High Risk For Peritoneal Metastases Research Articles

Diagnostic Nodes of Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Among Colorectal Cancer Patients: A Swiss National Multicenter Survey

BackgroundThe management of patients with colorectal cancer (CRC) with peritoneal metastases is challenging, and the roles of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are unclear and debated among experts. Materials and MethodsThe experts of the Swiss Peritoneal Cancer Group were contacted and agreed to participate in this analysis. Experts from 9 centers in Switzerland provided their decision algorithms for CRS/HIPEC for patients with or at high risk for peritoneal metastases from CRC. Their responses were converted into decision trees on the basis of objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies. ResultsThe final treatment algorithms included a total of 5 decision criteria (age, Peritoneal Cancer Index [PCI], extraperitoneal metastases, Peritoneal Surface Disease Severity Score, and various risk factors [RF]) and 2 treatment options (HIPEC, yes or no). HIPEC was never recommended for patients without peritoneal metastases in the absence of RF for peritoneal metastases. For patients with a PCI ≤15 without organ metastases, all centers recommended CRS/HIPEC. There was also a consensus not to perform CRS/HIPEC in elderly patients (80 years and older), those with a PCI >20, and those with unresectable metastases. For patients with a PCI = 16 to 20, there was no consensus. ConclusionMultiple decision criteria relevant to all participating centers were identified. Because patient selection for CRS/HIPEC remains difficult, uniform criteria for the term “high risk” for peritoneal metastases and systemic metastases are helpful. Future trials and guidelines should take these criteria into account.

Adjuvant HIPEC in patients with colon cancer at high risk of peritoneal metastases: Primary outcome of the COLOPEC multicenter randomized trial.

482 Background: Patients with T4 or perforated colon cancer are at high risk (~25%) of peritoneal metastases (PM). Sensitivity of imaging modalities for PM is limited and the majority of patients is diagnosed in a palliative setting. This provides a rationale for adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). In this study, the effectiveness of adjuvant HIPEC in reducing the risk of PM was determined. Methods: In this multicenter trial, patients with T4 (either cT4 or pT4, N0-2, M0) or perforated colon cancer, who underwent curative resection were randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy or to adjuvant systemic chemotherapy alone (1:1). Adjuvant HIPEC with oxaliplatin was performed simultaneously (9%) or within five-eight weeks (91%) after the primary tumor resection. Patients without evidence of recurrent disease at 18 months based on CT imaging underwent diagnostic laparoscopy in both arms. The primary endpoint was PM free survival (PMFS) at 18 months using Kaplan Meier analysis. Results: Between April 2015 and January 2017, 204 patients were randomized: 102 in the control arm (0 drop-outs), 102 in the experimental arm (two drop-outs). Surgical exploration at the start of the HIPEC procedure at five-eight weeks postoperatively revealed metastases in 11 patients (PM in 9/11) in the experimental arm, and adjuvant HIPEC was not applied. Adjuvant systemic chemotherapy was administered in 89/100 eligible patients after median 6 weeks (IQR 5-7) in the control arm and in 84/89 after 10 weeks (IQR 9-12) in the experimental arm. PM rate after completion of 18 months follow-up was 22/102 and 18/100, respectively. In the ITT analysis no difference in 18 months PMFS was observed: 77% (control) versus 81% (experimental), HR 0.836 (0.489-1.428)). Also, no differences were observed in 18 months DFS (HR 1.016 (0.646-1.598)) and OS (HR 1.139 (0.532-2.439)). One patient developed encapsulating peritoneal sclerosis after HIPEC. Conclusions: Adjuvant HIPEC with oxaliplatin for patients with T4 or perforated colon cancer does not result in improved 18 months PMFS. Long-term results have to be awaited to assess the role of HIPEC in the adjuvant setting. Clinical trial information: NCT02231086.

