nevertheless, some CPM patients amenable to the complete peritoneal cytoreductive surgery (CRS) combined with HIPEC may achieve long-term survival. The prognostic factors of CPM comprise peritoneal carcinomatosis index (PCI), completeness of cytoreduction score (CC score), the presence of extraperitoneal metastasis (liver, etc.), Peritoneal Surface Disease Severity Score (PSDSS), Japanese peritoneal staging, and so forth. Taken together, literature data suggest that a multimodality approach combining complete peritoneal CRS plus HIPEC, systemic chemotherapy, and targeted therapy may be the best treatment option for PM from colorectal cancer.
It is hoped that injectional-based intraperitoneal (IP) chemotherapy can help treat peritoneal metastases and abdominal tumors in cancer patients. Nevertheless, drug penetration into the tumor with IP injection in many cases is insufficient. Therefore, it is essential to improve our understanding of the mechanisms and parameters affecting drug penetration to optimize treatment, introduce new treatment methods, and minimize drug toxicity. Computational models, due to their highly controllable features compared to laboratory experiments, allow for the investigation of many biological phenomena and mechanisms during regular and IP chemotherapy of various anticancer drugs. Computational models are comprehensive and are able to reasonably replicate tumor behavior, drug delivery, and estimate important drug biotransport-based parameters within the tumor microenvironment. Computational models have provided healthcare professionals with extremely useful and valuable information by taking into account the essential mechanisms modulating drug transport and interaction in tumor tissue including blood flow, diffusion and convection processes, distribution of the drug in the interstitial space, binding of drugs to receptors on the cell surface, internalization of the drug into tumor cells and release/excretion of the drug, on a variety of length and time scales. In general, these models provide more precise forecasts of the effectiveness of treatment. The present study investigates drug delivery during IP chemotherapy, examines barriers to IP delivery, and evaluates the importance of computational models. These models can be used to examine how drugs reach tumors in the abdominal cavity, such as ovarian and colorectal cancers. Finally, modeling approach of nano-sized drug delivery systems (e.g., using magnetic nanoparticles and thermosensitive liposomes) is investigated and discussed in detail.
Fibroblast activation protein inhibitor (FAPI)-PET imaging holds great promise for improving the clinical management of colorectal cancer. High fibroblast activation protein expression is particularly observed in lymph node metastases, in the aggressive Consensus Molecular Subtype 4, in peritoneal metastases, and in tumors that respond poorly to immunotherapy. We have defined six clinical dilemmas in the diagnosis and treatment of colorectal cancer, which FAPI-PET may help solve. Future clinical trials should include patients undergoing tumor resection, allowing correlation of FAPI-PET signals with in-depth histopathological, cellular, and molecular tissue analyses.
Background
Peritoneal Cancer Index (PCI) and complete cytoreduction are the best outcome predictors following cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Lesions in critical areas, regardless of PCI, complicate surgery and impact oncological outcomes. We prospectively defined “Critical lesions” (CL) as penetrating the hepatic hilum, diaphragm at hepatic outflow, major blood vessels, pancreas, or urinary tract.
Methods
Retrospective analysis of a prospective database of 352 CRS + HIPEC patients from 2015 to 2019. Excluded patients with aborted/redo operation (n = 112), or incomplete data (n = 19). Patients categorized by CL status and compared: operative time, estimated blood loss (EBL), PCI, transfusions, hospital stay, post-operative complications and mortality, overall survival (OS) and disease-free survival (DFS).
Results
Included 221 patients (78 CL; 143 no-CL). No difference in patients' characteristics: age, BMI, gender or co-morbidities noted. Operative time longer (5.3 h vs 4.3 h, p < 0.01), EBL higher (769 ml vs 405 ml, p < 0.01), transfusions higher (1.9 vs 0.7 Units, p < 0.001) and PCI higher (15.5 vs 9.5, p < 0.01) in CL. No difference in major complications. Postoperative complications, CL, OR-time and transfusions were predictive of OS in univariate analysis, while only complications remained on multivariate analysis. Median follow up of 21.4 months, 3-year DFS/OS was 22% vs 30% (p < 0.037) and 73% vs 87% (p < 0.014) in CL and non-CL, respectively. Despite CL complete resection, 17/38 patients (44.7%) that recurred had recurrence at previous CL site.
Conclusions
Critical lesions complicate surgery and may be associated with poor oncological outcomes with high local recurrence rate, despite no significant difference in complications. Utilizing adjuvant or intra-operative radiation may be beneficial.
Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC. Methods: The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38–43 °C/60 min). Results: Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat. Conclusion: Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC.
Background:
This study examines the impact of intraoperative macroscopic tumour consistency on short-term and long-term outcomes after cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) for appendiceal adenocarcinoma with peritoneal metastases.
Methods:
Macroscopic intraoperative tumour consistency was classified in three groups as soft (jelly-like geltatinous tumours), hard (hard tumour nodules without gelatinous features) and intermediate (both soft and hard features). In-hospital mortality, major morbidity, intensive care unit (ICU), high dependency unit (HDU) and total hospital stay, disease-free survival (DFS) and overall survival (OS) were compared.
Results:
The three groups had similar perioperative short-term outcomes. Patients with soft, intermediate and hard tumours revealed differences in OS (p < 0.001) and DFS (p = 0.03). Multivariable analysis revealed a shorter OS for patients with hard versus soft tumours (HR for hard tumours = 4.43, 95%CI 2.19-9.00).
Conclusions:
Intraoperative macroscopic tumour consistency may be used as a prognostic marker for survival in patients with appendiceal adenocarcinoma with peritoneal metastases.
