18. Distant metastases – Cervical Carcinoma
Major changes in the chapter on distant metastases
This chapter has been revised. The following statements have been amended or expanded: 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, and 18.9.
T. Fehm, P. Mallmann, M.C. Koch, M.W. Beckmann, A. Sturdza, C. Grimm, A. Letsch, V. Hagen
18.1 Epidemiology in metastases
In the new 2018 FIGO classification, the para-aortic lymph nodes are designated as N1 — i.e., regional disease — and no longer as M1 metastases. FIGO has thus standardized the individual classifications, since para-aortic lymph nodes are also classed as regional lymph nodes in endometrial and ovarian cancer [149], [713].
A distinction is thus made between regional lymph-node metastases and distant metastases. In addition, extensive peritoneal spread into the pelvic serosa or primary infiltration of neighboring organs is often referred to as a locally advanced stage (see Table 9). Since the rate of treatment failure here is high — i.e., the rate of early recurrences and the trend toward persistent tumor and also secondary early organ metastases — patients with locally advanced tumor stages (≥ FIGO stage IIB) and those with metastases are often combined in many studies (see Chapter 17 and Table 9). This, and the small number of patients in absolute terms who have isolated organ metastases without simultaneous local recurrence, means that conclusions regarding the choice of treatment and its effectiveness can only be drawn to a limited extent.
18.2 Imaging
In patients with local recurrences of or metastases from cervical carcinoma, regional imaging diagnosis is carried out with pelvic MRI or vaginal ultrasonography to assess the extent of pelvic tumor spread. Extrapelvic spread also has to be diagnosed using CT of the abdomen and chest. PET-CT is mainly used to differentiate between benign findings and recurrence/metastasis. This applies in particular to the assessment of enlarged/suspicious lymph nodes (see Chapter 6).
If pulmonary findings suspicious for malignancy are identified during the metastatic work-up, it should be borne in mind that in addition to a recurrence of the cervical carcinoma, the patient may also have a primary lung carcinoma as a differential diagnosis. Lim et al. (2010) noted this in 29% of cases examined, particularly when a history of nicotine abuse was known [714]. Histological confirmation is therefore desirable if possible.
18.3 Treatment options in distant metastases
18.3.1 Isolated distant metastases
With an isolated metastasis, the option of local therapy in the form of surgery, local irradiation, or locally destructive treatment procedures should be considered on an interdisciplinary basis at the tumor conference.
- Consensus
- Strong consensus
Despite systematic research (see the guideline report), no RCTs, nonrandomized controlled prospective studies, or prospective comparative observational studies were identified on this issue (see section 2.2.6). The recommendation is based on the 2008 SIGN guideline and must be regarded as an expert consensus. If multiple metastases have been excluded with the relevant imaging diagnostic methods, then it may be considered whether surgical resection of the metastasis is possible on the basis of the imaging findings [715].
There is evidence from a retrospective single-center analysis that with an isolated distant metastasis in strictly selected patients, complete surgical resection of the metastasis or locally destructive procedures such as radiofrequency ablation can lead to an increase in the progression-free survival and overall survival [716]. No prospective randomized and controlled studies or matched-pair controlled studies are available on this topic. In patients with a metastasis in whom surgery is not possible and who have not previously received any radiotherapy or radio(chemo)therapy, or in whom the metastasis is located outside of the previous irradiation field, the indication for radiotherapy, with radio(chemo)therapy if appropriate, should be examined. Radio(chemo)therapy of metastases is carried out in the same way as primary therapy, in the form of monotherapy with cisplatin [717].
18.3.2 Regional metastases (pelvic/para-aortic)
With the primary presence of regional lymph-node metastases, the irradiation field is based on the histologically identified pattern of spread.
With isolated secondary para-aortic metastases, the option of surgical resection should be examined using imaging, with laparoscopy or exploratory laparotomy if appropriate. If surgical resection is not possible, there is an option here for isolated para-aortic radio(chemo)therapy (see also section 17.3.5).
18.3.3 Osseous metastases
In contrast to regional metastases, systemic metastases (pulmonary, hepatic, osseous) usually only present the option of systemic drug therapy (see Chapter 11, Drug treatment). In the case of (isolated) osseous metastasis, the possibility of local radiotherapy and/or osteo-oncological therapy (bisphosphonate therapy, denosumab) should be examined, especially if there is a risk of fracture. If the lesion is located in a previously irradiated area, osseous radionecrosis should be excluded.
