Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines.

Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.

Adjuvant Chemotherapy of Locally Advanced Colon Cancer: Final Results of a Randomized Trial Comparing 5-Fluorouracil and Folinic Acid with Folfiri.

BACKGROUND: There is still the need to optimize adjuvant treatment of colon cancer (CC). Standard adjuvant chemotherapy using 5-fluorouracil (FU) and folinic acid (FA) was compared with a combination including irinotecan (Folfiri). The aim of the present report was to analyze overall survival (OS) after long-term follow-up, to summarize final recurrence rates and toxicity data, and to identify possible clinical and pathological factors associated with prognosis. METHODS: Patients (CC stage IIb and III) were randomized to a 6-month treatment with FUFA or Folfiri. The trial was closed after 275 of 588 planned patients, 269 of which were included in the intention-to-treat analysis. RESULTS: 133 and 136 patients received FUFA and Folfiri, respectively. Adjuvant therapy was not completed for 16 FUFA (12.0%) and 44 Folfiri (32.4%) patients. Toxicities grade III and IV were observed in 17 (12.8%) patients treated with FUFA and in 50 (36.8%) patients treated with Folfiri. Recurrences occurred in 46 of 133 (34.6%) and in 47 of 136 (34.6%) patients who received FUFA and Folfiri, respectively. 5-year OS rates were 69.9% (95% confidence interval (CI): 61.2-77.1) for FUFA and 72.7% (95% CI: 63.9-79.8) for Folfiri. OS was associated with tumor grading (1 & 2 vs. 3), tumor sub-stage (II vs. IIIa vs. IIIb vs. IIIc), and tumor location (left vs. right colon). CONCLUSION: Folfiri cannot be generally recommended for adjuvant chemotherapy of CC. Besides tumor grading and sub-staging, prognosis of CC may depend on tumor location. Left-sided tumors had a significantly better prognosis irrespective of treatment.

Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer.

Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term "CRC" should no longer be used as a single entity in basic and clinical research as well as other areas of classification.

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.

Minimum Volume Discussion in the Treatment of Colon and Rectal Cancer: A Review of the Current Status and Relevance of Surgeon and Hospital Volume regarding Result Quality and the Impact on Health Economics.

BACKGROUND: To answer the question whether minimum caseloads need to be stipulated in the German S3 (or any other) guidelines for colorectal cancer, we analyzed the current representative literature. The question is important regarding medical quality as well as health economics and policy. METHODS: A literature research was conducted in PubMed for papers concerning 'colon cancer' (CC), 'rectal cancer' (RC), and 'colorectal cancer' (CRC), with 'results', 'quality', and 'mortality' between the years 2000 and 2016 being relevant factors. We graded the recommendations as 'pro', 'maybe', or 'contra' in terms of a significant correlation between hospital volume (HV) or surgeon volume (SV) and treatment quality. We also listed the recommended numbers suggested for HV or SV as minimum caseloads and calculated and discussed the socio-economic impact of setting minimum caseloads for CRC. RESULTS: The correlations of caseloads of hospitals or surgeons turned out to be highly controversial concerning the influence of HV or SV on short- and long-term surgical treatment quality of CRC. Specialized statisticians made the point that the reports in the literature might not use the optimal biometrical analytical/reporting methods. A Dutch analysis showed that if a decision towards minimum caseloads, e.g. >50 for CRC resections, would be made, this would exclude a lot of hospitals with proven good treatment quality and include hospitals with a treatment quality below average. Our economic analysis envisioned that a yearly loss of EUR <830,000 might ensue for hospitals with volumes <50 per year. CONCLUSIONS: Caseload (HV, SV) definitely is an inconsistent surrogate parameter for treatment quality in the surgery of CC, RC, or CRC. If used at all, the lowest tolerable numbers but the highest demands for structural, process and result quality in the surgical/interdisciplinary treatment of CC and RC must be imposed and independently controlled. Hospitals fulfilling these demands should be medically and socio-economically preferred concerning the treatment of CC and RC patients.