Background
Measurement of cell-free DNA (cfDNA) in plasma – the so called liquid biopsy - is a novel method for early detection of cancer. Necrotic cancer cells release various DNA fragments that can be detected in plasma or serum. The aim of our study was to investigate the concentration of circulating ALU115, LINE79 and LINE297 fragments in plasma from venous and arterial blood of colorectal cancer (CRC) patients before, during and 5 days after surgical intervention.
Patients and methods
Thirty patients (16 female, 14 male, median age 56 years), undergoing surgery for colorectal and appendix cancer, and 17 healthy volunteers were included in this study. Plasma samples were collected from patients and healthy individuals. Qualitative polymerase chain reaction (PCR) and quantitative real-time PCR analyses were conducted using specific primers for ALU115, LINE79 and LINE297.
Results
The concentration of ALU115 was significantly increased in plasma of CRC patients compared to the control group (p = 0.002). Interestingly, the concentration of LINE297 was significantly higher in healthy individuals than patients (p = 0.031). We did not find any difference regarding LINE79 between the two groups (p = 0.893). The total cfDNA concentration was slightly increased in plasma after the surgery (p < 0.056), however, the difference was not significant. Interestingly, no correlation was detected between the peritoneal carcinosis index (PCI) and conventional tumor markers.
Conclusion
According to our results, the concentration of ALU115 in cfDNA could be a potential biomarker for diagnosis of CRC. LINE79 or the conventional tumor markers CEA or CA19-9 do not seem useful for the detection of malignant tumors. Whether the amount of LINE297 in cfDNA represents a reliable biomarker for early diagnosis has yet to be confirmed.
The treatment of peritoneal carcinomatosis (PC) of colorectal origin with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has a 5-year recurrence-free or cure rate of at least 16%, so it is no longer labeled as a fatal disease, and offers prolonged survival for patients with a low peritoneal carcinomatosis index. Metachronous PC of colorectal origin is so predictable that there is a model which has been used to successfully determine the individual risk of each patient. Patients at risk are clearly identified; those with the highest risk have small peritoneal nodules present in the first surgery (70% probability of developing PC), ovarian metastases (60%), perforated tumor onset or intraoperative tumor rupture (50%). Current clinical, biological and imaging techniques still lack sufficient sensitivity to diagnose PC in its initial stages, when CRS plus HIPEC has a greater impact and a higher cure rate. Second-look surgery with HIPEC or prophylactic HIPEC at the time of the first intervention have been proposed as means of preventing and/or anticipating clinical or radiological relapse in at-risk patients. Both techniques have shown Submit a Manuscript a significant decrease in peritoneal relapses and should be considered essential weapons in the management of colorectal cancer.
Introduction:
Peritoneal cancer index (PCI) has been suggested to be the most important prognostic factors for the outcomes in colorectal peritoneal carcinomatosis (CRPC).
Methods:
This was a retrospective study of prospectively collected data of 168 consecutive patients with CRPC following cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). Patients were divided into five groups according to their PCI.
Results:
Hospital mortality was 0%. Patients in low PCI groups had a significantly lower major morbidity rate, shorter intensive care unit and high dependency unit stay and higher overall survival (p=0.017, 0.001, 0.046, p<0.001 respectively).
Conclusion:
Combined CRS with PIC can be safely performed to provide encouraging survival benefits for patients with CRPC. Our findings suggest that this approach is particularly beneficial for patients with low volume of disease. Early referral to specialist centre for evaluation is warranted for better survival outcomes.
A game-changing therapy for peritoneal metastasis (PM), now called “comprehensive treatment” was first established in the late 1990s. The treatment consists of aggressive cytoreductive surgery (CRS) combined with perioperative intraperitoneal/systemic chemotherapy. PM is considered as local disease, and the rationale behind the treatment is to remove macroscopic tumors and eradicate residual micrometastasis using perioperative chemotherapy (POC). Comprehensive treatment consists of laparoscopic evaluation of the tumor load, POC, and CRS. POC includes six procedures including laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC), extensive intraoperative peritoneal lavage (EIPL), early postoperative intraperitoneal chemotherapy (EPIC), and late postoperative systemic chemotherapy. In a study of gastric cancer patients with P0/Cy1 status that employed comprehensive treatment, POC was confirmed to eradicate intraperitoneal micrometastasis. For clinical standardization of HIPEC, the concept of the thermal dose should be introduced. One thermal dose is equivalent to 30-min treatment at 43 °C. In gastric cancer, one thermal dose of HIPEC has been shown to reduce the peritoneal cancer index of 3.5, and changed the peritoneal cytology from positive to negative in 70 % of patients.
In gastric cancer, ovarian cancer, colorectal cancer, mesothelioma and pseudomyxoma peritonei, meta-analyses of randomized controlled studies demonstrated that HIPEC significantly improved survival after CRS.
These results suggest that comprehensive treatment is a breakthrough that improves the prognosis of patients with PM.
Peritoneal Surface Oncology International (PSOGI) issued international recommendations for the management of CPM on October 17-19, 2014, in Amsterdam. The recommendations are follows: (1) CRS combined with HIPEC is the treatment indicated for selected patients with moderate to small-volume CPM; (2) Treatment should be avoided in patients with a PCI score higher than the threshold level and in patients who are unlikely to undergo a complete resection, or who are unlikely to achieve full recovery because of old age or comorbidities; (3) CRS and HIPEC should not be offered at institutions where there is insufficient knowledge or insufficient skill; and (4) Developing centers should be supported by experienced teams until the learning curve is completed. Action regarding acceptance of this important comprehensive treatment in Japan is overdue.
Background. Prolonged survival of patients affected by peritoneal metastasis (PM) of colorectal origin treated with complete cytoreduction followed by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported. However, two-thirds of the patients after complete cytoreduction and perioperative chemotherapy (POC) develop recurrence. This study is to analyze the prognostic factors of PM from colorectal cancer following the treatment with cytoreductive surgery (CRS) + POC.
