Kong et al. Adjuvant radiotherapy for stage I endometrial cancer. Cochrane Database Syst Rev 2012. (9) Summary: This meta-analysis from the Cochrane Gynaecological Cancer Review Group updates their previous study published in 2007 (10). An abridged version of the 44-page update appeared in a recent issue of the Journal of the National Cancer Institute (11). The meta-analysis recapitulates the essential findings of the 2007 study, namely that external beam radiation therapy (EBRT) reduces locoregional recurrence (LRR), without significantly affecting overall survival. The 2012 study includes data for 1454 additional patients (3624 in total) from 4 additional trials (4 trials in total). Not all of the trials could be used for all of the analyses, and some estimates were derived from only 1 or 2 trials. Five trials (2965 women) were used for time-to-event analysis. The quality of trials was generally deemed high, but 2 trials were considered to have moderate or high risk of bias. The trials were heterogeneous in terms of the risk factors and inclusion criteria, use of lymphadenectomy, and use of vaginal brachytherapy in either the EBRT or control arm. The study estimated that EBRT significantly reduces the hazard for LRR (hazard ratio [HR] 0.36; 95% confidence interval [CI] 0.25-0.52), with no significant effect on distant recurrence (HR 1.04; 95% CI 0.40-1.35), endometrial cancer mortality (HR 0.96; 95% CI 0.72-1.24), or overall survival (HR 0.99; 95% CI 0.42-1.20). In 2 trials including 334 high-risk women (grade 3 with deep myometrial invasion), EBRT nonsignificantly reduced endometrial cancer mortality (HR 0.44; 95% CI 0.51-1.40) and overall mortality (HR 0.91; 95% CI 0.60-1.39). Grade ≥3 acute and late toxicity were more frequent with EBRT (relative risk 4.64; 95% CI 1.35-16.2, and relative risk 2.54; 95% CI 1.61-4.11, respectively). Comment: The results of this meta-analysis reconfirm the effectiveness of EBRT in reducing LRR for women with early-stage endometrial cancer but do not find evidence that EBRT improves overall survival. The advantages of improved LRR with EBRT must be weighed against its increased toxicity and detriments to quality of life. Notably, the included trials span a 40-year era during which EBRT techniques have evolved. Ideally a meta-analysis would comprise a large number of identically designed trials spanning a contemporaneous period, with sufficient power to obtain robust estimates within subgroups. Through no fault of the authors, this meta-analysis unfortunately falls short of this ideal, owing to the paucity of randomized trial data and changes in EBRT techniques. Although the major findings are unchanged from the 2007 analysis, the sample size was essentially doubled, yielding important additional information, including the apparent lack of a survival benefit in low- and intermediate-risk subgroups. So, how should the findings of this study impact EBRT utilization in early-stage endometrial cancer? This answer depends critically on how one evaluates the goals of EBRT and mechanism of its expected benefit(s). Is reduction in LRR is sufficient justification in its own right to recommend EBRT? In favor of this view, proof of a survival benefit is not a universally accepted necessary condition for the application of medical interventions, even potentially toxic therapies. For example, despite finding no significant survival difference between surgery or primary endocrine therapy for operable breast cancer in elderly women, the Cochrane group concluded that surgery is preferred except for women with estrogen receptor-positive tumors who are medically unfit for or who refuse surgery (12). Still, the effectiveness of EBRT for early-stage endometrial cancer should be judged independently, and EBRT should be applied if, and only if, the benefits outweigh the risks. Application of EBRT in low- and intermediate-risk groups is not supported by high-level data, even considering that modern EBRT techniques could reduce toxicity and improve quality of life. Furthermore, the preponderance of LRR events is likely to be prevented by vaginal brachytherapy, which should be preferred when adjuvant radiation is considered for intermediate-risk disease. If we persist in defending EBRT utilization despite contrary evidence, we ultimately do our patients a disservice. Conversely, if we are quick to dismiss EBRT despite shaky data, we may also do our patients a disservice by depriving them access to potentially beneficial therapy. For high-intermediate and high-risk subgroups, an interesting and fundamental question emerges, namely, what is the mechanism by which EBRT would benefit patients? Is it solely reducing LRR, or could it actually improve survival? Because isolated pelvic progression is not the dominant cause of mortality in these patients, for EBRT to substantially improve survival it must eradicate locoregional disease that would otherwise seed distant metastases. This effect must overcome the competing causes of mortality due to comorbid disease, progression of radioresistant clones, spread of metastases already present at diagnosis, and the background subset rendered disease-free by hysterectomy—a tall order for EBRT! Adequately powered randomized trials to prove or disprove a small benefit would be large and costly, crowding out other uses of scarce resources. Anyway, if one were to adopt this position, supporting evidence is weak. The meta-analysis by Kong et al provides no evidence of an effect of EBRT on distant recurrence or mortality from endometrial cancer. Advocates of EBRT, however, might point to the effects within high-risk patients, which do trend in the direction of a benefit. The data become sparse within this subgroup, suggesting room for growth in knowledge. Notably, it took the Early Breast Cancer Trialists 10,401 women from 17 randomized trials to prove a benefit of EBRT on breast cancer mortality, to say nothing of overall mortality (13). If a survival benefit of EBRT does exist, realistically it would be best detected in an appropriately chosen risk group: one simultaneously at high risk of distant recurrence and low risk of competing causes of mortality. Testing this hypothesis, however, would require support for a randomized trial in high-risk patients of EBRT versus something less. 9.Kong A, Johnson N, Kitchener HC, et al. Adjuvant radiotherapy for stage I endometrial cancer. Cochrane Database Syst Rev. 2012;4:CD003916 View In Article 10.Kong A, Johnson N, Cornes P, et al. Adjuvant radiotherapy for stage I endometrial cancer. Cochrane Database Syst Rev. 2007;2:CD003916 View In Article 11.Kong A, Johnson N, Kitchener HC, et al. Adjuvant radiotherapy for stage I endometrial cancer: An updated Cochrane systematic review and meta-analysis. J Natl Cancer Inst. 2012;104:1625–1634 View In ArticleCrossRef 12.Hind D, Wyld L, Beverley CB, et al. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev. 2006;1:CD004272