18.3.4 Disseminated metastases
Palliative drug therapy should be administered in the form of platinum-containing combination chemotherapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1+
- Consensus
- Strong consensus
- References
- [454] [452] [718] [707]
Change note
Palliative drug therapy should be in the form of platinum-containing combination chemotherapy.With metastases that are not isolated and are not suitable for local treatment in the form of surgery or radiotherapy, palliative drug treatment is an option. This is capable of achieving a response and reducing the progression of the disease [454]. It can lead to a longer overall survival with the combination therapy (cisplatin plus topotecan) in comparison with cisplatin monotherapy [719]. In a phase III study including 253 patients, carboplatin/paclitaxel was found to have a comparable effect to cisplatin/paclitaxel, with better tolerability. There were no significant differences in the overall survival (HR 0.99; 90% CI, 0.79 to 1.25) or overall response rate (63% versus 59%) [452]. No comparisons with “best supportive care” are available [454]. With metastases in a previously irradiated area, chemotherapy should be avoided due to the significantly lower response, or it can be discussed with the patient on an individual basis [454]. Two other older meta-analyses support the view that, with a generally small absolute prolongation of the overall survival, cisplatin-containing combination therapies appear to be the most promising option with metastases [718], [707].
18.3.5 Drug treatment in the metastatic situation
Following radio(chemo)therapy with cisplatin as a “radiosensitizer,” cisplatin administration can be repeated.
In recurrences/metastases after prior chemotherapy with cisplatin, repeat administration of cisplatin can be carried out in combination with topotecan, paclitaxel, gemcitabine, or vinorelbine, or carboplatin can be administered with paclitaxel.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 1+
- Consensus
- Strong consensus
- References
- [454] [720] [452]
Change note
After radio(chemo)therapy with cisplatin as „radiosensitizer“, cisplatin may be administered again. In case of recurrence/metastases after previous chemotherapy with cisplatin, a new administration of cisplatin combined with topotecan, paclitaxel, gemcitabine or vinorelbine or the administration of carboplatin with paclitaxel can be given.Combination therapies are associated with higher rates of morbidity and toxicity than the monotherapy.
Combination therapies have a better response rate.
In relation to overall survival, a slight absolute survival benefit has so far only been demonstrated for the combination of cisplatin with topotecan.
According to the 2012 Cochrane analysis, systemic drug therapy for metastases should optimally include administration of cisplatin [454]. Following radio(chemo)therapy with cisplatin as “radiosensitizer,” cisplatin administration can be repeated at 50 mg/m2. An increase in the dosage to 100 mg/m2 every 21 days, or 20 mg/m2 on days 1–5 every 21 days, increased the response rate, but not the survival. Combination chemotherapies with cisplatin significantly improved the response rate and progression-free survival in comparison with monotherapy. It was only with a combination of cisplatin plus topotecan that a slight improvement in the overall survival was achieved [455]. When all of the combination therapies were compared with monotherapy, no improvement in the overall survival was observed in this meta-analysis [454].
In comparison with cisplatin-containing monotherapy, combination therapy with cisplatin as expected increases the risk of side effects. The Cochrane review calculated the following toxicity rates (based on the 2006 Common Terminology Criteria for Adverse Events, CTCAE) for combination therapy with cisplatin in comparison with monotherapy:
- Neutropenia, grade 3/4 (four studies, n = 1073): risk ratio 0.04; 95% CI, 0.02 to 0.12 (1.4% vs. 36.7%)
- Thrombocytopenia, grade 3/4 (four studies, n = 1104): risk ratio 0.16; 95% CI, 0.05 to 0.48 (2.1% vs. 18.3%)
- Infections, grade 3/4 (two studies, n = 552): risk ratio 0.42; 95% CI, 0.22 to 0.81 (4% vs. 9.8%)
- Renal dysfunction, grade 3/4 (three studies, n = 980): risk ratio 0.81; 95% CI, 0.46 to 1.41 (5% vs. 5.5%, n.s.)
- Neuropathy, grade 3/4 (two studies, n = 552): risk ratio 1.39; 95% CI, 0.45 to 4.33 (2.5% vs. 1.8%, n.s.)
