7556 Background: Treatment of patients (pts.) with progressive malignant pleural mesothelioma (MPM) after multimodal therapy remains a therapeutic challenge. Survival of the pts. is low and the treatment options are sparse. We report on a phase II study on isolated thoracic perfusion with subsequent chemofiltration as a locoregional therapeutic strategy in this situation. Methods: 21 pts. (19 male, 2 female, mean age 65.5 yrs.) with epitheliolid mesothelioma were included in this study after informed consent. 10 pts. had prior surgical resection, all pts. had adjuvant/additive therapy, general including cisplatin and pemetrexed. Following multimodal therapy all pts. demonstrated progress in CT scan. No pt. had abdominal, cerebral or bone metastases. After insertion of a venous and arterial 21 ch. stop flow catheter via a femoral access, the inferior caval vein was blocked distal the right atrium, the arterial catheter was blocked in the aorta at the diaphragm. Chemotherapy consisted of 60 mg/m2 cisplatinum and 15 mg/m2 mitoxantron q 3 weeks till progress. The agents were administered via the arterial access, followed by 15 min of thoracic perfusion followed by chemofiltration for 45 min. The procedure was done under general anesthesia. Endpoint of the study was overall survival. Median follow-up was 48 month. Results: A total of 107 cycles (mean 5) were administered. Toxicity was low with leucopenia and thrombocytopenia CTC grad I in 9 pts. and mucositis grad II in 6 pts.. Surgical complications CTC grad I occurred in 40 % of the pat. (lymphatic fistula). There was no gastrointestinal or neuro- toxicity. One year survival was 50% (Kaplan-Meier), 2 year survival was 37.5% and 3 year survival was 37.5%. Median survival was 12 months. Conclusions: Intraarterial, isolated thoracic perfusion with subsequent chemofiltration (ITP-F) for pretreated patients with MPM, which are progressive after multimodal therapy, is a valuable additional treatment option with low side effects. It offers in a palliative situation a reasonable survival with good quality of life.

Background Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy.Methods In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50.4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076.Findings Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75.9% (95% CI 72.4-79.5) in the investigational group and 71.2% (95% CI 67.6-74.9) in the control group (hazard ratio [HR] 0.79, 95% CI 0.64-0.98; p=0.03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group.Interpretation Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.

141 Background: Treatment of patients (pts.) with progeressive stage IV gastric cancer remains a therapeutical problem. Survival of the pretreated pts. is low and the therapeutic options are sparse. In this situation, locoregional therapeutic strategies could be an option. Methods: 28 pretreated pts. (17 male, 11 female, mean age 59 y.) after resection and at least second line systemic chemotherapy were included in a phase II study of isolated abdominal perfusion and subsequent chemofiltration. All pts. had liver metastases (mets.), 50% (n = 14) had peritoneal carcinomatosis with malignant ascites. No pat. had cerebral, pulmonal or bone mets.. After insertion of a venous and arterial 21 ch. stop flow catheter via a femoral access, the v. cava was blocked beneath the right atrium, the arterial catheter was blocked above the celiac trunk. The thighs were blocked by pneumatic cuffs. Chemotherapy consisted of 35 mg/m2 cisplatinum, 20 mg/m2 adriamycin and 12 mg/m2 mitomycin q 3 weeks till progress or dead. The agents were administered via the arterial access, followed by 15 min of hypoxic abdominal perfusion via an external pump, followed by chemofiltration for 45 min. The procedure was done under general anaesthesia. Primary endpoint of the study were overall survival, secondary endpoint was control of the ascites. Results: A total of 92 cycles (mean 3.25) were administered. Toxicity was low with leucopenia CTC grad I in 9 pts., gastrointestinal disorders grad II in 8 pts. and surgical complications grad II in 40 % of the pat. (lymphatic fistula). In 9/14 (65%) of pts. with ascites, the ascites was at least controlled or vanished. One year survival was 28.6% (Kaplan-Meier), 2 year survival was 11.4%. Median survival was 6 months. Conclusions: Intra-arterial, isolated abdominal chemoperfusion with consecutive chemofiltration in heavily pretreated patients with gastric cancer metastasized to the abdominal cavity is a valuable option for palliative treatment with low side effects. In 65% of the affected pts., malignant ascites was controlled sufficiently, ameliorating the quality of life.

