Evaluation of Baseline Characteristics and Therapeutic Management Strategies in Metastatic Cervical Cancer in Germany: A Multicentric Retrospective Longitudinal Observational Study

Abstract

Introduction

Real-world data on treatment patterns and outcomes in recurrent or metastatic cervical cancer (r/mCC) are lacking.

Methods

This first national quality assurance initiative was a retrospective analysis of patients with r/mCC diagnosed between 2018 and 2022, who were identified from medical records of 31 gynecologic cancer centers in Germany. Patient demographic and clinical characteristics, treatment patterns, and clinical outcomes were assessed descriptively. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier analysis.

Results

A total of 503 eligible patients (median age 55 years) were analyzed for r/mCC. 276/503 patients (55%) received first-line (1L) chemotherapy (platinum combination: 247/276; 79%) followed by targeted antibody therapy with bevacizumab (177/247; 72%), immunotherapy (19/247; 8%), or both combined (50/247; 20%). 111/503 (22%) received chemotherapy only (platinum combination: 64/111; 58%, platinum mono: 35/111; 31%, or platinum-free: 12/111; 11%), and 110/503 (22%) did not receive any systemic treatment (the remaining 6/503 patients received immunotherapy only). For these subgroups after a median follow-up of 16 months, the PFS was 12 months (95% CI 11–14), 8.8 months (95% CI 7.1–11), and 3 months (95% CI 2.3–4.8), and OS was 25 months (95% CI 21–31), 17 months (95% CI 14–22), and 3.6 months (95% CI 2.8–5.3), respectively. 176/283 (62%) patients who developed progressive disease (PD) were treated with second-line (2L) therapy.

Conclusion

Only half of the patients with r/mCC were treated 1L with platinum-combination therapy including antibody therapy according to national guidelines. Moreover, 22% at initial diagnosis and 38% of patients at PD were not treated with systemic therapy at all. This might reflect poor general performance status, patients’ preference, and/or lack of effective therapies especially in 2L treatment.

Zusammenfassung

Einleitung

Es fehlt an Real-World-Daten zu den Behandlungsmustern und -ergebnissen beim rezidivierenden und metastatischen Gebärmutterhalskrebs (r/mCC) in Deutschland.

Methoden

Diese erste nationale Qualitätssicherungsinitiative besteht aus einer retrospektiven Analyse von Patientinnen mit r/mCC, die zwischen 2018 und 2022 diagnostiziert wurden. Die Patientinnen wurden in den Krankenakten von 31 gynäkologischen Krebszentren in Deutschland identifiziert. Die demografischen und klinischen Merkmale der Patientinnen sowie die Behandlungsmuster und klinischen Ergebnisse wurden deskriptiv evaluiert. Progressionsfreies Überleben (PFÜ) und Gesamtüberleben (GÜ) wurden mithilfe der Kaplan-Meier-Method berechnet.

Ergebnisse

Insgesamt wurden 503 geeignete Patientinnen (Durchschnittsalter 55 Jahre) in Bezug auf r/mCC analysiert. 276/503 der Patientinnen (55%) erhielten eine Primärtherapie (1L) bestehend aus einer Chemotherapie (Platin-Kombinationstherapie: 247/276; 79%), gefolgt von einer gezielten Antikörpertherapie mit Bevacizumab (177/247; 72%), einer Immuntherapie (19/247; 8%) oder eine Kombination von beiden (50/247; 20%). 111/503 (22%) erhielten Chemotherapie allein (Platin-Kombinationstherapie: 64/111, 58%; Monotherapie mit Platin: 35/111, 31%; oder platinfreie Monotherapie: 12/111; 11%). 110/503 (22%) erhielten keine systemische Therapie (die verbleibenden 6/503 Patientinnen erhielten nur eine Immuntherapie). Nach einer durchschnittlichen Nachbeobachtungszeit von 16 Monaten betrug das PFÜ für diese Untergruppen 12 Monate (95%-KI 11–14), 8,8 Monate (95%-KI 7,1–11) resp. 3 Monate (95%-KI 2,3–4,8), und das GÜ betrug 25 Monate (95%-KI 21–31), 17 Monate (95%-KI 14–22) resp. 3,6 Monate (95%-KI 2,8–5,3). 176/283 (62%) der Patientinnen mit progredienter Erkrankung (PE) erhielten eine Second-Line-(2L-)Therapie.