Data on quality of life were only reported in three of 26 studies. Despite the increased toxicity data, the available data showed no significant differences between cisplatin-containing monotherapy and combination therapy with cisplatin [454].
Despite the increased toxicity with the combination therapies, patients who respond to palliative chemotherapy have hardly any reduction in their quality of life [454].
According to the comparative studies available, combination therapy with cisplatin and paclitaxel is superior to the other chemotherapy regimens with regard to response rates and progression-free survival [721], [722]. In the absence of superiority for any of the four drug combinations, leading to the research studies being stopped, the end point of survival was not pursued. It was extrapolated that the combinations of cisplatin with topotecan and cisplatin with paclitaxel are equipotent. The recommended dosages are: cisplatin 50 mg/m2, paclitaxel 135 mg/m2 every 3 weeks. Administration of cisplatin in combination with gemcitabine is an alternative [718].
Long et al. (2005) observed a slightly but significantly longer overall survival (6.5 vs. 9.4 months; HR 0.76) with combination therapy with cisplatin/topotecan in comparison with cisplatin monotherapy [719]. The study was also included in the 2012 Cochrane analysis. However, due to the incomplete and inadequate presentation of overall survival data in the other studies (e.g., often with the response rate as the primary end point), it was not possible to carry out a pooled analysis. The results of the individual studies were therefore presented descriptively in the Cochrane analysis [454].
As an alternative to cisplatin, carboplatin can also be used in monotherapy and combination therapy.
Cisplatin should be preferred in patients who have not previously received it.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1-
- Consensus
- Strong consensus
- References
- [452]
Evidence tables (1)
Kitagawa et al. 2015Cisplatin can be replaced with carboplatin. This applies in particular to patients with impaired renal function and patients who have already received cisplatin as part of radiochemotherapy. In the JCOG-0505 study, patients received either six cycles of cisplatin (50 mg/m2) d2 / paclitaxel (135 mg/m2) d1 or carboplatin AUC5 d1 / paclitaxel (175 mg/m2) d1 every 3 weeks [452]. Among the patients, 43% or 50% had already received radiochemotherapy with cisplatin or carboplatin, respectively (only two patients). There were no significant differences in the overall survival (HR 0.99; 90% CI, 0.79 to 1.25) or in the overall response rate (63% versus 59%). Significantly less neutropenia and rates of renal failure, nausea, and vomiting were seen in the carboplatin arm. However, rates of thrombocytopenia and sensory neuropathy were higher. A retrospective analysis showed that previous administration of cisplatin affected the treatment response to carboplatin. There were no differences in survival in the cisplatin-pretreated group. By contrast, patients with no previous chemotherapy who received carboplatin tended to have a shorter survival (median survival 13 months versus 23 months; HR 1.57; 95% CI, 1.06 to 2.23). A systematic review including a total of 17 studies with over 1181 patients confirmed the JCOG-0505 results. Although there was a significant difference between cisplatin/Taxol and carboplatin/Taxol in relation to the PFS (6.9 months versus 5 months; P = 0.03), there were no differences in relation to OS (12.87 months versus 10 months; P = 0.17)) or RR (48.5% versus 49.3%) [720].
For patients who have already received cisplatin in primary or adjuvant radio(chemo)therapy, carboplatin is thus also available in palliative chemotherapy as an alternative to repeat treatment with cisplatin [723].
