Second and third look laparoscopy in pT4 colon cancer patients for early detection of peritoneal metastases; the COLOPEC 2 randomized multicentre trial.
ABSTRACT: 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.
Project description:Background:Peritoneal metastasis (PM) is the second most common site of recurrence in colon cancer (CC) patients and accounts for approximately one-third of all recurrences. Patients with T4 or intraperitoneal perforated colon cancers have an increased risk of developing PM, and since manifest PM is difficult to treat, high-risk patients should be offered prophylactic treatment. Here, we propose a study of adjuvant oxaliplatin administered as pressurized intraperitoneal aerosol chemotherapy (PIPAC OX) in patients with high-risk colon cancer (T4, perforated tumors, ovarian metastasis). Methods:PIPAC-OPC3 CC is a non-randomized, non-blinded phase 2 cohort study designed to treat high-risk colon cancer patients with adjuvant PIPAC-directed therapy. Based on an expected 90?% peritoneal recurrence-free survival with adjuvant PIPAC against the estimated 75?% without, 60 patients are needed (?: 0.05, power: 0.8). Eligible patients will receive two PIPAC treatments with oxaliplatin (92?mg/m2) at 4-6 week intervals. During laparoscopy, the peritoneum is biopsied at two locations, and peritoneal lavage with 500?mL of saline and laparoscopic ultrasound is performed. The patients are screened for adverse medical events and surgery-related complications after each PIPAC procedure. After the second PIPAC procedure, the patients will be examined in the outpatient clinic and followed with CT scans 12, 24 and 36 months after resection. The primary outcome of the PIPAC-OPC3 CC trial is to evaluate if PIPAC-directed adjuvant therapy can reduce the risk of PM. Secondary outcomes include the number of conversions from positive to negative peritoneal lavage cytology after one PIPAC procedure, completion rate of two adjuvant PIPAC treatments, toxicity and complication rate and recurrence-free and overall survival rates after 1, 3 and 5 years. Results:It is expected that PIPAC-directed adjuvant therapy can provide an absolute risk reduction of 15?% regarding the development of PM in high-risk colon cancer patients, and that this may result in increased survival rates. We expect that free intraperitoneal tumor cells (FITC) may be detected by peritoneal lavage performed just prior to the administration of PIPAC-directed therapy, and that this treatment may convert FITC-positive patients to a FITC-negative status. Conclusions:This study may provide important knowledge to be used in designing additional studies on PIPAC in the adjuvant setting of other primary cancers. Trial registration:ClinicalTrials.gov Identifier NCT03280511 (2017-09-12). European Clinical Trials Database (EudraCT) 2017-002637-37.
Project description:Aim:Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum. Methods:Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasis (PM) and comprehensive miRNA expression analysis was carried out. Expressions of candidate miRNAs were then validated in all 58 samples using TaqMan Advanced miRNA Assays. Results:In initial screening, we carried out comprehensive analysis of exosomal miRNA using peritoneal fluids from 11 and 14 patients with or without PM, respectively, and identified 11 dysregulated miRNAs in PM (+) samples. Validation analysis showed that four miRNAs (miR-21-5p, miR-92a-3p, miR-223-3p, and miR-342-3p) were significantly upregulated in 12 PM (+) samples, and their expression levels showed positive correlation with peritoneal cancer index. In contrast, miR-29 family were all downregulated in patients with PM (+) samples. Moreover, in 24 patients with pT4 tumor, miR-29 at gastrectomy tended to be lower in six patients with peritoneal recurrence with significant differences in miR-29b-3p (P = .012). Conclusion:Expression pattern of miRNAs in peritoneal exosomes well reflects the tumor burden in the peritoneal cavity and could be a useful biomarker in the treatment of PM.