Patients and Methods. During the last 8 years, 142 patients with PM of colorectal origin have been treated with CRS and perioperative chemotherapy. The surgical resections consisted of a combination of peritonectomy procedures.
Results. Complete cytoreduction (CCR-0) was achieved at a higher rate in patients with peritoneal cancer index (PCI) score less than 10 (94.7%, 71/75) than those of PCI score above 11 (40.2%, 37/67). Regarding the PCI of small bowel (SB-PCI), 89 of 94 (91.5%) patients with ≤2 and 22 of 48 (45.8%) patients with SB-PCI ≥ 3 received CCR-0 resection (P < 0.001). Postoperative Grade 3 and Grade 4 complications occurred in 11 (7.7%) and 14 (9.9%). The overall operative mortality rate was 0.7% (1/142). Cox hazard model showed that CCR-0, SB-PCI ≤ 2, differentiated carcinoma, and PCI ≤ 10 were the independent favorite prognostic factors. Conclusions. Complete cytoreduction, PCI, SB-PCI threshold, and histologic type were the independent prognostic factors.
Peritoneal carcinomatosis (PC) is one manifestation of metastatic colorectal cancer (CRC). Tumor growth on intestinal surfaces and associated fluid accumulation eventually result in bowel obstruction and incapacitating levels of ascites, which profoundly affect the quality of life for affected patients. PC appears resistant to traditional 5-fluorouracil-based chemotherapy, and surgery was formerly reserved for palliative purposes only. In the absence of effective treatment, the historical prognosis for these patients was extremely poor, with an invariably fatal outcome. These poor outcomes likely explain why PC secondary to CRC has received little attention from oncologic researchers. Thus, data are lacking regarding incidence, clinical disease course, and accurate treatment evaluation for patients with PC. Recently, population-based studies have revealed that PC occurs relatively frequently among patients with CRC. Risk factors for developing PC have been identified: right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis. During the past decade, both chemotherapeutical and surgical treatments have achieved promising results in these patients. A chance for long-term survival or even cure may now be offered to selected patients by combining radical surgical resection with intraperitoneal instillation of heated chemotherapy. This combined procedure has become known as hyperthermic intraperitoneal chemotherapy. This editorial outlines recent advancements in the medical and surgical treatment of PC and reviews the most recent information on incidence and prognosis of this disease. Given recent progress, treatment should now be considered in every patient presenting with PC.
The study compared the outcome in patients with advanced colonic cancer at high risk of peritoneal metastases (mucinous or signet-ring cell) without peritoneal or systemic spread, treated with standard colectomy or a more aggressive combined surgical approach. The study included patients with colonic cancer with clinical T3/T4, any N, M0, and mucinous or signet ring cell histology. The 25 patients in the experimental group underwent hemicolectomy, omentectomy, bilateral adnexectomy, hepatic round ligament resection, and appendectomy, followed by HIPEC. The control group comprised 50 patients treated with standard surgical resection during the same period in the same hospital by different surgical teams. Outcome data, morbidity, peritoneal recurrence rate, and overall, and disease-free survival, were compared. Peritoneal recurrence developed in 4% of patients in the experimental group and 22% of controls without increasing morbidity (P < 0.05). Actuarial overall survival curves disclosed no significant differences, whereas actuarial disease-free survival curves showed a significant difference between groups (36.8 versus 21.9 months, P < 0.01). A more aggressive preventive surgical approach combined with HIPEC reduces the incidence of peritoneal recurrence in patients with advanced mucinous colonic cancer and also significantly increases disease-free survival compared with a homogeneous control group treated with a standard surgical approach without increasing morbidity.
The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites > or =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.
To compare the long-term survival of patients with isolated and resectable peritoneal carcinomatosis (PC) in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC).
All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC from 1998 to 2003 were evaluated. The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time.
Forty-eight patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively. All characteristics were comparable except age and tumor differentiation. There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group. Two-year and 5-year overall survival rates were 81% and 51% for the HIPEC group, respectively, and 65% and 13% for the standard group, respectively. Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (P < .05, log-rank test).
Patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%.
In patients with metastatic colorectal cancer (mCRC), several prognostic factors such as performance status (PS), number of metastatic sites, carcinoembryonic antigen (CEA), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) have been reported. The objective of this study was to clarify the prognostic impact of Baseline Sum of Longest Diameter (BSLD) of target lesions by Response Evaluation Criteria in Solid Tumor (RECIST) in patients with mCRC.
The subjects of this study were consecutive 103 patients with mCRC who had been received the first line systemic chemotherapy between September 2002 and March 2005.
The chemotherapy regimens included leucovorin-modulated 5-fluorouracil (5-FU) (n = 27) and 5-FU plus irinotecan (n = 76). The median overall survival time was 547 days. The median BSLD was 14.3 cm (range, 1.1-54.7). In univariate analysis, identified prognostic variables on survival were PS (0, 1 versus 2), number of metastatic sites (1 versus >1), peritoneal dissemination (+ versus -), pleural effusion (PE) and/or ascites, white blood cell (> or = versus <10,000/mm(3)), ALP (> or = versus <300 IU), LDH (> or = versus <300 IU), CEA (> or = versus <5 ng/ml), chemotherapy regimen, presence of liver metastasis, and BSLD. In multivariate analysis with covariates of the above significant factors, BSLD (> or = versus <10 cm) (HR 0.431, 95% CI 0.237-0.785, P = 0.0059), PS (HR 0.248, 95% CI 0.107-0.577, P = 0.0012), PE and/or ascites (HR 0.402, 95% CI 0.228-0.708, P = 0.0016) were independent prognostic factors.
BSLD of target lesions by RECIST representing tumor volume might be an independent prognostic factor of patients with mCRC after systemic chemotherapy.