18.3.5.1 Targeted therapy
Patients with metastatic or recurrent/persistent cervical cancer should receive concurrent bevacizumab — independently of prior treatment with radio(chemo)therapy — for first-line palliative chemotherapy with cisplatin/paclitaxel or topotecan/paclitaxel.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1+
- Consensus
- Consent
- References
- [724]
Change note
Targeted antibody therapy with bevacizumab in the metastatic or relapsed/persistent situation in the patient with cervical carcinoma as combination therapy simultaneously with palliative first-line chemotherapy with cisplatin/paclitaxel or topotecan/paclitaxel shows a small absolute survival benefit. Combination therapies with bevacizumab have higher morbidity and toxicity. Combination therapies with bevacizumab have a higher response rate.The value of adding bevacizumab administration (15 mg/kg, q3w) to platinum-containing (cisplatin/paclitaxel) or platinum-free combination therapy (topotecan/paclitaxel) was investigated in the four-arm randomized GOG study 240 (phase III). In the final analysis, it showed that the addition of bevacizumab (a VEGF inhibitor) to palliative chemotherapy (cisplatin/paclitaxel or topotecan/paclitaxel) resulted in a combined survival benefit for both therapies of 3.5 months (13.3 months vs. 16.8 months; HR 0.77; 95% CI, 0.062 to 0.95; P = 0.007) and an improved progression-free interval (8.2 months vs. 6 months; HR 0.68; 95% CI, 0.56 to 0.84; P = 0.0002), as well as higher response rates (49% vs. 36%; P = 0.003). A negative rebound effect (shorter survival after bevacizumab) was excluded, as there were no significant differences in survival after progression (“postprogression survival”; 8.4 months vs. 7.1 months; HR 0.83; 95% CI, 0.66 to 1.05; P = 0.06) [724]. On the basis of these data, bevacizumab received approval in Germany in 2015 for this indication with the corresponding chemotherapy regimens. In everyday clinical practice, however, cisplatin is often replaced with carboplatin due to the comparable efficacy (JCOG-0505 study) and its lower rates of neutropenia and renal insufficiency. A recently published network meta-analysis has confirmed this approach on the basis of the presumed equivalent effectiveness [457].
Both chemotherapy regimens (cisplatin/paclitaxel with or without bevacizumab vs. topotecan/paclitaxel with or without bevacizumab) were found to have similar overall survival, but a significantly shorter progression-free survival was observed in the topotecan/paclitaxel group [14]. No direct comparison is available of the administration of cisplatin/paclitaxel/bevacizumab versus the only combination therapy approved in Germany — cisplatin/topotecan — in this situation. The chemotherapy partners for bevacizumab in the GOG-240 study [14] were selected on the basis of the data published by Monk et al. [9], which were also mentioned in the 2012 Cochrane meta-analysis [14].
The additional administration of bevacizumab leads to increased side effects, which include high blood pressure (CTCAE grade II or higher: 25% vs. 2%), thromboembolic events (CTCAE grade III or higher: 8% vs. 1%), neutropenia (CTCAE grade IV or higher: 36% vs. 26%) and gastrointestinal fistulas (grade III or higher: 3% vs. [He, D. et al. 2015]. Febrile neutropenia (CTCAE grade III or higher), gastrointestinal bleeding (CTCAE grade III or higher), and pain (CTCAE grade II or higher) occurred in both groups, without any significant differences [233]. The patients’ quality of life was assessed in this study using a combination of individual questions from various instruments ((FACT-Cx-TOI, BPI, FACT/GOG-NTX). No significant differences between the study arms were observed with regard to quality of life up to 9 months after the first cycle [233].
18.3.5.2 Second-line therapies in cervical carcinoma
For patients who have progression after first-line therapy, monotherapy is usually recommended if treatment is desired. There are currently no treatment studies available showing an overall survival benefit in this setting in comparison with best supportive care. Possible treatment options include: Nab-paclitaxel (125 mg/m2 d1, 8, 15 q3w) [725], vinorelbine (30 mg/m2, d1, 8, q3w) [726], ifosfamide (1.2 mg/m2, d1–5, q4w) [727], topotecan (1.5 mg/m2 d1–5, q3w) [728], pemetrexed (500 mg/m2 q3w) [729], or irinotecan (125 mg/m2 q1w) [730].
In patients with PD-L1-positive metastatic cervical carcinoma, checkpoint inhibitors are another therapeutic option.
- Consensus
- Consent
Another option for the second-line or a higher line of therapy is the checkpoint inhibitor pembrolizumab (200 mg q3w) for patients with PD-L1-positive cervical cancer (CPS score ≥ 1) (see section 7.3) [711]. In the single-arm Keynote 028 trial (phase Ib), the overall response rate with pembrolizumab (10 mg/kg q2w) in the cohort of multiply pretreated cervical carcinoma patients with PD-L1 expression was 17% (95% CI, 5% to 37%) with a median duration of response of 5.4 months (4.1–7.5 months). With regard to treatment-related side effects, rash (21%) and pyrexia (17%) were the most common. Testing for a PD-L1 should be carried out during the first line of therapy, if possible. Currently, testing for PD-L1 can take several days. It is therefore advisable to perform testing at the onset of metastasis, in order to avoid a time delay in the second line.
