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

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466 Leitlinie Comment Currently, the available data are not sufficient for this kind of treatment. It should only be done as part of a clinical trial. Recommendation There is no indication for intraoperative radiation therapy for pancreatic carcinoma. Recommendation grade: D, evidence level 4, strong consensus Recommendation Targeted therapies and immunotherapeutic approaches do not play a role in adjuvant or neoadjuvant therapies for pancreatic carcinoma. Recommendation grade: A, evidence level 5, strong consensus Comment Currently, a recommendation cannot be given, because the published data are insufficient. All the data from the literature on this topic are applicable to Germany. Topic 5: Palliative therapy ! Introduction Since the studies of Mallinson [200], Palmer [201], and Glimelius [202], chemotherapy in the palliative situation has been shown to be better than the best supportive therapy with respect to survival and quality of life. This is confirmed by a recent Cochrane-analysis [203]. Gemcitabine was established as standard in palliative chemotherapy for pancreatic carcinoma by the Burris trial [204]. The role of new combination therapies was investigated in several phase-III studies, and the role of molecular therapies (“targeted therapies”) was and is being established in phase-III studies. Most of the completed trials have not been published in journals. They are only available as conference presentations or abstracts. Indication for chemotherapy Recommendation Metastatic pancreatic cancer is an indication for palliative chemotherapy. Recommendation grade: A, evidence level 2b, strong consensus Comment Palliative chemotherapy leads to longer survival, an improvement of quality of life, and “clinical benefit” i. e. especially use of less pain medication and less weight loss [200–202, 204]. Recommendation Chemotherapy should be immediately initiated after metastases have been detected. It should not be postponed until tumor size progression, metastasis-induced symptoms, or other complications have developed. Recommendation grade: B, evidence level 5, strong consensus Recommendation Weight course, serum albumin, CA 19–9-value, hemoglobin value, and tumor differentiation grade at diagnosis do not influence the decision for or against chemotherapy. Recommendation grade: C, evidence level 3, strong consensus Adler G et al. S3-Guideline “Exocrine Pancreatic… Z Gastroenterol 2008; 46: 449–482 Comment The benefit of chemotherapy is questionable for patients in poor general condition (KI < 70% ECOG > 2) [196, 205 –207]. This is confirmed by a subgroup analysis of a phase-III study that so far is only available in abstract form [208]. Recommendation Patients with locally advanced, inoperable pancreatic carcinoma should also be treated from the time of diagnosis. Recommendation grade: B, evidence level 2b, strong consensus Comments In the subgroup of patients with locally advanced, inoperable pancreatic carcinoma current phase-III studies demonstrate a similar benefit of chemotherapy as for the metastatic situation [204, 206, 207, 209, 210]. Drugs for palliative first line therapy Recommendation Data from several phase-III studies establish gemcitabine as a standard first line therapy for systemic palliative treatment. Recommendation grade: A, evidence level 1, consensus Comments This recommendation is based among others on several phase- III studies that show a consistent 1-year survival of 18 – 20% with gemcitabine therapy [204, 206, 207, 209, 210]. Recommendation Gemcitabine should be given in conventional doses (1000 mg/m 2 over 30 minutes). Recommendation grade: B, evidence level 2b, consensus Comments There is a pharmacokinetic rationale for protracted infusion of gemcitabine as a so-called fixed-dose-rate-infusion (10 mg/ m 2 /min over 150 min; FDR). There is one published randomized phase-II study on this topic, which was negative in its primary endpoint (time to treatment failure) [211]. A phase-III study that compares the conventional gemcitabine therapy with FDR-infusion is only preliminary. However, it does not show a significant advantage of FDR-infusion [212]. Recommendation 5-FU/folinic acid is not recommended as a standard therapy. Recommendation grade: C, evidence level 4, consensus Comments Only phase-II data are available on protracted infusion of 5-FU for pancreatic carcinoma and these show inconsistent results. A direct comparison with gemcitabine in a phase-III study is missing [213–215]. Recommendations Currently, combination chemotherapies with gemcitabine cannot be generally recommended as standard first line therapies for metastatic or locally advanced, inoperable pancreatic carcinoma. Recommendation grade: A, evidence level 1, consensus This is explained for individual combinations in the following in more detail. Downloaded by: Thieme Verlagsgruppe. Copyrighted material.
