Leitlinienprogramm OnkologieEndometrial Cancer

8. Adjuvant drug therapy of endometrial carcinoma – Endometrial Cancer

Version 2.0 · September 2022 · AWMF 032/034-OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

8.1 Adjuvant drug therapy for endometrial carcinomas

8.1.1 Adjuvant progestogen therapy

8.1 · Evidence-based Recommendation · checked 2022

Adjuvant progestin therapy after surgery for endometrial cancer shall not be performed.

Recommendation grade
A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence
1
Consensus
Strong consensus
References
[631]
Evidence tables (1)8.1.1 EvT 8.1

Background

In view of the comparatively low side effects, high-dose progestogens have been intensively studied as adjuvant therapy after surgical treatment and adjuvant radiotherapy of endometrial carcinoma. There are 7 RCTs involving 4,556 endometrial cancer patients that have been repeatedly analyzed by the Cochrane Collaboration [632]. 

The most recent meta-analysis (search by 04/2009) [632], llike the previous ones, found no difference for overall survival at 4, 5, and 7 years. The risks of dying from endometrial cancer, cardiovascular and intercurrent disease were also not affected by adjuvant progestin therapy. In one study, the risk of recurrence of endometrial cancer was reduced. This was not confirmed in another study. Effects of adjuvant progestin therapy on patients' quality of life were not investigated in any study. 

The authors of the meta-analysis conclude that there are now several RCTs showing that adjuvant progestin therapy after primary therapy for endometrial cancer has no benefit. Further studies on this question are probably not justified.

8.1.2 Adjuvant chemotherapy

8.2 · Consensus-based Recommendation · modified 2022

Patients with primary type I endometrial carcinoma stage pT1a/b G1 and G2 cN0/ pNsn0, p53-wt, shall not receive adjuvant chemotherapy.

Consensus
Strong consensus
Change notePatients with endometrioid or other type I endometrial carcinoma (ICD-0: 8380/3, 8570/3, 8263/3, 8382/3, 8480/3) at stage pT1a/b G1 and G2 cN0/pN0 should not receive adjuvant chemotherapy.
8.3 · Evidence-based Statement · modified 2022

For patients with endometrioid or other type I endometrial carcinoma at stage pT1a G3 cN0 or pN0, p53-wt, there are insufficient data on the benefit of adjuvant chemotherapy.

Level of evidence
2
Consensus
Strong consensus
References
[520]
Change noteFor patients with endometrioid or other type I endometrial carcinoma at stage pT1a G3 cN0 or pN0, there are insufficient data on the benefit of adjuvant chemotherapy.
Evidence tables (1)8.1.2 EvT 8.3
8.4 · Evidence-based Recommendation · modified 2022

For patients with type I endometrial carcinoma G3 pT1b, without POLE mutation or stage pT2 (each pN0), adjuvant chemotherapy with 3 or 6 cycles (see Statement 8.13) may be considered as an adjunct to vaginal brachytherapy (see Radiation Therapy recommendation) or percutaneous radiotherapy alone without chemotherapy.

Recommendation grade
0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence
2
Consensus
Strong consensus
References
[633] [520]
Change noteAdjuvant chemotherapy can be given to patients with type II endometrial carcinoma and to patients with type I endometrial carcinoma G3 pT1b and stage pT2 (both pN0).
Evidence tables (1)8.1.2 EvT 8.4
8.5 · Consensus-based Recommendation · new 2022

Patients with type I endometrial carcinoma G3 pT1b or stage pT2 (both pN0) with POLE mutation should not receive adjuvant chemotherapy.

Consensus
Strong consensus
8.6 · Evidence-based Recommendation · new 2022

Patients with serous endometrial carcinoma in FIGO stage I – III should receive adjuvant therapy according to the PORTEC-III regimen (= radiochemotherapy followed by chemotherapy). For stage III serous endometrial carcinoma, adjuvant chemotherapy alone can be given as an alternative (carboplatin AUC 6 / paclitaxel 175 mg/m2).

Recommendation grade
B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence
2
Consensus
Strong consensus
References
[606] [634]
Evidence tables (2)MateiD_2019; deBoer_2019
8.7 · Consensus-based Recommendation · new 2022

Patients with type 1 endometrial carcinoma and abnormal p53 status on immunohistochemistry (type I endometrial carcinoma stage 1a or higher, with infiltration into the myometrium, or clear cell endometrial carcinoma) should be treated like patients with serous endometrial carcinoma.

Consensus
Consent
8.8 · Evidence-based Recommendation · modified 2022

Patients with primary endometrial cancer stage pT3 and/or pN1 shall receive adjuvant chemotherapy or adjuvant therapy according to the PORTEC-3 regimen.

Recommendation grade
A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence
2
Consensus
Strong consensus
References
[606] [601] [602] [603]
Change notePatients with stage pT3 and/or pN1 endometrial cancer should receive adjuvant chemotherapy.
Evidence tables (1)8.1.2 EvT 8.5
8.9 · Evidence-based Recommendation · modified 2022

Patients with stage pT4a or M1 endometrial cancer who have undergone macroscopic complete tumor resection or have a maximum postoperative residual tumor less than 2 cm should receive adjuvant chemotherapy, if applicable in combination with radiotherapy.

Recommendation grade
B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence
1
Consensus
Strong consensus
References
[606] [520] [633]
Change notePatients with stage pT4a or M1 endometrial cancer who have undergone macroscopic tumor-free surgery or have a maximum postoperative residual tumor less than 2 cm should receive chemotherapy.
Evidence tables (1)LeonCastillo2020
8.10 · Evidence-based Recommendation · modified 2022

Adjuvant chemotherapy for endometrial cancer shall be given with carboplatin AUC 6 and paclitaxel 175 mg per square meter. After percutaneous radiotherapy, carboplatin AUC 5 should be dosed.

Recommendation grade
A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence
2
Consensus
Strong consensus
References
[635] [636] [606]
Change noteAdjuvant chemotherapy for endometrial cancer should be given with carboplatin AUC 6 and paclitaxel 175 mg per square meter. When combined with percutaneous radiotherapy, carboplatin AUC 5 should be dosed. Adriamycin and cisplatin may also be used if contraindications exist.
Evidence tables (1)NomuraH_2019
8.11 · Evidence-based Recommendation · modified 2022

If chemotherapy alone indicated and paclitaxel or carboplatin are contraindicated, adriamycin and cisplatin may also be used.

Recommendation grade
0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence
2
Consensus
Strong consensus
References
[606] [635] [636]
Change noteAdjuvant chemotherapy for endometrial cancer should be performed with carboplatin and paclitaxel.

Background

The benefit of adjuvant chemotherapy as an alternative to or in addition to adjuvant radiotherapy after primary surgery for EC has been intensively studied and has been the subject of several large, randomized trials (PORTEC-3, GOG 258, and GOG 249).

