9. Follow-up/recurrence/metastases of endometrial carcinoma – Endometrial Cancer
9.1 Approaches in follow-up
A medical history with specific query of symptoms and clinical gynecological examination with speculum and rectovaginal palpation examination should be performed at 3- to 6-month intervals for the first 3 years after completion of primary therapy and semi-annually in years four and five.
- Consensus
- Strong consensus
Imaging studies and tumor marker determinations should not be performed in asymptomatic patients.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 4
- Consensus
- Consent
- References
- [649] [653] [654] [219]
Evidence tables (1)
9.1 EvT 9.3Background
The follow-up of patients with EC serves the early detection of a recurrence, which can be treated with curative intention, e.g. in case of an isolated vaginal tumor manifestation. Furthermore, since patients with EC and their relatives face physical, psychological, sexual, social, and spiritual/religious stresses, the need for psychosocial, psycho-oncological, and sexual medicine counseling should be actively sought during follow-up and, if necessary, provided by a multiprofessional team. See Chapter 11.
EC recurs in about 13% of all cases, and in low-risk cases even in only < 3% of cases [658]. Some retrospective studies show that more asymptomatic than symptomatic recurrences are detected by organized follow-up programs. This means that systematized follow-up can identify recurrences earlier than in women who present for medical evaluation only when they have symptoms such as vaginal bleeding or pain, independent of a follow-up program. For those patients who present for treatment with an asymptomatic recurrence, longer survival times have been reported in some cases [656], [657], [659]. These findings, obtained from retrospective analyses, are the rationale for regular follow-up at initially closer intervals after completion of primary therapy for EC, with a focus on detection of recurrence of the vagina, vulva or pelvis that is still amenable to curative treatment. However, it is not proven whether the longer survival in asymptomatic women in the aforementioned studies can be explained by the advance time of recurrence diagnosis (so-called “lead time bias”) or by earlier therapy after recurrence diagnosis.
In a review of the above retrospective cohort studies, Salani et al. [655] describe a detection rate for vaginal recurrence by gynecologic examination including rectovaginal palpation of 35% to 68%. Therefore, regular gynecologic examination including rectovaginal palpation may be performed as part of follow-up. Cytologic smear of the vaginal blind sac leads to the diagnosis of recurrence in only 0% to 13% of asymptomatic patients with recurrence [657]and therefore does not appear to be a useful measure. Furthermore, the use of cytological smear in the follow-up of women with EC is not cost-effective [650].
In the aforementioned review, Salani et al. [655] put the proportion of women with symptomatic recurrence at 41% to 83%. Depending on the study, 68% to 100% of recurrences occurred within the first three years after the end of primary therapy. Approximately half were either local recurrences (vagina and pelvis) or distant metastases. Yalamanchi et al. 2018 and Nomura et al. 2019 found the proportion of isolated vaginal recurrences to be 20% and 37%, respectively, in their study collectives [660]; [661]. Patients with isolated vaginal recurrence had a 3-year survival rate after isolated vaginal recurrence of 73% versus 14% in the case of pelvic recurrence and 8% in the case of distant metastasis in the prospective randomized PORTEC-1 trial (comparing adjuvant pelvic radiotherapy with no adjuvant therapy for early endometrial cancer) [652].
In a systematic review of 16 retrospective cohort studies, no advantage was found for the detection of recurrence by intensified imaging follow-up in terms of overall survival [658]. Therefore, Dutch and US guidelines do not recommend routine imaging in the follow-up of women with EC [219], [229], [655]. Along the same lines, a retrospective analysis of 149 women for asymptomatic recurrences, 80% of which were detected by imaging, showed no advantage in overall survival and recurrence-free survival over symptomatic recurrences [660].
Ultrasound has not been studied as a tool in the follow-up of endometrial cancer in the last 15 years. An older work has shown high detection rates for recurrences of gynecologic malignancies for the combination of a transvaginal and transabdominal ultrasound [662]. Abdominal ultrasonography also allows early diagnosis of urinary retention, which can occur as a complication of surgery or radiation therapy in addition to tumor recurrence. Ultrasound has numerous advantages due to its general availability in gynecologic practices, ease and speed of use, low cost and lack of radiation exposure, so this examination method can be used in the follow-up of endometrial cancer.
The importance of tumor markers in the follow-up of women with EC is unclear. In an older work from 1995, the tumor marker CA 125 was elevated in only 6/23 asymptomatic recurrence cases, especially with non-endometrioid histology and after advanced tumor stage [654].
Current studies address the question of whether follow-up in high risk recurrence should be intensified and performed with regular imaging [663] or, conversely, whether follow-up in low risk EC can be patient-directed or designed by telephone interviews. Three randomized studies showed higher patient satisfaction when follow-up of stage I EC was performed by telephone interviews or when patients instructed on critical symptoms were able to initiate appropriate examinations themselves [664], [665], [666]. These studies are also potentially relevant in terms of cost savings for the health care system [666].
In a Cochrane review on the follow-up of different tumor entities, 20,832 cases of adult female patients were evaluated, including 4 studies with 770 cases after EC [667]. Different intensity follow-up modalities (e.g. follow-up by specialist vs. non-specialist or nursing, closer and more elaborate protocols vs. simple clinical examination and follow-up with or without additional educational programs) were compared with each other in terms of quality of life, cost, time interval between primary therapy and recurrence diagnosis, and overall survival. The authors saw no detectable effect on overall survival, quality of life and costs.
A scientific topic of interest in the follow-up of different tumor entities is the improvement or replacement of follow-up by so-called “cancer survivorship plans” (CSP), which aim to support patients in their physical, psychological, social and economic rehabilitation by providing concrete instructions. In a prospective study in 12 Dutch hospitals with 221 patients after EC, patients felt better informed during follow-up with CSP but were also more concerned and dissatisfied [668].
In summary, there are currently no convincing data to support the introduction of alternative follow-up strategies.
9.2 Procedure for locoregional recurrences
If local recurrence in the vagina or pelvis is suspected or if distant metastases are suspected, histological confirmation shall be sought.
- Consensus
- Strong consensus
Cross-sectional imaging shall be performed if vaginal recurrence, pelvic recurrence or distant metastasis is suspected or after histologic confirmation of vaginal recurrence, pelvic recurrence or distant metastasis.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [669] [217] [219]
Evidence tables (1)
9.2 EvT 9.5Background
At least half of all cases of women with EC recurrence are noticed by symptoms outside the follow-up examinations. If possible, histologic confirmation shall be sought in cases of suspected recurrence, and the most accurate diagnosis of spread should be pursued to protect the patient from unnecessary, burdensome therapy.
Reliable data from randomized trials on the value of different imaging modalities or other follow-up in symptomatic women with EC in terms of response rate, overall survival, survival duration or time to further progression after completion of recurrent therapy are not available.
In 2013, Kadkhodayan et al. [670] investigated the detection of EC recurrence by PET-CT in a meta-analysis: in 11 cohort studies with 541 symptomatic and asymptomatic patients, a sensitivity of 95.8% (95%-CI 92.2–98.1%) and a specificity of 92.5% (89.3– 94.9%) were found for PET-CT. These parameters were verified by a so-called combined reference standard, i.e., partly by histological examination of lesions suspected of recurrence and partly by follow-up of lesions on imaging. An increase in size of a lesion was considered a confirmation of suspected malignancy, whereas a decrease in size without therapy or a lack of change in size during progression was considered tumor-negative. PET-CT results led to a change in treatment plan in 22–35% of patients.
Another meta-analysis confirmed the high sensitivity and specificity of 18F-FDG PET/CT (95% and 91%, respectively) for the diagnosis of EC recurrence, although the studies evaluated were predominantly retrospective and did not distinguish between symptomatic and asymptomatic recurrences. Not all cases were verified by histologic examination [671].
Transabdominal sonography is of limited use for recurrence detection in the lesser pelvis and retroperitoneum due to intestinal gas superimposition, among other reasons, whereas MRI and CT are examination methods free of superimposition.
