S3-Guideline “Exocrine Pancreatic Carcinoma” 20071 ... - DGVS

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464 Leitlinie c) Number of lymph nodes examined Recommendation grade: C, evidence level 4, consensus d) Lymph node micrometastases Recommendation grade: B, evidence level 3, consensus e) R-classification Recommendation grade: B, evidence level 2a, strong consensus f) Status at the resection area of the remaining pancreas Recommendation grade: B, evidence level 2a, strong consensus g) Status at the retropancreatic resection area Recommendation grade: B, evidence level 2a, strong consensus h) Lymph vessel invasion Recommendation grade: B, evidence level 3, strong consensus i) Blood vessel invasion Recommendation grade: B, evidence level 3; strong consensus j) Nerve sheath invasion Recommendation grade: B, evidence level 3, strong consensus Comments A recommendation by the UICC is only available on the least number of lymph nodes that should be removed. To determine pN0 at least 10 lymph nodes should be examined. This number is not supported by data in the literature. The number of examined lymph nodes should be documented in the histopathologic report. The UICC-definition (0.2 – 2 mm) should be applied for the identification of lymph node micrometastases. This does not include so-called disseminated tumor cells [195]. Recommendation The histologic results are most important for the frozen section analysis. Histology and perhaps immunohistology are necessary for paraffin embedded tissue [193, 194]. Recommendation grade: A, evidence level 1c, consensus Topic 4: Adjuvant and neoadjuvant non-surgical therapy of pancreatic carcinoma ! The only curative therapy option for pancreatic carcinoma is surgical therapy. However, the long-term survival after resection is still under 20%. Local relapse as well as distant metastases play a role in recurrence. The curative intended pancreatic resection is a prerequisite for adjuvant therapy (R0/R1). Following surgery, the tumor should be histopathologically staged. It is especially important to pay attention to the resection margins, particularly the retroperitoneal margins. This should be documented (see also Topic 3 surgical therapy). Recommendation Following R0 resection of pancreatic carcinoma, adjuvant chemotherapy is indicated for UICC-stage I-III. Recommendation grade: A, evidence level 1b, consensus Comments Adjuvant chemotherapy should be done after R0 resection (primary tumor-M0). An advantage in the disease-free survival was shown in two randomized phase-III studies and a meta-analysis [196 –198]. However, this may not mean an improved overall survival [196]. Frequently, the patient’s quality of life rapidly worsens if pancreatic carcinoma recurs. Therefore, to delay re- Adler G et al. S3-Guideline “Exocrine Pancreatic… Z Gastroenterol 2008; 46: 449–482 lapse an adjuvant therapy is recommended for all patients after R0 resection if no distant metastases are present. If possible, patients should be included in clinical trials to assess the optimal duration and type of adjuvant therapy. If a patient is treated outside of clinical studies, the patient’s disease course should be documented with respect to relapse, survival, and side effects as part of the tumor documentation/quality assurance. Recommendation Adjuvant/additive chemotherapy can be done after R 0 resection of metastases. Recommendation grade: D, evidence level 5, consensus Comments Currently, the importance of additive chemotherapy after R 0 resection of metastases cannot be conclusively evaluated. Similar to the role of metastasis resection, the role of additive chemotherapy also cannot be evaluated with the data available. As already shown in Chapter 3, outside of clinical trials pancreatic cancer should generally not be resected if distant metastases are detectable even if it were possible. Recommendation Tumor associated risk factors (e.g. G 3-, T 4-stage) are not important for the decision to initiate adjuvant chemotherapy. Recommendation grade: A, evidence level 1b, consensus Comments Currently, no differentiated procedures can be derived from the studies available for the adjuvant situation based on pancreatic carcinoma grading and staging [196, 197]. General contraindications for adjuvant therapy are summarized in l " Table 9. Table 9 Contraindications of adjuvant chemotherapy for pancreatic carcinoma general condition of health poorer than ECOG 2 uncontrolled infections liver cirrhosis Child B and C severe coronary heart disease; heart failure (NYHA III and IV) preterminal and terminal kidney failure restricted bone marrow function inability to have regular follow-up examinations Recommendation There is no general restriction with respect to age for the implementation of adjuvant chemotherapy. Recommendation grade: A, evidence level 1b, consensus Comments Patients that were over 80 years of age were also included in the published trials. An unfavorable side effect profile was not observed for this age group [196, 197]. Recommendation Adjuvant chemotherapy should be done for ECOG-status 0 – 2. Recommendation grade: A, evidence level 1b, consensus Comments This recommendation follows the general practical experience. Patients with a Karnofsky-performance-status of ‡ 50% (corresponding to maximum ECOG 3) were also included in the CON- Downloaded by: Thieme Verlagsgruppe. Copyrighted material.