In the international Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-3 trial, adjuvant concurrent radiochemotherapy followed by adjuvant chemotherapy resulted in a significant improvement in overall survival in women with high-risk EC compared with radiotherapy alone [634]. In this study, patients (n = 660) with high-risk EC were studied. Approximately 45% were stage III, 26% were stage IIIC, i.e., with lymph node metastases, 25% of patients had serous or clear cell (type 2) EC, and 32% had poorly differentiated (G3) endometrioid EC. In the overall population, 5-year overall survival was 81.4% (95%-CI 77.2 – 85.8) in the chemotherapy and radiotherapy group vs. 76.1% (71.6 – 80.9) in the radiotherapy alone group (HR: 0.7; 95%-CI = 0.51 – 0.97; p = 0.034) (median follow-up 72.6 months). The 5-year failure-free survival was 76.5% (95%-CI = 71.5 – 80.7) vs. 69.1% (63.8 – 73.8; HR 0.7; 95%-CI 0.52 – 0.94; p = 0.01). In most patients, distant metastases were the first manifestation of recurrence. They occurred in 21.4% of women in the chemo/radiotherapy group and in 29.1% of women in the radiotherapy alone group. In a subgroup analysis of patients with stage I and II EC, no significant differences in overall survival and failure-free survival were found with the addition of chemotherapy. However, in the subgroups of patients with stage III and serous EC, the addition of chemotherapy resulted in a significant improvement in 5-year overall survival: 78.5 vs. 68.5% (stage III; p = 0.043) and 71.4 vs. 52.8% (serous EC; p = 0.037), respectively, and failure-free survival: 70.9 vs. 58.4% (stage III; p = 0.011) and 59.7 vs. 47% (serous EC; p = 0.008).

After 5 years, adverse event rates were similar in both groups. Only sensory neuropathies were more common in the chemo/radiotherapy arm. The authors conclude that combined chemo/radiotherapy consisting of pelvic irradiation with 2 simultaneous administrations of cisplatin followed by 4 cycles of carboplatin/paclitaxel should be recommended to patients with serous and/or stage III EC. This includes all patients with pelvic and/or para-aortic lymph node metastases, regardless of the local spread of the primary tumor.

The US GOG-258 trial assessed whether adjuvant radiochemotherapy with cisplatin followed by 4 cycles of adjuvant chemotherapy with carboplatin/paclitaxel results in a survival benefit over adjuvant chemotherapy alone (6 cycles of carboplatin/paclitaxel) in patients with high-risk EC [606]. This was not the case. 736 patients with high-risk EC, of whom > 97% were stage III (50% stage IIIC1, 25% stage IIIC2; 21% serous or clear cell) were treated adjuvantly after surgery with either chemotherapy alone or combined chemo/radiotherapy analogous to the PORTEC-3 trial. If the para-aortic lymph nodes were affected (IIIC2), this region was also irradiated. The median follow-up time was 47 months. The 5-year recurrence-free survival was 59% (95%-CI = 53 – 64%) in the chemo/radiotherapy group and 58% (53 – 64%) in the chemotherapy alone group (HR 0.9; 90% CI 0.74 – 1.10). According to the study hypothesis, additional radiotherapy resulted in both fewer vaginal recurrences (2 vs. 7%; HR: 0.36; 95%-CI = 0.16 – 0.82) and fewer pelvic recurrences and para-aortic lymph node recurrences (11 vs. 20%; HR: 0.43; 95%-CI = 0.28 – 0.66). However, distant metastases were more frequent in the chemo/radiotherapy group than in the chemotherapy alone group (27 vs. 21%; HR: 1.36; 95%-CI = 1.00 – 1.86). Side effects ≥ grade 3 were observed in 58% of the chemo/radiotherapy group and in 63% of patients with chemotherapy alone. The addition of radiotherapy to chemotherapy did not improve relapse-free survival. It remains to be seen whether in the further follow-up period the reduction in the incidence of distant metastases in the chemotherapy alone group will have an effect on overall survival.

Finally, data are available from the GOG 249 trial, which tested whether adjuvant vaginal brachytherapy followed by shortened chemotherapy (3 cycles) is more effective than percutaneous radiotherapy ± brachytherapy [613] in high/intermediate-risk and high-risk stage I and II EC. This was not the case. High/intermediate risk was defined as age of ≥ 70 years plus 1 uterine risk factor, age of ≥ 50 years plus 2 risk factors, or age ≥ 18 years plus 3 risk factors. Uterine risk factors were G2 and G3 tumors, pT1b, and lymphatic invasion. Pelvic and para-aortic lymphonodectomy were recommended and performed in 90% of patients. Alternatively, postoperative CT or MRI was used to exclude enlarged lymph nodes. 21% of patients had endometrioid EC, G3, 20% had serous or clear cell EC [618]. 75% of patients were stage I, 25% were stage II. Patients with stage I or II serous or clear cell EC and positive peritoneal cytology were not eligible for the GOG-249 trial but were recommended for participation in the GOG-258 trial.

After a median follow-up of 53 months, 5-year recurrence-free survival was 76% (95%-CI = 0.70 – 0.81) for the percutaneously irradiated group and 76% (0.70 – 0.81) for the brachytherapy/chemotherapy group. The hazard ratio was 0.92 (90% CI = 0.69 – 1.23). The 5-year overall survival was 87% (95%-CI = 83 – 91%) for the percutaneously irradiated patients and 85% (95%-CI: 81 – 90%) for the brachytherapy/chemotherapy group (HR: 1.04; 90% CI = 0.71 – 1.52). Vaginal recurrences and distant metastases were similarly frequent in both groups; pelvic and para-aortic recurrences were more frequent in the brachytherapy/chemotherapy group (9 vs 4%) [618]. Acute toxicity was higher in the brachytherapy/chemotherapy group; late toxicities were comparable.

Interpretation of these 3 studies can be used to formulate clear recommendations for action. The GOG-249 trial addressed the question of whether “little” chemotherapy and vaginal brachytherapy is better than external pelvic irradiation combined with optional vaginal brachytherapy. The GOG-258 trial, on the other hand, investigated whether adding radiation to chemotherapy is beneficial in advanced disease. The PORTEC-3 trial, in contrast, was designed to investigate whether the addition of chemotherapy to radiation was associated with improved overall survival. The PORTEC-3 study clearly shows that the addition of chemotherapy to percutaneous radiation, especially in stage III or serous EC, provides a significant and, above all, clinically relevant improvement in overall survival compared to radiation therapy alone.

The PORTEC-3 study does not answer the question whether radiotherapy is still necessary at all in patients with high-risk EC who receive sufficient adjuvant chemotherapy. Answering this question was the goal of the U.S. GOG-258 trial. Although the additional radiotherapy improved locoregional control, distant metastases occurred more frequently than in the chemotherapy alone group. Reasons for this could be the reduction of full chemotherapy cycles from 6 to 4 or the delayed onset of combination chemotherapy. In any case, the additional radiotherapy did not improve recurrence-free survival. Overall survival has so far been the same in both groups.

Therefore, if a patient is treated with adjuvant chemotherapy according to the standard arm of the GOG-258 trial, additional brachytherapy may be discussed to reduce the rate of vaginal recurrences. In contrast, if a patient is treated according to the experimental arm of the GOG-258 trial, it should be discussed with the patient whether the reduction of pelvic and para-aortic recurrences by percutaneous radiotherapy justifies the acceptance of more distant metastases, since pelvic and/or para-aortic recurrences can also be irradiated secondarily with good results if percutaneous irradiation has not yet been performed.

Recent data from Nomura et al. and Miller et al. [635], [637] emphasize the value of adjuvant chemotherapy with carboplatin and paclitaxel over alternative regimens. Nomura et al. In a randomized trial of patients with high-risk stage I-IV EC demonstrated that the following 3 regimens: doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2; docetaxel 70 mg/m2 plus cisplatin 60 mg/m2; and paclitaxel, 180 mg/m2 plus carboplatin AUC 6 were equivalent in terms of progression-free survival and overall survival. In a randomized trial (GOG 209) of patients with stage III and IV EC or recurrence, Miller et al., showed that 7 cycles of paclitaxel 175 mg/m2 plus carboplatin AUC 6 were non-inferior compared with doxorubicin 45 mg/m2 plus cisplatin 50 mg/m2 plus paclitaxel 160 mg/m2 (with GCSF support). Adjuvant chemotherapy in early or advanced EC stages should therefore be given with carboplatin AUC 6 and paclitaxel 175 mg/m2. When combined with percutaneous radiotherapy, carboplatin AUC 5 should be dosed. Adriamycin and cisplatin may also be used if contraindications exist.