Inhalt 1. Informationen zu dieser Leitlinie 462 1.1. Herausgeber 462 1.1.1. Federführende Fachgesellschaft 462 1.1.2. Kontakt 462 1.1.3. Verfügbare Dokumente zur Leitlinie 462 1.2. Besonderer Hinweis 462 1.3. Autoren dieser Leitlinie 462 1.4. Ziele des Leitlinienprogramms Onkologie 462 2. Einführung 463 2.1. Geltungsbereich und Zweck 463 2.1.1. Zielsetzung und Fragestellung 463 2.1.2. Adressaten 464 2.1.3. Verbreitung u. Implementierung d. Leitlinien 464 2.1.4. Finanzierung der Leitlinie und Darlegung möglicher Interessenskonflikte 464 2.1.5. Gültigkeitsdauer u. Aktualisierungsverfahren 465 2.2. Grundlagen der Methodik 465 2.2.1. Schema der Evidenzgraduierung nach Oxford 465 2.3. Verwendete Abkürzungen 466 3. Konsentierte und abgestimmte Empfehlungen 466 3.1. Risikofaktoren 466 3.1.1. Helicobacter pylori 466 3.1.2. Weitere Risikofaktoren 467 3.2. Risikogruppen 468 3.2.1. Familiäres Risiko 468 3.2.2. Hereditäres nonpolypöses kolorektales Karzinom (HNPCC) 469 3.3. Screening und Prävention 470 3.3.1. Screening 470 3.3.2. Prävention 471 3.4. Primärdiagnostik 472 3.4.1. Endoskopische Untersuchung 472 3.4.2. Staging 472 3.4.3. Histologie 472 3.5. Staging 473 3.5.1. Ultraschalldiagnostik 473 3.5.2. Röntgendiagnostik 474 3.5.3. Laparoskopie 475 3.5.4. Laborchemische Parameter 476 3.6. Histopathologie 476 3.7. Endoskopische Therapie 477 3.7.1. Resektion 477 3.7.2. Rezidiv 479 3.7.3. Komplikationen 479 3.7.4. Nachsorge 479 3.8. Chirurgische Therapie 479 3.8.1. Resektion 479 3.8.2. Rezidiv 483 3.8.3. Definitive Radiochemotherapie 483 3.9. Multimodale Therapie 483 3.9.1. Perioperative Chemotherapie 483 3.9.2. Präoperative Radiochemotherapie 488 3.9.3. Präoperative Antikörper-Therapie 488 3.9.4. Restaging nach neoadjuvanter Therapie 488 3.9.5. Postoperative Therapie 489 3.9.6. Adjuvante Therapiekonzepte 491 3.10. Tumorgerichtete palliative Therapie 493 3.10.1. Medikamentöse Tumortherapie 493 3.10.2. Vorgehen bei Tumoren ohne HER-2-Überexpression 494 3.10.3. Vorgehen bei HER-2-überexprimierenden/-amplifizierenden Tumoren 498 3.10.4. Zweit-Chemotherapie 498 3.11. Weitere palliative Situationen u. deren Therapie 499 3.11.1. Palliative Therapieoptionen 499 3.11.2. Therapie der Tumorblutung 500 3.11.3. Palliative operative Therapie 500 3.11.4. Chemotherapie-refraktärer maligner Aszites 500 3.12. Supportive Maßnahmen 501 3.12.1. Fatigue-Syndrom 501 3.12.2. Zusammenfassung weiterer Maßnahmen 501 3.13. Ernährung 505 3.13.1. Allgemeine Entscheidungshilfen 505 3.13.2. Präoperative Ernährungstherapie 506 3.13.3. Postoperative Ernährungstherapie 507 3.13.4. Ernährung unter Chemotherapie oder Strahlentherapie 507 3.13.5. Ernährung in der Sterbephase 509 3.14. Nachsorge und Rehabilitation 509 3.14.1. Lebensqualität 509 3.14.2. Substitutionen nach Gastrektomie 509 3.14.3. Rehabilitationsmaßnahmen 509 3.14.4. Bestimmung von Tumormarkern 510 3.15. Psychoonkologie 510 3.15.1. Patientennahes Informationsmanagement 510 3.15.2. Lebensqualität 510 3.15.3. Psychoonkologische Betreuung 511 3.16. Komplementäre Therapie 512 3.16.1. Abgestimmte Empfehlungen 512 3.16.2. Weitere Hinweise der Arbeitsgruppe zur komplementären Therapie 514 4. Qualitätsindikatoren 515 Literatur 517