Carcinoma of the colon complicated by obstruction or perforation has been recognized as having a poorer prognosis than tumors without obstruction or perforation. To clarify the natural history, failure patterns, and implications for adjuvant treatment after resection with curative intent, a review of the recent Massachusetts General Hospital (MGH) experience was undertaken. From 1970 to 1977, 77 patients with obstructive colonic carcinoma and 34 patients with localized perforation at the tumor site were identified and compared with a control group of 400 patients without obstruction or perforation undergoing curative resection. All patients were observed for a minimum of five years or until the patient's death. The actuarial five-year survival and disease-free survival rates in patients with obstruction was 31% and 44%, respectively, in contrast to 59% and 75% in control patients. For patients with localized perforation, the five-year actuarial survival and disease-free survival rates were 44% and 35%, re...
Objective:
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.
Patients and methods:
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.
Results:
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.
Conclusions:
The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
Background: Nonresectable colorectal cancer often causes malignant intestinal obstruction due to peritoneal dissemination. However, no previous report has specifically investigated which patients, with peritoneal dissemination from colorectal cancer, would actually benefit from palliative surgery. This study defines the selection criteria for patients who are likely to benefit from palliative surgery.
Methods: Twenty-one patients underwent palliative surgery for malignant bowel obstruction due to peritoneal dissemination from colorectal cancer. In all cases, the advanced and nonresectable nature of the tumor was confirmed at laparotomy. Clinical factors such as age, gender, serum level of carcinoembryonic antigen, amount of ascites, location of the primary cancer, surgical procedure, and postoperative chemotherapy were analyzed for prognostic significance in symptom-free and overall survival using the Kaplan–Meier product limit method and the log-rank test.
Results: All the postoperative courses were uneventful. Obstruction recurred after a median symptom-free interval of 61 days in the group with less than 100 ml of ascites, whereas it recurred after 9 days in the group with more than 100 ml of ascites. Symptom-free survival rates in patients who manifested ascites were significantly lower than in those without ascites (P = 0.0321, log-rank method). The symptom-free and overall survival rates in patients who underwent postoperative chemotherapy were significantly higher (P = 0.0225 and 0.0003).
Conclusions: Palliative surgery can be performed effectively for patients without ascites. For patients who do not meet this criterion, a non-surgical procedure may be preferable.
Background
Complete cytoreductive surgery (CCRS) plus hyperthermicintraperitoneal chemotherapy (HIPEC) is on the verge of becoming the gold standard treatment for selected patients presenting peritoneal metastases (PM) of colorectal origin. PM is scored with the peritoneal cancer index (PCI), which is the main prognostic factor. However, small bowel (SB) involvement could exert an independent prognostic impact.
Aim
To define an adequate cut-off for the PCI and to appraise whether SB involvement exerts an impact on this cut-off.
Patients and methods
Patients (n=139) treated with CCRS plus HIPEC were prospectively verified and retrospectively analyzed. One hundred presented with SB involvement of different extents and at different locations.
Results
All the patients with a PCI ≥ 15 exhibited SB involvement. Five-year overall survival was 48% when the PCI was < 15 vs 12% when it was ≥ 15 (p<0.0001. The multivariate analysis retained two prognostic factors: PCI ≥ 15 (p=0.02, HR=1.8), and the involvement of area 12 (lower ileum) (p=0.001, HR=3.1). When area 12 was invaded, it significantly worsened the prognosis: 5-year overall survival of patients with a PCI < 15 and area 12 involved was 15% , close to that of patients with a PCI ≥15 (12%) and far lower than that of patients with a PCI < 15 and no area 12 involvement (70%).
Conclusion
A PCI greater than 15 appears to be a relative contraindication for treatment of colorectal PM with CCRS+HIPEC. Involvement of the lower ileum is also a negative prognostic factor to be taken into consideration.
BACKGROUND
Peritoneal carcinomatosis (PC) is a common evolution of digestive cancer, associated with a poor prognosis. Yet it is poorly documented in the literature.METHODS
Three hundred seventy patients with PC from non-gynecologic malignancies were followed prospectively: the PC was of gastric origin in 125 cases, of colorectal origin in 118 cases, of pancreatic origin in 58 cases, of unknown origin in 43 cases, and of miscellaneous origins in 26 cases. A previously reported PC staging system was used to classify these 370 patients.RESULTSMean and median overall survival periods were 6.0 and 3.1 months, respectively. Survival rates were mainly affected by the initial PC stage (9.8 months for Stage I with malignant peritoneal granulations less than 5 mm in greatest dimension, versus 3.7 months for Stage IV with large, malignant peritoneal masses more than 2 cm in greatest dimension). The presence of ascites was associated with poor survival of patients with gastric or pancreatic carcinoma. Differentiation of the primary tumor did not influence the prognoses of patients with PC.CONCLUSIONSA better knowledge of the natural history of PC is needed, in view of the many Phase I, II, and III trials currently being conducted to evaluate aggressive multimodal therapeutic approaches to treating patients with PC from non-gynecologic malignancies. Cancer 2000;88:358–63. © 2000 American Cancer Society.
Inadvertent perforation of the bowel during curative resection for colorectal cancer has serious consequences. In 174 curative
resections with spillage, five-year survival was 29 per cent. In 67 patients where the cancer itself was disrupted during
dissection, five-year surival fell to 14 per cent in the colon and to 9.3 per cent in the rectum. Local recurrence developed
in 65 per cent of spillage cases. In Dukes' C tumors that were perforated during surgery, local recurrence occurred in 87
per cent. As surgeons, our efforts must be directed toward preventing injury to the bowel during definitive resection of colorectal
cancers. The instillation of tumoricidal solutions within the bowel lumen and the application of bowel ligatures prior to
dissection may help toward preventing recurrence, should inadvertent perforation and spillage occur.
To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC).