Of particular interest for the recommendations included in this Guideline were the first retrospective evaluations of the PORTEC-2 study and the PORTEC-3 study regarding the predictive value of molecular subtypes. Wortmann et al. were able to show by combined molecular and immunohistochemical profiling of the PORTEC-2 collective that patients with “high-intermediate risk”-EC (defined as FIGO [1988] 1C G1/2 > 60 years or FIGO [1988] 1B G3 > 60 years or FIGO [1988] 2A – except G3 with deep stromal invasion), who had evidence of a risk profile (p53-mutant or L1CAM+ or extensive LVSI) benefited from adjuvant pelvic irradiation [342]. According to this work, therefore, conversely, adjuvant vaginal brachytherapy alone should be given to patients with “high-intermediate risk” EC without evidence of a risk profile (p53-mutant or L1CAM+ or extensive LVSI).

Leon-Castillo et al. investigated the predictive value of the 4 molecular subtypes (p53 abnormal, POLE-ultramutant, MMR-deficient and no specific molecular profile) with respect to the therapeutic outcome of adjuvant radiochemotherapy followed by 4 x carboplatin/paclitaxel in the PORTEC-3 trial [359]. It was shown that only the group with p53-abnormal EC benefited from adjuvant radiochemotherapy followed by chemotherapy. Therefore, from these data it can be hypothesized that in patients with serous EC, stage FIGO III (including pN1/2) or with “high-risk” constellation (FIGO 1A G3 with LVSI, FIGO 1B G3, FIGO II, FIGO III, FIGO I-III with serous or clear cell histology), adjuvant radiochemotherapy with cisplatin followed by 4 cycles of carboplatin/paclitaxel should be performed only in case of detection of a p53-abnormal molecular subtype. However, the authors emphasize that due to the small numbers of cases in the subgroups, the incomplete coverage of tissue samples, and the retrospective nature of the analysis, it can only be considered hypothesis-generating.
Therefore, as a limitation, it should be considered that no prospective data are currently available on the question of the predictive value of molecular subtypes. The currently still recruiting prospective randomized PORTEC-4a study will show whether combined molecular and immunohistochemical risk profiling in patients with high-intermediate risk EC can improve the choice between foregoing adjuvant radiation, adjuvant brachytherapy and adjuvant percutaneous radiation [638]. Prospective studies that could define the predictive utility of molecular classification for treatment decisions in high risk EC do not yet exist.

8.1.3 Adjuvant drug therapy for carcinosarcoma.

8.12 · Evidence-based Recommendation · modified 2022

Patients with carcinosarcoma FIGO stage I or II may receive adjuvant chemotherapy with carboplatin/paclitaxel (at a dosage of paclitaxel 175 mg/m² day 1 carboplatin AUC 6 day 1) or cisplatin/ifosfamide (at a dosage of ifosfamide 1.6 g/m² day 1–4 and cisplatin 20 mg/m² day 1–4).

Recommendation grade
0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence
4
Consensus
Strong consensus
References
[639]
Change notePatients with carcinosarcoma FIGO stage I or II may receive adjuvant chemotherapy with cisplatin/ifosfamide at a dose of ifosfamide 1.6 g/m2 i. v. day 1-4 and cisplatin 20 mg/m2 i. v. day 1-4 or carboplatin/paclitaxel at a dose of paclitaxel 175 mg/m2 day 1 and carboplatin AUC 5.
Evidence tables (1)8.2 EvT 8.8
8.13 · Evidence-based Statement · checked 2022

For patients with stage FIGO III or IV carcinosarcoma, adjuvant chemotherapy with ifosfamide/paclitaxel or ifosfamide/cisplatin was shown to have a significant survival benefit over monotherapy with ifosfamide.

Level of evidence
1
Consensus
Strong consensus
References
[640] [641] [642]
Evidence tables (1)8.2 EvT 8.9
8.14 · Consensus-based Recommendation · modified 2022

Given the high toxicity of ifosfamide-containing combinations, the combination of carboplatin and paclitaxel can also be used as adjuvant chemotherapy in patients with stage FIGO III or IV carcinosarcoma at a dosage of paclitaxel 175 mg/m2 day 1 and carboplatin AUC 6 or cisplatin/ifosfamide at a dosage of ifosfamide 1.6 g/m2 i.v. Day 1–4 and cisplatin 20 mg/m2 i.v. Day 1–4.

Consensus
Strong consensus
Change noteGiven the high toxicity of ifosfamide-containing combinations, the combination of carboplatin and paclitaxel may also be used as adjuvant chemotherapy in patients with carcinosarcoma.

Background

Only one retrospective multicenter case series of 111 women exists regarding adjuvant therapy in stages I and II carcinosarcoma. Of these, 44 (40%) had received no adjuvant therapy, 23 (20%) had received adjuvant radiotherapy, 29 (26%) had received adjuvant chemotherapy and 15 women (14%) had received radiochemotherapy. Women who received chemotherapy had better PFS than those who received radiotherapy alone or were observed only (HR = 0.28; CI = 0.12–0.64 in multivariate Cox model). Sixteen patients had received the cisplatin/ifosfamide combination and 18 had received the carboplatin/paclitaxel combination [643]. On the question of “off-label use”, see above. 

In patients with recurrent carcinosarcoma, the U.S. Gynecologic Oncology Group (GOG) demonstrated in a series of phase II trials that the highest objective response (OR) rates were achieved with ifosfamide (36%).

Paclitaxel (OR = 18%), cisplatin (OR = 18%), doxorubicin (OR = 9.8%) and topotecan (OR = 10%) were less effective [644].

The combination of ifosfamide and cisplatin improved recurrence-free survival compared with ifosfamide alone in stage III and IV carcinosarcomas (HR = 0.73; CI = 0.55–0.98); overall survival was not significantly improved by the combination (HR = 0.80; CI = 0.60–1.08) [645].

The combination of ifosfamide (ifosfamide 1.6 g/m2 d 1–3, or reduced to 1.2 mg/m2 if pre-radiation) and paclitaxel (135 mg/m2 over 3 hours d 1 i. v.) significantly improved progression-free (HR = 0.71; CI = 0.52–0.97) and overall survival (HR = 0.69; CI = 049–0.97) in stage III and IV carcinosarcomas [646].

In the Cochrane Collaboration meta-analysis [647], combination therapy of ifosfamide and cisplatin or paclitaxel significantly improved PFS (HR = 0.72; CI = 0.58–0.90) and OS (HR = 0.75; CI = 0.60–0.94) compared with ifosfamide monotherapy. Side effects, except for nausea and vomiting (HR = 3.53; CI = 1.33–9.37), were not significantly different in the combination group compared with those in the ifosfamide monotherapy group. 

Specifically, the side effects were: diarrhea/other gastrointestinal toxicities (RR = 1.51, 95%-CI 0.31–7.52); hematologic toxicities (RR = 1.56, 95%-CI 0.84–2.90); genitourinary toxicities (RR = 1.68, 95%-CI 0.54–5.18); cardiovascular toxicities (RR = 0.63, 95%-CI 0.13–3.11); liver toxicities (RR = 2.05, 95%-CI 0.73–5.74); neuropathies (RR = 1.59, 95%-CI 0.99–2.55) [647].

