Background
In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal ...cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging.
Patients and methods
Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS).
Results
The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48 % (A) and 52 % (B,
P
= 0.81) and (y)pN0 was 30 % (A) vs. 39 % (B,
P
= 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis;
P
= 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B;
P
= 0.79).
Conclusion
This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.
Summary
In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective ...literature review addresses follow‐up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced‐stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.
CONTEXT The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists. OBJECTIVE To test the hypothesis that adjuvant chemotherapy with ...gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more. DESIGN, SETTING, AND PATIENTS Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups. INTERVENTION Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation (control n = 175). MAIN OUTCOME MEASURES Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat). RESULTS More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank). CONCLUSIONS Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN34802808
The aim of this study was to analyze the long-term results of different locoregional treatments for colorectal cancer liver metastases (CRLM), including transarterial chemoembolization (TACE), ...laser-induced thermotherapy (LITT) and microwave ablation (MWA). A total of 2140 patients with CRLM treated at our department between 1993 and 2020 were included in this retrospective study. The patients were divided into the following groups: LITT (573 patients; median age: 62 years), TACE + LITT (346 patients; median age: 62 years), MWA (67 patients; median age: 59 years), TACE + MWA (152 patients; median age: 65 years), and TACE (1002 patients; median age: 62 years). Median survival was 1.9 years in the LITT group and 1.7 years in the TACE + LITT group. The median survival times in the MWA group and TACE + MWA group were 3.1 years and 2.1 years, respectively. The median survival in the TACE group was 0.8 years. The 1-, 3-, and 5-year survival rates were 77%, 27%, and 9% in the LITT group and 74%, 18%, and 5% in the TACE + LITT group, respectively. The corresponding survival rates were 80%, 55%, and 33% in the MWA group, 74%, 36%, and 20% in the TACE + MWA group and 37%, 3%, and 0% in the TACE group, respectively. The long-term results of this study demonstrate the efficacy of locoregional treatments in treating patients with CRLM. The longest survival was found in the MWA group, followed by the combination therapy of TACE and MWA.
The aim of this study was to retrospectively evaluate the effects of conventional transarterial chemoembolization (cTACE) for the treatment of hepatocellular carcinoma over 20 years regarding overall ...survival (OS) and prognostic factors for OS. During the period from 1996 to 2016, 836 patients with HCC were treated with cTACE. Data evaluation was performed on the basis of pre- and postinterventional MRI and CT scans. Survival analysis was performed by Kaplan-Meier estimator; prognostic factors were determined by the use of Cox regression analysis. Overall, 4084 (mean 4.89 TACE sessions/patient) procedures were assessed. Median OS was 700 days (99% CI, 632.8-767.2). Depending on the indication, patients treated with a neoadjuvant intention showed the best OS (1229 days, 99% CI 983.8-1474.2) followed by curative intention (787 days, 99% CI 696.3-877.7), and then palliative intention (360 days, 99% CI 328.4-391.6). Portal vein thrombosis (HR 2.19, CI 1.63-2.96, and
< 0.01) and Child-Pugh class B or worse (HR 1.44, CI 1.11-1.86, and
< 0.001) were significantly associated with shorter OS. Patients with HCC benefit from TACE after careful patient selection. Portal vein thrombosis and Child-Pugh class B or worse are significantly unfavorable prognostic factors for patients' survival.
Incidence of cholangiocarcinoma (CCA) in western countries is rising. In the palliative setting, chemotherapy is the only established treatment. The evidence for other treatments including ...locoregional therapy is low. However, such individual treatments are offered in a real-world setting. The aim of this study is to document the offered treatments and to analyze the survival of patients with unresectable CCA treated at a tertiary referral center.
Data from 220 consecutive patients with CCA treated at a German university cancer center from January 1, 2008, until December 31, 2012. Of those, 105 patients were unresectable. Survival curves were calculated according to the Kaplan-Meier method; log-rank test was applied for survival analysis.
Any palliative treatment was beneficial for patients with unresectable CCA when compared to best supportive care (BSC) alone; median OS with BSC was 10 weeks (BSC vs. transarterial chemoembolization TACE p = 0.017, HR 0.36; BSC vs. TACE/chemotherapy p < 0.001, HR 0.24; BSC vs. chemotherapy p < 0.001, HR 0.31). Combination of TACE and chemotherapy prolonged overall survival as compared to TACE alone (105 vs. 43 weeks, p = 0.045).
Prognosis in advanced stage CCA is still very poor. However, multimodal treatment in palliative patients significantly prolong survival.
Metastatic colorectal cancer (mCRC) patients with liver‐limited disease (LLD) have a chance of long‐term survival and potential cure after hepatic metastasectomy. However, the appropriate ...postoperative treatment strategy is still controversial. The CELIM and FIRE‐3 studies demonstrated that secondary hepatic resection significantly improved overall survival (OS). The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen‐specific cancer vaccine tecemotide (L‐BLP25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE‐3‐LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease‐free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median OS in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE‐3‐LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE‐3. Secondarily resected patients of LICC, CELIM and FIRE‐3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival.
What's new?
The management of liver‐limited disease (LLD) in patients with metastatic colorectal cancer (mCRC) is controversial, the optimal treatment has not been defined. Here, data from mCRC patients with LLD and secondary hepatic resection from the prospective randomized trials CELIM, FIRE‐3 and LICC were compared. Secondarily resected patients from these trials showed an impressive overall survival (OS), with a tendency for improved OS in LICC. Reasons might be the deep response induced by chemotherapy and surgery combined with close surveillance after surgery. Further prospective, randomized clinical trials are strongly needed to clarify these benefits.
Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme ...Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein-protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.
Background & Aims Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, ...aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Methods Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. Results Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients ( p = 0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT ( p = 0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes ( p >0.3). More important, donor IL28B rs12979860 CC vs . CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin ( p = 0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well ( p = 0.0046, 0.115, 0.118, respectively). Conclusions We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
PDF