According to the current European and German S3 guidelines, neoadjuvant chemotherapy is now an integral part of the treatment of locally advanced gastric cancer and adenocarcinoma of the esophagogastric junction. Neoadjuvant therapy seeks to achieve downsizing of the primary tumor, lowering of the T and N categories and eradication of micrometastases. As the indications for neoadjuvant treatment are based on pretherapeutic information alone, a sophisticated clinical staging plays a central role. Despite all progress made in the field of diagnostic work-up, clinical staging often fails. Despite this fact, controlled randomized trials showed that neoadjuvant chemotherapy enhances the rate of curative (R0) resections and reduces the likelihood of systemic relapse. Overall, survival can be improved by neoadjuvant chemotherapy. The current research is focused on the molecular prediction of response and early response monitoring with functional imaging. New targeted drugs are being integrated into the peri-operative treatment.

The appropriate extent of lymph node dissection in tumors of the upper gastro-intestinal tract continues to be debated. The basic tenet of surgical oncology that cancerous lymph nodes are indicators not governors of survival is under question and derives from the different theories of metastasis. Is the metastatic flow linear (indicators) or does it occur in parallel to tumorigenesis (governor)? If the latter theory is true there would be only a limited indication for lymphadenectomy (LA).Extended LA leads to an ameliorated staging of the N category. Following LA locoregional tumor control is significantly improved for esophageal and gastric cancer. In case of gastric cancer it is evident that there is a group of patients in which extended LA lead to improved long-term survival. This gain in prognosis affects patients in which lymph node metastasis is not or only slightly advanced. In locally advanced tumors there is no prognostic benefit. Patients who might benefit from the extended procedure cannot be assessed during preoperative staging. Therefore, the indications for the procedure should be liberally carried out by experienced hands and in experienced centers. According to randomized studies there is no indication for extended radical LA in pancreatic cancer.

Following several randomized trials, neoadjuvant therapy in adenocarcinoma of esophagus and the esophagogastric junction can be seen as an international standard. However, in a large proportion of patients the objective response achieved is unsatisfactory. These patients do not benefit from neoadjuvant therapy, but do suffer from toxic side effects; sometimes progressive and appropriate surgical therapy is delayed. For this reason, a diagnostic test that can accurately assess tumor response to neoadjuvant therapy might be of crucial importance. Response evaluation using CT scan, endoluminal ultrasound, or rebiopsy is not reliable. In recent times, response evaluation using 18FGD PET after and during neoadjuvant treatment is in the focus of clinical and scientific interest. Most studies have evaluated the diagnostic modalities for response to neoadjuvant treatment after completion of the treatment. Following the published data so far, FDG-PET seems to be less accurate after and during chemoradiation than after chemotherapy alone. The data of early response evaluation (14 days after the onset of chemotherapy) are very much encouraging; however, they have to be evaluated in an international randomized trial. Standardization of PET technology as well as defining the thresholds used for the estimation of early response is mandatory. So far, FDG-PET does not change treatment in esophageal and gastric cancer.

Der Stellenwert der Lymphadenektomie (LA) als grundlegender Baustein der operativen Therapie der Tumoren des oberen Gastrointestinaltrakts wird derzeit in Frage gestellt. Es wird die Frage aufgeworfen, ob es überhaupt eine lineare Metastasierung gibt oder ob nicht die Fernmetastasierung parallel zur Tumorigenese erfolgt. Nach letzterem Konzept hätte die LA keine therapeutische Bedeutung.

Who may treat early Barrett's carcinoma of the oesophagus? The incidence of adenocarcinoma of the oesophagus developing within Barrett's mucosa has substantially risen in the past few years. Furthermore, treatment of preneoplastic lesions or early carcinoma is controversial. From an endoscopist's point of view high-grade intraepithelial neoplasia (HG-IEN) should be resected endoscopically rather than destroyed endoscopically while early Barrett's carcinoma should undergo endoscopic staging resection. Surgical resection is rarely necessary because lymph node metastases are rare and there is some morbidity and mortality associated with the procedure. However, surgeons argue that complete surgical resection is required because no imaging technique reveals the exact extent of the lesion and, ultimately, the degree of infiltration can only be determined within the resected specimen. Also, only surgical procedures may remove all potentially involved regional lymph nodes. Furthermore, only within surgical resections we can eliminate all pre-existing Barrett's mucosa easily while endoscopic clearance of Barrett's mucosa is difficult and requires multiple sessions. The Merendino-Siewert procedure may be an option with very low morbidity and mortality. It is worthy of note that new endoscopic resection procedures have not been studied in a controlled fashion against conventional surgical procedures. Therefore, patients with HG-IEN or early Barrett's carcinoma of the esophagus should be recruited into controlled studies and be treated in specialised high-volume centres.

