Purpose: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. Patients and Methods: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m² day 1 followed by 250 mg/m² weekly) plus irinotecan (350 mg/m² every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). Results: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms. Conclusion: Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

Purpose: Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines. Patients and Methods: Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required. Results: This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466). Conclusion: This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).

This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2–73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1–70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42–0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7–22.1) and 9.9 months (95% CI 9.3–13.7), respectively. This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.

Purpose: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). Patients and Methods: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m² as a 2-hour infusion and FU 2.6 g/m² by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m² preceded by irinotecan 80 mg/m² administered over 30 minutes (experimental group, n = 214). Results: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). Conclusion: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Purpose: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer. Patients and Methods: Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS). Results: Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3–related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%). Conclusion: Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial.

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