The better tolerated combination of carboplatin and paclitaxel (PC) had similar efficacy to ifosfamide combinations in some phase II trials and in retrospective series, with significantly less toxicity. This combination is currently being compared to the combination of ifosfamide and paclitaxel (PI) by the GOG in a phase III trial. At the abstract level, PC was non-inferior to PI in terms of OS, with longer PFS and comparable QoL [648].

8.1.4 Supportive therapy

8.1.4.1 Supportive measures in connection with system therapy

 The S3 Guideline on supportive therapy for oncology patients addresses the following topics in detail in the context of system therapy:

  • Tumor therapy-induced anemia
  • Prophylaxis of tumor therapy-induced neutropenia with granulopoietic growth factors
  • Tumor therapy-induced nausea and vomiting
  • Tumor therapy-induced diarrhea 
  • Oral mucositis induced by systemic tumor therapy 
  • Tumor therapy induced skin toxicity
  • Neurotoxicity – chemotherapy-induced peripheral neuropathy (CIPN) 
  • Osseous complications
  • Osseous manifestations
  • Drug intervention
  • Surgical intervention
  • Radiotherapeutic intervention
  • Radionuclide therapy
  • Therapy associated osteoporosis
  • Extravasation

(S3 Guideline Supportive therapy in oncology patients long version 1.3 – February 2020 AWMF register number: 032/054OL https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Supportivtherapie/LL_Supportiv_Langversion_1.3.pdf) 

Evidence tables

8.1.1 EvT 8.1

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Martin-Hirsch 2011

Metaanalyse von 7 randomisiert-kontrollierten Studien (Cochrane-Review)

LoE 1

4.556 Frauen mit Endometrium-karzinom insgesamt.

3 Studien: Frauen mit einem Endometrium-karzinom im FIGO Stadium I.

4 Studien: Frauen mit einem fortgeschritteneren Endometrium-karzinom.

Hysterektomie erfolgte vorab (Staging in den Studien gemäß FIGO [vor 1988]).

Summarische Angaben der Interventions-/ Kontrollarme: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Gynaecological Cancer Group Trials Specialised Register, im Cochrane Central Register of Controlled Trials (CENTRAL) Ausgabe 2, 2009. MEDLINE und EMBASE bis 2009/April.

 

 

 

 

 

 

 

 

 

 

Keine adjuvante Therapie mit Progestagenen.

1. Outcome:

Gesamtüberleben.

2. Outcome:

Krankheitsspezifisches Überleben; nicht-krankheitsspezifisches Überleben; kardiovaskulär-spezifisches Überleben; progressionsfreies Überleben; Lebensqualität.

 

Es gibt keine Evidenz, dass adjuvante Progestagene in der Therapie des frühen Endometrium-karzinoms einen Benefit haben.

Effektschätzer:

Metaanalyse von 4 Studien = kein signifikanter Unterschied zwischen adjuvanter Therapie mit Progestagen und keiner derartigen adjuvanten Therapie: RR = 1,00 (95 % CI: 0,85–1,18).

 

Keine Verblindung des auswertenden Studienpersonals angegeben.

Angaben zu Publication Bias vorhanden.

Random-effects-Modell: DerSimonian/Laird-Methode 1986.

Adjuvante Therapie mit Progestagenen (etwa Medroxypro-gesteronacetat oder Hydroxypro-gesteroncaproat).

 

 

8.1.2 EvT 8.3

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Johnson 2011

Metaanalyse von 9 randomisiert-kontrollierten Studien (Cochrane-Review)

LoE 1

2.197 Frauen mit neu diagnostiziertem Endometrium-karzinom insgesamt, welche eine Hysterektomie mit kurativer Intention erhalten hatten und welche für fit genug für eine adjuvante Chemotherapie eingeschätzt wurden.

(Staging in den Studien gemäß FIGO [vor 1988]).

Summarische Angaben der Interventions-/ Kontrollarme: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Ausgabe 3), MEDLINE und EMBASE bis 2010/ August. Zudem Suche in Online-Datenbanken klinischer Studien, grauer Literatur, Kontaktaufnahme zu Experten.

 

 

 

 

 

 

 

 

 

 

 

Andere Behandlung, inklusive keine zusätzliche adjuvante Therapie.

1. Outcome:

Gesamtüberleben.

2. Outcome:

Progressionsfreies Überleben; an welchen Stellen Rezidive auftreten können; Lebensqualität; Nebenwirkungen.

Platinbasierte Chemotherapie ist mit einem schwachen Benefit für progressionsfreies und Gesamtüberleben assoziiert. Zusätzliche Strahlentherapie spielt dabei keine Rolle.

Effektschätzer:

Gesamtüberleben wird durch Chemotherapie signifikant verbessert: RR = 0,88 (95% CI: 0,79–0,99. HR = 0,74 (95 % CI: 0,64–0,89).

Progressionsfreies Überleben

HR = 0,75 (95 % CI: 0,64–0,89).

Zusätzliche Chemotherapie reduziert das Risiko für die Erstmanifestation von Fernmetastasen (RR = 0,79 [95 % CI: 0,68 – 0,92], 5 % Risikoreduktion, Anzahl der notwendigen Behandlungen (NNT) = 20.

Analyse zu pelvinen Metastasen war underpowered (Trend = Vorteil von Kombination Strahlentherapie + Chemotherapie).

Keine Analyse zu potenziellem Publication Bias. Random-effects-Modell: DerSimonian/Laird-Methode 1986. Selection Bias gegen fortgeschrittenes Stadium, inoperable Fälle und palliative Operationen.

Keine Verblindung möglich in den hier analysierten Studiensettings.

Adjuvante Chemotherapie allein oder kombiniert mit einer anderen adjuvanten Therapie.

(5 Studien: Chemotherapie versus nihil nach vorangegangener Hysterektomie + Strahlentherapie.)

(4 Studien: platinbasierte Kombinations-Chemotherapie versus Strahlentherapie.)

 

 

8.1.2 EvT 8.4

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Galaal 2014

Systematischer Review (Cochrane Review) von 4 randomisiert-kontrollierten Studien: LoE 1

1.269 Frauen (ab 18 Jahren) mit einem fortgeschrittenen Endometrium-karzinom FIGO Stadium III/IV.

Operative Zytoreduktion erfolgte vorab.

Genaue Angaben zu Interventions-/ Kontrollarmen: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Gynaecological Cancer Collaborative Review Group’s Trial Register, im the Cochrane Central Register of Controlled Trials (CENTRAL) (Ausgabe 10 2013), MEDLINE und EMBASE bis 2013/November. Zudem Suche in Online-Datenbanken klinischer Studien.

 

1. Outcome:

Gesamtüberleben.

 

2. Outcome:

Progressionsfreies Überleben; Nebenwirkungen.

 

Mit adjuvanter Chemotherapie (Beginn innerhalb von 8 Wochen nach OP) überlebten Patientinnen etwa 25 % länger als nur mit Strahlentherapie nach der OP.

Effektschätzer:

1. Vergleich:

Gesamtüberleben und progressionsfreies Überleben waren länger mit adjuvanter Chemotherapie versus adjuvanter Strahlentherapie (Gesamtüberleben: Hazard Ratio 0,75, 95 % CI: 0,57–0,99, I² = 22 %. Progressionsfreies Überleben: Hazard Ratio 0,74, 95 % CI: 0,59–0,92, I² = 0 %).

2. Vergleich: adjuvante Chemotherapie CPD (Cisplatin/Paclitaxel/Doxorubicin) versus CD (Cisplatin/Doxo-rubicin): Hazard Ratio 0,90, 95 % CI: 0,6– 1,17).

Verblindung in diesem Studiensetting nicht möglich.

Intention-to-treat-Analyse wurde gemacht, wo möglich.