The results of the single-arm Keynote 158 study (phase II) were published in 2019 and led to the approval of pembrolizumab in the USA [458]. This was a basket trial that included 77 cervical cancer patients with positive PD-L1 expression and progression during or after first-line therapy. The patients received pembrolizumab for a period of 2 years, or until progression. The overall response rate was 14.6% (95% CI, 7.8% to 24.2%), with two complete responders in the PD-L1-positive cohort after first-line treatment failure. The estimated 6-month PFS rate was 25%, with a median overall survival of 11 months (95% CI, 9.1 to 14.1 months) in the PD-L1-positive overall cohort (9.4 months in the overall group; 95% CI, 7.7 to 13.1). The main side effects noted were hypothyroidism (10.2%) and loss of appetite (9.2%), as well as fatigue (9.2%) and diarrhea (8.2%). Grade 3/4 toxicities occurred in 12.2% of the patients. The main immune-mediated toxicities were hypothyroidism (11.2%) and hyperthyroidism (9.2%). In June 2018, the FDA approved pembrolizumab for the treatment of recurrent or metastatic PD-L1-positive cervical cancer after failure of first-line treatment, based on the results of Keynote study 158 in this subgroup. In Germany, the health-insurance companies require applications to be made for cost coverage if the treatment is indicated and the patient has a positive PD-L1 status.
Evidence tables
Kitagawa et al. 2015
|
Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, et al. Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505. J Clin Oncol. 2015;33(19):2129-35. |
|||
|
Studiendesign |
Population |
Interventionen |
Endpunkte |
|
Open-label RCT |
Erwachsene mit histologisch abgesichertem Zervixkarzinom im Stadium IVB (inklusive persistierend) oder zum ersten oder zweiten Mal rezidiviertes Zervixkarzinom ohne Aussicht auf kurative Intervention. ECOG-Status ≤2
253 Patientinnen eingeschlossen |
Paclitaxel + Cisplatin (N=127) vs. Paclitaxel + Carboplatin (N=126) |
|
|
Evidenzgrad |
|||
|
1- |
|||
|
Vertrauen in Effekte |
|||
|
gering |
|||
|
Ergebniszusammenfassung
Anmerkungen zum Vertrauen in die Effektschätzer
|
|||
|
Endpunkt |
Paclitaxel + Cisplatin (N=127) |
Paclitaxel + Carboplatin (N=126) |
Paclitaxel + Cisplatin vs. Paclitaxel + Carboplatin |
|
Gesamtüberleben [Median, Monate] |
18,3 [16,1; 22,9] |
17,5 [14,2; 20,3] |
HR 0,994; 95% KI: [0,789; 1,253]; p=0,032* |
|
Progressionsfreies Überleben [Median, Monate] |
6,9 [5,7; 7,9] |
6,2 [5,5; 7,2] |
HR 1,041; 95% KI: [0,803; 1,351]; p=0,053* |
|
Vollständiges Tumoransprechen |
3,9% |
7,1% |
|
|
Vollständiges oder partielles Tumoransprechen |
58,8% [48,6; 68,5] |
62,6% [52,3; 72,2] |
p=0,665 |
|
Unerwünschte Ereignisse [n (%)] |
|
|
|
|
Unerwünschte Ereignisse nach Preferred Term, CTCAE-Grad ≥3 |
|||
|
Neutropenie [%], Grad 3-4 [n (%)] |
106 (85,5%) |
96 (76,22%) |
N/A |
|
Neutropenie [%], Grad 4 [n (%)] |
93 (75,0%) |
57 (45,2%) |
N/A |
|
Febrile Neutropenie [n (%)] |
20 (16,0%) |
9 (7,1%) |
N/A |
|
Anämie [n (%)] |
39 (31,2%) |
56 (44,4%) |
N/A |
|
Thrombozytopenie |
4 (3,2%) |
31 (24,6%) |
N/A |
|
Infektionskrankheiten, Grad 2 |
9 (7,2%) |
6 (4,8%) |
N/A |
|
Infektionskrankheiten, Grad 3-4 |
3 (2,4%) |
0 |
N/A |
|
Übelkeit und Erbrechen |
8 (6,4%) |
4 (3,2%) |
N/A |
|
Fatigue |
5 (4,0%) |
10 (7,9%) |
|
|
Sensorische Neuropathie |
0 |
6 (4,8%) |
|
|
Therapieabbruch aufgrund unerwünschter Ereignisse |
9,5% |
11,8% |
N/A |
|
Schwerwiegende unerwünschte Ereignisse |
N/A |
N/A |
N/A |
Lorusso et al. 2014
|
Lorusso D, Petrelli F, Coinu A, Raspagliesi F, Barni S. A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer. Gynecol Oncol. 2014;133(1):117-123. |
|||
|
Studiendesign |
Population |
Interventionen |
Endpunkte |
|
Systematischer Review / Meta-Analyse |
Patienten mit rezidiviertem, persistierendem oder metastasiertem Zervixkarzinom in der Erstlinientherapie.
