Karl-Heinrich Link

Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment

AIM Adjuvant chemotherapy is recommended for stage III colon cancer. The aim of this study was to identify important prognostic factors among patients with colon cancer receiving adjuvant 5-FU-based treatment. METHODS Data sets of 855 colon cancer patients treated between 1992 and 1999 within a multicenter adjuvant trial comparing 5-FU modulation with folinic acid or interfereron-alpha were examined. Backward elimination in a proportional hazards model was used to identify prognostically relevant clinical and pathological factors. RESULTS Tumor recurrence (p<0.001), duration of adjuvant treatment (p<0.001), tumor substage (p=0.004), age (p=0.005), grading (p=0.016), treatment-related toxicity (p=0.021), and treatment (p=0.031) were identified in descending order of importance as prognostic factors for overall survival. CONCLUSIONS Adjuvant 5-FU-based treatment should be performed for at least 6months with a stepwise adjustment of 5-FU doses until toxicity >WHO II. Substages should be reported separately and used for stratification in future trials due to their broad variation in outcome. In the future, this may result in adjuvant treatment of stage III colon cancer adjusted for the risk of substages.

Regional Celiac Artery Infusion as Adjuvant Treatment after Pancreatic Cancer Resection

BACKGROUND/AIMS The dismal course of pancreatic adenocarcinoma patients after resection is determined by the biology of the disease preventing R-0 resections. In the spontaneous course after resection, patients frequently develop either local recurrences, liver metastases and/or peritoneal metastases. Postoperative radiochemotherapy may extend survival and reduce local recurrences without influence on hepatic progression. We performed adjuvant celiac artery infusion in pancreatic cancer, to find out whether this treatment prolongs survival and changes the biology of the disease after resection, especially by reducing liver metastasis. METHODS 20 patients received cyclic celiac artery infusions (CAI) after resection of their pancreatic cancer (18 ductal, 2 cystadenocarcinoma). The treatment consisted of 6 cycles intraarterial infusion using Seldingers technique with mitoxantrone (Novantron, Wyeth-Lederle, Germany) 10 mg/m2 dl, 5-fluorouracil + folinic acid (Fluroblastin, Farmitalia, Germany + Leucovorin, Wyeth-Lederle) 600 mg/m2 + 170 mg/m2 d2-4, and cis-platinum (Cisplatin, Bristol, München, Germany) 60 mg/m2 d5. The patients were monitored for toxicity, development of disease progression and survival. RESULTS The median survival time was 21 months, and only 15% of the patients developed liver metastases. The median survival time of the CAI-treated patient group compared favorably to the median survival of 9.3 months in a matched historical control group. CONCLUSION Adjuvant celiac artery infusion seemed to prolong median survival and the occurrence of liver metastases appeared to be delayed or reduced.

Regional Treatment of Advanced Nonresectable and of Resected Pancreatic Cancer via Celiac Axis Infusion

Thirty-two patients with advanced nonresectable pancreatic cancer of UICC stages III (17 patients) and IV (15 patients; palliative group) received regional chemotherapy with mitoxantrone, 5-FU + folinic acid, and cisplatin via celiac axis infusion with the Seldinger technique. Twenty patients received this treatment after resection of their primary tumors (adjuvant group). Overall 202 cycles [4(1-11)/patient] were applied. Toxicities in all cycles were as follows: gastrointestinal ulcers 6%, gastritis 5%, severe stomatitis 0.5%, nausea/vomiting WHO I+ 11 44%, leukopenia WHO I+ II 11% and WHO III 0.5%. A false aneurysm and a hematoma developed in 1 patient each. The median survival times were 7.5 months in the palliative group (UICC III 12 months, UICC IV 4 months) and 15.1 months in the adjuvant group. Pain decreased significantly in the palliative group.

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.

Multimodal therapies in ductal pancreatic cancer. The future.