From 1999 to 2009, 41 patients without any sign of recurrence on imaging studies underwent second-look surgery aimed at treating limited PC earlier and more easily. They were selected based on 3 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 25), synchronous ovarian metastases (n = 8), and perforation (n = 8).
PC was found and treated with complete surgery plus HIPEC in 23 of the 41 (56%) patients. The other patients underwent complete abdominal exploration plus systematic HIPEC. Median follow-up was 30 (9-109) months. One patient died postoperatively at day 69. Grade 3-4 morbidity was low (9.7%). The 5-year overall survival rate was 90% and the 5-year disease-free survival rate was 44%. Peritoneal recurrences occurred in 7 patients (17%), 6 of whom had macroscopic PC discovered during the second-look (26%), and one patient had no macroscopic PC (6%). In the univariate analysis, the presence of PC at second-look surgery was a significant risk factor for recurrence (P = 0.006).
Selection criteria for high-risk patients appear to be accurate. In these patients, the second-look strategy treated peritoneal carcinomatosis preventively or at an early stage, yielding promising results. This study has allowed us to design a multicentric randomized trial (comparing the second-look + HIPEC approach versus standard follow-up alone), which is beginning.
To evaluate the role of modern systemic therapies and its role as palliative or curative therapy for patients with colorectal peritoneal carcinomatosis with an emphasis on patient selection with the colorectal Peritoneal Surface Disease Severity Score (PSDSS).
From three specialized treatment centers, patients with colorectal peritoneal carcinomatosis were identified between December 1988 to December 2009 to receive best supportive care, standard, or modern systemic therapies. Intent was classified as palliative or curative (if treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy). Patients were stratified according to the PSDSS. Survival was estimated by the Kaplan-Meier method.
Palliative and curative treatment achieved a median survival of 9 (95% confidence interval [95% CI] 5.9-12.8) and 38 (95% CI 30.2-45.2) months, respectively (P < 0.001). The type of chemotherapy in the palliative and curative group influenced outcome (P < 0.001, P = 0.011, respectively). In the palliative group, PSDSS I/II had a median survival of 24 (95% CI 15.6-32.6) and PSDSS III/IV had a median survival of 6 (95% CI 4.9-8.0) months (P < 0.001). In the curative group, PSDSS I/II had a median survival of 49 (95% CI 40.0-58.3) and PSDSS III/IV had a median survival of 31 (95% CI 20.4-40.9) months (P = 0.002).
Modern systemic therapies were associated with improved outcome in patients with colorectal peritoneal carcinomatosis treated systemically alone or with cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Preoperative evaluation with the PSDSS may improve patient selection and optimize outcomes.
Peritoneal carcinomatosis (PC) from nonovarian malignancies long has been regarded as a terminal disease. Over the past decade, new locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved that have demonstrated improved survival.
A retrospective, multicenter cohort study was performed in French-speaking institutions to evaluate toxicity and principal prognostic factors after cytoreductive surgery and PIC (hyperthermic intraperitoneal chemotherapy [HIPEC] and/or early postoperative intraperitoneal chemotherapy [EPIC]) for PC from nongynecologic malignancies.
The study included 1290 patients from 25 institutions who underwent 1344 procedures between February 1989 and December 2007. HIPEC was performed in 1154 procedures. The principal origins of PC were colorectal adenocarcinoma (N = 523), pseudomyxoma peritonei (N = 301), gastric adenocarcinoma (N = 159), peritoneal mesothelioma (N = 88), and appendiceal adenocarcinoma (N = 50). The overall morbidity and mortality rates were 33.6% and 4.1%, respectively. In multivariate analysis, patient age, the extent of PC, and institutional experience had a significant influence on toxicity. The overall median survival was 34 months; and the median survival was 30 months for patients with colorectal PC, not reached for patients with pseudomyxoma peritonei, 9 months for patients with gastric PC, 41 months for patients with peritoneal mesothelioma, and 77 months for patients with PC from appendiceal adenocarcinoma. Independent prognostic indicators in multivariate analysis were institution, origin of PC, completeness of cytoreductive surgery, extent of carcinomatosis, and lymph node involvement.
A therapeutic approach that combined cytoreductive surgery with PIC was able to achieve long-term survival in a selected group of patients who had PC of nonovarian origin and had acceptable morbidity and mortality. The current results indicated that this treatment should be centralized to institutions with expertise in the management of PC.
The aim of our study was to provide population-based data on incidence and prognosis of synchronous peritoneal carcinomatosis and to evaluate predictors for its development. Diagnosed in 1995-2008, 18,738 cases of primary colorectal cancer were included. Predictors of peritoneal carcinomatosis were analysed by multivariable logistic regression analysis. Median survival in months was calculated by site of metastasis. In the study period, 904 patients were diagnosed with synchronous peritoneal carcinomatosis (4.8% of total, constituting 24% of patients presenting with M1 disease). The risk of peritoneal carcinomatosis was increased in case of advanced T stage [T4 vs. T1,2: odds ratio (OR) 4.7, confidence limits 4.0-5.6), advanced N stage [N0 vs. N1,2: OR 0.2 (0.1-0.2)], poor differentiation grade [OR 2.1 (1.8-2.5)], younger age [<60 years vs. 70-79 years: OR 1.4 (1.1-1.7)], mucinous adenocarcinoma [OR 2.0 (1.6-2.4)] and right-sided localisation of primary tumour [left vs. right: OR 0.6 (0.5-0.7)]. Median survival of patients with peritoneum as single site of metastasis remained dismal [1995-2001: 7 (6-9) months; 2002-2008: 8 (6-11) months], contrasting the improvement among patients with liver metastases [1995-2001: 8 (7-9) months; 2002-2008: 12 (11-14) months]. To conclude, synchronous peritoneal metastases from colorectal cancer are more frequent among younger patients and among patients with advanced T stage, mucinous adenocarcinoma, right-sided tumours and tumours that are poorly differentiated. The prognosis of synchronous peritoneal carcinomatosis remains poor with a median survival of 8 months and even worse if concomitant metastases in other organs are present.
Survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis. Because of a recent substantial improvement in chemotherapy, the authors analyzed treatment options of colorectal carcinomatosis in the current era.
Consecutive patients with colorectal carcinomatosis treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion from 2001 to 2007 were included. The control group patients with carcinomatosis received contemporary chemotherapy alone. Overall survival was the primary endpoint.
All patients underwent systemic chemotherapy. The cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion group (n=67) was similar to the control group (n=38) in sex, tumor grade, site of tumor origin, T status, and N status. The control group was, however, older (59 vs 51 years; P<.001). Median survival measured from the diagnosis of peritoneal disease was longer with cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion (34.7 months vs 16.8 months; P<.001). Presence of liver metastasis was a significant negative predictor of survival (hazard ratio, 2.13).
The authors concluded that 1) contemporary chemotherapy is associated with prolonged survival among patients with carcinomatosis as compared with historical controls, and 2) addition of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion to modern chemotherapy regimens may significantly prolong survival. Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion and systemic chemotherapy are not competitive therapies, and they both have a role in a multidisciplinary approach to patients with carcinomatosis.
Purpose
Peritoneal carcinomatosis (PC) from colorectal cancer traditionally is considered a terminal condition. Approaches that combine cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with that strategy.
Patients and Methods
A retrospective-cohort, multicentric study from French-speaking countries was performed. All consecutive patients with PC from colorectal cancer who were treated with CRS and PIC (with or without hyperthermia) were included. Patients with PC of appendiceal origin were excluded.
Results
The study included 523 patients from 23 centers in four French-speaking countries who underwent operation between 1990 and 2007. The median follow-up was 45 months. Mortality and grades 3 to 4 morbidity at 30 days were 3% and 31%, respectively. Overall median survival was 30.1 months. Five-year overall survival was 27%, and five-year disease-free survival was 10%. Complete CRS was performed in 84% of the patients, and median survival was 33 months. Positive independent prognostic factors identified in the multivariate analysis were complete CRS, PC that was limited in extent, no invaded lymph nodes, and the use of adjuvant chemotherapy. Neither the grade of disease nor the presence of liver metastases had a significant prognostic impact.
Conclusion
This combined treatment approach against PC achieved low postoperative morbidity and mortality, and it provided good long-term survival in patients with peritoneal scores lower than 20. These results should improve in the future, because the different teams involved will gain experience. This approach, when feasible, is now considered the gold standard in the French guidelines.
The objective of the present meta-analysis was to analyze the survival outcomes of patients with colorectal peritoneal carcinomatosis (CRPC), with particular focus on cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC).
A search was conducted on Medline from 1950 to February 2009 and Pubmed from 1950 to February 2009 for original studies on CRS with PIC. All articles included in this study were assessed with the application of predetermined selection criteria. Results regarding the overall survival in the meta-analysis were expressed as hazard ratios with 95% confidence intervals.
Forty-seven manuscripts were selected in the present systematic review, including 4 comparative studies and 43 observational studies of CRS with PIC. From the meta-analysis, it can be seen that a significant improvement in survival was associated with treatment by CRS and hyperthermic intraperitoneal chemotherapy compared with palliative approach (P < 0.0001). The pooled data did not show a significant improvement in overall survival for patients treated by CRS and early postoperative intraperitoneal chemotherapy versus surgery and systemic chemotherapy (P = 0.35). The overall effect of PIC is significantly better than the control group (P = 0.0002). The current literature suggests that patients with liver metastasis amendable to resection should not be excluded from CRS and PIC. However, there is a need for further evaluation of the prognostic significance of lymph node and liver involvement, ideally in large prospective trials.
The meta-analysis showed that combined therapy involving CRS and PIC had a statistically significant survival benefit over control groups.
Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been demonstrated to have an improved survival over systemic chemotherapy for patients with colorectal peritoneal carcinomatosis (CRPC) in a randomized controlled trial. Despite the increasing clinical evidence, controversies still exist regarding the standard treatment for these patients.
Between January 1997 and October 2007, 50 patients with isolated CRPC underwent CRS and HIPEC at the St. George Hospital, Sydney. All patients underwent preoperative chest, abdominal and pelvic computed tomography scans, and positron emission tomography. All clinicopathologic and treatment-related data were obtained prospectively and computed in univariate and multivariate analyses to determine their prognostic significance for overall survival.
The mean age at the time of CRS was 55 (SD = 14) years. There were 19 (38%) male patients. The overall median survival was 29 months (range 1-102) with a 3-year survival rate of 39%. Three clinicopathologic factors were found to be significant for overall survival: tumor differentiation (P < 0.001), peritoneal cancer index (P = 0.021), and completeness of cytoreduction (P < 0.001). In the multivariate analysis of overall survival, 2 factors were identified to be independently associated with an improved survival: well-differentiated tumor (P = 0.045) and complete cytoreduction (P = 0.023).
CRPC patients with low tumor volume, well/moderately differentiated tumors and complete cytoreduction may potentially benefit from the combined treatment. The combined treatment for patients with isolated colorectal peritoneal carcinomatosis should be considered to be the current standard of care.