Project description:BACKGROUND: Perioperative staging laparoscopy is a useful tool for the detection of occult peritoneal metastases in gastrointestinal cancers. This retrospective study aimed to determine the clinical value of staging laparoscopy for advanced or recurrent gastric cancer. METHODS: A total of 178 patients with advanced or recurred gastric cancer who underwent perioperative staging laparoscopy were enrolled. In the absence of peritoneal deposits (P1) and positive peritoneal cytology (CY1), gastrectomy with lymph node dissection was indicated with curative intent. If P1 or CY1 was detected intraoperatively, patients received intensive chemotherapy and laparoscopic surgical intervention. RESULTS: Curative gastrectomy was performed in 104 patients after confirmation of P0 and CY0 status. P1 or CY1 was detected for the first time in 23 (15%) patients. A total of 13 patients were converted from gastrectomy to intensive chemotherapy after detection of P1 or CY1. Additional laparoscopic interventions included insertion of intraperitoneal reservoir port in 54 patients, insertion of a metallic stent in five, ileostomy for colon stricture in six, jejunostomy in 19, and gastrojejunostomy in 16. Of eight patients treated with intensive chemotherapy who underwent R0 gastrectomy after second-look laparoscopy, five are currently free from recurrence of gastric cancer for 25.5 months. CONCLUSIONS: Occult peritoneal dissemination was detected in about 14% in patients with tumors deeper than T2. Moreover, additional laparoscopic interventions can be utilized for P1 or CY1 patients. The excellent surgical outcomes of R0 gastrectomy after chemotherapy and second-look laparoscopy indicate that confirmation of P0 and CY0 status by staging laparoscopy is of value to determine treatment strategy in patients with advanced gastric cancer.
Project description:Primary tumor location is an established prognostic factor in patients with (metastatic) colon cancer. Colon tumors can be divided into left-sided and right-sided tumors. The aim of this study was to determine the impact of primary tumor location on treatment and overall survival (OS) in patients with peritoneal metastases (PM) from colon cancer. This study is a retrospective, population-based cohort study. Records of patients diagnosed with colon cancer and synchronous PM, from 1995 through 2016, were retrieved from the Netherlands Cancer Registry (NCR). Data on diagnosis, staging, and treatment were extracted from the medical records by specifically trained NCR personnel. Information on survival status was updated annually using a computerized link with the national civil registry. In total, 7930 patients were included in this study; 4555 (57.4%) had a right-sided and 3375 (42.6%) had a left-sided primary tumor. In multivariable analysis right-sided primary tumor was associated with worse OS (HR: 1.11, 95% CI 1.03-1.19, P = .007). Of all patients diagnosed with PM, 564 (7.1%) underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Patients with left-sided primary tumors were more often candidates for CRS-HIPEC (6.5% vs. 8.0%, P = .008). OS of patients with right- and left-sided tumors who underwent CRS-HIPEC did not significantly differ. In conclusion, primary right-sided colon cancer was an independent prognostic factor for decreased OS in patients diagnosed with synchronous PM. In patients treated with CRS-HIPEC location of the primary tumor did not influence survival.
Project description:BACKGROUND:Multivisceral resection for T4b colon cancer constitutes a heterogeneous group of surgical procedures. The purpose of this study was to explore clinically distinct categories of multivisceral resection, with subsequent correlation to postoperative complications and oncological outcomes. METHODS:In this multicenter cohort study, all consecutive patients without metastases who underwent multivisceral resection for pT4bN0-2M0 colon cancer between 2000 and 2014 were included. Multivisceral resection was divided into four categories: (i) gastrointestinal (including the stomach), (ii) urologic ((partial) bladder and ureter), (iii) solid organ (spleen, kidney, liver, pancreas, and uterus), and (iv) abdominal wall/omentum/ovaries. The primary outcome was surgical complications and secondary outcomes were 5-year intra-abdominal recurrence, disease-free survival, and overall survival. RESULTS:In total, 130 patients who underwent curative intent resection of pT4 colon cancer were included. Patients who underwent multivisceral resection within multiple categories were assigned to one of the categories based on hierarchy of clinical impact after exploratory analysis. For the primary endpoint, 55 patients were assigned to gastrointestinal, 14 to urologic, 14 to solid organ, and 47 to abdominal wall/omentum/ovaries multivisceral resection. Gastrointestinal multivisceral resection was independently associated with surgical complications (HR 3.9, 95% CI 1.4-10.6). Abdominal wall/omentum/ovaries multivisceral resection was significantly related with intra-abdominal recurrence (HR 7.8, 95% CI 1.0-57.8). The 5-year disease-free survival and overall survival showed no significant differences per multivisceral resection category. CONCLUSIONS:Multivisceral resections for T4b colon cancer are heterogeneous procedures considering risk profiles. The proposed multivisceral resection subclassification needs validation, but might improve comparability between studies and hospitals (auditing).