In summary, the value of cross-sectional imaging and especially PET-CT lies primarily in the more accurate diagnosis of tumor spread when recurrence is confirmed. This may help to avoid unnecessary recurrence surgery or optimize the individual therapy plan. The ACR guideline calls sectional imaging by PET-CT, MRI and CT suitable (“usually appropriate”) for recurrence diagnosis of EC [210].
9.2.1 Isolated vaginal or vaginal stump recurrence.
Women with isolated vaginal or vaginal stump recurrence after endometrial cancer without prior radiation therapy as part of primary treatment should receive radiation therapy with curative intent, consisting of external pelvic radiation and brachytherapy with or without local tumor resection.
- Consensus
- Strong consensus
Women with isolated vaginal or vaginal stump recurrence after endometrial cancer with adjuvant brachytherapy alone as part of primary treatment, radiotherapy with or without local tumor resection may be given with curative intent.
- Consensus
- Strong consensus
Women with vaginal or vaginal stump recurrence in status post external pelvic irradiation with or without brachytherapy, should be evaluated to determine whether new radiotherapy as external irradiation or brachytherapy with or without local tumor resection in curative intention is possible.
- Consensus
- Strong consensus
Local late effects of radiotherapy shall be treated according to the S3 Guideline “Supportive therapy in oncology patients” [Wright, J. D. et al. 2008]. *
* See also chapter 8.1.4 „Supportive therapy“.
- Consensus
- Strong consensus
Background
Patients with isolated vaginal stump recurrence after EC without adjuvant radiotherapeutic pretreatment or at least without adjuvant percutaneous radiotherapy in the history can be treated by radiotherapy and/or by surgical tumor resection.
Randomized comparative studies on the superiority of either treatment option are not available. Provided that radiotherapy has not been administered previously in the adjuvant setting, radiotherapy may achieve durable remission.
In the PORTEC-1 trial, 32 of the previously non-radiated patients developed isolated vaginal stump recurrence [672]. Of these, 30 patients were treated with curative intent, and of these 24 were treated with radiotherapy alone, two with surgery alone, three with surgery and radiotherapy and one with radiotherapy and endocrine therapy. Details of radiotherapy (dose of external pelvic radiation, combination with brachytherapy) were not provided. The overall rate of complete remission after salvage radiotherapy and/or salvage tumor resection was 87% (26/30). The 5-year survival rate in this group of patients treated adjuvantly without radiation and for vaginal recurrence with curative intent was 65%.
In 2014, Vargo et al [673] retrospectively studied an adjuvantly nonirradiated cohort with isolated vaginal stump recurrence treated with an external pelvic irradiation (median dose 45 Gy in IMRT technique) and image-guided brachytherapy (median 24 Gy in 5 fractions) approach. After a follow-up of 3 years, local control was 95% and recurrence-free survival was 68%. Hardarson et al. [674] studied a collective of 31 radiation-naive patients with isolated vaginal recurrence. In 26 patients who received radiotherapy, the 2-year progression rate was 40% versus 0% in 5 patients treated by tumor resection. Jereczek-Fossa et al. [675] put the 3-year survival rate of 73 radiation-naive patients with vaginal stump recurrence after salvage radiotherapy (predominantly combined brachytherapy and teletherapy) at 62% for recurrences confined to the vaginal epithelium and 53% for recurrences with subvaginal infiltration.
Ng et al. [676] report complete remission in 6/6 patients treated with re-radiation therapy (external only, brachytherapy only or combination ) with or without tumor resection for isolated vaginal stump recurrence after adjuvant brachytherapy alone as part of primary therapy. Thus, according to the data of the aforementioned case series, irradiation of vaginal recurrence appears to be the first-line therapy, unless percutaneous radiotherapy has been performed previously. However, due to the retrospective nature of the studies and the small number of subjects, the evidence base is very low.
The combination of high-dose brachytherapy with teletherapy (mean EQD2 dose of 68.3 Gray) achieved a 5-year survival rate of 77% and a cancer-specific 5-year survival rate of 83% in 30 patients with isolated vaginal EC recurrence without prior adjuvant radiotherapy [677].
9.3 Surgical therapy of the recurrence
Provided that complete resection of the recurrent tumor appears achievable and cross-sectional imaging has shown no evidence of distant metastasis, surgical therapy for endometrial cancer recurrence can be performed.
- Consensus
- Strong consensus
Exenteration has not been shown to improve duration fof survival, survival rate or progression-free survival in women with recurrence after endometrial cancer compared with other therapies or best supportive care.
- Consensus
- Consent
Exenteration may be considered in individual cases in women with recurrence after endometrial cancer.
- Consensus
- Strong consensus
Background
Surgical therapy is also available for the treatment of EC recurrence, but this has never been investigated in prospective studies. In a 2010 retrospective study of 14 cohorts with advanced or recurrent EC (n = 672), Barlin et al. [574] demonstrated that, on univariate analysis, progression-free survival and overall survival are significantly improved when surgery achieves complete removal of the recurrent tumor. Comparing the cohorts studied, each 10% increase in recurrences operated on macroscopically free of tumor resulted in a 9.3-month improvement in overall survival (p = 0.04) [574].
The safety and efficacy of exenteration for recurrence after EC is poorly established. A 2014 systematic literature review by the Cochrane Collaboration did not identify a single controlled trial assessing the safety and effectiveness of exenteration in women with recurrence after gynecologic malignancies [678].
In retrospective case series, high success rates after exenteration were found in selected patients. For example, Andikyan et al. [679] reported a 100% rate of complete cytoreductions after anterior exenteration with complete colpectomy [679] in 11 patients from Memorial Sloan-Kettering Cancer Center with tumor persistence or recurrence after gynecologic malignancies (3 of whom had EC). However, in this case series, the median tumor size was only 0.9 cm, suggesting a highly selected patient population.
Chiantera et al. [680] reported on 21 gynecologic patients treated with exenteration in a retrospective cohort study, reporting a perioperative mortality rate of 5% and a serious complication rate of 43% [680]. In another study of a larger collective of 230 patients with various locally advanced or recurrent gynecologic carcinomas, perioperative mortality after exenteration was 3% and the rate of serious complications was 21% [681] (Note: the aforementioned study examined only endometrial carcinomas; the latter examined various malignancies). In the subgroup of 28 patients with endometrial carcinomas operated on by exenteration, the 5-year survival was 40%, which increased to 53% if macroscopic complete tumor resection was achieved by surgery.
Brain metastases of EC are rare events with an incidence of < 1% of all recurrences. Two case series and a meta-analysis have recently been published [682][683]. In the meta-analysis by Beucler, 87 cases were retrospectively studied. Median overall survival was significantly longer after combined surgical and radiotherapeutic treatment, 15 months, compared with radiotherapeutic or surgical treatment alone (5.2 and 4.8 months, respectively). Prognostic favorable factors were the presence of singular brain metastases and extracranially stable EC disease.
9.4 Endocrine therapy in recurrence
There is no evidence that endocrine therapy improves duration of survival or survival rate or progression-free survival in women with recurrence after endometrial cancer compared with other therapies or best supportive care.
- Consensus
- Strong consensus (100%)
Endocrine therapy with MPA (200-250 mg/d) or MGA (160 mg/d) or tamoxifen (20 mg/d or 40 mg/d) or a combination of tamoxifen and MPA/MGA can be given to women with recurrence after endometrial cancer.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 3
- Consensus
- Strong consensus (100%)
- References
- [684] [685] [686] [38] [687]
Change note
Endocrine therapy with MPA (200 mg/d) or MGA (160 mg/d) can be given to women with recurrence after ECIn women with recurrence after endometrial cancer, endocrine therapy with MPA or tamoxifen results in higher response rates when progesterone receptor expression or estrogen receptor expression or well to-moderate tumor differentiation (G1/G2) is detectable.
Change note
In women with recurrence after EC, endocrine therapy with MPA results in higher response rates when progesterone receptor expression or estrogen receptor expression or good-to-moderate tumor differentiation (G1/G2) is detectable.Evidence tables (1)
9.4 EvT 9.14Background
A commonly used therapy in women with EC recurrence and reduced general health or advanced age is endocrine therapy with progestogens (e.g., medroxyprogesterone acetate [MPA], megestrol acetate [MGA]) or tamoxifen. However, the efficacy of endocrine therapy for recurrence after EC versus chemotherapy or “Best Supportive Care” has not been established by controlled trials.