KO1-study [196]. The study by Neoptolemos et al. does not mention the performance status of the patients that were included. Therefore, the indication for adjuvant chemotherapy can be assessed individually for ECOG-stage 3. Recommendation The following adjuvant chemotherapy protocols can be implemented: a) 5-FU/folinic acid (Mayo-protocol) Recommendation grade: none, evidence level 2b, consensus Comments The study by Neoptolemos et al. was evaluated by the group as an RCT of low quality with 2b because of its methodologic weakness (method of randomization, quality control of surgical and radiation therapy) [198]. b) 5-FU/folinic acid (AIO-scheme) Recommendation grade: D, evidence level 5, consensus Comment Although there are no studies available on infusional 5-FU-protocols for adjuvant pancreatic carcinoma therapy, if 5-FU is chosen, all 5-FU-protocols were considered possible. c) Gemcitabine Recommendation grade: A, evidence level 1b, consensus Comment The largest controlled, randomized study is presently available for gemcitabine [196]. d) Loco-regional chemotherapy Recommendation grade: none, evidence level 5, consensus Comment A recommendation cannot be given, because sufficient data are not available. Recommendation Adjuvant chemotherapy should last 6 months. Recommendation grade: A, evidence level 3, consensus Comment This recommendation is based on the treatment duration that was selected in the randomized studies [196, 198]. For pancreatic carcinoma there are no studies that have compared the effect of long-term versus short-term adjuvant therapy. Recommendation If possible, adjuvant chemotherapy should be initiated within 6 weeks after surgery. Recommendation grade: B, evidence level 3, consensus Comment There are no systematic investigations on the best time to begin adjuvant chemotherapy after pancreatic resection. The recommendation is based on the procedure used in the available studies (therapy start 10 – 42 days after surgery [196] or start of therapy median 46 days after surgery [198]). Leitlinie 465 Recommendation An additive chemotherapy should be performed for R1 resected pancreatic carcinoma. Recommendation grade: B, evidence level 3, majority consensus Comment This recommendation is based on a subgroup analysis of the CONKO1-study in which 61 patients with R1 resection were treated either with placebo (n = 27) or gemcitabine (n = 34). Patients treated with gemcitabine demonstrated a significantly better disease-free survival and a better overall survival than the placebo treated group [196]. Recommendation The additive therapy with gemcitabine should be performed for 6 months. Recommendation grade: A, evidence level 3, majority consensus Comment A similar therapy duration as for the adjuvant situation applies. Following an R0 resection for pancreatic carcinoma, there is no indication for an adjuvant radiochemotherapy outside of clinical trials. Recommendation grade: A, evidence level 1b, consensus Comment A current meta-analysis [197] as well as the ESPAC-1-study [198] show no benefit of adjuvant radiochemotherapy for pancreatic carcinoma. Recommendation Additive radiochemotherapy for pancreatic carcinoma cannot be generally recommended after R1 resection. For individual cases it may be an option that should be individually discussed. Ideally these patients should be treated as part of randomized, controlled study protocols. Recommendation grade: D, evidence level 3, consensus Comment Currently, only few data are available on the efficacy of radiochemotherapy following R1 resection. There is no direct comparison between the efficacy of chemotherapy and radiochemotherapy [199]. The distinct side effects of radiochemotherapy compared to chemotherapy have to be considered. A continuous infusion of 5-FU is recommended after R1 resection if additive radiochemotherapy is done outside of trials followed by treatment with gemcitabine as monotherapy. Preferably the treatment should be done as part of a clinical trial. Recommendation Surgery is the only curative therapeutic procedure for pancreatic cancer. Chemotherapy, radiochemotherapy, or radiation therapy without surgery are not indicated if the intention is curative. Recommendation grade: A, evidence level 4, consensus Recommendation Neoadjuvant radiation therapy, radiochemotherapy, or chemotherapy are presently not indicated for pancreatic carcinoma outside of clinical trials. This applies to patients with locally advanced, inoperable tumors as well as for patients with T4-tumors. Recommendation grade: D, evidence level 3, consensus Adler G et al. S3-Guideline “Exocrine Pancreatic… Z Gastroenterol 2008; 46: 449–482 Downloaded by: Thieme Verlagsgruppe. Copyrighted material.
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Page 3 and 4: Table 1 (Fortsetzung) members G. Ba
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S3-Guideline “Exocrine Pancreatic Carcinoma” 20071 ... - DGVS

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