Project description:The standard of care for colorectal peritoneal carcinomatosis is evolving from chemotherapy to cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with disease limited to the peritoneum. Peritoneal carcinomatosis from colorectal cancer treated with chemotherapy alone results in median survival of 5 to 13 months, whereas CRS with HIPEC for early peritoneal carcinomatosis from colorectal cancer resulted in median survival of 48-63 months and 5 year survival of 51%.Completeness of cytoreduction and limited disease are associated with longer survival, yet early peritoneal carcinomatosis is undetectable by conventional imaging. Exploratory laparotomy can successfully identify early disease, but this approach can only be justified in patients with high risk of peritoneal carcinomatosis. Historical data indicates that patients presenting with synchronous peritoneal carcinomatosis, ovarian metastases, perforated primary tumor, and emergency presentation with bleeding or obstructing lesions are at high risk of peritoneal carcinomatosis. Approximately 55% of these patient populations will develop peritoneal carcinomatosis. We hypothesize that performing a mandatory second look laparotomy with CRS and HIPEC for patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer will lead to improved survival as compared to patients who receive standard of care with routine surveillance.This study is a prospective randomized trial designed to answer the question whether mandatory second look surgery with CRS and HIPEC will prolong overall survival compared to the standard of care in patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer (CRC). Patients with CRC at high risk for developing peritoneal carcinomatosis who underwent curative surgery and subsequently received standard of care adjuvant chemotherapy will be evaluated. The patients who remain without evidence of disease by imaging, physical examination, and tumor markers for 12 months after the primary operation will be randomized to mandatory second look surgery or standard-of-care surveillance. At laparotomy, CRS and HIPEC will be performed with intraperitoneal oxaliplatin with concurrent systemic 5-fluorouracil and leucovorin. Up to 100 patients will be enrolled to allow for 35 evaluable patients in each arm; accrual is expected to last 5 years.ClinicalTrials.gov ID: NCT01095523.
Project description:Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity. Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed. Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3-4 AEs. Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.
Project description:Background:Brain metastases are a common complication of advanced non-small cell lung cancer (NSCLC). Patients with brain metastases were excluded from the registration trials of bevacizumab that showed a survival benefit with the use of angiogenesis inhibition. Methods:In this study, we pooled data from two separate trials designed to evaluate the risk of central nervous system (CNS) hemorrhage in patients with stable treated brain metastases to look specifically at both the safety and efficacy of bevacizumab and pemetrexed when used as second-line treatment in NSCLC patients with stable treated brain metastases. Results:We report acceptable safety and promising efficacy from our analysis. Conclusions:Our study adds further evidence of safety of administering pemetrexed and bevacizumab to patients with stable brain metastases. There is increasing roles for systemic therapies to treat stable brain metastases for patients with advanced NSCLC.
Project description:Investigating epidemiology of metastatic colon and rectal cancer is challenging, because cancer registries seldom record metastatic sites. We used a population based approach to assess metastatic spread in colon and rectal cancers. 49,096 patients with colorectal cancer were identified from the nationwide Swedish Cancer Registry. Metastatic sites were identified from the National Patient Register and Cause of Death Register. Rectal cancer more frequently metastasized into thoracic organs (OR?=?2.4) and the nervous system (1.5) and less frequently within the peritoneum (0.3). Mucinous and signet ring adenocarcinomas more frequently metastasized within the peritoneum compared with generic adenocarcinoma (3.8 [colon]/3.2 [rectum]), and less frequently into the liver (0.5/0.6). Lung metastases occurred frequently together with nervous system metastases, whereas peritoneal metastases were often listed with ovarian and pleural metastases. Thoracic metastases are almost as common as liver metastases in rectal cancer patients with a low stage at diagnosis. In colorectal cancer patients with solitary metastases the survival differed between 5 and 19 months depending on T or N stage. Metastatic patterns differ notably between colon and rectal cancers. This knowledge should help clinicians to identify patients in need for extra surveillance and gives insight to further studies on the mechanisms of metastasis.
Project description:BACKGROUND:Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier. OBJECTIVE:We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. PATIENTS AND METHODS:In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ??1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. RESULTS:Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n?=?37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n?=?22)]. In patients who received ??1 prior second-generation ALK TKI [EXP3B-5 (n?=?139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n?=?94) and 55% vs. 12% (n?=?45), respectively). CONCLUSIONS:Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS. GOV IDENTIFIER:NCT01970865.