A 2010 systematic literature review by the Cochrane Collaboration identified 6 randomized trials assessing the safety and effectiveness of endocrine therapy in women with primary advanced EC or recurrence after EC [689]. None of the studies reviewed compared endocrine therapy with systemic chemotherapy or “Best Supportive Care”. High-dose MPA (1000 mg/d) was surprisingly associated with a significantly increased risk of mortality and a shortened progression-free interval compared with lower-dose MPA (200 mg/d). Hormone replacement therapy in addition to chemotherapy or radiotherapy provided no benefit. Similarly, a combination of tamoxifen and megestrol acetate resulted in no benefit over megestrol acetate alone.
A recent review reported response rates for tamoxifen ranging from 10% to 53%, and for combination therapy with tamoxifen and a progestin ranging from 19% to 58% [38]. The authors note that response rates can be increased by selecting patients with well- or moderately-differentiated endometrioid adenocarcinomas with progesterone and/or estrogen receptor expression.
In a systematic review with a meta-analysis of 39 retrospective studies of endocrine therapy for EC, Ethier et al. described a response rate (ORR) of recurrent EC to progestins and tamoxifen or to the combination thereof of 21% in first-line treatment. Aromatase inhibitors achieved an ORR of 8%. Response was significantly higher in EC with positive hormone receptors and in low-gradecarcinomas. A limitation of the meta-analysis is the lack of standardization of hormone receptor determination. Jerzak et al. refer to different response rates of EC to endocrine therapy depending on different isoforms of hormone receptors [687].
Since the biological characteristics of the tumor may change during progression, reassessment of receptors and grading on recurrent tissue seems reasonable.
Endocrine therapy is an alternative to chemotherapy worth considering in elderly and multimorbid EC patients because of the few side effects. Therefore, the decision to perform endocrine therapy can be made considering individual decision criteria and with reference to the good tolerability.
Similar to hormone receptor-positive breast carcinoma, targeted therapies to inhibit the PI3K/AKT/mTOR pathway and cyclin-dependent kinases have been investigated in advanced EC [690].
9.5 Chemotherapy for recurrence
Chemotherapy can be given to women with locally non-treatable endometrial cancer recurrence or distant metastasis.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [691] [219]
Change note
Systemic chemotherapy may be given to women with EC recurrence that cannot be treated locally or distant metastasis.Evidence tables (1)
9.5 EvT 9.16The superiority of a particular chemotherapy regimen in women with recurrence after endometrial carcinoma has not been established. The carboplatin/paclitaxel and doxorubicin/cisplatin/paclitaxel combinations have been shown to be equally effective agents for chemotherapeutic therapy of advanced or recurrent endometrial carcinoma. Because of better tolerability, carboplatin (AUC 6) should be used with paclitaxel (175 mg/m2).
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
- Consensus
- Strong consensus (100%)
- References
- [691] [636]
Change note
The superiority of a particular chemotherapy regimen in women with recurrence after EC has not been established. Platinum salts, anthracyclines, and taxanes are considered the most effective agents for chemotherapeutic therapy of advanced or recurrent EC. The combination of carboplatin with paclitaxel has been established as a relatively well-tolerated and safe therapy.Evidence tables (1)
9.5 EvT 9.17Background
The safety and efficacy of systemic chemotherapy for recurrence after EC, in contrast to surgical therapy and hormone replacement therapy, has been investigated in a large number of randomized trials. However, there are no studies comparing chemotherapy with best supportive care, endocrine treatment or other non-chemotherapy treatment interventions.
A 2012 systematic literature review by the Cochrane Collaboration identified 14 randomized trials assessing the safety and effectiveness of systemic chemotherapy in women with primary advanced EC or recurrence after EC [692]. Eight randomized trials including 1,519 patients compared combination chemotherapies (doublet and triplet combinations) with less intensive chemotherapy regimens. In a meta-analysis of these eight trials, more intensive chemotherapy significantly increased overall survival and duration of progression-free survival. Specifically, more intensive chemotherapy reduced the relative risk of mortality by 14%. However, the difference in median survival was only 1.5 months in favor of combination chemotherapies. More intensive chemotherapy regimens also resulted in significantly higher toxicity, especially myelosuppression and gastrointestinal side effects.
The other randomized trials in this meta-analysis compared different chemotherapy doublets or different single-substance regimens. No differences were seen, so an optimal chemotherapy agent or chemotherapy combination cannot be recommended. Active agents are doxorubicin, cisplatin, carboplatin, cyclophosphamide, paclitaxel, docetaxel, methotrexate, vinblastine and ifosfamide.
In recent years, the combination of carboplatin and paclitaxel has been established in practice as a relatively well-tolerated and safe therapy.
A prospective randomized phase III trial of 1381 patients with primary advanced or recurrent EC compared the two regimens carboplatin (AUC 6) and paclitaxel (175 mg/m2) q1, d21 x 7 and doxorubicin (45 mg/m2; d1), cisplatin (50 mg/m2; d1), paclitaxel (160 mg/m2; d2) + granulocyte colony-stimulating factor (GCSF) [636]. Non-inferiority in terms of overall survival and progression-free survival and better tolerability for the carboplatin/paclitaxel regimen were shown.
In a retrospective analysis of 216 patients in the SGSG012/GOTIC004/INTERGROUP trial, Nagao et al. [693] reported that the sequence 1) platinum/taxane palliative after platinum/taxane adjuvant was more effective than the sequence 2) platinum/taxane palliative after anthracycline/platinum adjuvant or the sequence 3) anthracycline/platinum palliative after platinum/taxane adjuvant. Progression-free interval and overall survival were significantly longer after sequence 1) treatment at 10 and 48 months than after sequence 2) at 9 and 23 months and 3 and 12 months after sequence 3), respectively [693].
9.6 Immunotherapy for recurrence of EC
In patients with locally advanced or recurrent serous endometrial cancer with her2/neu overexpression, systemic chemotherapy with carboplatin (AUC 5) and paclitaxel (175 mg/m2) combined with trastuzumab (8 mg/kg as initial dose, followed by 6 mg/kg as maintenance therapy) can be given.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [294]
Patients with recurrent or primary advanced endometrial cancer with microsatellite-stable/mismatch-repair functional tumor tissue and progression after at least one line of chemotherapy should receive combined immune and multikinase inhibitor therapy with pembrolizumab (200 mg i.v. d1, q21 or 400 mg i.v. d1, q42) and lenvatinib (20 mg p.o. 1 x daily). The high toxicity should be noted.
In patients with recurrent or primary advanced endometrial cancer with microsatellite unstable/mismatch repair deficient tumor tissue (MSI-H or dMMR), immunotherapy with dostarlimab (4 cycles 500mg i.v. d1, q3w followed by 1000mg i.v. d1, q6w) or with pembrolizumab (200 mg i.v. d1, q21 or 400 mg i.v. d1, q42). Can be performed after preceding platinum-based therapy.
Background
Approximately 30% of all serous EC overexpress her2/neu and thus exhibit an “actionable target” for targeted therapy with trastuzumab. In a randomized phase II trial of 61 subjects with serous EC (FIGO stage III/IV or recurrence) and her2/neu overexpression, therapy with trastuzumab during and after carboplatin/paclitaxel significantly improved progression-free survival (8.0 months vs. 12.9 months) and overall survival (24.4 months vs. 29.6 months) [294]. Subjects with FIGO stage III/IV benefited in terms of progression-free survival and overall survival, while subjects with recurrence benefited only in terms of progression-free survival.
EC, and particularly variants with mismatch repair deficiency (dMMR) and/or microsatellite instability (MSI-H), are “mutation-prone” tumors with increased expression of antigens, making them a target for immunotherapeutic approaches in general and immune checkpoint inhibitors in particular [696]. Approximately 13% to 30% of EC recurrences show mismatch repair deficiency (dMMR) and/or microsatellite instability [363].