Baseline Treatment war ausgeglichen in: GOG 122, GOG 184.

Angaben zu Publication Bias vorhanden.

1. Vergleich:

Adjuvante Chemotherapie (n = 2 Studien).

Adjuvante Strahlentherapie

2. Vergleich:

Adjuvante Chemotherapie (n = 1 Studie).

Ein sich davon unterscheidendes Chemotherapie-Regime.

3. Vergleich:

Adjuvante Chemotherapie

(n = 0 Studien: 1 Studie ohne Daten).

Adjuvante Chemo-Strahlentherapie-Kombination; Strahlentherapie/
Chemo-Strahlentherapie-Kombination.

Johnson 2011

Metaanalyse von 9 randomisiert-kontrollierten Studien (Cochrane-Review)

LoE 1

2.197 Frauen mit neu diagnostiziertem Endometrium-karzinom insgesamt, welche eine Hysterektomie mit kurativer Intention erhalten hatten und welche für fit genug für eine adjuvante Chemotherapie eingeschätzt wurden.

(Staging in den Studien gemäß FIGO [vor 1988]).

Summarische Angaben der Interventions-/ Kontrollarme: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Ausgabe 3), MEDLINE und EMBASE bis 2010/ August. Zudem Suche in Online-Datenbanken klinischer Studien, grauer Literatur, Kontaktaufnahme zu Experten.

 

 

 

 

 

 

 

 

 

 

 

Andere Behandlung, inklusive keine zusätzliche adjuvante Therapie.

1. Outcome:

Gesamtüberleben.

2. Outcome:

Progressionsfreies Überleben; an welchen Stellen Rezidive auftreten können; Lebensqualität; Nebenwirkungen.

Platinbasierte Chemotherapie ist mit einem schwachen Benefit für progressionsfreies und Gesamtüberleben assoziiert. Zusätzliche Strahlentherapie spielt dabei keine Rolle.

Effektschätzer:

Gesamtüberleben wird durch Chemotherapie signifikant verbessert: RR = 0,88 (95% CI: 0,79–0,99. HR = 0,74 (95 % CI: 0,64–0,89).

Progressionsfreies Überleben

HR = 0,75 (95 % CI: 0,64–0,89).

Zusätzliche Chemotherapie reduziert das Risiko für die Erstmanifestation von Fernmetastasen (RR = 0,79 [95 % CI: 0,68 – 0,92], 5 % Risikoreduktion, Anzahl der notwendigen Behandlungen (NNT) = 20.

Analyse zu pelvinen Metastasen war underpowered (Trend = Vorteil von Kombination Strahlentherapie + Chemotherapie).

Keine Analyse zu potenziellem Publication Bias. Random-effects-Modell: DerSimonian/Laird-Methode 1986. Selection Bias gegen fortgeschrittenes Stadium, inoperable Fälle und palliative Operationen.

Keine Verblindung möglich in den hier analysierten Studiensettings.

Adjuvante Chemotherapie allein oder kombiniert mit einer anderen adjuvanten Therapie.

(5 Studien: Chemotherapie versus nihil nach vorangegangener Hysterektomie + Strahlentherapie.)

(4 Studien: platinbasierte Kombinations-Chemotherapie versus Strahlentherapie.)

 

 

MateiD_2019
Matei, D. et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer. N Engl J Med. 380. 2317-2326. 2019
Population Intervention - Comparison Outcomes/Results
Evidence level:  2

Study type:  Randomized phase 3 trial

Number of Patient:  707

Recruitung Phase:  June 29, 2009, and July 28, 2014

Inclusion Criteria:  Women who were 18 years of age or older and who had surgical stage III or IVA endometrial carcinoma according to FIGO 2009 staging criteria of any histologic subtype or had FIGO 2009 surgical stage I or II clear-cell or serous endometrial carcinoma and peritoneal washings that were positive for cancer cells. Hysterectomy and bilateral salpingo-oophorectomy had to have been performed within 8 weeks before trial entry. No single residual tumor mass could be larger than 2 cm in greatest dimension. Pelvic and paraaortic lymph-node biopsy or dissection was optional. Normal organ function and a GOG performance status score of 2 or lower were required (scores range from 0 to 5, with higher scores reflecting greater disability).

Exclusion Criteria:  Patients with carcinosarcoma or recurrent endometrial carcinoma were excluded.		 Intervention:  6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy)

Comparison:  Six cycles of combination chemotherapy alone		 Primary:  Relapse-free survival

Secondary:  Overall survival, acute and chronic toxic effects, and quality of life

Results:  Relapse free survival
The median follow-up period was 47 months. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Therefore, the null hypothesis that chemoradiotherapy is not superior to chemotherapy alone could not be rejected (P=0.20 by one-tailed test).
Overall survival
A total of 165 deaths have been reported to date — 86 in the chemoradiotherapy group and 79 in the chemotherapy-only group. Of those deaths, 73% and 81%, respectively, were due to endometrial cancer progression. The data on overall survival are not sufficiently mature to allow comparison between the groups.
Recurrence
Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.
Quality of life
After adjustment for age and baseline scores, the leastsquares mean Trial Outcome Index score at 18 weeks in the chemoradiotherapy group was 5.2 points lower (97.5% CI, 2.7 to 7.8) than that in the chemotherapy-only group. The difference in this score remained significant at 70 weeks (3.4 points lower in the chemoradiotherapy group; 97.5% CI, 0.7 to 6.2) but did not exceed the 6-point difference that had been preset as clinically meaningful.


Author's Conclusion:  Chemotherapy plus radiation was not associated with longer relapse-free survival
than chemotherapy alone in patients with stage III or IVA endometrial carcinoma.
Methodical Notes
Funding Sources:  Funded by the National Cancer Institute

COI:  Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org

Randomization:  Randomization was stratified according to age and the presence or
absence of gross residual disease.

Blinding:  Not described

Dropout Rate/ITT-Analysis:  ITT-Analysis was performed

Notes:  Oxford Level of Evidence 2011: EL 2 randomized controlled trial
Blinding was not described, however measures were objective except quality of life and chemotherapy-induced neurotoxic effects.
deBoer_2019
de Boer, S. M. et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 20. 1273-1285. 2019
Population Intervention - Comparison Outcomes/Results
Evidence level:  2

Study type:  Randomized phase 3 trial

Number of Patient:  660

Recruitung Phase:  Between Nov 23, 2006, and Dec 20, 2013

Inclusion Criteria:  Patients were eligible if they had endometrial cancer with either International Federation of Gynecology and Obstetrics (FIGO) 2009 stage 1A endometrioid endometrial cancer grade 3 with documented LVSI; stage IB endometrioid endometrial cancer grade 3; stage II endometrioid endometrial cancer; stage IIIA, IIIB (parametrial invasion), or IIIC endometrioid endometrial cancer; or serous or clear-cell histology endometrial cancer with stages IA (with invasion), IB, II, or III. WHO performance score 0–2; adequate bone marrow function (white blood cells ≥3·0×10⁹/L, platelets ≥100×10⁹/L), liver function (bilirubin ≤1·5×upper normal limit [UNL], aspartate aminotransferase and alanine aminotransferase ≤2·5×UNL), kidney function (creatinine clearance >60 mL per min calculated according to Cockroft and Gault10 or >50 mL per min EDTA clearance), and aged 18 years or older (without an upper age limit, because elderly women might benefit from the study treatment if deemed fit enough to undergo chemotherapy).