17 Studien eingeschlossen: 8 Phase II-Studien, 4 Phase III-Studien*, 5 retrospektive Patientenserien, 1 prospektive Patientenserie Insgesamt 1.181 Patientinnen *eine davon Phase II und Phase III |
Cisplatin-basierte Behandlungsregime vs. Carboplatin-basierte Behandlungsregime |
|
|
Evidenzgrad |
|||
|
1- |
|||
|
Vertrauen in Effekte |
|||
|
Sehr gering |
|||
|
Ergebniszusammenfassung:
Anmerkungen zum Vertrauen in die Effektschätzer
|
|||
|
Endpunkt |
Cisplatin (CDDP)* |
Carboplatin (CBDCA)* |
Cisplatin vs. Carboplatin |
||
|
N [Studien] |
Absoluter Effekt |
N [Studien] |
Absoluter Effekt |
||
|
Objektive Gesamt-Ansprechrate |
18 |
49,3% [41,1; 57,5]; I2=77,7% |
18 |
48,5% [37,9; 59,3]; I2=75,0% |
N/A |
|
Nicht CCDP-naiv |
5 |
42,3% |
4 |
43,9% |
p=0,54 |
|
CCDP-naiv |
4 |
68,3% |
4 |
59,1% |
p=0,73 |
|
Progressionsfreies Überleben [Median, Monate] |
9 |
6,9 (4,8 – 8,3) |
7 |
5,0 (2,9 – 7,0) |
p=0,03 |
|
Gesamtüberleben |
17 |
12,87 (9 – 39) |
17 |
10,0 (8,4 – 21,0) |
p>0,05 |
|
Anämie |
N/A |
23,3% |
N/A |
39,5% |
N/A |
|
Febrile Neutropenie |
N/A |
15,6% |
N/A |
7,6% |
N/A |
|
Thrombozytopenie |
N/A |
9,2% |
N/A |
21,6% |
N/A |
|
Neutropenie |
N/A |
60,6% |
N/A |
51,5% |
N/A |
|
Erbrechen |
N/A |
7,5% |
N/A |
2,8% |
N/A |
|
Neurotoxizität |
N/A |
17,9% |
N/A |
3,3% |
N/A |
|
Diarrhöe |
N/A |
3,3% |
N/A |
1,5% |
N/A |
|
Stomatitis |
2 |
0,7% |
2 |
0% |
N/A |
|
*jeweils in Kombination mit Paclitaxel |
|||||
References
[149] Nagao, S., Miwa, M., Maeda, N., Kogiku, A., Yamamoto, K., Morimoto, A., et.al. Clinical Features of Neuroendocrine Carcinoma of the Uterine Cervix: A Single-Institution Retrospective Review, Int J Gynecol Cancer, 2015. 25(7): p. 1300-5., https://www.ncbi.nlm.nih.gov/pubmed/26166556
[713] Schmidt, A. M., Imesch, P., Fink, D., Egger, H., Indications and long-term clinical outcomes in 282 patients with pelvic exenteration for advanced or recurrent cervical cancer, Gynecol Oncol, 2012. 125: p. 604-9., https://www.ncbi.nlm.nih.gov/pubmed/22406639
[714] Estape, R., Angioli, R., Surgical management of advanced and recurrent cervical cancer, Semin Surg Oncol, 1999. 16: p. 236-41., https://www.ncbi.nlm.nih.gov/pubmed/10225302
[715] Wittekind, C, Meyer, HJ, TNM-Klassifikation maligner TumorenViley-VCH Verlag, 2010.