In the KEYNOTE-158 trial of 49 patients with EC recurrence with dMMR or MSI-H, pembrolizumab monotherapy achieved a response rate of 57% and a complete response rate of 16% (8/49 patients) [697]. 3/49 patients showed grade 4 toxicity (Guillain-Barré syndrome, liver dysfunction, neutropenia). In the Garnet trial, another non-randomized phase 1 study with a PD-1 directed antibody, 71 patients were treated with dMMR/MSI-H EC. In the post-platinum chemotherapy condition, dostarlimab was given as intravenous monotherapy at 500 mg i.v. d1, q21 for 4 cycles, followed by 1000mg i.v. q42. In a preliminary analysis of efficacy and toxicity data, a response rate of 42% and complete remission of 13% were found after a median follow-up of 11.2 months [698]. The authors highlighted long-lasting efficacy in “responders” and acceptable toxicity with only 1.9% treatment discontinuations due to treatment-related serious adverse events. Another phase 2 trial evaluated the PD-L1 directed antibody avelumab in EC relapse and found virtually no clinical effect in tumors without microsatellite instability. Among the 15 cases with dMMR/MSI-H, 3 partial remissions and one complete remission were observed [699].
However, since the majority of EC recurrences do not have microsatellite instability and monotherapy with an immune checkpoint inhibitor has proven to be ineffective in these, new combinations are currently being tested. Combination therapy of pembrolizumab and lenvatinib, an oral multikinase inhibitor, was investigated in the KEYNOTE-146 trial [694]. In 94 patients with MMR-proficient (i.e. non-dMMR) EC relapse or primary advanced EC, combination therapy achieved a response rate of 36%. However, grade 3-/4 toxicities were observed in 69% of cases, and 2 deaths were classified as treatment-related.
The acceptable discontinuation rate of 17.7% could be achieved only by a high rate of dose reductions.
These results could be confirmed in the randomized phase III study KEYNOTE-775. Here, combination therapy of pembrolizumab and lenvatinib was evaluated versus investigator's choice of chemotherapy (doxorubicin or paclitaxel). Dual primary endpoints were defined as overall survival (OS) and progression-free survival (PFS).
For the combination therapy of pembrolizumab and lenvatinib, median overall survival was shown to be prolonged compared with chemotherapy in both the pMMR population (N=697) and the overall population (pMMR and dMMR populations, N=827) [pMMR population: 17.4 vs. 12.0 months (HR=0.68; P< 0.001); overall population: 18.3 vs. 11.4 months (HR=0.62; P< 0.001)].
Median PFS also showed an advantage for combination therapy in both the pMMR [6.6 vs. 3.8 months (HR=0.60; P< 0.001)] and overall populations [7.2 vs. 3.8 months (HR = 0.56; P< 0.001)].
The safety profile of combination therapy was consistent with the known profile from prior studies [695].
Thus, immunotherapy has expanded the treatment spectrum of recurrent EC, for which there was no standard of second-line treatment until recently. Phase III data are available on combination therapy of pembrolizumab with lenvatinib (KEYNOTE-775). Additional phase III data on pembrolizumab, lenvatinib, dostarlimab and atezolizumab (LEAP-001, NRG-GY018, RUBY, AtTEND) are expected [695].
The use of trastuzumab and avelumab in women with EC recurrence is an off-label use. This must be taken into account in education and therapy implementation (case-by-case review by the medical service). Pembrolizumab, dostarlimab (each as monotherapy) and the combination of pembrolizumab with lenvatinib have been approved by the EMA.
For palliative chemotherapy of carcinosarcoma of the endometrium, see Chapter 8.
9.7 Post-actinic changes in the irradiation field
9.7.1 Vaginal atrophy
Symptoms of vaginal atrophy in patients after therapy for endometrial cancer shall be treated primarily with inert lubricating gels or creams.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [700]
Evidence tables (1)
9.6.1 EvT 9.18Background
Percutaneous radiotherapy of the lesser pelvis and brachytherapy in the treatment of EC can lead to acute (mucositis, ulceration, necrosis formation, cystitis, proctitis) and chronic post-actinic changes in the radiation field (atrophic vaginitis, telangiectasia, vaginal stenosis, shortening/obliteration of the vagina, fistula formation, urethral stricture) [701]. This can lead to significant dysfunction (vaginal dryness, dyspareunia, post-coital bleeding, urge and stress urinary incontinence), and thus impaired sexuality and quality of life. Therapeutic options include antiseptic vaginal irrigation, inert lubricating gels and creams, locally and systemically administered estrogens, vaginal dilators, hyperbaric oxygen treatments and surgical measures.
Because of inconclusive data in this regard, an increase in the risk of recurrence by local estrogen application after treated endometrial carcinoma cannot be excluded [702], [703], [704], [705]. Therefore, for first-line treatment of symptoms of atrophic vaginitis, non-estrogen-containing lubricating gels (water-, glycerin-, silicone- or hyaluronic acid-based) and/or moisturizers are recommended [706]. PH-stabilized preparations with a pH of 4 to 4.5 (lactic acid) have proven particularly effective in treating atrophic vaginitis in breast cancer patients [707].
9.7.2 Local estrogen treatment
Local estrogen treatment after primary therapy for endometrial cancer may be considered, after unsatisfactory treatment with inert lubricating gels or creams.
- Consensus
- Consent
Background
The beneficial effect of local estrogens on contact bleeding and dyspareunia after radiotherapy of the vagina was shown as early as 1971 by Pitkin et al. [708], in a study involving patients after cervical carcinoma. In a meta-analysis, the rehabilitation of sexual function after radiotherapy of the lesser pelvis by local and systemic estrogen application could be confirmed [709]. In contrast, Hintz et al. [710] demonstrated that locally administered estrogens can be reabsorbed by the irradiated vaginal skin and thus become systemically effective. In this context, transvaginal absorption of estrogens seems to occur much more slowly after radiotherapy [711].
In various retrospective cohort studies and case-control studies, an increased recurrence rate in EC of stages I and II could neither be demonstrated for the local (vaginal) use of estrogens [705] nor for systemic hormone replacement therapy (HRT) (compilation of studies at [712]; [713]; [704]. Nevertheless, the overall data situation appears to be too weak to pronounce a harmlessness with regard to the oncological risk for local and systemic hormone application. The authors of the Cochrane analysis on systemic HRT after EC recommended an individualized approach taking into account the patient's symptoms/preferences. This was due to insufficient evidence regarding the possible benefits or potential risks of estrogen treatment after primary therapy of EC in FIGO stage I. No information was found in the literature regarding the impact of HRT in patients after treatment of higher tumor stages of EC [714].
n patients after therapy of an EC with vaginal complaints caused by estrogen deficiency or postactinic complaints, the possibly increased risk of recurrence should be weighed against the advantages of hormone application before application of local estrogens and discussed with the patient in the sense of an “informed consent”. Legally sound documentation is recommended (see also S3 Guideline “Peri- and Postmenopause - Diagnostics and Interventions”, 01/2020, DGGG, OEGG, SGGG, AWMF register number 015/062, [147]). The NCCN panel also advises caution with HRT after primary therapy in patients with EC, recommending restriction to early stages with low risk of recurrence and treatment initiation only 6 to 12 months after the end of primary therapy [229].
9.7.3 Treatment and prophylaxis of vaginal stenosis
Vaginal dilators can be used for the treatment and prophylaxis of vaginal stenosis in patients with endometrial cancer after the end of radiotherapy and resolution of acute radiation sequelae.
- Consensus
- Strong consensus
Background
Due to acute and chronic radiation sequelae (see above) in the area of the vagina and surrounding organs, bleeding after sexual intercourse, dyspareunia and limited clinical assessability of local findings at tumor follow-up due to synechiae of the vaginal wall may occur.
Postactinic vaginal discomfort occurred in 35% after brachytherapy and in 17% after percutaneous radiotherapy of the lesser pelvis in the PORTEC-2 study [715]. The risk for the occurrence of clinically relevant late toxicity (vaginal stenosis) depends on radiooncological factors (radiation dose, dose fractionation, irradiated volume) and on tumor-specific (tumor location, tumor volume) and patient-specific circumstances (age, nicotine abuse, concomitantly administered chemotherapy). In a literature review by Morris L. et al. the incidence of vaginal stenosis after radiation varied from 1.25 to 88% [701].