Schlussfolgerung

Nur die Hälfte der Patientinnen mit r/mCC erhielten eine First-Line-Platin-Kombinationstherapie einschließlich Antikörpertherapie gemäß den nationalen Richtlinien. Dazu kommt noch, dass 22% der Patientinnen bei der Erstdiagnose und 38% der Patientinnen mit PE überhaupt keine systemische Therapie erhielten. Dies könnte die Folge eines generell schwachen Leistungstandes sein oder aber es spiegelt die Präferenzen der Patientinnen und/oder den Mangel an wirksamen Therapien wider, besonders in Hinblick auf 2L-Therapien.

Keywords

metastatic cervical cancer - real-world data - quality assurance

Schlüsselwörter

metastatischer Gebärmutterhalskrebs - Real-World-Daten - Qualitätssicherung

Introduction

It has been estimated that in 2022 around 4000 patients will be newly diagnosed with cervical cancer of whom about 20% will have metastatic disease at initial presentation in Germany [1]. Many of these patients are treated at gynecological cancer centers certified by the German Cancer Society [2].

In women with metastatic cervical cancer the only reasonable therapeutic approach – beside palliative care – is the administration of systemic treatment until best response or unbearable toxicity to prolong survival and maintain a good quality of life.

According to the national German S3-Guideline a platinum-based therapy should be administered as first-line treatment [3] since available data support the use of a platinum-based combination rather than single-agent treatment.

This recommendation is based on a phase-3 randomized controlled trial comparing a cisplatin mono therapy with a cisplatin-topotecan combination, which was able to demonstrate a significantly prolonged survival in patients with metastatic cervical cancer who received the above-mentioned combination [4].

Due to the toxicity seen with cisplatin-based combination chemotherapy, carboplatin appears to be a reasonable substitute for cisplatin, particularly for patients with comorbidities (e.g., pre-existing renal failure) and those patients previously already treated with cisplatin-based chemoradiation. This is based on the results of the Japanese Clinical Oncology Group 0505 trial [5], in which 253 women with stage IVB cervical cancer were randomly assigned to treatment with cisplatin plus paclitaxel or carboplatin plus paclitaxel administered every three weeks for six cycles. Prior cisplatin therapy (primarily with chemoradiation) was noted in 43% and 50% of each group, respectively. Compared with cisplatin plus paclitaxel, treatment with carboplatin and paclitaxel resulted in a similar overall response rate, no difference in overall survival, but significantly less serious neutropenic events (45% versus 75%, p < 0.0001). There were also less serious incidences of renal insufficiency (0 versus 2.4%), nausea and vomiting (3% versus 7%).

However, a post-hoc analysis showed that prior platinum exposure may impact outcomes such that those women not previously treated with cisplatin had a shorter OS when paclitaxel was combined with carboplatin rather than cisplatin (median 13 versus 23 months; HR 1.57; 95% CI 1.06–2.32).

Besides those platinum options, it has been unclear which combination partner drug should be used in first-line setting.

In this respect, the GOG 204 enrolled 434 patients with metastatic cervical cancer and randomly assigned them to treatment with cisplatin plus paclitaxel (as reference control arm) or one of three experimental regimens (cisplatin plus vinorelbine, cisplatin plus gemcitabine, or cisplatin plus topotecan) with the following results [6]:

There was no difference in response rates and no difference in the risk of death among any of the experimental regimens compared with cisplatin plus paclitaxel.

Cisplatin plus gemcitabine resulted in less serious febrile neutropenia compared with cisplatin in combination with paclitaxel, vinorelbine, or topotecan. However, cisplatin plus paclitaxel resulted in less serious thrombocytopenia compared with the other arms.

Moreover, regarding the addition of a specific antibody treatment, the German national S3-Guideline advises the addition of bevacizumab within first-line treatment [3].

This recommendation is based on the results of the GOG 240 trial, in which patients with metastatic, persistent, or recurrent cervical carcinoma were randomly assigned to combination chemotherapy with or without bevacizumab [7] [8]. Chemotherapy plus bevacizumab resulted in a significant improvement in progression-free and overall survival compared with chemotherapy alone.

Finally, recently the PD-1-Inhibitor pembrolizumab has been approved in Germany as an option to be added to the above mentioned first-line treatment regimen in a subset of patients with metastatic cervical cancer (programmed cell death ligand 1 [PD-L1] combined positive score (CPS) of ≥ 1).