SummaryConclusions. Intra-arterial infusion chemotherapy via the celiac axis combined with external beam radiotherapy might be an effective method for palliative and perioperative multimodal treatment in pancreatic cancer. To improve the dismal prognosis in resectable and nonresectable pancreatic cancer, the results of multimodal palliative, adjuvant, and neoadjuvant therapies were reviewed and put into perspective with the results of two intra-arterial palliative and adjuvant treatment studies conducted at our department. The benefits and pitfalls of each method were outweighted, resulting in a concept for performing intra-arterial chemotherapy with radiotherapy in nonresectable stage UICC-III pancreatic cancer that eventually will be developed as a combined neoadjuvant/adjuvant treatment of all potentially resectable ductal pancreatic carcinomas.

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

PurposeInterleukin-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.MethodsExpression 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.ResultsAll 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.ConclusionsExpression 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.

Celiac artery adjuvant chemotherapy. Results of a prospective trial.

SummaryConclusionCeliac artery infusion (CAI) seems to be a qualified and successful method for adjuvant treatment of pancreatic cancer. To improve the dismal prognosis of resected pancreatic cancer patients, we performed postoperative regional chemotherapy via the celiac axis.BackgroundFrom 1994–1995, 20 patients with pancreatic cancer (18 ductal adenocarcinoma, 2 cystadenocarcinoma) received adjuvant celiac axis intra-arterial infusions (CAI) after resection of their tumors. Sixteen patients had macroscopically complete tumor removal (R0/R1 resection, 80% of the patients), whereas four patients had gross residual disease remaining after resection (R2 resection, 20% of the patients). Postoperative tumor stages were UICC I in 1 patient, UICC II in 3 patients, and UICC III in 16 patients.MethodsCAI was performed for six postoperative cycles via catheters placed into the celiac artery using Seldingers technique. The chemotherapeutic protocol consisted of mitoxantrone (Novantron®), Wyeth-Lederle (Münster, Germany) 10 mg/m2 (d 1), folinic acid (Leucovorin®, Wyeth-Lederle, or Rescuvolin®, Medac, Hamburg, Germany) 170 mg/m2 for 10 min, followed, by 5-FU (Fluoroblastin®, Farmitalia, Freiburg, Germany), 600 mg/m2 for 120 min (d 2–4), and Cisplatin (Cisplatin-medac®, Medac) 60 mg/m2 (d5). The cycles were repeated after a rest period of 4 wk. Cisplatin infusions were accompanied by supportive antiemetic (8 mg Tropisetrone iv [Navoban®, Sandoz, Nürnberg, Germany] and 8 mg Dexametason iv) and diuretic measures.ResultsToxicity WHO III occurred in 8%, of 100 cycles, and no toxic side effects WHO IV were encountered. The median survival of 21 mo in the treated group was nearly twice as long as the 9.3 mo of a historical matched control group (p<0.0003) CAI seems to be a qualified and successful method for adjuvant treatment of pancreatic cancer.

Cost Effectiveness of Adding Folinic Acid to Fluorouracil Plus Levamisole as Adjuvant Chemotherapy in Patients with Colon Cancer in Germany

AbstractObjective: 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/T4 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-Meer 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 per df-LYG and €51 225 per LYG (costs and effects discounted at 5%). The Markov model yielded ICERs of €11 176 per df-LYG and €11 020 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/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.

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.

Multimodale Therapie von Kolon- und Rektumkarzinomen: Qualitätsparameter

Diese Arbeit beschreibt die Basis für grundlegende Qualitätsanforderungen an chirurgische Abteilungen, welche an der interdisziplinären Versorgung von Kolon- und Rektumkarzinompatienten beteiligt sind. Der vorgestellte Katalog basiert auf den aktuellen Entwicklungen zur Diagnostik und Therapie bei Dick-und Enddarmkarzinomen, einschließlich der Mindestmengendiskussion und eigenen Daten.