Carcinoma of the colon complicated by obstruction or perforation has been recognized as having a poorer prognosis than tumors without obstruction or perforation. To clarify the natural history, failure patterns, and implications for adjuvant treatment after resection with curative intent, a review of the recent Massachusetts General Hospital (MGH) experience was undertaken. From 1970 to 1977, 77 patients with obstructive colonic carcinoma and 34 patients with localized perforation at the tumor site were identified and compared with a control group of 400 patients without obstruction or perforation undergoing curative resection. All patients were observed for a minimum of five years or until the patient's death. The actuarial five-year survival and disease-free survival rates in patients with obstruction was 31% and 44%, respectively, in contrast to 59% and 75% in control patients. For patients with localized perforation, the five-year actuarial survival and disease-free survival rates were 44% and 35%, respectively. Of the 77 patients with obstructing tumors, 32 patients (42%) developed local failure--nine with local failure only and 23 patients with local failure and distant metastases. Thirty-four patients (44%) developed distant metastases. Fifteen (44%) patients of 34 with perforative colonic carcinoma had local failure. Distant metastases occurred in 15 patients (44%). The incidence of local failure and distant metastases in the control group was 14% and 21%, respectively. The rate of local failure and distant metastases increased with stage and was generally higher stage for stage than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
A treatment plan to be used in patients with peritoneal carcinomatosis was devised and tested as a Phase II study.
Peritoneal carcinomatosis from appendical or colorectal cancer has been regarded as a fatal clinical entity. Treatment protocols have not been reported previously.
The authors used cytoreductive surgery and intraperitoneal chemotherapy to treat 181 consecutive patients with peritoneal carcinomatosis. There were 51 patients with colorectal cancer and 130 patients with appendiceal cancer. Mean follow-up is 24 months, with a range of 0 to 149 months.
Clinical features that showed prognostic significance included appendiceal versus colorectal primary tumors (p = 0.0001), grade 1 versus grades 2 and 3 histopathology (p = 0.0003), complete versus incomplete cytoreductions (p = 0.0001), lymph node-negative versus lymph node-positive primary tumors (p = 0.0001), and volume of peritoneal carcinomatosis present preoperatively for colon cancer (p = 0.0006). Features with no statistical prognostic significance included preoperative tumor volume for appendiceal cancer, age, sex, number of cycles of chemotherapy, operative time, complications, blood loss, and institution providing treatment. From these prognostic features, four prognostic groups were identified, and 3-year survival was estimated by the product-limit survival method. Group I patients (n = 76) were those with grade 1 histology, no lymph node metastases, and complete cytoreductions (survival at 3 years = 99%). Group II patients (n = 23) were those with grade 2 or 3 histology, no lymph node metastases, and complete cytoreductions (65%). Group III patients (n = 24) had any histology, lymph node metastases, and complete cytoreductions (66%). Group IV patients (n = 58) had incomplete cytoreductions (20%).
The following methodologies may be strictly applied to quantitatively evaluate patients with peritoneal carcinomatosis or sarcomatosis in regard to disease progression or regression: (1) Preoperative CT scan and the intraoperative assessment of cancer extent is analyzed region by region (AR-0-12) and an estimation of tumor volume (V0-V3) is evaluated according to the standardized scoring system previously described. At laparotomy, the volume of tumor nodules to adjacent organs, the viscosity (mucinous vs. solid) of tumor mass, and the pattern of distribution is assessed. (2) Radiologic abdominopelvic CT parameters that predict an incomplete cytoreduction are focal obstructions of bowel by CT assessment and tumor involvement of proximal ileum (AR-11). (3) The extent of prior surgical interventions (PS-1 through PS-3) must be recorded because aggressive deep dissections without perioperative chemotherapy severely jeopardize the possibility for complete cytoreduction. (4) Many tumor samples should be sent for histopathologic analysis. A proportion of mucin > 80% confirms a mucinous cancer. The malignant differentiation of cells, stroma morphology, the presence of signet ring cells, and evidence of invasion are used to grade cancers as mucinous tumor grade 0-3 (MTG-0 through MTG-3). (5) Once the cytoreductive procedure is accomplished, the surgeon estimates the residual volume of disease. (6) Objective response criteria from CT scan, tumor marker, and radiolabeled monoclonal antibody studies are necessary in a regular follow-up schedule.
Peritoneal carcinomatosis (PC) is a common evolution of digestive cancer, associated with a poor prognosis. Yet it is poorly documented in the literature.
Three hundred seventy patients with PC from non-gynecologic malignancies were followed prospectively: the PC was of gastric origin in 125 cases, of colorectal origin in 118 cases, of pancreatic origin in 58 cases, of unknown origin in 43 cases, and of miscellaneous origins in 26 cases. A previously reported PC staging system was used to classify these 370 patients.
Mean and median overall survival periods were 6.0 and 3.1 months, respectively. Survival rates were mainly affected by the initial PC stage (9.8 months for Stage I with malignant peritoneal granulations less than 5 mm in greatest dimension, versus 3.7 months for Stage IV with large, malignant peritoneal masses more than 2 cm in greatest dimension). The presence of ascites was associated with poor survival of patients with gastric or pancreatic carcinoma. Differentiation of the primary tumor did not influence the prognoses of patients with PC.
A better knowledge of the natural history of PC is needed, in view of the many Phase I, II, and III trials currently being conducted to evaluate aggressive multimodal therapeutic approaches to treating patients with PC from non-gynecologic malignancies.
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.
Colorectal peritoneal carcinomatosis (PC) is a frequent and very lethal event. However, cure may be possible with maximal cytoreductive surgery associated with early postoperative intraperitoneal chemotherapy (EPIC).
Between 1996 and 2000, we conducted a two-center prospective randomized trial comparing EPIC plus systemic chemotherapy with systemic chemotherapy alone, both after complete cytoreductive surgery of colorectal PC. Only 35 patients could be included among the 90 who were theoretically required, mainly because of patient dissatisfaction with the inclusion criteria. For this reason, the trial was stopped prematurely.
Analysis of these 35 patients showed that complete resection of PC resulted in a 2-year survival rate of 60%-far above the classic 10% survival rate among patients with colorectal PC treated with systemic chemotherapy and symptomatic surgery. In this small series, EPIC did not demonstrate any advantage for survival.