Gemcitabine/oxaliplatin or gemcitabine/cisplatin Recommendation This combination should not be used as standard. Recommendation grade: A, evidence level 1, consensus Comments There are 2 randomized, controlled studies on the combination of gemcitabine with oxaliplatin. Both show a benefit with respect to tumor response and a consistent trend towards longer survival for the combination therapy. However, the difference in survival did not reach significance in either study. The combination therapy, however, has a higher rate of side effects [206 –212]. There are 2 randomized, controlled studies on the combination of gemcitabine with cisplatin. They demonstrate a consistent trend towards longer survival. However, these studies also show no statistically significant difference in survival. Clearly more side effects were seen than with the monotherapy [207, 216]. 5-FU/oxaliplatin Recommendation This combination should not be used as standard treatment. Recommendation grade: A, evidence level 2a, strong consensus Comment There is only one small phase-II study with few numbers of patients that show an advantage of a combination of 5-FU and oxaliplatin compared to monotherapy with 5-FU or oxaliplatin [217]. Gemcitabine/capecitabine or gemcitabine/5-FU Recommendation The combination gemcitabine and capecitabine or 5-FU is not recommended as standard therapy until definite publications are available. Recommendation grade: C, evidence level 2, consensus Comments The combination of gemictabine and oral fluoropyrimidin capecitabine was investigated in 2 randomized, controlled studies. A significantly better median and 1-year survival of the total population was shown for the combination in only one study [208, 218]. So far, these studies have merely been published as abstracts. Randomized, controlled studies on the combination of 5-FU and gemcitabine showed no significant difference in survival [209, 219, 220]. Gemcitabine/erlotinib Recommendation A statistically significant difference in survival was demonstrated in favor of the combination of gemcitabine and the EGF-receptor tyrosine kinase inhibitor erlotinib [221]. The difference in median survival is about 2 weeks. The 1-year survival is 24% for the group receiving the combination therapy compared to 19% for the group receiving gemcitabine monotherapy. Recommendation grade: A, evidence level 1, consensus Comments An evaluation of the study that was published online by the CHMP of EMEA shows that there is a 22% increase in the median survival of patients with metastatic pancreatic carcinoma Leitlinie 467 receiving gemcitabine plus erlotinib compared to gemcitabine plus placebo. However, the survival of patients with locally advanced, inoperable pancreatic carcinoma did not differ between both arms of the trial. Thus, the EMEA recommended the approval of a combination of gemcitabine and erlotinib for the indication “metastastic pancreatic carcinoma”. Particularly patients receiving a combination therapy with erlotinib who have a skin reaction (‡ grade 2) after 4 – 8 weeks seem to benefit. For patients who do not develop skin rash within the first 8 weeks of treatment, therapy with erlotinib should be reconsidered if there is no tumor response detectable with imaging techniques (i. e. mere stabilization of the disease, no partial or complete remission). Gemcitabine/bevacizumab Recommendation This combination is not recommended. Recommendation grade: B, evidence level 2, strong consensus Comments In a phase-II study it was shown that a combination of gemcitabine and the VEGF-antibody bevacizumab was beneficial. However, the toxicity was increased [222]. A current prematurely terminated phase-III study did not show a better survival of the combination treatment compared to monotherapy. So far the study is only available as an abstract [223]. Capecitabine/oxaliplatin Recommendation The data available for the combination of capecitabine and oxaliplatin is insufficient. Recommendation grade: B, evidence level 2b, strong consensus. Recommendation Patients with a good Karnofsky-index (‡ 90% or ECOG 0 – 1) may benefit more from a therapy with gemcitabine/oxaliplatin, gemcitabine/cisplatin, or gemcitabine/capecitabine than from monotherapy. Recommendation grade: B, evidence level 3, consensus Comment Subgroup analyses of phase-III-studies demonstrate that patients with KPS ‡ 90% who receive combination therapy have a greater survival advantage [206 – 208]. Other drugs Drugs such as mitomycin C (recommendation grade: A, evidence level 1) [213], a combination of cisplatin, epirubicine, 5-FU, and gemcitabine (PEFG) (recommendation grade: A, evidence level 2) [224], and a combination of gemcitabine and docetaxel (recommendation grade: B, evidence level 2b) [225 –228] are not important in first line therapy of metastatic or locally advanced, inoperable pancreatic carcinoma. Second line treatment Recommendation If the first line therapy fails, a second line therapy can be done. This is especially true if the patient is in good general health, it is the patient’s wish, pretreatment was insufficient, or there is a good tumor response during first line therapy. Recommendation grade: B, 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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S3-Guideline “Exocrine Pancreatic Carcinoma” 20071 ... - DGVS

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