[716] Coleman, R. L., Keeney, E. D., Freedman, R. S., Burke, T. W., Eifel, P. J., Rutledge, F. N., Radical hysterectomy for recurrent carcinoma of the uterine cervix after radiotherapy, Gynecol Oncol, 1994. 55: p. 29-35., https://www.ncbi.nlm.nih.gov/pubmed/7959262
[717] Mahe, M. A., Gerard, J. P., Dubois, J. B., Roussel, A., Bussieres, E., Delannes, M., et.al. Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: report of the French intraoperative group on 70 patients, Int J Radiat Oncol Biol Phys, 1996. 34: p. 21-6., https://www.ncbi.nlm.nih.gov/pubmed/12118553
[718] Windschall, A., Ott, O. J., Sauer, R., Strnad, V., Radiation therapy and simultaneous chemotherapy for recurrent cervical carcinoma, Strahlenther Onkol, 2005. 181: p. 545-50., https://www.ncbi.nlm.nih.gov/pubmed/16044224
[707] Lopez-Graniel, C., Dolores, R., Cetina, L., Gonzalez, A., Cantu, D., Chanona, J., et.al. Pre-exenterative chemotherapy, a novel therapeutic approach for patients with persistent or recurrent cervical cancer, BMC Cancer, 2005. 5: p. 118., https://www.ncbi.nlm.nih.gov/pubmed/16171526
[454] Strauss, H. G., Haensgen, G., Dunst, J., Hayward, C. R., Burger, H. U., Scherhag, A., et.al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer, Int J Gynecol Cancer, 2008. 18: p. 515-24., https://www.ncbi.nlm.nih.gov/pubmed/17645506
[452] Bishop, A. J., Allen, P. K., Klopp, A. H., Meyer, L. A., Eifel, P. J., Relationship between low hemoglobin levels and outcomes after treatment with radiation or chemoradiation in patients with cervical cancer: has the impact of anemia been overstated?, Int J Radiat Oncol Biol Phys, 2015. 91(1): p. 196-205., https://www.ncbi.nlm.nih.gov/pubmed/25446609
[719] Haasbeek, C. J., Uitterhoeve, A. L., van der Velden, J., Gonzalez, D. G., Stalpers, L. J., Long-term results of salvage radiotherapy for the treatment of recurrent cervical carcinoma after prior surgery, Radiother Oncol, 2008. 89: p. 197-204., https://www.ncbi.nlm.nih.gov/pubmed/18237803
[720] Grigsby, P. W., Prospective phase I/II study of irradiation and concurrent chemotherapy for recurrent cervical cancer after radical hysterectomy, Int J Gynecol Cancer, 2004. 14: p. 860-4., https://www.ncbi.nlm.nih.gov/pubmed/15361195
[455] Gupta, S., Singh, P. K., Bisth, S. S., Bhatt, M. L., Pant, M., Gupta, R., et.al. Role of recombinant human erythropoietin in patients of advanced cervical cancer treated "by chemoradiotherapy", Cancer Biol Ther, 2009. 8: p. 13-7., https://www.ncbi.nlm.nih.gov/pubmed/18981719
[721] Westermann, A., Mella, O., Van Der Zee, J., Jones, E. L., Van Der Steen-Banasik, E., Koper, P., et.al. Long-term survival data of triple modality treatment of stage IIB-III-IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia - an update, Int J Hyperthermia, 2012. 28: p. 549-53., https://www.ncbi.nlm.nih.gov/pubmed/22788973
[722] Mundt, A. J., Roeske, J. C., Lujan, A. E., Yamada, S. D., Waggoner, S. E., Fleming, G., et.al. Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic malignancies, Gynecol Oncol, 2001. 82(3): p. 456-63., https://www.ncbi.nlm.nih.gov/pubmed/11520140
[723] Liu, S. P., Huang, X., Ke, G. H., Huang, X. W., 3D radiation therapy or intensity-modulated radiotherapy for recurrent and metastatic cervical cancer: the Shanghai Cancer Hospital experience, PLoS One, 2012. 7(6): p. e40299., https://www.ncbi.nlm.nih.gov/pubmed/22768273