To prevent this complication, vaginal dilators are often used and recommended along with lubricant 2 to 4 weeks after radiotherapy as expert consensus [716]; [717]. However, there is limited evidence for the benefit of vaginal dilators. For example, in the Cochrane analysis published in 2014 on the treatment of women with vaginal dilators after pelvic radiotherapy, Miles T. et al. found no study that met the evaluability criteria for a meta-analysis on the topic [716]. Even in more recent work, the use of dilators after radiotherapy did not prevent functionally limiting vaginal stenosis in 2/3 of patients [718]; [719]; [720]; [721]. To objectify the efficacy of dilators, vaginal length and width, among other parameters, were measured and documented during follow-up. From 2 recent prospective studies, it is clear that lack of compliance for regular use of dilators is the limiting factor for the effectiveness of this preventive and therapeutic measure [720]; [721].
Laser therapy is a possible therapeutic option for vulvovaginal atrophy in postmenopause. It is postulated that laser stimulates increased synthesis of collagen and extracellular matrix as well as fibroblast proliferation, thereby increasing vaginal elasticity and hydration. Currently, laser therapy is being studied for the treatment of post-actinic change after radiotherapy for endometrial and cervical carcinoma [722]. There are no results of prospective randomized studies on this therapeutic approach.
9.8 Palliative radiotherapy
As a palliative measure for vaginal bleeding or pain from vaginal stump or pelvic wall recurrence, low total dose radiotherapy can be used even after previous radiotherapy.
- Consensus
- Strong consensus
Background
The recommendations of the S3 Guideline “Supportive Therapy in Oncological Patients” [628] should be taken into account when performing medicinal and/or radiotherapeutic measures.
In the presence of an incurable disease situation as well as current and expected physical and psychosocial stress, the recommendations of the S3 Guideline “Palliative care for patients with a non-curable cancer” , [723] as well as recommendations 11.12.1, 11.12.2, 11.12.3 should be considered.
Evidence tables
9.1 EvT 9.1
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Fung-Kee-Fung 2006 |
Systematischer Review (gepoolte Daten von 16 nicht-vergleichenden retrospektiven Studien3 + 2 systematischen Reviews) LoE 4 |
Frauen mit Endometrium-karzinom: 2.929 Frauen in den Follow-up-Studien (Table 1 im Review). |
Systematische Literatursuche in MEDLINE, EMBASE und in den Cochrane Library Datenbanken (1980–2005/Oktober). |
Keine. |
Lokoregionäre Rezidive; Fern-Rezidive; Gesamtüberleben; Lebensqualität – gemessen an einem optimalen Follow-up-Schema. |
Es gibt nur begrenzte Evidenz dafür, dass intensive Follow-up-Protokolle mit multiplen diagnostischen Routineuntersuchungen einen Überlebens-Benefit nach sich ziehen. Effektschätzer: Gesamt-Rezidiv-Risiko = 13 % für alle Patientinnen (95 % CI: 11–14 %), verglichen mit 77 % für symptomatische Rezidive (95% CI: 74–81 %). (3 % weniger für Low-risk-Patientinnen.) 68 %–100 % der Rezidive traten in den ersten 3 Jahren des Follow-ups auf. Symptomatische Rezidive = 70 %. Keine verlässlichen Überlebens-Unterschiede zwischen asymptomatischen und symptomatischen Patientinnen. |
Keine Daten zur Lebensqualität. Einschluss von zumeist Studien mit niedrigem Evidenzlevel. |
|
Follow-up-Schema. |
|||||||
|
Gadducci 2000 |
Retrospektive Fallserie LoE 4 |
152 konsekutiv eingeschlossene Frauen mit Endometrium-karzinom FIGO-Stadium I. Im Follow-up: n = 133. 89 Frauen erhielten postoperative adjuvante Therapien. 24 Frauen bekamen ein Rezidiv in 10 Jahren. Operatives Staging erfolgte gemäß FIGO 1988. |
Hysterektomie und beidseitige Salpingo-Oopherektomie + paraaortale und/oder pelvine Lymphadenek-tomie. |
Keine. |
Krankheitsfreies Überleben; Gesamtüberleben; Überleben nach Rezidiv – gemessen an einem optimalen Follow-up-Schema. |
Ein intensives Follow-up-Protokoll scheint keinen signifikanten Einfluss auf das Outcome von Patientinnen mit Endometriumkarzinom im FIGO Stadium I zu haben. Vorschlag für Follow-up-Protokoll bei Low-risk-Patientinnen: Alle 4 Monate körperliche Untersuchung in den ersten 2 Jahren nach OP; danach alle 6 Monate. Dazu Ultraschall (Abdomen/Becken) und Thorax-Röntgen in den ersten 3 Jahren nach OP. Effektschätzer: 5-Jahres-krankheitsfreies Überleben: 94,2 % bei Low-risk-Patientinnen versus 76,0 % bei High-risk-Patientinnen (p = 0,0472). Medianes Gesamtüberleben: 10 Monate. Überleben nach Rezidiv war höher bei Spät-Rezidiven, verglichen mit früh diagnostizierten Rezidiven (= Überleben war höher, wenn die Rezidiv-Diagnose nach 17,5 Monaten gestellt wurde, verglichen mit davorliegender Diagnosestellung [p = 0,02]). Überleben nach Rezidiv ist nicht korreliert mit initialem FIGO-Stadium, Tumorgrad oder myometraner Invasion. |
Sehr kleine Fallserie über langen Zeitraum (1988–1997). |
|
Sartori 2007 |
Retrospektive Fallserie LoE 4 |
84 Frauen mit Endometrium-karzinom insgesamt. (147 Frauen insgesamt: 84 Frauen mit Endometrium-karzinom + 63 Frauen mit Zervixkarzinom). |
Nachsorge 1. Jahr alle 3 Monate; 2. Jahr alle 4 Monate; 3.–5. Jahr alle 6 Monate, dann jährlich; jedes Mal gyn. Untersuchung; PAP-Test und Röntgen-Thorax einmal jährlich; wenn klinisch indiziert: abdom. Ultraschall; CT des Beckens/Abdo-mens; Biopsie. |
Keine. |
Gesamtüberleben: Benefit von Nachsorgeprotokollen für Patientinnen mit rezidivierendem Zervix- und Endometrium-karzinom. |
Endometrium-karzinom-Patientinnen zeigten eine signifikant bessere Prognose, wenn ein Rezidiv bei Follow-up entdeckt wurde, als Zervixkarzinom-Patientinnen. Effektschätzer: 78 % der Rezidive (Endometriumkarzinom) in den ersten drei Jahren nach Erstbehandlung; Rezidive in Scheide und Becken hatten besseres Überleben; 55 % Fernmetas-tasen, 52 % hatten Symptome, von den asymptomatischen Rezidiven konnten 92 % mit Ultraschall und CT entdeckt werden. |
Gut analysierte Fallstudie. |
|
Smith 2007 |
Retrospektive Fallserie LoE 4 |
280 (aus 438) Frauen mit rezidivierendem Endometrium-karzinom. |
Nachsorge mit gynäkologischer Zytologie zweimal pro Jahr alle 3 Monate die ersten 2 Jahre, dann alle 6 Monate (3 Jahr), dann jährlich; wenn klinisch indiziert: CT und CA-125. |
Keine. |
Gesamtüberleben. |
Patientinnen mit Low/-intermediate-Risiko könnten von einem intensiven Follow-up-Protokoll profitieren; High-risk-Patientinnen vielleicht mehr von einer alternativen Follow-up-Strategie mit Schwerpunkt auf Bildgebung und klinischer Untersuchung in Kombination mit Patientenaufklärung bezüglich der Symptome. Effektschätzer: 71 % symptoma-tisches Rezidiv; 29 % asymptomatisch; 5-Jahres-Gesamtüberlebens-wahrscheinlichkeit: 41 % (asympto-matisch), verglichen mit 28,9 % (symptomatisch) (p = 0,013). Asymptomatische Patientinnen mit Low-/intermediate-Risiko hatten etwas bessere Prognosen: 38 % (asympto-matisch) versus 25,7 % (sympto-matisch), p = 0,05. |
Gut aufgearbeitete Fallstudie. |
|
Carrara 2012 |
Retrospektive multizentrische (8 italienische Zentren) Fallserie LoE 3 |
282 konsekutiv eingeschlossene Frauen mit rezidivierendem Endometrium-karzinom. |
n.a. |
n.a. |
Untersuchen und bewerten der gängigen Praxis von Follow-up-Strukturen in der Endometriumkarzinom-Überwachung: Sind diese effektiv, um asymptomatische Rezidive zu entdecken? Rezidiv-Schema je Follow-up-Vorgehen beschreiben.
