Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Transanal endoscopic microsurgery versus total mesorectal excision of T1 rectal adenocarcinomas with curative intention.

PURPOSE: After total mesorectal excision (TME) for rectal cancer, pathology is standardized with margin status as a predictor for recurrence. This has yet to be implemented after transanal endoscopic microsurgery (TEM) and was investigated prospectively for T1 rectal adenocarcinomas. PATIENTS AND METHODS: Eighty patients after TEM were compared to 75 patients after TME. The study protocol included standardized pathology. TEM patients were eligible when excision margins were negative. RESULTS: TEM was safer than TME as reflected by operating time, blood loss, hospital stay, morbidity, re-operation rate and stoma formation (all P<0.001). Mortality after TEM was 0% and after TME 4%. At 5 years after TEM and TME, both overall survival (TEM 75% versus TME 77%, P=0.9) and cancer-specific survival (TEM 90% versus TME 87%, P=0.5) were comparable. Local recurrence rate after TEM was 24% and after TME 0% (HR 79.266, 95% CI, 1.208 to 5202, P<0.0001). CONCLUSION: For T1 rectal adenocarcinomas TEM is much saver than TME and survival is comparable. After TEM local recurrence rate is substantial, despite negative excision margins.

High sustained virological response in chronic hepatitis C by combining induction and prolonged maintenance therapy.

Chronic hepatitis C patients with genotype 1 infection, liver cirrhosis, high viral load, or those who have not responded to anti-viral treatment in the past have limited chances of clearing the virus, even with pegylated interferon-ribavirin therapy. In this study we treated such patients with a treatment schedule that combines high dose induction Interferon (IFN), prolonged daily IFN and ribavirin treatment. Twenty-four consecutive patients were included in this study with either genotype 1 infection, cirrhosis, previous non-response to IFN or a combination of these poor-response characteristics. Patients were treated with 10 million units (MU) of IFN daily for 4 weeks followed by 5 MU/day until week 24, 3 MU/day until week 52 and 3 MU thrice weekly until week 76 in combination with 1-1.2 g ribavirin daily. HCV RNA levels were assessed weekly until week 4 and at least once every 3 months thereafter, by a validated assay with a detection limit below 500 copies/mL. Both intention to treat (ITT) and per protocol (PP) analysis showed a high sustained virological response (ITT 67%, PP 80%). A virological response occurred rapidly (before 8 weeks of treatment) in all patients with a sustained response. Relapse after stopping therapy was observed in only 5%. Side-effects were observed frequently, and six patients had to be hospitalized. With this new treatment regimen that combines induction- and prolonged daily interferon treatment with ribavirin it seems possible to eliminate hepatitis C virus in the majority of patients that have an a priori limited chance of sustained response. Further clinical evaluation of intensive interferon and ribavirin combination therapy (now also including PEG-interferon) is recommended in centres that can provide close patient monitoring and experienced hepatological support.

Hepatitis C viral kinetics in difficult to treat patients receiving high dose interferon and ribavirin.

BACKGROUND/AIMS: Hepatitis C viral (HCV) kinetic studies have demonstrated the increased antiviral effect of higher than standard dosages of interferon and of daily treatment schedules. Since interferon has a short half-life, twice-daily administration of interferon may be even more effective. METHODS: We evaluated the HCV kinetics in daily vs. twice-daily high dose interferon (IFN) therapy in combination with ribavirin in 24 difficult to treat patients. Patients were randomised to 10 MU IFN daily or 5 MU twice-daily for 4 weeks. RESULTS: Interferon efficacy (epsilon) was similar and very high for both groups (range 99.83-99.97%). Clearance of infected cells (beta phase) tended to be slightly faster for patients on 5 MU bd (T1/2 70 vs. 90 h, ns). Clearance of infected cells was strongly related to initial viral load (T1/2 103 vs. 53 h, P = 0.002, for above versus below 2 x 10(6) copies/ml). In this study an additional phase with a temporary rise in viral load was observed between the alpha and the beta phase. CONCLUSION: Daily high induction dose is associated with nearly complete inhibition of viral replication even in difficult to treat patients. A twice-daily schedule did not lead to further improvement. Clearance rate of infected cells was significantly correlated with initial viral load.

Estimation of early hepatitis C viral clearance in patients receiving daily interferon and ribavirin therapy using a mathematical model.

Patients with hepatitis C virus (HCV) genotype 1 infection are resistant to standard interferon (IFN) therapy. We used a mathematical model to estimate the duration of daily therapy necessary to maximize the number of patients achieving viral negativity before 12 weeks of therapy. Patients from a study to determine HCV RNA reduction over 4 weeks using 3 million units (MU), 5 MU, or 10 MU of IFN alfa daily plus Ribavirin were compared with a group receiving IFN alfa 3 MU three times a week. By extending the linear regression and prediction interval lines, the estimated time to negativity was greater than 12 weeks for the standard IFN group, 42 to greater than 84 days for the 3 MU IFN daily plus Ribavirin, 39 to 60 days for 5 MU IFN daily plus Ribavirin and 25 to 45 days for the 10 MU IFN daily and Ribavirin group, respectively. Thus, the use of a predictive model based on log transformation and linear regression of the early HCV RNA response suggests daily doses of 5 or 10 million units of IFN plus Ribavirin will be theoretically necessary for longer than 4 weeks to maximize the number of patients who clear virus by 12 weeks of therapy. This model may be useful in predicting response in groups of patients receiving other therapies.