This supports the use of complete cytoreductive surgery in selected patients and calls for a prospective randomized trial comparing adjuvant systemic chemotherapy with intraperitoneal chemohyperthermia after complete resection.
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.
The three principal studies dedicated to the natural history of peritoneal carcinomatosis (PC) from colorectal cancer consistently showed median survival ranging between 6 and 8 months. New approaches combining cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest improved survival.
A retrospective multicenter study was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy). PC from appendiceal origin was excluded.
The study included 506 patients from 28 institutions operated between May 1987 and December 2002. Their median age was 51 years. The median follow-up was 53 months. The morbidity and mortality rates were 22.9% and 4%, respectively. The overall median survival was 19.2 months. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (P <.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, and poor histologic differentiation were negative independent prognostic indicators.
The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with PC from colorectal origin with acceptable morbidity and mortality. The complete cytoreductive surgery was the most important prognostic indicator.
To report the results of standard therapy for peritoneal carcinomatosis of colorectal origin, which consists of conventional surgery and systemic chemotherapy.
In a prospective study 50 patients with proven peritoneal carcinomatosis of colorectal origin were treated with conventional surgery combined with 5-fluorouracil and leucovorin, or irinotecan in patients treated by 5-fluorouracil within 12 months prior to entry. Survival and progression-free survival were studied and prognostic factors were analysed.
The median survival time was 12.6 months. The median time to progression was 7.6 months. Location of primary tumour and result of conventional surgery and systemic chemotherapy were prognostic factors related to survival.
The survival time of patients with peritoneal carcinomatosis of colorectal origin seems to be increased in patients treated by conventional surgery and systemic chemotherapy when compared to minimal treatment.
Among 125 patients with peritoneal dissemination (P1-3) of colorectal cancer, including those with other synchronous metastases, the 5-year overall survival (OS) rate was 13.3% for P1 patients (n=30), 12.8% for P2 patients (n=39), and 1.8% for P3 patients (n=56) (P1 vs. P2, p=N.S.; P2 vs. P3, p=0.02; P1 vs. P3, p=0.001), while the median survival time (MST) was 12.0, 14.1, and 3.1 months, respectively. The 5-year OS rates for patients who had peritoneal dissemination without other metastases were 17.6% (n=17), 12.5% (n=19), and 3.4% (n=28) (P1 vs. P2, p=N.S.; P2 vs. P3, p=N.S.; P1 vs. P3, p=0.039), while the MST was 25.1, 15.1, and 12.5 months, respectively. In the P3 short survival group (SSG; n=13), TS expression was high in 7.7% (1/13) and low in 92.3% (12/13) of tumors, while DPD expression was high in 38.5% (5/13) and low in 61.5% (8/13) of tumors. In the P3 long survival group (LSG; n=15), the corresponding values were 80.0% (12/15), 20.0% (3/15), 33.3% (5/15), and 66.7% (10/15). High TS and low DPD expression was found in only 7.7% (1/13) of the SSG tumors vs. 46.7% (7/15) of the LSG tumors (p=0.028). These results suggest that the prognosis of stage IV colorectal cancer with P3 peritoneal dissemination is extremely poor. In addition, patients fitting the SSG criteria are unlikely to respond to treatment with 5-FU+LV, and may need combination chemotherapy using CPT-11 and/or L-OHP.
The efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for patients with peritoneal carcinomatosis from colorectal carcinoma remains to be established.
A systematic review of relevant studies before March 2006 was performed. Two reviewers independently appraised each study using a predetermined protocol. The quality of studies was assessed. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies.
Two randomized controlled trials, one comparative study, one multi-institutional registry study, and 10 most recent case-series studies were evaluated. The level of evidence was low in 13 of the 14 eligible studies. The median survival varied from 13 to 29 months, and 5-year survival rates ranged from 11% to 19%. Patients who received complete cytoreduction benefited most, with median survival varying from 28 to 60 months and 5-year survival ranging from 22% to 49%. The overall morbidity rate varied from 23% to 44%, and the mortality rate ranged from 0% to 12%.
The current evidence suggests that cytoreductive surgery combined with perioperative intraperitoneal chemotherapy is associated with an improved survival, as compared with systemic chemotherapy for peritoneal carcinomatosis from colorectal carcinoma.
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.
The aim of this prospective study was to analyze the impact of second-look surgery in an attempt to treat peritoneal carcinomatosis (PC) at an early stage in a series of patients at high risk of developing PC from colorectal cancer.
The prognosis of colorectal PC has recently been improved with hyperthermic intraperitoneal chemotherapy (HIPEC) after complete cytoreductive surgery (CCRS), and could be further improved if PC could be treated at an early stage. But, currently, the diagnosis of early PC is not accessible to imaging.
From 1999 to 2006, 29 patients without any sign of recurrence on imaging studies underwent second-look surgery 13 months after resection of the primary tumor. Patients were selected according to primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 16), synchronous ovarian metastases (n = 4), perforated primary tumor (n = 9).
PC was found and treated with CCRS plus HIPEC in 16 of 29 (55%) cases, corresponding to 10 of 16 patients with initial PC, 3 of 4 patients with synchronous ovarian metastases and 3 of 9 patients with a perforated primary tumor. There was no postoperative mortality, and morbidity (grade III/IV) occurred in 14% of cases. After a median follow-up of 27 months (range, 6-96), 8 of 16 patients treated with CCRS and HIPEC are free of disease, 4 relapsed in the peritoneum, and 4 developed isolated visceral metastases.
Performing second-look surgery at 1 year in selected patients at high risk of developing PC allowed the early detection and treatment of PC in 55% of cases. Our preliminary results have encouraged us to pursue this strategy and to evaluate it in a prospective multicenter trial.
Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis
- Jacquet
Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study
- Lemmens