Exclusion Criteria:  Exclusion criteria were uterine (carcino)sarcoma; malignancy in the 10 years before diagnosis of endometrial cancer; previous pelvic radiotherapy, hormonal therapy, or chemotherapy; bulky cervical involvement with radical hysterectomy; inflammatory bowel disease; residual macroscopic tumour; impaired renal or cardiac function; grade 2 or worse neuropathy; grade 3 or worse hearing impairment; or congenital hearing disorder		 Intervention:  Chemoradiotherapy

Comparison:  Radiotherapy alone		 Primary:  Overall survival and failure-free survival

Secondary:  Vaginal, pelvic, or distant recurrence; treatment-related toxicity;
and health-related quality of life

Results:  At a median follow-up of 72.6 months (IQR 59.9–85.6), 5-year overall survival was 81.4% (95% CI 77.2–85.8) with chemoradiotherapy versus 76.1% (71.6–80.9) with radiotherapy alone (adjusted hazard ratio [HR] 0.70 [95% CI 0.51–0.97], p=0.034), and 5-year failure-free survival was 76.5% (95% CI 71.5–80.7) versus 69.1% (63.8–73.8; HR 0.70 [0.52–0.94], p=0.016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21.4%; 95% CI 17.3–26.3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29.1%; 24.4–34.3) in the radiotherapy-alone group (HR 0.74 [95% CI 0.55–0.99]; p=0.047). Isolated vaginal recurrence was the first site of recurrence in one patient (0.3%; 95% CI 0.0–2.1) in both groups (HR 0.99 [95% CI 0.06–15.90]; p=0.99), and isolated pelvic recurrence was the first site of recurrence in three women (0.9% [95% CI 0.3–2.8]) in the chemoradiotherapy group versus four (0.9% [95% CI 0.3–2.8]) in the radiotherapy-alone group (HR 0.75 [95% CI 0·17–3·33]; p=0.71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0.24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0.002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.

Author's Conclusion:  This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.
Methodical Notes
Funding Sources:  Funding Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant,
Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

COI:  None.

Randomization:  Patients were randomly allocated (1:1) to chemoradiotherapy or radiotherapy alone. Treatment was allocated with a biased-coin minimisation procedure, ensuring balance overall and within each stratum of the stratification factors (participating centre, lymphadenectomy, stage of cancer, and histological type).

Blinding:  Participants and investigators were not masked to treatment allocation.

Dropout Rate/ITT-Analysis:  All analyses were done by intention to treat, excluding patients who immediately withdrew informed consent and ineligible patients

Notes:  Oxford CEBM Level of Evidence 2011: EL 2 Randomized controlled trial
Post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up of de Boer et al. (2018)
8.1.2 EvT 8.5

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Galaal 2014

Systematischer Review (Cochrane Review) von 4 randomisiert-kontrollierten Studien: LoE 1

1.269 Frauen (ab 18 Jahren) mit einem fortgeschrittenen Endometrium-karzinom FIGO Stadium III/IV.

Operative Zytoreduktion erfolgte vorab.

Genaue Angaben zu Interventions-/ Kontrollarmen: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Gynaecological Cancer Collaborative Review Group’s Trial Register, im the Cochrane Central Register of Controlled Trials (CENTRAL) (Ausgabe 10 2013), MEDLINE und EMBASE bis 2013/November. Zudem Suche in Online-Datenbanken klinischer Studien.

 

1. Outcome:

Gesamtüberleben.

 

2. Outcome:

Progressionsfreies Überleben; Nebenwirkungen.

 

Mit adjuvanter Chemotherapie (Beginn innerhalb von 8 Wochen nach OP) überlebten Patientinnen etwa 25 % länger als nur mit Strahlentherapie nach der OP.

Effektschätzer:

1. Vergleich:

Gesamtüberleben und progressionsfreies Überleben waren länger mit adjuvanter Chemotherapie versus adjuvanter Strahlentherapie (Gesamtüberleben: Hazard Ratio 0,75, 95 % CI: 0,57–0,99, I² = 22 %. Progressionsfreies Überleben: Hazard Ratio 0,74, 95 % CI: 0,59–0,92, I² = 0 %).

2. Vergleich: adjuvante Chemotherapie CPD (Cisplatin/Paclitaxel/Doxorubicin) versus CD (Cisplatin/Doxo-rubicin): Hazard Ratio 0,90, 95 % CI: 0,6– 1,17).

Verblindung in diesem Studiensetting nicht möglich.

Intention-to-treat-Analyse wurde gemacht, wo möglich.

Baseline Treatment war ausgeglichen in: GOG 122, GOG 184.

Angaben zu Publication Bias vorhanden.

1. Vergleich:

Adjuvante Chemotherapie (n = 2 Studien).

Adjuvante Strahlentherapie

2. Vergleich:

Adjuvante Chemotherapie (n = 1 Studie).

Ein sich davon unterscheidendes Chemotherapie-Regime.

3. Vergleich:

Adjuvante Chemotherapie

(n = 0 Studien: 1 Studie ohne Daten).

Adjuvante Chemo-Strahlentherapie-Kombination; Strahlentherapie/
Chemo-Strahlentherapie-Kombination.

Johnson 2011

Metaanalyse von 9 randomisiert-kontrollierten Studien (Cochrane-Review)

LoE 1

2.197 Frauen mit neu diagnostiziertem Endometrium-karzinom insgesamt, welche eine Hysterektomie mit kurativer Intention erhalten hatten und welche für fit genug für eine adjuvante Chemotherapie eingeschätzt wurden.

(Staging in den Studien gemäß FIGO [vor 1988]).

Summarische Angaben der Interventions-/ Kontrollarme: sind in den Einzelstudien zu finden.

Systematische Literatursuche im Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Ausgabe 3), MEDLINE und EMBASE bis 2010/ August. Zudem Suche in Online-Datenbanken klinischer Studien, grauer Literatur, Kontaktaufnahme zu Experten.

 

 

 

 

 

 

 

 

 

 

 

Andere Behandlung, inklusive keine zusätzliche adjuvante Therapie.

1. Outcome:

Gesamtüberleben.

2. Outcome:

Progressionsfreies Überleben; an welchen Stellen Rezidive auftreten können; Lebensqualität; Nebenwirkungen.

Platinbasierte Chemotherapie ist mit einem schwachen Benefit für progressionsfreies und Gesamtüberleben assoziiert. Zusätzliche Strahlentherapie spielt dabei keine Rolle.

Effektschätzer:

Gesamtüberleben wird durch Chemotherapie signifikant verbessert: RR = 0,88 (95% CI: 0,79–0,99. HR = 0,74 (95 % CI: 0,64–0,89).

Progressionsfreies Überleben

HR = 0,75 (95 % CI: 0,64–0,89).

Zusätzliche Chemotherapie reduziert das Risiko für die Erstmanifestation von Fernmetastasen (RR = 0,79 [95 % CI: 0,68 – 0,92], 5 % Risikoreduktion, Anzahl der notwendigen Behandlungen (NNT) = 20.

Analyse zu pelvinen Metastasen war underpowered (Trend = Vorteil von Kombination Strahlentherapie + Chemotherapie).

Keine Analyse zu potenziellem Publication Bias. Random-effects-Modell: DerSimonian/Laird-Methode 1986. Selection Bias gegen fortgeschrittenes Stadium, inoperable Fälle und palliative Operationen.

Keine Verblindung möglich in den hier analysierten Studiensettings.

Adjuvante Chemotherapie allein oder kombiniert mit einer anderen adjuvanten Therapie.

(5 Studien: Chemotherapie versus nihil nach vorangegangener Hysterektomie + Strahlentherapie.)

(4 Studien: platinbasierte Kombinations-Chemotherapie versus Strahlentherapie.)