[Short- and long-term results in operable pancreatic ductal adenocarcinomas from a cooperation between two departments gastroenterology-visceral surgery at non-university hospitals benchmarked to results of expert-centers]. / Kurz- und Langzeitergebnisse bei operablen duktalen Pankreasadenokarzinomen aus der Kooperation zwischen zwei Abteilungen Gastroenterologie-Viszeralchirurgie an nicht universitären Kliniken im Vergleich mit Resultaten aus Spitzenzentren.

The only curative approach in pancreatic ductal adenocarcinoma (PDAC) is resection, which is possible only in 15 - 30 % of patients. Local tumor spread or distant metastases are contraindications for resection in the majority of patients. Surgical-oncological quality with short- and long-term results are varying tremendously, so that "expertise/quality" are associated to hospital- or surgeon's volume and/or center formation. The treatment results also depend, to a great extent, on the medical diagnostic quality. With our retrospective study, we aim to compare the results-quality of cooperative pancreatic cancer treatment based on an extensive preoperative diagnostic procedure for staging and risk estimation in a specialized GI-medical department and visceral surgical-oncological expertise in pancreatic cancer surgery at a general hospital with the results-quality of expert centers. Fifty-three patients with PDAC had diagnosis and resection of their cancer between 1/2002 and 12/2009. The 30 day hospital-mortality was 3.8 % and the median survival time after demission from the hospital was 23.1 months. The 5-year-survival rate of R0-resected patients, all of whom had received adjuvant chemotherapy, was high with 31 %. The survival data and the extraordinarily high resection rate of 98.1 % in the patient group, whose primary tumor stage was pT3 in 81 %, reflects the excellent cooperation of high standards in medical diagnostic processes, visceral pancreatic surgery, and adjuvant medical chemotherapy. The results are well comparable to those of "high volume centers". The responsible heads of the two departments have been trained at university expert centers. Expertise in the treatment of pancreatic cancer patients may be successfully transferred from an expert center to a general hospital, if the team has high expertise.

Stratified Survival Analysis After Adjuvant Chemotherapy of Colon Cancer Reveals a Benefit for Older Patients.

AIM: Adjuvant treatment is still controversially discussed for elderly colon cancer (CC) patients. Our aim was to investigate the benefit of adjuvant treatment for younger (<70 years) and elderly (≥70 years) patients. PATIENTS AND METHODS: The long-term outcome of patients (n=855) enrolled in a randomized controlled trial comparing adjuvant chemotherapy with 5-FU alone, 5-FU plus folinic acid (FA), and 5-FU plus interferon-alpha (IFNa) was compared in younger (<70 years) and elderly (≥70 years) patients using a quotient of each patient's survival time and his expected residual life expectancy (QSL) and a multivariate Cox proportional hazards model. RESULTS: Eight-year overall survival (OS) rates were 58.3% and 57.4% for younger (n=653) and elderly (n=202) patients, respectively. In elderly patients, 8-year OS rates were 51.4%, 61.8%, and 56.3, and median QSL scores were 0.338, 0.371, and 0.343 for 5-FU (n=59), 5-FU plus FA (n=76), and 5-FU plus IFNa (n=67), respectively. In elderly patients treatment with 5-FU plus FA decreased the risk for an event by 1.5-fold compared to 5-FU (HR=0.657, 95%CI=0.495-0.870, p=0.004) and 5-FU plus INFa (HR=0.685, 95%CI=0.515-0.912, p=0.009). CONCLUSION: Our analysis clearly demonstrates for the first time an additional benefit of FA for adjuvant treatment of elderly CC patients. We conclude that this regimen is very safe and effective for adjuvant treatment of elderly patients.

Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial.

BACKGROUND: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients. METHODS: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. RESULTS: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination. CONCLUSIONS: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/- irinotecan in stage II/III colorectal cancer.

Long-term results of 2 adjuvant trials reveal differences in chemosensitivity and the pattern of metastases between colon cancer and rectal cancer.

UNLABELLED: Two identical randomized controlled trials designed to optimize adjuvant treatment of colon cancer (CC) (n =855) and rectal cancer (RC) (n = 796) were performed. Long-term evaluation confirmed that the addition of folinic acid (FA) to 5-fluorouracil (5-FU) improved 7-year overall survival (OS) in CC but not in RC and revealed different patterns of recurrence in patients with CC and those with RC. BACKGROUND: Our aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU). METHODS: We separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon-alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation. RESULTS: Median follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5-FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5-61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525). CONCLUSION: FA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future.

Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer.

PURPOSE: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease. METHODS: Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance. RESULTS: All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival. CONCLUSIONS: Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.

Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase: results of a randomised multicentre trial.

BACKGROUND: Molecular markers to predict response to 5-fluorouracil (FU)-based treatment of recurrent or metastasised colorectal cancer (mCRC) are not established. The aim of this trial was to determine the value of thymidylate synthase (TS), a key enzyme of DNA synthesis and target of 5-FU, to predict response to chemotherapy of mCRC. METHODS: Tumour tissue was obtained from 168 patients with mCRC for relative thymidylate synthase (TS) mRNA quantitation. Patients were randomised to receive either 5-FU/folinic acid (FA, FUFA) alone or in combination with irinotecan 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) stratified by TS (low versus high). Primary end-point was overall response to first-line treatment among TS high patients. All parties, except for the randomisation centre, were blinded for TS status. RESULTS: Biopsies (n=168) were taken without complications. TS levels were available for 147 patients (87.5%). Analysing response to FUFA and FOLFIRI in the per protocol set (n=119) after un-blinding TS in the data base revealed a trend to better overall response to FOLFIRI (9/19, 47%) in TS high compared to FUFA (5/23, 22%, p=0.077). In patients with biopsies taken from liver lesions (n=91) overall response to FOLFIRI and FUFA in TS high was 53% (9/17) and 18% (3/17), respectively (p=0.035). In patients with low TS, no remarkable difference in overall response to FOLFIRI and FUFA was observed. CONCLUSIONS: Taking a pre-treatment biopsy is a safe and feasible procedure in mCRC. After validation of our data in a larger group TS determination may have the potential to better help direct systemic treatment in patients with primarily non-resectable mCRC.

Cost effectiveness of adding folinic acid to fluorouracil plus levamisole as adjuvant chemotherapy in patients with colon cancer in Germany.

OBJECTIVE: To assess the cost effectiveness of the addition of folinic acid to fluorouracil plus levamisole in patients with colon cancer from the perspective of the German Social Health Insurance. STUDY DESIGN AND METHODS: Patients with International Union Against Cancer (Union International Contre Cancer; UICC) II/T(4) or UICC III colon cancer enrolled in an open-label randomised clinical trial in Germany (Forschungsgruppe Onkologie Gastrointestinaler Tumoren-1 [FOGT-1]) received either fluorouracil plus levamisole (A, standard) or fluorouracil plus levamisole and folinic acid (B) for 12 months as adjuvant chemotherapy after curative intended surgery. Outcome measures for economic evaluation were disease-free life-years gained (df-LYG) and overall life-years gained (LYG) derived from the respective Kaplan-Meier survival curves. Direct medical costs from the perspective of the German Social Health Insurance were estimated retrospectively (2000 values) and incremental cost-effectiveness ratios (ICERs) were calculated. A Markov model was used to project the trial results beyond 5 years for the patients' remaining life expectancy. RESULTS: Adding folinic acid to the fluorouracil/levamisole regimen results in an increase in time to progression and survival in patients with locally advanced colon cancer. Within the trial period of 5 years ICERs (B versus A) were 33,008 Euro per df-LYG and 51,225 Euro per LYG (costs and effects discounted at 5%). The Markov model yielded ICERs of 11,176 Euro per df-LYG and 11,020 Euro per LYG (costs and effects discounted at 5%). The model was robust for variations of key variables in the sensitivity analysis. CONCLUSIONS: Results of this cost-effectiveness analysis suggest that the addition of folinic acid offers clinical benefits at additional costs which are likely to be acceptable for decision makers in the long term. Cost-effectiveness ratios calculated within the clinical trial period were just above 50,000 Euro/LYG. Because treatment benefits, i.e. prolonged survival, are sustained beyond 5 years whereas incremental costs are mainly incurred in the first year, results of the Markov model yielded cost-effectiveness ratios that compare more favourably with other published ICERs.