|
Patientinnen mit einem asymptomatischen Rezidiv zeigten ein besseres klinisches Outcome als solche mit einem symptomatischen Rezidiv. Auch mit Überleben korreliert war, wo das Rezidiv auftrat: Patientinnen mit einem Rezidiv des Scheidengewölbes lebten signifikant länger. Effektschätzer: Verteilung der Rezidive: 12 % Scheidengewölbe; 18 % zentrales Becken; 5 % Beckenwand; 14 % Lymphknoten; 45,3 % Fernmetastasen; 5,3 % beides. 41 % symptomatisch; 59 % asympto-matisch. Asymptomatische Patientinnen hatten ein besseres Überleben (35 versus 13 Monate, p = 0,0001), verglichen mit symptomatischen Patientinnen. Rezidive des Scheidengewölbes versus andere Rezidive, 1. OR1 = 2,90 (96 % CI: 1,35–6,27; p = 0,006); |
Sehr fundierte Analyse. |
|
Creutzberg 2003 |
Randomisiert-kontrollierte Studie (Update-Analyse: 8-Jahres-Überleben) aus Daten der PORTEC-Studie2) LoE 2 |
714 (von 715 eingeschlossenen) Frauen insgesamt mit einem Endometrium-karzinom FIGO Stadium I, davon 39 Frauen mit isoliertem vaginalen Rezidiv. Hysterektomie erfolgte vorab, aber keine Lymphadenektomie. Staging gemäß FIGO 1988. Interventionsarm: 354 Frauen. Kontrollarm: 360 Frauen. Drop-out-Rate: n = 1 (Lost to Follow-up). |
Externe (pelvine) Strahlentherapie (46 Gy). |
Keine. |
Lokoregionäre Rezidive; Fern-Rezidive; Gesamtüberleben.
|
Durch die kurative Bestrahlung des vaginalen Rezidivs = 89 % Komplettremission des vaginalen Rezidivs in der Gruppe der nicht vorbestrahlten Patientinnen (Interventionsarm). Effektschätzer: Lokoregionäre Rezidiv-Rate (nach Follow-up von 73 Monaten): 4 % (Strahlentherapie) versus 15 % (Kontrollgruppe) (p < 0,0001). 8-Jahres-Rate an Fernmetastasen: 10 % (Strahlentherapie) versus 6 % (Kontrollgruppe) (p = 0,20). Gesamtüberleben nach Follow-up: 71 % (Strahlentherapie) versus 77 % (Kontrollgruppe) (p = 0,18) = kein Unterschied. |
Keine Angabe zur Verblindung (in diesem Studien-setting schwer umsetzbar). Intention-to-treat-Analyse. |
|
Reddoch 1995 |
Retrospektive Kohortenstudie zum Follow-up-Schema
LoE 4 |
412 Frauen mit Endometriumkar-zinom-Rezidiv nach Diagnose der klinischen Krankheitsfreiheit nach Endometrium-karzinom Stadium I nach Primär-therapie, innerhalb eines Zeitraumes von 7 Jahren (1985/01–1992/12). Staging erfolgte gemäß FIGO 1971 (oder zumindest vor 1988). 14 Frauen (3,4 %) entwickelten eine Tumorprogression während der Primärtherapie. 398 Frauen in der Nachbeobachtungs-phase wurden in die Analyse einge-schlossen: mittleres Follow-up von 64 Mon. |
Übliches Nachbeobach-tungsprotokoll nach Beendigung der Primär-therapie: ärztliche Untersuchung + Pap-Test alle 3 Mon. in den ersten 2 Jahren; alle 4 Mon. nach 3 Jahren; alle 6 Mon. nach 4 bis 5 Jahren; einmal jährlich Röntgenthorax; bei ausgewählten Patientinnen Testung der CA-125-Level. |
Keine. |
Nachbeobachtungs-protokoll für das Follow-up nach Endometrium-karzinom. |
44 Rezidive (11 %), Drop-out von 5 Fällen, deren Unterlagen nicht zugänglich waren = 39 Patientinnen mit Rezidiv (traten alle innerhalb von 39 Mon. auf): 16 symptomatisch (41 %), 23 asymptomatisch (59 %); von diesen überlebten nur 3 (7,7 %) nach operativer Behandlung oder Bestrahlung. Keine der Patientinnen mit Rezidiv konnte von Chemotherapie profitieren. Vorschlag für neues Nachbeobachtungs-protokoll: Follow-up-Zeitraum: 60 Mon.: ärztliche Untersuchung + Pap-Test einmal jährlich Patientinnen mit High-risk-Endometrium-karzinomen: alle 6 Mon. Testung der CA-125-Level: nur für fortgeschrittene Stadien (II–IV) oder histologische High-risk-Subtypen. Röntgenthorax/Labor-untersuchung: sollte nicht routinemäßig angeboten werden. |
------------------------------ |
|
Bristow 2006 |
Retrospektive Kohortenstudie zur Kosteneffizienz von vaginaler Zytologie als Screeningtool
LoE 4 |
377 hysterektomierte Frauen mit Endometrium-karzinom (Datenbank zur Tumorregistrierung, Maryland/USA). 2.134 Pap-Tests wurden durchgeführt (1997/01–2005/06). |
Pap-Test. |
Keine. |
Kosteneffizienz von vaginalem Routine-Zytologie-Screening zur Detektion von isolierten asymptomatischen vaginalen Rezidiven. |
61 Patientinnen mit Rezidiv (16,2 %); 11 Patientinnen mit einem isolierten Vaginalrezidiv (2,9 %). Bei 2/377 (0,5 %) wurde ein isoliertes asymptomatisches Vaginalrezidiv entdeckt, pro Entdeckung wurden 1.067 Pap-Tests benötigt, mit Kosten von 44,049 $ jeweils. Zudem haben weniger als 1 % der Patientinnen einen Benefit von vaginaler Zytologie zur Detektion eines Endometrium-karzinoms = zu teuer und ineffizient. |