Intraperitoneal doxorubicin achieves access to mesenteric lymph nodes, case series of two patients

BackgroundIntraperitoneal chemotherapy has been used extensively to treat cancers that metastasize to the peritoneal surfaces. In the operating room the intraperitoneal chemotherapy is administered with moderate heat. The chemotherapy is used after surgery when there is minimal residual disease. Alternatively, intraperitoneal chemotherapy can be used long-term in an attempt to prevent the progression of disease in patients at high risk for peritoneal metastases to occur during follow-up. MethodsHyperthermic intraperitoneal chemotherapy (HIPEC) with doxorubicin was used to treat peritoneal metastases in two patients. These two patients required generous sampling of mesenteric lymph nodes because involvement of these lymph nodes was suspected on preoperative radiologic studies by computed tomography (CT). The lymph nodes, peritoneal fluid and plasma along with tumor tissue in one patient were subjected to a determination of doxorubicin chemotherapy concentrations by high pressure liquid chromatography (HPLC). ResultsThe ratio of doxorubicin present in peritoneal fluid as compared to plasma was 80 in patient 1 and 50 in patient 2. There was an increased doxorubicin concentration within lymph nodes as compared to plasma. The accumulation of doxorubicin in lymph nodal tissue was 40 times that of plasma in patient 1 and 30 times that in patient 2. In patient 2, the concentration of doxorubicin in lymph nodes was very similar to the concentration of chemotherapy within tumor nodules. ConclusionDoxorubicin chemotherapy was not only present in peritoneal surface tissue but also a surprisingly high level was present in mesenteric lymph nodes in patients treated by HIPEC. This observation may have implications for interpreting clinical future studies performed with HIPEC. To our knowledge, this is the first time this pharmacologic information regarding intraperitoneal chemotherapy access to mesenteric lymph nodes has been reported.

Locally Advanced Colorectal Cancer: True Peritoneal Tumor Penetration is Associated with Peritoneal Metastases

BackgroundFindings show T4 colorectal cancer (CRC) to be a risk factor for the development of peritoneal metastases (PM). Heterogeneity regarding peritoneal involvement of T4 tumors might explain the wide range of reported PM incidences (8–50%). Hyperplastic and mesothelial inflammatory reactions complicate evaluation of the exact primary tumor involvement of the peritoneal layer. This retrospective cohort study aimed to assess the association between either inflammatory peritoneal reaction or peritoneal involvement of the primary tumor and the risk of PM.MethodsSince 2010, pathologists at UZ Leuven have systematically categorized peritoneal involvement in peritoneal reaction with tumor less than 1 mm from the peritoneal surface or true peritoneal penetration. All patients undergoing resection of CRC between January 2010 and July 2013 who fulfilled either of these pathologic criteria were included in this study.ResultsThe study enrolled 159 CRC patients. Peritoneal reaction with tumor less than 1 mm from the peritoneal surface was present in 43 patients and true peritoneal penetration in 116 patients. Overall, 29 patients (18%) had synchronous PM, and 30 patients (23%) had metachronous PM. In the multivariable analysis, true peritoneal penetration, in contrast to peritoneal reaction with tumor less than 1 mm from the peritoneum, was associated with greater risk of PM (odds ratio [OR], 2.518; range, 1.038–6.111; p = 0.041) and lymph node involvement (N1: OR, 1.572; range, 0.651–3.797 vs N2: OR, 4.046; range, 1.549–10.569; p = 0.014).ConclusionHistologically confirmed true peritoneal penetration by CRC, rather than inflammatory peritoneal reaction constitutes a high risk for PM. With evolving treatment strategies that aim to treat PM in an earlier phase, identification of high-risk patients becomes highly important clinically.

Colorectal cancer at high risk of peritoneal metastases: long term outcomes of a pilot study on adjuvant laparoscopic HIPEC and future perspectives.

ObjectiveEarly detection of peritoneal metastases (PM) of colorectal cancer (CRC) is difficult and treatment options at a clinically overt stage are limited. Potentially, adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) is of value. The aim of this study was to present long term oncological outcomes of a pilot study on adjuvant HIPEC to reduce development of PMCRC, with systematic review of literature.MethodsLong term oncological outcomes of ten patients who underwent laparoscopic HIPEC within eight weeks after resection of primary CRC in the pilot study were retrospectively collected. A systematic search of literature was performed on studies describing the use of HIPEC in patients with CRC at high risk of developing PM.ResultsThe median follow-up was 54 months (range 49-63). All patients were alive at the last follow-up moment and none of them had developed PM. Two patients had developed pulmonary metastases. Systematic review revealed five small cohort studies, including two matched comparisons. Peritoneal recurrences were found in 0% to 9% after adjuvant HIPEC, which was 28% and 43% in the two control groups, respectively. Disease free and overall survival were significantly higher in favour of HIPEC.ConclusionLong term follow-up of ten patients included in a pilot study on adjuvant HIPEC revealed no peritoneal recurrences. This result is in line with other published pilot studies, a promising observation. However, the outcomes of the Dutch randomized COLOPEC trial and similar trials worldwide should be awaited for definitive conclusions on the effectiveness of adjuvant HIPEC.