 

 

LeonCastillo2020
León-Castillo, A. et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. J Clin Oncol. . Jco2000549. 2020
Population Intervention - Comparison Outcomes/Results
Evidence level:  2

Study type:  RCT (phase-III-trial, molecular analysis)

Number of Patient:  FFPE tissue samples of 423 patients of the PORTEC-3 trial!

Recruitung Phase:  n.a.

Inclusion Criteria:  Patients with high-risk EC (endometrioid EC [EEC] grade 3 stage IA with documented
lymphovascular space invasion [LVSI]; EEC grade 3 stage IB; EEC stage II-III; and nonendometrioid invasive EC stages I, II, or III).

Exclusion Criteria:  n.s.		 Intervention:  Of the original PORTEC-trial:
Abdominal or laparoscopic hysterectomy with bilateral salpingooophorectomy was performed on all patients.
Combined adjuvant chemotherapy and EBRT (CTRT, (2 cycles of cisplatin followed by 4 cycles of carboplatin and paclitaxel)) versus EBRT alone.

In this follow-up analysis:

Immunohistochemical staining for p53 and MMR proteins (MLH1, PMS2, MSH2, and MSH6) was performed on all cases. If p53 immunohistochemistry was not evaluable, TP53 mutational status was used (n 5 9; 2.1% of the total 423 EC cases). If MMR immunohistochemistry was not evaluable, microsatellite instability (MSI) was assessed (n 5 8; 1.9%).
Tumors with >1 classifying feature (multiple-classifier EC) were allocated in 1 of the 4 molecular subgroups. ECs with a pathogenic POLE EDM with p53 abnormal expression and/or MMR protein loss were classified as POLEmut EC, whereas ECs with loss of any
MMR protein or MSI-high with a p53 mutant staining pattern were classified as MMRd EC.

Comparison:  See Intervention.		 Primary:  RFS, defined as time from randomization to date of first relapse or death, whichever occurred first.



Secondary:  The secondary end point was overall survival (OS), defined as the time from randomization to date of death of any cause.

Results:  Molecular testing was successful for 410 tumors (=97%). Patient and tumor
characteristics of these 410 ECs were comparable to the original trial population. Median follow-up was 6.1 years (range, 0.52-11.03 years).
Tumors were classified:
1. 93 (22.7%) were p53abn
2. 51 (12.4%) were POLEmut
3. 137 (33.4%) were MMRd
4. 129 (31.5%) were NSMP ECs.

The respective five-year RFS for patients was:
- p53abn EC: 48%
- POLEmut EC: 98%
- MMRd EC: 72% and
- NSMP EC: 74% (P <.001>
The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC.

Author's Conclusion:  In conclusion, our study shows the strong prognostic information the EC molecular classification carries, as well as its great potential to guide adjuvant treatment. It is essential to implement the molecular EC classification in clinical diagnostics and decision-making. Patients with p53abn EC may be considered for adjuvant treatment including chemotherapy, whereas adjuvant treatment de-escalation should be considered for those with POLEmut EC; additional studies are needed especially for MMRd and NSMP EC. Future clinical trials should include molecular subgroups in their design and study specific targeted adjuvant treatments.
Methodical Notes
Funding Sources:  Supported by the Dutch Cancer Society (KWF Kankerbestrijding; Grant No. 10418/2016-1 [T.B.]). E.J.C. is supported by National Institute for Health Research Manchester Biomedical Research Centre (Grant No. ISBRC-1215-20007).

COI:  Declared online-

Randomization:  Patient allocation in the original trial was performed randomly 1:1 to EBRT alone or CTRT.

Blinding:  Sequencing and immunohistochemistry results were evaluated blinded for patient outcome.

Dropout Rate/ITT-Analysis:  If ≥ 1 of the molecular features (p53, MMR, and/or POLE status) could not be determined (eg, not enough tumoral material or testing failed), and thus the molecular subgroup could not be determined, the case was classified as EC, not otherwise specified and excluded from the study (n = 13).
ITT was done, but data not shown.

Notes:  Oxford CEBM Level of Evidence (2011): EL 2 (randomized trial)

This study was not a standard RCT, but a follow up molecular analysis. Limiting factor may be the small study groups, discussed by the authors.
NomuraH_2019
Nomura, H. et al. Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. JAMA Oncol. 5. 833-840. 2019
Population Intervention - Comparison Outcomes/Results
Evidence level:  2

Study type:  Multicenter, open label, phase 3 randomized trial.

Number of Patient:  788 patients were enrolled at 118 clinical sites.

Recruitung Phase:  November 24, 2006, through January 7, 2011.

Inclusion Criteria:  Patients with endometrial cancer at a high risk of progression following surgery.
(1)patients who had undergone total abdominal hysterectomy with bilateral salpingooophorectomy and pelvic lymph node dissection in which the residual tumor was 2 cm or less, (2) patients scheduled to receive chemotherapy within 8 weeks postsurgery, (3) patients without prior chemotherapy or radiotherapy, (4) patients aged between 20 and 74 years at registration, (5) patients having an Eastern Cooperative Oncology Group performance status of 0 to 2, and (6) patients with adequate function of major organs
(eg, bone marrow, heart, liver, kidneys).

Exclusion Criteria:  Sarcomatous component, serious complications, concurrent infection, or a simultaneous cancer or a history of other cancer within the past 5 years.		 Intervention:  docetaxel plus cisplatin or paclitaxel plus carboplatin

Comparison:  doxorubicin plus cisplatin		 Primary:  Progression-free survival (PFS).

Secondary:  Overall survival, occurrence of adverse events (AEs), tolerability of treatment, and status of lymph node dissection.

Results:  AP: 263 patients to the doxorubicin plus cisplatin treatment group,
DP: 263 patients to the docetaxel plus cisplatin treatment group, and
TC: 262 patients to the paclitaxel plus carboplatin treatment group.

After median of follow-up of seven years:
The 5-year PFS was
AP: 73.3%
DP: 79.0%
TC: 73.9% with no significant differences among the 3 groups(2-sided P = .12).
The 5-year overall survival was
AP: 82.7%
DP: 88.1%
TC: 86.1% with no significant differences among the 3 groups (2-sided P = .67).

The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different.

Author's Conclusion:  In conclusion, taxane plus platinum regimens did not demonstrate a survival benefit over treatment with doxorubicin plus cisplatin; therefore, doxorubicin plus cisplatin remains the standard postoperative adjuvant chemotherapy regimen for endometrial cancer at a high risk of progression. Nevertheless, considering efficacy and tolerability, taxane plus platinum regimens may be an alternative to treatment with doxorubicin plus cisplatin.
Methodical Notes
Funding Sources:  See publication

COI:  see publication

Randomization:  1:1:1 ratio using surgical stage (I or II vs III or IV) and tumor histology (G1 or G2 vs G3 or histology with a poor prognosis) as stratification factors.

Blinding:  n.a.

Dropout Rate/ITT-Analysis:  To robustly detect these clinical improvement swith 80% power, which is defined by the probability that the global null hypothesis and any paired null hypotheses were rejected simultaneously, under the aforementioned procedure in an enrollment period of 4 years and a follow-up period of 5 years, 250 patients per treatment group were required in 10 000 simulation studies.The recruitment target was 260 patients with 10 dropouts per treatment group.

Notes:  Oxford CEBM Level of evidence 2011: EL 2 (randomized trial)
8.2 EvT 8.8

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Cantrell 2012

Retrospektive multizentrische Kohortenstudie

LoE 4

111 Frauen mit uterinem Karzinosarkom (94 FIGO I, 17 FIGO II).

Interventionsarm: 52 Frauen insgesamt, im Detail:

adjuvante Chemotherapie: n = 29.

