Ösophaguskarzinom

Erstellt am 08 Aug 2018 13:16
Zuletzt geändert: 07 May 2020 19:44

C15.- Bösartige Neubildung des Ösophagus
C16.- Bösartige Neubildung des Magens inklusive des ösophagogastrischen Übergangs (AEG-Tumor)

Leitlinien, Fachliteratur

Arzneitherapien beim Ösophaguskarzinom (spez. Plattenepitelkarzinom; Nicht-AEG)

2018

Design, Setting, and Participants:
In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months.
Results:
Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment.
Conclusions and Relevance:
Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted.
Trial Registration: clinicaltrials.gov Identifier: NCT02335411.

Although there are currently no randomized trial data on immune checkpoint inhibitors in ESCC, results of a phase II study conducted in Japan were reported in Lancet Oncology by Kudo and colleagues (15). Patients with advanced ESCC refractory or intolerant to fluoropyrimidine-, platinum- and taxane-based chemotherapy were treated with nivolumab 3 mg/kg every 2 weeks. Of the 64 patients assessable for the primary endpoint of ORR, 11 (17%) had an objective response (1 complete response), while 27 patients (42%) achieved disease control. Median PFS was 1.5 months, and median OS was 10.8 months. Median duration of response was not reached. Treatment was well tolerated with grade 3 or worse events in 17% of patients. The most common serious treatment-related adverse event was interstitial lung disease in three patients, which resolved with supportive care. No biomarker analysis (PD-L1, tumor mutation burden, CD8 cells, etc.) was reported for this trial. In this heavily pretreated population (38% of patients had received 3 or more systemic therapies), nivolumab showed remarkable activity compared to historical controls of systemic therapy, in terms of both ORR and OS (16,17). It is also important to note that PD-L1 positivity was not required for enrollment in this study. However, biomarker analysis, including PD-L1 expression, may identify predictors of response to nivolumab and enable better patient selection for future immune checkpoint inhibitor trials.
Another recent study confirmed the promising clinical activity of PD-1 inhibition in advanced esophageal cancer. The results from the esophageal cancer cohort of KEYNOTE-028, a multicohort, phase IB trial of pembrolizumab in patients with PD-L1 positive advanced solid tumors, were reported in the Journal of Clinical Oncology (18). The study included patients with either ESCC or esophageal adenocarcinoma, in whom standard therapy failed. PD-L1 positivity was defined as membranous staining on at least 1% of cells or the presence of a distinctive interface pattern in both neoplastic cells and contiguous mononuclear inflammatory cells. Patients were treated with pembrolizumab 10 mg/kg every 2 weeks. Of 83 patients, 37 patients had PD-L1 positive tumors, and 23 of those were enrolled. The majority of patients (18 patients, 78%) had ESCC, and 87% received ≥2 prior therapies for advanced/metastatic disease. ORR was 28% (5 of 18 patients) for patients with ESCC and 40% (2 of 5 patients) for those with adenocarcinoma. Median duration of response was 15 months, median PFS was 1.8 months and median OS was 7.0 months. Toxicity was manageable with the most common treatment-related adverse event being rash. In an effort to identify a biomarker of response to pembrolizumab, tumors were assayed for a six-gene interferon-γ expression signature (CXCL9, CXCL10, HLA-DRA, IDO1, IFNG, and STAT1), which has been shown to predict response in melanoma, head and neck and gastric cancer. The signature score showed trends toward an association with PFS (P=0.053, one-sided) and ORR (P=0.107, one-sided) in patients treated with pembrolizumab.
Both studies demonstrated encouraging preliminary efficacy of PD-1 blockade in advanced, refractory ESCC, a disease for which new, better therapies are sorely needed. The Kudo et al. study was larger and included only patients with ESCC, whereas KEYNOTE-028 was smaller and included both ESCC and adenocarcinoma patients. However, Kudo and colleagues conducted the trial only in Japan, whereas KEYNOTE-028 was a global trial which enrolled patients in Asia, Europe and the United States. The major difference between the two trials was that KEYNOTE-028 enrolled only patients with PD-L1 positive tumors, whereas in the Kudo et al. study patients were not preselected based on PD-L1 expression. It will be important to evaluate patient samples from both studies to identify biomarkers that could predict response to PD-1 inhibition. A potential biomarker of response to pembrolizumab, the interferon-γ gene signature, was suggested in KEYNOTE-028. However, this signature needs further exploration in a larger patient population. Finally, these data are only suggestive of efficacy of PD-1 blockade in esophageal cancer and need to be validated in the currently ongoing randomized phase III clinical trials …

2017

METHODS:
We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy…
FINDINGS:
Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths.
INTERPRETATION:
Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma.
FUNDING: Ono Pharmaceutical, Bristol-Myers Squibb. clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422.

Studien - Phase 3, aktiv, in Deutschland

Hinweis: In der Richtlinie des Gemeinsamen Bundesausschuss zur ambulanten spezialfachärztlichen Versorgung nach § 116 b SGB V sind in der Anlage 1a unter "Onkologische Erkrankungen – Tumorgruppe 1" gastrointestinale Tumoren und Tumoren der Bauchhöhle aufgeführt. Hier werden konkret angeführt: Ösophaguskarzinome, bei denen eine PET bzw. PET-CT zur Detektion von Fernmetastasen eingesetzt wird sowie resektable Lebermetasen eines kolorektalen Karzinoms, mit dem Ziel der Vermeidung einer unnötigen Laparotomie. In diesen Indikationen ist in der genannten Anlage die PET bzw. PET-CT als GKV-Leistung enthalten, die bislang nicht im EBM aufgeführt ist.
Wenn eine entsprechende Indikation bei Patienten, die gemäß § 116 b SGB V behandelt werden, nicht vorliegt, kommen auch in der ambulanten spezialärztlichen Versorgung nicht die genannten Regelungen zum Tragen, sondern es muss eine sozialmedizinische Bewertung wie im Rahmen der allgemeinen ambulanten vertragsärztlichen Versorgung erfolgen.

Die Beiträge in diesem Wiki zu "Erkrankungen und Behinderungen", gesundheitlichen Problemlagen und Indikationen erheben weder den Anspruch, umfassend noch hinsichtlich der Einsortierung in einer Rubrik immer unstrittig zu sein.
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* Zitat nach: Bach, Otto: ''Über die Subjektabhängigkeit des Bildes von der Wirklichkeit im psychiatrischen Diagnostizieren und Therapieren''. In: Psychiatrie heute, Aspekte und Perspektiven, Festschrift für Rainer Tölle, Urban & Schwarzenberg, München 1994, ISBN 3-541-17181-2, (Zitat: Seite 1)

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