Pilot study of adjuvant hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer at high risk for the development of peritoneal metastases.

The prognosis of peritoneal metastases from colorectal cancer has recently improved with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Although outcomes are further improved when early stage peritoneal metastases are treated, adjuvant hyperthermic intraperitoneal chemotherapy has never been thoroughly addressed. This prospective pilot study assessed feasibility, safety and efficacy of hyperthermic intraperitoneal chemotherapy combined with primary curative surgery in colorectal cancer at high risk for peritoneal metastases. Twelve patients were prospectively selected according to predetermined risk factors for the development of peritoneal metastases. Patients underwent conventional colon surgery, closed-abdomen mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy, and cytoreductive surgical procedures, as needed. Preoperative tumor-related risk factors were confirmed by intraoperative findings and pathological examination in all patients: minimal synchronous peritoneal metastases (n = 2), synchronous ovarian metastases (n = 1), positive peritoneal washing cytology (n = 2), primary tumor directly invading other organs (n = 6), or penetrating visceral peritoneum (n = 1). Major morbidity occurred in 2 patients and operative death in none. Median follow-up was 49 months (range, 22-72). Peritoneal metastases occurred in 1 patient and distant metastases in 2. Five-year overall survival was 83.3%. Preoperative/early intraoperative assessment can reliably identify colorectal cancer patients at high risk for peritoneal metastases. Adjuvant hyperthermic intraperitoneal chemotherapy is well tolerated and safe. These preliminary results would support the design of future phase-III trials of adjuvant hyperthermic intraperitoneal chemotherapy.

Update on the prevention of local recurrence and peritoneal metastases in patients with colorectal cancer.

The prevention of a disease process has always been superior to the treatment of the same disease throughout the history of medicine and surgery. Local recurrence and peritoneal metastases occur in approximately 8% of colon cancer patients and 25% of rectal cancer patients and should be prevented. Strategies to prevent colon or rectal cancer local recurrence and peritoneal metastases include cytoreductive surgery and hyperthermic perioperative chemotherapy (HIPEC). These strategies can be used at the time of primary colon or rectal cancer resection if the HIPEC is available. At institutions where HIPEC is not available with the treatment of primary malignancy, a proactive second-look surgery is recommended. Several phase II studies strongly support the proactive approach. If peritoneal metastases were treated along with the primary colon resection, 5-year survival was seen and these results were superior to the results of treatment after peritoneal metastases had developed as recurrence. Also, prophylactic HIPEC improved survival with T3/T4 mucinous or signet ring colon cancers. A second-look has been shown to be effective in two published manuscripts. Unpublished data from MedStar Washington Cancer Institute also produced favorable date. Rectal cancer with peritoneal metastases may not be so effectively treated. There are both credits and debits of this proactive approach. Selection factors should be reviewed by the multidisciplinary team for individualized management of patients with or at high risk for peritoneal metastases.

Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases.

A major problem in treating patients with peritoneal spread from colorectal cancer is that at diagnosis wide peritoneal involvement often precludes all curative attempts. A possible solution is to identify those patients at risk for peritoneal metastases and intervene early to prevent locoregional disease spread before it develops and, thus, to improve outcome. We analyzed long-term results from a previous study and compared outcomes in 25 patients with advanced colon cancer considered at high risk for peritoneal spread (pT3/pT4 and mucinous or signet ring cell histology) prospectively included and managed with a proactive surgical approach including target organ resection for peritoneal spread plus hyperthermic intraperitoneal chemotherapy (HIPEC) and in 50 retrospectively well-matched controls who underwent standard surgical resection during the same period and in the same hospital by different surgical teams. At 48 months after the study closed, peritoneal metastases and local recurrence developed significantly less often in proactively managed patients than in controls (4 vs 28%) (p < 0.03). Patients in the proactive group also survived longer than control patients (median overall survival 59.5 vs 52 months). Despite similar morbidity, Kaplan-Meier survival curves disclosed significantly longer disease-free and overall survival in the proactive than in the control group (p < 0.05 and <0.04). In patients with advanced colon cancer at risk for peritoneal recurrence, the proactive surgical approach plus HIPEC seems to achieve good locoregional control preventing peritoneal spread thus improving outcome without increasing morbidity. These advantages merit investigation in a multicentric randomized trial.