Risiko für Selection Bias. |
|
Salani 2011 |
Retrospektive Fallserie LoE 4 |
154 Frauen mit FIGO Stadium IA Endometrium-karzinom (Staging gemäß FIGO 1988).
|
Nachsorge nach frühem Endometrium-karzinom gemäß Guideline der NCCN6 und Empfehlungen der ACOG7 (vaginale Zytologie alle 6 Monate in den ersten 2 Jahren nach Diagnose). |
Keine. |
Rezidiv-Schemata; klinische und Kostenfaktoren. |
Die vaginale Zytologie hat keinen Benefit für das Entdecken von Rezidiven und es kann explizit für diese Gruppe zugunsten einer Kostenreduktion darauf verzichtet werden. 4 Rezidive (16–73 Monate nach Follow-up) , 3 symptomatische Rezidive im Intervall; 1 asymptomatisches Vaginalrezidiv bei gynäkologischer Untersuchung. Die 154 Patientinnen in dieser Studie bedeuteten Kosten von ca. 7,760 $ pro Jahr durch vaginale Zytologie. |
------------------------------
|
9.1 EvT 9.3
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Fung-Kee-Fung 2006 |
Systematischer Review (gepoolte Daten von 16 nicht-vergleichenden retrospektiven Studien3 + 2 systematischen Reviews) LoE 4 |
Frauen mit Endometrium-karzinom: 2.929 Frauen in den Follow-up-Studien (Table 1 im Review). |
Systematische Literatursuche in MEDLINE, EMBASE und in den Cochrane Library Datenbanken (1980–2005/Oktober). |
Keine. |
Lokoregionäre Rezidive; Fern-Rezidive; Gesamtüberleben; Lebensqualität – gemessen an einem optimalen Follow-up-Schema. |
Es gibt nur begrenzte Evidenz dafür, dass intensive Follow-up-Protokolle mit multiplen diagnostischen Routineuntersuchungen einen Überlebens-Benefit nach sich ziehen. Effektschätzer: Gesamt-Rezidiv-Risiko = 13 % für alle Patientinnen (95 % CI: 11–14 %), verglichen mit 77 % für symptomatische Rezidive (95% CI: 74–81 %). (3 % weniger für Low-risk-Patientinnen.) 68 %–100 % der Rezidive traten in den ersten 3 Jahren des Follow-ups auf. Symptomatische Rezidive = 70 %. Keine verlässlichen Überlebens-Unterschiede zwischen asymptomatischen und symptomatischen Patientinnen. |
Keine Daten zur Lebensqualität. Einschluss von zumeist Studien mit niedrigem Evidenzlevel. |
|
Follow-up-Schema. |
|||||||
|
Gadducci 2000 |
Retrospektive Fallserie LoE 4 |
152 konsekutiv eingeschlossene Frauen mit Endometrium-karzinom FIGO-Stadium I. Im Follow-up: n = 133. 89 Frauen erhielten postoperative adjuvante Therapien. 24 Frauen bekamen ein Rezidiv in 10 Jahren. Operatives Staging erfolgte gemäß FIGO 1988. |
Hysterektomie und beidseitige Salpingo-Oopherektomie + paraaortale und/oder pelvine Lymphadenek-tomie. |
Keine. |
Krankheitsfreies Überleben; Gesamtüberleben; Überleben nach Rezidiv – gemessen an einem optimalen Follow-up-Schema. |
Ein intensives Follow-up-Protokoll scheint keinen signifikanten Einfluss auf das Outcome von Patientinnen mit Endometriumkarzinom im FIGO Stadium I zu haben. Vorschlag für Follow-up-Protokoll bei Low-risk-Patientinnen: Alle 4 Monate körperliche Untersuchung in den ersten 2 Jahren nach OP; danach alle 6 Monate. Dazu Ultraschall (Abdomen/Becken) und Thorax-Röntgen in den ersten 3 Jahren nach OP. Effektschätzer: 5-Jahres-krankheitsfreies Überleben: 94,2 % bei Low-risk-Patientinnen versus 76,0 % bei High-risk-Patientinnen (p = 0,0472). Medianes Gesamtüberleben: 10 Monate. Überleben nach Rezidiv war höher bei Spät-Rezidiven, verglichen mit früh diagnostizierten Rezidiven (= Überleben war höher, wenn die Rezidiv-Diagnose nach 17,5 Monaten gestellt wurde, verglichen mit davorliegender Diagnosestellung [p = 0,02]). Überleben nach Rezidiv ist nicht korreliert mit initialem FIGO-Stadium, Tumorgrad oder myometraner Invasion. |
Sehr kleine Fallserie über langen Zeitraum (1988–1997). |
|
Reddoch 1995 |
Retrospektive Kohortenstudie zum Follow-up-Schema
LoE 4 |
412 Frauen mit Endometriumkar-zinom-Rezidiv nach Diagnose der klinischen Krankheitsfreiheit nach Endometrium-karzinom Stadium I nach Primär-therapie, innerhalb eines Zeitraumes von 7 Jahren (1985/01–1992/12). Staging erfolgte gemäß FIGO 1971 (oder zumindest vor 1988). 14 Frauen (3,4 %) entwickelten eine Tumorprogression während der Primärtherapie. 398 Frauen in der Nachbeobachtungs-phase wurden in die Analyse einge-schlossen: mittleres Follow-up von 64 Mon. |
Übliches Nachbeobach-tungsprotokoll nach Beendigung der Primär-therapie: ärztliche Untersuchung + Pap-Test alle 3 Mon. in den ersten 2 Jahren; alle 4 Mon. nach 3 Jahren; alle 6 Mon. nach 4 bis 5 Jahren; einmal jährlich Röntgenthorax; bei ausgewählten Patientinnen Testung der CA-125-Level. |
Keine. |
Nachbeobachtungs-protokoll für das Follow-up nach Endometrium-karzinom. |
44 Rezidive (11 %), Drop-out von 5 Fällen, deren Unterlagen nicht zugänglich waren = 39 Patientinnen mit Rezidiv (traten alle innerhalb von 39 Mon. auf): 16 symptomatisch (41 %), 23 asymptomatisch (59 %); von diesen überlebten nur 3 (7,7 %) nach operativer Behandlung oder Bestrahlung. Keine der Patientinnen mit Rezidiv konnte von Chemotherapie profitieren. Vorschlag für neues Nachbeobachtungs-protokoll: Follow-up-Zeitraum: 60 Mon.: ärztliche Untersuchung + Pap-Test einmal jährlich Patientinnen mit High-risk-Endometrium-karzinomen: alle 6 Mon. Testung der CA-125-Level: nur für fortgeschrittene Stadien (II–IV) oder histologische High-risk-Subtypen. Röntgenthorax/Labor-untersuchung: sollte nicht routinemäßig angeboten werden. |
------------------------------ |
9.2 EvT 9.5
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Kadkhodayan 2013 |
Systematischer Review und Metaanalyse der Literatur (11 retrospektive Studien zur diagnostischen Güte) LoE 3 |
541 Frauen insgesamt mit Verdacht auf Endometrium-karzinom-Rezidiv und/oder Rezidiv gesichert, teils asymptomatisch. Genaue Angaben zu Interventions-/ |
PET oder PET-CT. |
Die anschließenden histologischen Befunde der Pathologen und/oder Follow-up. |
Diagnostische Güte zur Detektion von Rezidiven.