[724] Blohmer, J. U., Paepke, S., Sehouli, J., Boehmer, D., Kolben, M., Wurschmidt, F., et.al. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study, J Clin Oncol, 2011. 29(28): p. 3791-7., http://www.ncbi.nlm.nih.gov/pubmed/21860000, http://jco.ascopubs.org/content/29/28/3791.full.pdf
[457] Lutgens, L., van der Zee, J., Pijls-Johannesma, M., De Haas-Kock, D. F., Buijsen, J., Mastrigt, G. A., et.al. Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma, Cochrane Database Syst Rev, 2010. p. CD006377., https://www.ncbi.nlm.nih.gov/pubmed/20091593
[14] Krebs in Deutschland für 2015/2016, Berlin 2019, https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/krebs_in_deutschland_node.html;jsessionid=CBD18C719CEBE68AD0F1AF7AB03A9E5F.1_cid372
[9] Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (GEKID), 2014. 2014:, https://www.gekid.de/
[233] Horn, L. C., Hentschel, B., Fischer, U., Peter, D., Bilek, K., Detection of micrometastases in pelvic lymph nodes in patients with carcinoma of the cervix uteri using step sectioning: Frequency, topographic distribution and prognostic impact, Gynecol Oncol, 2008. 111: p. 276-81., https://www.ncbi.nlm.nih.gov/pubmed/18722005
[725] Fokdal, L., Sturdza, A., Mazeron, R., Haie-Meder, C., Tan, L. T., Gillham, C., et.al. Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: Analysis from the retroEMBRACE study, Radiother Oncol, 2016. 120(3): p. 434-440., https://www.ncbi.nlm.nih.gov/pubmed/27113795
[726] Seo, Y., Kim, M. S., Yoo, H. J., Jang, W. I., Rhu, S. Y., Choi, S. C., et.al. Salvage stereotactic body radiotherapy for locally recurrent uterine cervix cancer at the pelvic sidewall: Feasibility and complication, Asia Pac J Clin Oncol, 2016. 12(2): p. e280-8., https://www.ncbi.nlm.nih.gov/pubmed/24889550
[727] Krengli, M., Pisani, C., Deantonio, L., Surico, D., Volpe, A., Surico, N., et.al. Intraoperative radiotherapy in gynaecological and genito-urinary malignancies: focus on endometrial, cervical, renal, bladder and prostate cancers, Radiat Oncol, 2017. 12(1): p. 18., https://www.ncbi.nlm.nih.gov/pubmed/28100242
[728] Stelzer, K. J., Koh, W. J., Greer, B. E., Cain, J. M., Tamimi, H. K., Figge, D. C., et.al. The use of intraoperative radiation therapy in radical salvage for recurrent cervical cancer: outcome and toxicity, Am J Obstet Gynecol, 1995. 172(6): p. 1881-6; discussion 1886-8., https://www.ncbi.nlm.nih.gov/pubmed/7778648
[729] Hockel, M., Horn, L. C., Einenkel, J., (Laterally) extended endopelvic resection: surgical treatment of locally advanced and recurrent cancer of the uterine cervix and vagina based on ontogenetic anatomy, Gynecol Oncol, 2012. 127: p. 297-302., https://www.ncbi.nlm.nih.gov/pubmed/22864112
[730] Jurado, M., Alcazar, J. L., Martinez-Monge, R., Resectability rates of previously irradiated recurrent cervical cancer (PIRCC) treated with pelvic exenteration: is still the clinical involvement of the pelvis wall a real contraindication? a twenty-year experience, Gynecol Oncol, 2010. 116(1): p. 38-43., https://www.ncbi.nlm.nih.gov/pubmed/19878978
[711] Marnitz, S., Kohler, C., Muller, M., Behrens, K., Hasenbein, K., Schneider, A., Indications for primary and secondary exenterations in patients with cervical cancer, Gynecol Oncol, 2006. 103: p. 1023-30., https://www.ncbi.nlm.nih.gov/pubmed/16890276
[458] Harima, Y., Ohguri, T., Imada, H., Sakurai, H., Ohno, T., Hiraki, Y., et.al. A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer, Int J Hyperthermia, 2016. 32(7): p. 801-8., https://www.ncbi.nlm.nih.gov/pubmed/27418208