Hyperthermic intraperitoneal chemotherapy with mitomycin C and 5-fluorouracil in patients at high risk of peritoneal metastasis from colorectal cancer: A preliminary clinical study.

Although hyperthermic intraperitoneal chemotherapy (HIPEC) has been extensively used to treat patients with peritoneal metastases (PM) from colorectal cancer (CRC), a standard protocol has not yet been established. The aim of this preliminary clinical study was to confirm in vitro the efficacy of mitomycin C combined with 5-fluorouracil (MMC-5FU) under hyperthermic conditions in CRC and investigate the pharmacokinetics and feasibility of HIPEC with MMC-5FU for patients at high risk of PM from CRC. To simulate HIPEC in vitro, we used the collagen gel droplet-embedded culture drug sensitivity test with the HCT166 colorectal cell line to assess the antitumor efficacy of MMC and 5FU as single-agent and combination treatments following incubation with HCT116 cells for 30 min at either 37 or 42°C. In addition, five patients at high risk of PM from CRC underwent surgical tumor resection followed by HIPEC with MMC-5FU. Our results demonstrated that the combined administration of MMC-5FU suppressed tumor cell proliferation more efficiently compared to either agent used alone. In addition, hyperthermia at 42°C significantly enhanced drug sensitivity. During the clinical application of HIPEC with MMC-5FU, no grade 4 hematological toxicities or surgical adverse events were recorded. In addition, there was no evidence of peritoneal recurrence during a median observational period of 38 months. Of note, two patients with positive intraoperative peritoneal cytology at the first surgery developed no peritoneal recurrence and exhibited negative peritoneal cytology at the second surgery. In conclusion, HIPEC using MMC-5FU was shown to be a feasible therapeutic option, with an acceptable toxicity profile, for patients at high risk of PM from CRC. Therefore, HIPEC with MMC-5FU may be a promising novel therapeutic option for such patients, which merits further verification of its safety and efficacy in large-scale clinical trials.

Pilot study of adjuvant hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer at high risk for the development of peritoneal metastases

The prognosis of peritoneal metastases from colorectal cancer has recently improved with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Although outcomes are further improved when early stage peritoneal metastases are treated, adjuvant hyperthermic intraperitoneal chemotherapy has never been thoroughly addressed. This prospective pilot study assessed feasibility, safety and efficacy of hyperthermic intraperitoneal chemotherapy combined with primary curative surgery in colorectal cancer at high risk for peritoneal metastases. Twelve patients were prospectively selected according to predetermined risk factors for the development of peritoneal metastases. Patients underwent conventional colon surgery, closed-abdomen mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy, and cytoreductive surgical procedures, as needed. Preoperative tumor-related risk factors were confirmed by intraoperative findings and pathological examination in all patients: minimal synchronous peritoneal metastases (n = 2), synchronous ovarian metastases (n = 1), positive peritoneal washing cytology (n = 2), primary tumor directly invading other organs (n = 6), or penetrating visceral peritoneum (n = 1). Major morbidity occurred in 2 patients and operative death in none. Median follow-up was 49 months (range, 22-72). Peritoneal metastases occurred in 1 patient and distant metastases in 2. Five-year overall survival was 83.3%. Preoperative/early intraoperative assessment can reliably identify colorectal cancer patients at high risk for peritoneal metastases. Adjuvant hyperthermic intraperitoneal chemotherapy is well tolerated and safe. These preliminary results would support the design of future phase-III trials of adjuvant hyperthermic intraperitoneal chemotherapy.

Prevention of Peritoneal Metastases from Colon Cancer in High-Risk Patients: Preliminary Results of Surgery plus Prophylactic HIPEC

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.