|
Es gibt eine hohe Sensitivität und Spezifität für die Detektion von Rezidiven. Effektschätzer: Gesamt-Rezidiv-Rate: (11 Studien/n = 541) Sensitivität 95,8 % (95 % CI: 92,2–98,1 %); Spezifität 92,5 % (95 % CI: 89,3–94,9 %). Subgruppen-Analyse – Verdacht auf Rezidiv: Sensitivität 95,1 % (95 % CI: 90,5–97,8 %); Spezifität 93,3 % (95 % CI: 88,4–96,6 %). Asymptomatische Patientinnen: Sensitivität 100 % (95 % CI: 86,3–100 %); Spezifität 92,7 % (95 % CI 88,1–96 %) Subgruppen-Analyse – PET: Sensitivität 93,4 % (95 % CI: 84,1–98,2 %); Spezifität 86,1 % (95 % CI: 79,2–91,4 %). PET-CT: Sensitivität 94,5 % (95 % CI: 89,5–97,6 %); Spezifität 93,6 % (95 % CI: 88,8–96,8 %). Subgruppen-Analyse – LoE-2 Studien: 5 Studien (324 Patient., 333 PETs), Sensitivität 93,0 % (95 % CI: 86,6–96,9 %); Spezifität 90,9% (95 % CI: 86,2–94,3 %). Behandlungsplan änderte sich in 22–35 % der untersuchten Patientinnen. |
Keine Verblindung in 6/11 Studien (allerdings ist das Verblinden in diesem Studiensetting teilweise schwer umsetzbar.) Zudem untersuchten die Studien nicht den Zusatznutzen der PET-CT bezogen auf patientenrelevante Parameter. Erstellt unter Berücksichtigung der Deville-Guideline4. Angaben zu Publication Bias vorhanden. |
9.4 EvT 9.14
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Thigpen 1999 |
Randomisiert-kontrollierte Studie (GOG 81 Protokoll) LoE 2 |
299 (aus 324) Frauen mit fortgeschrittenem oder rezidivierendem Endometrium-karzinom insgesamt. Interventionsarm: 145 Frauen. Kontrollarm: 154 Frauen. |
200 mg Medroxypro-gesteronacetat. |
1000 mg Medroxypro-gesteronacetat. |
1. Outcome: Objektives Ansprechen. 2. Outcome: Gesamtüberleben; progressionsfreies Überleben. |
Niedrig dosiertes, 200 mg MPA-Regime wirkt ebenso gut, wenn nicht besser als 1000 mg MPA, mit weniger Nebenwirkungen. Effektschätzer: OR bei 200 mg: 25 %; bei 1000 mg 15 %. Das Todesrisiko war um 31 % höher (p = 0,026) für die High-Dose-Gruppe. Das Risiko für Erstprogression war um 35 % höher (p = 0,0014) in der High-dose-Gruppe). Besseres Outcome bei positivem Progesteron-/ 37 % (17/46) Responserate für progesteronrezeptor-postiven Status vs. 8 % (7/86) für progesteronrezeptor-negativen Status (p < 0,001). 26 % Responserate (20/77) für östrogenrezeptor-postiven Status vs. 7 % (4/55) für östrogenrezeptor-negativen Status (p = 0,005). |
Sauberes RCT, das zum Verlassen der ultrahochdosierten MPA-Therapie geführt hat. |
|
Kokka 2010 |
Systematischer Review (nur Einzelstudien-analyse, ohne Metaanalyse) von 6 randomisiert-kontrollierten Studien (Cochrane-Review) LoE 4 |
542 Frauen mit Endometrium-karzinom insgesamt. Genaue Angaben zu Interventions-/ |
Systematische Literatursuche im Cochrane Gynaecological Cancer Group Trials Register, in MEDLINE, EMBASE bis 2009/Mai und in CENTRAL (Ausgabe 2, 2009). Zudem Suche in Online-Datenbanken klinischer Studien, grauer Literatur, Kontaktaufnahme zu Experten. |
Kombination von Chemotherapie-dubletten (Cisplatin/ Doxorubicin); Chemotherapie-tripletten (Paclitaxel/ Cisplatin/ Doxorubicin); Kombination Chemotherapie mit Hormontherapie; Strahlentherapie mit/ohne Chemotherapie; Best Supportive Care. |
1. Outcome: Gesamtüberleben. 2. Outcome: Progressionsfreies Überleben. |
Es gibt keinen Hinweis, dass Hormontherapie das Gesamtüberleben verbessert. Eine Studie zeigt, dass eine niedrig dosierte Hormontherapie (low dose) besser ist als eine hoch dosierte. Effektschätzer: Gesamtüberleben/ Niedrig dosierte Hormontherapie hat einen Benefit, verglichen mit hoch dosierter Hormontherapie: HR = 1,31, 95 % CI: 1,04–1,66 (Gesamtüberleben); HR = 1,35, 95 % CI: 1,07–1,71 (progressionsfreies Überleben). |
Keine Angaben zu Publication möglich, da nur Einzelstudien-Analyse. Es fehlen sinnvolle Studien, eingeschlossene Studien zudem teilweise sehr alt.5 |
|
Endokrine Therapie mit Progestagenen (u. a. MPA; MGA; Hydroxypro-gesteroncaproat); Aromatase-hemmern, Gnrh-Analoga oder Kombinationen; Kombinationen mit Chemothera-peutika. |
9.5 EvT 9.16
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Vale 2012 |
Systematischer Review (Cochrane Review) von 14 randomisiert-kontrollierten Studien: 8 zum Vergleich mehr versus weniger Chemotherapie; 5 zum Vergleich unterschiedlicher Chemotherapie-Dubletten LoE 2 (formal LoE 1, aber wegen methodischer Schwächen herabgestuft, s. methodische Bemerkungen) |
1.519 Frauen in den 8 Studien zum 1. Vergleich. Frauen mit fortgeschrittenem, rezidivierendem/ |
Systematische Literatursuche von 1966–2012/Januar in MEDLINE, EMBASE, CENTRAL; im Cochrane Gynaecological Cancer specialist trials register, in relevanten Studien-Datenbanken und grauer Literatur. |
Placebo; Best Supportive Care; andere Chemotherapie.
|
1. Outcome: Gesamtüberleben; progressionsfreies Überleben. 2. Outcome: Lebensqualität.
|
Mehr Chemotherapie könnte Gesamt- und progressionsfreies Überleben verbessern, „the optimum regimen has still to be defined.” Aber mehr Nebenwirkungen in den Gruppen mit mehr Chemotherapie. Effektschätzer: Mehr Chemotherapie war mit längerem Gesamtüberleben assoziiert: HR = 0,86; 95 % CI: 0,77 –0,96; p = 0,005) und mit längerem progressionsfreien Überleben: n = 1526; HR = 0,82; 95 % CI: 0,74–0,90; |
Veraltete Chemotherapie-protokolle mit wenig untersuchter Lebensqualität und Spätfolgen. Kein eindeutiges Ergebnis. Keine Angaben zu Publication Bias. Random-effects-Modell wurde verwendet. Keine Verblindung (hier schwer umsetzbar). |
|
1. Mehr Chemotherapie versus weniger Chemotherapie. 2. Chemotherapie-Dubletten versus versus andere Chemotherapie-Dubletten. 3. Vergleich verschiedener Einzelwirkstoffe. |
9.5 EvT 9.17
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Vale 2012 |
Systematischer Review (Cochrane Review) von 14 randomisiert-kontrollierten Studien: 8 zum Vergleich mehr versus weniger Chemotherapie; 5 zum Vergleich unterschiedlicher Chemotherapie-Dubletten LoE 2 (formal LoE 1, aber wegen methodischer Schwächen herabgestuft, s. methodische Bemerkungen) |
1.519 Frauen in den 8 Studien zum 1. Vergleich. Frauen mit fortgeschrittenem, rezidivierendem/ |
Systematische Literatursuche von 1966–2012/Januar in MEDLINE, EMBASE, CENTRAL; im Cochrane Gynaecological Cancer specialist trials register, in relevanten Studien-Datenbanken und grauer Literatur. |
Placebo; Best Supportive Care; andere Chemotherapie.
|
1. Outcome: Gesamtüberleben; progressionsfreies Überleben. 2. Outcome: Lebensqualität.
|
Mehr Chemotherapie könnte Gesamt- und progressionsfreies Überleben verbessern, „the optimum regimen has still to be defined.” Aber mehr Nebenwirkungen in den Gruppen mit mehr Chemotherapie. Effektschätzer: Mehr Chemotherapie war mit längerem Gesamtüberleben assoziiert: HR = 0,86; 95 % CI: 0,77 –0,96; p = 0,005) und mit längerem progressionsfreien Überleben: n = 1526; HR = 0,82; 95 % CI: 0,74–0,90; |
Veraltete Chemotherapie-protokolle mit wenig untersuchter Lebensqualität und Spätfolgen. Kein eindeutiges Ergebnis. Keine Angaben zu Publication Bias. Random-effects-Modell wurde verwendet. Keine Verblindung (hier schwer umsetzbar). |
|
1. Mehr Chemotherapie versus weniger Chemotherapie. 2. Chemotherapie-Dubletten versus versus andere Chemotherapie-Dubletten. 3. Vergleich verschiedener Einzelwirkstoffe. |
9.6.1 EvT 9.18
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Lee 2011 |
Doppelverblindete randomisiert-kontrollierte Studie LoE 3 |
98 Frauen nach Brustkrebs insgesamt (Menopause nach Brustkrebsbe-handlung + Score von mind. 5,0 auf der visuellen Analogskala für vaginale Trockenheit/ Interventionsarm: 49 (44 erhielten Intervent.) Frauen. Kontrollarm: 49 (42 erhielten Placebo) Frauen. Drop-out-Rate: n = 12. |
pH-neutrales Vaginalgel. |
Placebo. |
Visuelle Analogskala für vulvovaginale Trockenheit mit Schmerzen; Dyspareunie.
|
Die Anwendung eines pH-neutralen Vaginalgels konnte vaginale Symptome und die vaginale Gesundheit von Brustkrebsüberlebenden (Menopause nach Krebsbehandlung) verbessern. Effektschätzer: pH-neutrales Vaginalgel verbessert signifikant Scheidentrockenheit mit Schmerzen: p = 0,001 und Dyspareunie: p = 0,40. |
Brustkrebspatien-tinnen, Population enthält keine Frauen mit Endometrium-karzinom. Kleines Kollektiv, aber doppel-verblindet. |
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