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Therapie des Endometrium-Karzinoms

Allgemeines

 

Ladner - Ergebnisse

Operation (1)

totale Hysterektomie beidseitige Adnexexstirpation pelvine und paraaortaleLymphonodektomie

postoperative Bestrahlung

Bestrahlung des pelvinen Lymphabflusses Die Bestrahlung senkt die Rate an Lokalrezidiven (PORTEC1, ASTEC, GOG99). Wegen der Nebenwirkungen ist die Bestrahlung nur in Risikofällen indiziert. Mindestens 2 von 3 Risikofaktoren: G3-Tumor, ≥ 60 Jahre, tiefe Invasion ins Myometrium.
Brachytherapie des Uterus Lundberg-Kapseln
 Lundberg - Kapseln
Heymann'sche Packtechnik

In der Radium-Ära wurden Einzelfilter, so genannter Eier, mit dem Introduktor in das Uteruscavum geschoben und dort ausgeklinkt.
Die Einzelfilter hatten Bänder, die mit Nummern gekennzeichnet waren.
Die Entfernung musste unbedingt in umgekehrter Reihenfolge durchgeführt werden
Radium-Introduktor
Heyman Pack-Technik
Brachytherapie der Scheide Die Brachytherapie senkt die Rate an vaginalen Rezidiven(PORTEC2). Wegen der geringen Nebenwirkungen kann die Indikation großzügig gestellt werden.

Chemotherapie

GOG-Phase-III, first-line Therapie fortgeschrittener und rezidivierter Endometriumkarzinome.
StudieRekrutierungTherapiePatientinnenPFSOS
GOG 48 (4) 1979-1945 Doxorubicin 132 3,2 6,7
Doxorubicin/Cyclophosphamid 144 3,9 7,3
GOG 107 (5) 1944-1991 Doxorubicin 150 3,4 9,2
Doxorubicin/Cisplatin 131 5,7 9,0
GOG 139 (6) 1993-1996 Doxorubicin/Cisplatin 173 5,9 13,2
Doxorubicin/circadian Cisplatin 169 6,5 11,2
GOG 163 (7) 1996-1994 Doxorubicin/Cisplatin 157 7,2 12,6
Doxorubicin/Paclitaxel/G-CSF 160 6,0 13,6
GOG 177 (2) 1994-2000 Doxorubicin/Cisplatin 129 5,3 12,3
Doxorubicin/Cisplatin/Paclitaxel/G-CSF 134 4,3 15,3
GOG 209 (3) 2003-2009 Carboplatin/Paclitaxel 663 14,0 32,0
Doxorubicin/Cisplatin/Paclitaxel/G-CSF 642 14,0 34,0

endokrine Therapie

offene Protokolle

Quellen

1.) Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft e.V. (DKG) und der
Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG).
01/2004

2.) Fleming GF, et al.:
Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: A Gynecologic Oncology Group Study.
J Clin Oncol 22(2004):2159-2166

3.) Miller D, et al.:
Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: A Gynecologic Oncology Group study.
Gynecol Oncol 125(2012):771-773

4.) Thigpen JT, et al.:
A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study.
J Clin Oncol 12(1994):1404-1414

5.) Thigpen JT, et al.:
Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: A Gynecologic Oncology Group study.
J Clin Oncol 22(2004):3902-3904

6.) Gallion HH, et al.:
Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: A Gynecologic Oncology Group Study.
J Clin Oncol 21(2003):3404-3413

7.) Fleming GF, et al.:
Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: A Gynecologic Oncology Group study.
Ann Oncol 15(2004):1173-1174

8.) Meyer L, et al.:
Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline.
JCO 2015;33:2908-2913. DOI 10.1200/JCO.2015.62.5459

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