This approval is based on a phase-3 randomized controlled trial (KEYNOTE-826) including 617 patients receiving first-line chemotherapy for metastatic cervical cancer (approximately two-thirds of them also received bevacizumab) [9]. Those patients assigned to receive pembrolizumab additionally had a significant improvement in median progression-free survival versus placebo (10.4 versus 8.2 months). Moreover, overall survival at 24 months was 50% in the pembrolizumab group versus only 40% in the placebo group (HR 0.67, 95% CI 0.54–0.84).

Regarding second-line treatment for women who have progressed after first-line treatment there is usually the option to choose between several single agent chemotherapy drugs. However, there is no evidence that such a treatment in the second- or later-line setting improves overall survival compared with best supportive care. A choice among active agents must be tailored to the individual patient, with consideration to prior therapies received, toxicity, and performance status.

According to the German national S3-Guideline, it is moreover feasible to offer a checkpoint inhibitor to patients with a PD-L1 CPS of ≥ 1 after progression to first-line treatment if not used in the front-line setting.

Promising effects have been demonstrated for pembrolizumab during second-line treatment in PD-L1-positive immunotherapy-naive cancers [10].

Alternatively, cemiplimab has also demonstrated efficacy in platinum-resistant recurrent cervical cancer not previously treated with immunotherapy [11]. In a randomized trial in patients with disease progression after platinum-based chemotherapy, cemiplimab improved overall survival compared to single-agent chemotherapy (12.0 versus 8.5 months; HR 0.69, 95% CI 0.56–0.84) irrespective of a PD-L1-expression, and has therefore been approved for this indication in Germany.

Another recently emerged second-line option, also so far not mentioned in the German national S3-Guideline, is the administration of the antibody-drug conjugate tisotumab vedotin. This conjugate is a tissue factor-directed antibody and microtubule inhibitor drug combination, so far only approved by the US Food and Drug Administration (FDA: accelerated approval in 2021 followed by full approval in 2024) for recurrent or metastatic cervical cancer that has progressed on chemotherapy.

This is based on promising data from a multicentric phase-2 trial [12], which were finally confirmed in a randomized phase-3 trial, randomizing patients to tisotumab vedotin or single agent chemotherapy of physicians’ choice after one or two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen [13]. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8–14.9] versus 9.5 months [95% CI, 7.9–10.7]).

Considering these data providing growing evidence for the choice of systemic agents in metastatic cervical cancer, it is unclear if the recommendations of the German national S3 Guideline are followed in routine clinical practice.

Hence the goal of this multicentric retrospective quality assurance analyses is to assess – beside baseline characteristics – the recent and current management strategies and their outcome in patients with metastatic cervical cancer in Germany.

Material and Methods

Participating centers and inclusion criteria

All centers of the AGO study leading group (N = 27) and the AGO Organ-Committee Uterus (N = 25) were asked to participate in this retrospective, multicenter study, to which 31 centers finally contributed data from their designated patients. Patients were included if they had been diagnosed between 2018 and 2022 with primary metastatic (FIGO stage IVB, 2018) or disseminated recurrent squamous and/or adenocarcinoma of uterine cervix and follow-up was available. Since this quality assurance initiative focuses on systemic treatment, patients with loco-regional disease receiving only localized treatment were excluded from the reported analyses.

Documented and analyzed items

The centers were asked to document their patients’ data anonymously in a web-based electronic case report form. Afterward the forms were checked for completeness and plausibility.

The following items regarding patients and tumor base line characteristics, first- and second-line systemic treatment, as well as clinical outcome in terms of progression-free and overall survival were extracted:

Patients age at metastatic or recurrent disease, ECOG performance status, primary or secondary (including primary treatment) metastatic disease, histology, PD-L1-testing, type (including start, duration and schedule) of first- and second-line systemic treatment including antibody-therapy. The clinical outcome included best overall response, reason for termination as well as current disease status.

Progression-free survival (PFS) was defined as the time interval from the diagnosis of disseminated metastatic disease to relapse or progression. Overall Survival (OS) was defined as the time interval from the diagnosis of disseminated metastatic disease to death. In case of alive and lost-to-follow-up, the last date of contact is used as censored survival time.