Strahlentherapie: n = 23.

Chemo- + Strahlentherapie: n = 15.

Kontrollarm: 44 Frauen.

Adjuvante Chemotherapie, Strahlentherapie; Chemotherapie + Strahlentherapie.

Staging gemäß FIGO 1988.

Keine.

Progressionsfreies Überleben; Gesamtüberleben.

Bei einem uterinen Karzinosarkom im FIGO I–II Stadium ist Chemotherapie mit verbessertem progressionsfreien Überleben assoziiert, verglichen mit Strahlentherapie oder Zuwarten.

Effektschätzer:

Die multivariate Analyse zeigte, dass Chemotherapie (p = 0,003), Lymphgefäß-invasion (p < 0,0001) und vorherige Krebserkrankung (p = 0,004) prädiktiv für das progressions-freie Überleben waren.

Gesamtüberleben war schwach assoziiert mit Lymphgefäßinvasion, Hazard Ratio: 3,33 (1,31– 8,43; p = 0,01); Chemotherapie, Hazard Ratio 0,35 (0,12 – 1,04; p = 0,058) („In this population, overall survival was not significantly influenced by adjuvant chemotherapy.)

Kleines Kollektiv.

 

 

8.2 EvT 8.9

Referenz

Studientyp/
Evidenzklasse

Untersuchte Population

Intervention

Kontrolle

Untersuchte Endpunkte

Hauptergebnisse

Methodische Bemerkungen

Sutton 2000

Randomisiert-kontrollierte Phase-III-Studie

LoE 4

224 Fälle, davon 194 Frauen mit fortgeschrittenen oder rezidivierenden uterinen Karzinosarkomen eingeschlossen.

Drop-out-Rate: n = 30.

Interventionsarm: 102 Frauen.

Kontrollarm: 92 Frauen.

Ifosfamid (1,5 g/m2/Tag) 5 Tage alle 3 Wochen für 8 Zyklen (+ Zytoprotektor Mesna).

 

Ifosfamid (1,5 g/m2/Tag) 5 Tage alle 3 Wochen für 8 Zyklen (+ Zytoprotektor Mesna) + Cisplatin (20 mg/m2/Tag)1.

Gesamtüberleben; progressionsfreies Überleben.

Die zusätzliche Cisplatin-Gabe zum Ifosfamid-Regime beim fortgeschrittenen uterinen Karzinosarkom scheint eine schwache Verbesserung des progressionsfreien Überlebens zu bieten.

Allerding sprechen die hohen Toxizitäten gegen den Gebrauch dieser Kombination.

Effektschätzer:

Gesamtüberleben:

Kein signifikanter Vorteil, RR = 0,80, 95 % oberes CI: 1,03 (einseitig), p = 0,071.

Progressionsfreies Überleben:

Durch Kombinations-Chemotherapie leicht verbessert, RR = 0,73 (95 % oberes CI: 0,94 (einseitig), p = 0,02.

Mehr und schwerere Nebenwirkungen unter Kombinations-Chemotherapie (p = 0,05)2.

Hohes Risiko für Bias: Allocation Concealment; Selection Blending.

Homesley 2007

Randomisiert-kontrollierte Phase-III-Studie

LoE 2

214 Frauen insgesamt, davon 179 mit persistierendem oder rezidivierendem uterinen Karzinosarkom FIGO Stadium III oder IV.

Interventionsarm: 91 Frauen; 18 % (FIGO Stad. III); 31 % (FIGO Stad. IV); 52 % Rezidiv/Persistenz.

Kontrollarm: 88 Frauen; 18 % (FIGO Stad III); 29 % (FIGO Stad IV); 52 % Re-zidiv/Persistenz.

Drop-out-Rate: n = 35.

Ifosfamid 2,0 g/m2 täglich, über 3 Tage
(+ Zytoprotektor Mesna).

Ifosfamid 1,6 g/m2 täglich, über 3 Tage + Paclitaxel 135 mg/m2 als dreistündige Infusion am 1. Tag
+ Filgrastim ab Tag 4
(+ Zytoprotektor Mesna).

Progressionsfreies Überleben; Gesamtüberleben.

Kombinations-Chemotherapie verbesserte das Gesamtüberleben signifikant, wenn auch letztlich nur schwach bei dieser Entität.

Effektschätzer:

Medianes progressionsfreies Überleben:

Nur Ifosfamid = 3,6 Monate versus 5,8 Monate (Kombinations-Chemotherapie).

Medianes Gesamtüberleben:

Nur Ifosfamid = 8,4 Monate versus 13,5 Monate (Kombinations-Chemotherapie).

31 % Rückgang des Sterblichkeits-risikos Hazard Ratio = 0,69; 95 % CI: 0,49–0,97; p = 0,03) und 29 % Rückgang des Progressions-risikos Hazard Ratio = 0,71; 9 5% CI: 0,51–0,97; p = 0,03) in der Kombinations-Chemotherapie-Gruppe.

------------------------------

Galaal 2013

Systematischer Review (Cochrane Review) von 3 randomisiert-kontrollierten Studien: Homesley et al. 2007; Sutton et al. 2000; Wolfson et al. 2007

LoE 1

579 Frauen mit einem uterinen Karzinosarkom.

Operatives Staging erfolgte vorab (gemäß FIGO 2009).

Ifosfamid: 18 % Stage III, 31 % Stage IV, 52 % rezidivierende oder persistierende Erkrankung.

Ifosfamid + Paclitaxel: 18 % Stage III, 29 % Stage IV, 52 % Rezidiv/Persistenz.

Summarische Angaben der Interventions-/ Kontrollarme: sind in den Einzelstudien zu finden.

 

Systematische Literatursuche im Cochrane Gynaecological Cancer Group Trials Register, im Cochrane Central Register of Controlled Trials (CENTRAL), 2012, Ausgabe 10, MEDLINE und EMBASE bis 2012/ November. Zudem Suche in Online-Datenbanken klinischer Studien, grauer Literatur, Kontaktaufnahme zu Experten.

 

1. Outcome: Gesamtüberleben.

2. Outcome: progressionsfreies Überleben.

 

Die adjuvante Kombinations-Chemotherapie ist besser als Ifosfamid alleine; zusätzliche Strahlentherapie bleibt ohne Nutzen (2 Studien/373 Frauen).

Effektschätzer:

Mono-Chemo- versus Kombinations-Chemotherapie:

Gesamtüberleben:

Hazard Ratio = 0,75, 95 % CI: 0,60–0,94.

Progressionsfreies Überleben:

Hazard Ratio = 0,72, 95 % CI: 0,58–0,90.

Signifikant mehr Nebenwirkungen in der Kombinations-Chemotherapie-Gruppe: RR = 3,53, 95 % CI: 1,33–9,37.

Strahlentherapie + Kombinations-Chemotherapie = kein statistisch signifikanter Unterschied von Sterblichkeitsrisiko und Fortschreiten der Erkrankung (Gesamtüberleben: HR = 0,71, 95 %CI: 0,48–1,05; progressionsfreies Überleben: HR = 0,79, 95 % CI: 0,53–1,18) (1 Studie/206 Frauen).

Evidenzgrad der eingeschlossenen Studien: LoE 2–4.

Angaben zu Publication Bias vorhanden; Random-effects-Modell wurde verwendet.

Nomenklatur hier zur üblichen abweichend: „whole body irradiation“ statt „whole abdominal irradiation“.

1. Adjuvante Strahlentherapie versus Kombinations-Chemotherapie.

2. Adjuvante Mono-Chemotherapie versus Kombinations-Chemotherapie.

Nur Operation.

Best Supportive Care.

 

 

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