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis C patients: a case control study.

BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.

Acute pancreatitis attributed to the use of interferon alfa-2b.

Two patients experienced episodes of acute pancreatitis shortly after starting treatment with interferon alfa-2b (IFN-alpha) for a chronic hepatitis C infection. The first patient was a 40-year-old man who developed acute pancreatitis after 15 weeks of treatment with 3 MU IFN-alpha subcutaneously (SC) 3 times weekly and 1200 mg ribavirin. After disappearance of symptoms and normalization of laboratory values, oral intake of solid foods and IFN-alpha therapy were restarted. Within hours, a relapse of acute pancreatitis occurred. A rechallenge with IFN-alpha 4 days later was followed by a prompt increase in serum lipase level, and IFN-alpha therapy was discontinued. The second patient was a 38-year-old man who developed acute pancreatitis 2 hours after SC administration of 5 MU IFN-alpha. Ultrasound endoscopy showed sludge in the gallbladder. The patient was rechallenged 5 weeks later with 3 MU IFN-alpha SC. Although serum amylase and lipase levels increased after readministration of IFN-alpha, treatment was continued. The patient was readmitted 2 weeks later with severe abdominal pain, and IFN-alpha administration was discontinued. Considering the temporal relationship between the start of IFN-alpha treatment and development of acute pancreatitis, the absence of other clear etiologic factors for acute pancreatitis, disappearance of symptoms after discontinuation of IFN-alpha, and positive reactions to rechallenge, IFN-alpha is the most probable cause for development of acute pancreatitis in these patients.

New treatment strategies in non-responder patients with chronic hepatitis C.

There is solid evidence that retreatment of non-responders with standard regimens of interferon monotherapy is of no clinical value. On the other hand, combination therapy with interferon and ribavirin now produces sustained response rates in non-responders similar to those of interferon monotherapy in untreated patients. Consequently, retreatment of non-responders with the combination of interferon-ribavirin appears to be a valid treatment option. The efficacy of retreatment with the interferon-ribavirin combination can probably be increased by modifying the first weeks of interferon therapy from standard (3 MU tiw) to induction (10 MU daily), and by extending the treatment period to 12 months. In the next few years, the additive value of amantadine to interferon or to interferon-ribavirin combination in inducing sustained viral clearance should be explored. For the many patients who still do not respond with viral clearance despite these new approaches, the goal of therapy might be shifted towards persistent ALT normalization in order to reduce the progression of liver disease. Drugs that can normalize serum ALT such as interferon, ursodeoxycholic acid, ribavirin and glycyrrhizin should be evaluated for this objective.

Ultrarapid hepatitis C virus clearance by daily high-dose interferon in non-responders to standard therapy.

BACKGROUND/AIMS: To analyze the kinetics of the hepatitis C virus and the patterns of resistance to interferon alpha, we assessed HCV RNA levels early during retreatment with high-dose interferon in patients who did not respond to standard treatment. METHODS: Eleven non-responders to previous therapy with 3-6 MU interferon three times a week were retreated with daily 10 MU. Plasma was sampled at days 0, 1, 2, 3, 14 and 28; all samples were prepared within 2 h and stored at -70 degrees C without thawing until analysis. The quantitative HCV RNA level was assessed by the Superquant assay (NGI, USA). The Eurohep reference panel, tested blindly, confirmed the linearity of the assay with a detection limit for genotypes 1 and 3 between 10(2) and 10(3) copies/ml. RESULTS: All patients showed a fall in viral load between week 0 and week 2 (2.6 log, i.e. 99.7%, range 1.3-4.7 log), whereas no fall was detected after week 2. Closer examination in nine patients revealed that all had a dramatic fall in the first 2 days (first day 1.8 log, 0.8-3.5; second day 0.8 log, -0.2-1.3), without any significant fall thereafter. The calculated half-life of viral decay in plasma was 5 (2-8.9) h, corresponding to a clearance of 2.4 (0.2-13.7) x 10(11) virions per day. Sustained responders showed a significantly greater fall in viral load in the first day (3.2 log, 2.8-3.5) than those who did not respond (1.4 log, 0.8-2.1, p=0.001). All three sustained responders had undetectable plasma HCV RNA at day 14. CONCLUSION: In patients without a response to standard interferon, the hepatitis C virus has a high daily turnover rate similar to that reported in naive patients. Our findings suggest that an early clearance of HCV RNA from the circulation is the key to a sustained response, which might be induced in about 25% of these patients by treatment with high (10 MU) daily doses of interferon. These findings have important implications for the concept of treatment of hepatitis C, which should shift its focus from long-term mild treatment towards aggressive therapy aiming at a fast viral disappearance within the first few days.