Statistical analyses

The statistical data analysis was carried out using the program SPSS 24 (IBM Corp. Released 2016) for descriptive statistics and R 4.3.2 for survival analysis. Given that this was an exploratory study, the evaluation of all variables is primarily descriptive. The significance level (p ≤ 0.05, two-sided) is not adjusted. The Kaplan-Meier method was used to estimate survival times; the log-rank test was used to check for equality of survival distributions. Two-sided 95% confidence intervals were given for the effect estimate.

In addition, the influence of patient and tumor characteristics and treatment patterns were analyzed using a multivariable proportional hazards regression model (Cox model). Hazard ratios with 95% confidence intervals are reported for effect estimation. The significance level was set at two-tailed ≤ 5% (p ≤ 0.05).

This study was approved by the local ethics authority (Landesärztekammer Hessen, LAEKH 2023–3311evBO).

Results

Patient and tumor characteristics

In total, 585 individual patient data were entered into the study, 14 did not meet the inclusion criteria. After excluding patients with para-aortic lymph node metastasis only and patients with oligometastatic cervical cancer feasible for localized treatment only (68 patients), 503 patents were included in the present analysis. The median age was 55 years with an interquartile range from 45 to 63. With respect to performance status at diagnoses, 237 (48%) had ECOG 0, 140 (28%) had ECOG 1, 63 (12%) had an ECOG of 2 or more (in the remainig 63 patients these data were missing).

Of the entire cohort, 217 (43%) had primary disseminated metastatic disease, and 286 (57%) had recurrent disease. In those patients with recurrent disease, patients and treatment characteristics for initial curative treatment were available in 272 patients ([Table 1]).

Table 1 Patient and tumor characteristics as well as primary treatment in patients with secondary metastatic disease.

		N (%)
BT = brachytherapy; CHT = chemotherapy; EBRT = external beam radiation therapy; RCHT = radiochemotherapy; RT = radiotherapy; SUR = surgery * Adenosquamous cancers were included into adenocarcinomas for further analyses.
Histology	Squamous	372 (74%)
	Adenosquamous*	6 (1.2%)
	Adeno	125 (25%)
Grading	G1	12 (2.4%)
	G2	178 (35%)
	G3	251 (50%)
	Unknown	62 (12%)
LVSI	L0	100 (20%)
	L1	130 (26%)
	Unknown	273 (54%)
Metastatic status	Primary metastatic	217 (43%)
	Secondary metastatic	286 (57%)
Initial FIGO Stage (of secondary metastatic patients)	IA	7 (2.4%)
	IB	65 (23%)
	IIA	13 (4.5%)
	IIB	52 (18%)
	IIIA	11 (3.8%)
	IIIB	29 (10%)
	IIIC	81 (28%)
	IVA	14 (4.9%)
	Unknown	14 (4.9%)
Primary Management (of secondary metastatic patients)	SUR	78 (27%)
	SUR + RT	15 (5%)
	SUR + CHT	7 (2.4%)
	SUR + RCHT	48 (17%)
	RCHT	109 (38%)
	RT	13 (4.5%)
	CHT	2 (0.7%)
	Unknown	14 (4.9%)
Radiotherapy	Yes	185 (65%)
	No	87 (30%)
	Unknown	14 (4.9%)
EBRT	Yes	142 (77%)
	No	8 (4.3%)
	Unknown	35 (19%)
BT	Yes	103 (56%)
	No	48 (26%)
	Unknown	34 (18%)
Including Sensitizing	Yes	157 (85%)
	No	28 (15%)
Sensitizing Drug	Cisplatin	134 (85%)
	Carboplatin	12 (8%)
	Cis- to carboplatin	3 (1.9%)
	Cisplatin + 5-FU	2 (1.3%)
	Unknown	6 (3.8%)

At diagnosis of disseminated metastatic disease, 32 (6%) patients had been able to enter a clinical trial.

Clinical outcome

Patients with adenocarcinoma had a significantly longer PFS (12 versus 9 months, p = 0.01) and OS (21 versus 16 months, p = 0.006) compared to patients with squamous cell cancer ([Fig. 1]).

Fig. 1 PFS and OS according to histologic subtype.

Furthermore, it is of note that despite displaying a similar PFS for patients with primary and secondary disseminated metastatic disease, a significantly longer OS was observed in patients with secondary metastatic disease (21 versus 16 months, p = 0.04) ([Fig. 2]).