Das CUP-Syndrom („carcinoma of unknown primary“) ist definiert als Metastasierung eines durch klinische Routineuntersuchungen (inklusive Histologie) nicht lokalisierbaren Primärtumors. CUP-Patienten stellen den behandelten Arzt daher vor ein schwieriges diagnostisches und therapeutisches Problem. Patienten mit CUP machen an spezialisierten Zentren bis zu 10% aller Tumorpatienten aus. Die Besonderheiten dieser Entität bestehen im atypischen Metastasierungsmuster und einer ungewöhnlichen Wachstumskinetik. 60% der CUP-Patienten haben Metastasen eines Adenokarzinoms. Wichtig ist, dass möglichst schnell und eindeutig potenziell kurative (maligne Lymphome oder extragonadale Keinzelltumoren) oder zumindest gut behandelbare Tumormanifestationen (z. B. neuroendokrine Tumoren) identifiziert und damit einer adäquaten Therapie zugeführt werden. Ansonsten stehen je nach Ausdehnung und Lokalisation chirurgische, strahlentherapeutische und systemische Therapiemaßnahmen zur Verfügung. Für die große Mehrheit der Patienten mit CUP-Syndrom ist die Prognose mit einer Überlebenszeit von 4–11 Monaten sehr ungünstig. Populationsbasierte Analysen zeigen, dass nur 15% der Patienten ein Jahr nach der Diagnose eines CUP leben.

Complete tumor removal with an adequate safety margin - not only at the primary site but also in the lymphatic system - is the single most important prognostic factor in a patient with gastric cancer. Following recent controversies, the type of resection is now standardised. Distal gastric cancer (in particular, intestinal types of cancer) can mostly be treated by subtotal gastrectomy; for all other locations of primary and diffuse types of gastric cancer, total gastrectomy is recommended. For adenocarcinoma of the esophagogastric junction (AEG types II and III), transhiatal extended gastrectomy is the treatment of choice. Lymphadenectomy in gastric cancer is also standardised. After an intensive, international debate, extended lymphadenectomy (D2) is the standard procedure in cancer resection. If performed by experienced surgeons, morbidity and mortality are not increased. Reconstruction is mainly established via direct esophago-jejunostomy without preservation of the duodenal passage. In the case of gastrectomy, the building of a reservoir (jejunum pouch) is recommended.

Zusammenfassung Vor der Therapie des Ösophaguskarzinoms muss zwischen Plattenepithel- und Adenokarzinom unterschieden werden, auch wenn die R0-Resektion als entscheidendes Therapieziel für beide Tumorentitäten gilt. Inzwischen lässt sich das Stadium präoperativ sehr gut erfassen. Eine Risikoanalyse kann bei den aufwändigen Zweihöhleneingriffen zu einer adäquaten Patientenselektion beitragen. Unter den multimodalen Protokollen haben sich vor allem die neoadjuvante Radio-Chemo-Therapie für das Plattenepithelkarzinom und die neoadjuvante Chemotherapie für das Adenokarzinom des distalen Ösophagus bewährt. Bei Letzteren ist es möglich, mittels PET ein frühzeitiges Therapieansprechen zu detektieren. Auch die chirurgische Therapie ist standardisiert, die subtotale Ösophagektomie mit intrathorakaler Anastomose ist das Verfahren der Wahl. Ein modernes Komplikationsmanagement hat Morbidität und Letalität der Resektion signifikant gesenkt. Nach Ansprechen auf die Vorbehandlung und nach kompletter Resektion ist die Prognose der Patienten inzwischen deutlich verbessert worden. Damit sind auch aggressive Therapieoptionen durchführbar mit nachgewiesener Prognoseverbesserung für viele Patienten.