Fig. 2 PFS and OS for primary and secondary disseminated metastatic disease.

First-line treatment

After the diagnosis of disseminated metastatic disease, 393/503 patients (78%) received systemic treatment, with the vast majority (n = 387) receiving some form of chemotherapy. Six patients did receive immunotherapy solely, whereas 41 patients (8%) refused any treatment, and 69 patients (14%) only received best palliative care.

In total, 276/387 patients (71%) received first-line chemotherapy (platinum combination: 247/276; 79%) together with and followed by targeted antibody therapy with bevacizumab (177/247; 72%), immunotherapy (19/247; 8%), or both combined (50/247; 20%).

The remaining 111/387 (29%) received chemotherapy only (platinum combination: 64/111; 58%, platinum mono: 35/111; 31%, or platinum-free: 12/111; 11%).

Whenever platinum was used carboplatin (n = 218) was the preferred drug over cisplatin (n = 140).

After a median follow-up of 16 months, median PFS and OS was 12 months (95% CI 11–14) and 25 months (95% CI 21–31) in patients chemotherapy combined with antibody treatment, 8.8 months (95% CI 7.1–11) and 17 months (95% CI 14–22) in patients with chemotherapy only, and 3 months (95% CI 2.3–4.8) and 3.6 months (95% CI 2.8–5.3) in patients without any treatment, respectively; both differences were statistically significant (p < 0.001 for both comparisons, respectively) ([Fig. 3] a).

With respect to antibody treatment, the combination of bevacizumab and immunotherapy provided a significantly longer PFS (22 months), compared to bevacizumab alone (11 months), immunotherapy alone (13 months) or no antibody treatment at all (9 months) (p < 0.001) ([Fig. 3] b).

Fig. 3 a PFS and OS in patients with chemotherapy and antibody treatment, chemotherapy alone, and no treatment beside best palliation. b PFS and OS in patients with different antibody treatments compared to chemotherapy alone.

When comparing the type of initial chemotherapy, the PFS and OS was significantly longer in patients, who did receive a platinum-based chemotherapy (PFS 11 and 13 months; OS 22 and 27 months) compared to other regimens (PFS 6 months; OS 14 months, p < 0.001) ([Fig. 4] a).

No differences were found regarding PFS and OS between the use of cisplatin (11 and 23 months) versus carboplatin (11 and 21 months) ([Fig. 4] b).

Fig. 4 a PFS and OS in patients with platinum-combination compared to platinum mono, and platinum-free chemotherapy. b PFS and OS in patients with cisplatin versus carboplatin chemotherapy.

To quantify the impact of the different treatment approaches after adjustment for confounders, multivariate cox regression models were applied as shown in [Fig. 5] a–d.

Fig. 5 Forest plot with hazard ratios for PFS and OS regarding patient and tumor characteristics as well as different treatment approaches.

It is of note that from n = 108 patients diagnosed after the publication of the KEYNOTE-826 trial (09/21) [9] and the approval of pembrolizumab in first-line PD-L1 positive metastatic cervical cancer (04/22), n = 72 (67%) had been tested for PD-L1 expression. In 64/72 (89%) patients this testing included the recommended Combined Positivity Score (CPS), with 55/64 (86%) expressing a score higher than 1. All those 55 PD-L1 positive patients received pembrolizumab.

In contrast, before our chosen cutoff 1.1.2022 (between publication and approval) only 120/395 patients (30%) had been tested for PD-L1 expression. In 94/120 (78%) patients CPS was analyzed, with 72/94 (77%) expressing a score higher than 1. Only 29/72 (40%) of those patients received an immune checkpoint inhibitor.

Second-line treatment

From 283 patients who developed progressive disease only n = 176 (62%) were treated with second-line therapy. Thereof, 37 (21%) received a platinum-based chemotherapy including antibody treatment, 65 (37%) received chemotherapy only, 59 (33%) received immunotherapy only, and 15 patients (9%) received tisotumab vedotin.

The several different regimens, which had been used during second-line treatment are displayed in [Fig. 6] a.

The second-line PFS and OS for the combined groups described above are shown in [Fig. 6] b.

Fig. 6 a Second-line treatment regimens. b PFS and OS in patients with chemotherapy and antibody treatment, chemotherapy only, immunotherapy only, ADC only, and no further treatment beside best palliation.

Discussion

We report the results of the first national quality assurance initiative for metastatic cervical cancer in Germany. The reported number of patients with metastatic cervical cancer at first diagnosis is about 800 per year in Germany. Therefore, we estimate, that we included about 10 to 15% of patients diagnosed in Germany during the observed period.

Overall, patient demographics and clinical profiles in these analyses generally reflected those reported in the literature for metastatic cervical cancer [14].

Our findings from this multicentric retrospective longitudinal observational study show that only half of the patients with disseminated metastatic cervical cancer in Germany were treated with first-line guideline-recommended standard platinum-combination therapy including antibody treatment during the evaluated time period.

We observed a significantly longer survival in patients with secondary metastatic disease in comparison to patients with primary metastatic disease. The longer overall survival in patients with secondary metastatic disease remained significant even in multivariate analyses adjusting for several potential confounders like different treatment regimens. We can only speculate that this might be related to a postulated hypothesis of the so-called abscopal effect of local radiation therapy activating a systemic immune response against tumor cells in metastatic cancer patients [15]. These effects seem to be further augmented by the administration of immunotherapy resulting in increased T-cell activity [16].

Nevertheless, this effect has been reported so far only in patients who had already developed metastases at the time of radiotherapy and not in patients with secondary metastatic disease months or even years after radiation treatment. In this respect, it is unclear whether such a radiation-induced immune boost persists over time.

Notably, treatment approaches used in the investigated cohort were often below recommended standards.

In fact, 22% of the patients did not receive any form of systemic treatment at initial diagnosis beside best palliative care, and the reasons therefore remain unclear.

In addition, 29% of the patients who were treated with chemotherapy did not receive any form of additional antibody treatment.

Furthermore, from the 283 patients with confirmed progressive disease despite first-line treatment, only two thirds went on to receive second-line treatment, with a huge variety of several different regimens reflecting the moderate evidence for a substantial benefit of any specific drug.

This variety of several regimens reflecting no standard of care is in line with previous real-world publications from the US [14] [17] highlighting the need for novel, effective and tolerable treatment strategies in metastatic cervical cancer patients.

With respect to clinical outcome, in our real-world analyses we were able to mirror the GOG 240 and the KEYNOTE 826 results with a significantly prolonged progression-free as well as overall survival in patients, who received standard of care platinum-based combination-chemotherapy including antibody treatment (anti-VEGF bevacizumab and/or an immune checkpoint inhibitor), with the greatest benefit when both antibodies were combined [7] [8] [9].

Our results are also in line with previous publications analyzing real world outcome in patients with metastatic cervical cancer [18].

Moreover, we were able to confirm the results of Japanese Clinical Oncology Group 0505 trial, demonstrating no significant difference between the use of cisplatin versus carboplatin regarding progression-free and overall survival [5]. In our study, carboplatin was the preferred drug over cisplatin, even though only 74 of the 218 (34%) with carboplatin were patients with secondary metastatic disease after prior cisplatin exposure as radiosensitizer during initial chemo-radiation with a curative intent according to the existing evidence. This might be explained by the lower rates of toxicities with carboplatin as well as the more laborious supervision of a cisplatin-application.

In this respect furthermore, one might argue that to avoid a significant toxicity in patients with a poor performance status (ECOG 2 or more), a platinum mono treatment might be a reasonable alternative to a combination therapy, despite only limited evidence.

However, in our study 38/47 patients (83%) who received a platinum mono treatment had an ECOG of 0 or 1. Hence, it remains unclear, why only platinum mono was administered in this “healthy” cohort.

It is of note that according to our results the administration of platinum mono appears to be equally effective as a platinum combination therapy with a remarkable progression-free survival of 13 months and overall survival of 27 months, especially since 75% of them did not receive any form of additional antibody treatment. It should be noted, however, that the results for platinum mono in the 75% quartile are worse than with platinum combination therapy, and the survival curves only converge in the subsequent quartiles. However, since this group included only n = 47 patients, those encouraging results must be interpreted with caution, especially as only 26 (PFS) and 27 (OS) patients were still at risk at the time of matching.

With respect to the clinical outcome of second-line treatment, the administration of immunotherapy only appears to be equally effective as chemotherapy including antibody treatment with an overall survival of 15 versus 14 months. Moreover, despite a shorter progression-free survival (4 months versus 8 months immunotherapy only and 9 months chemotherapy including antibody treatment) the application of the ADC tisotumab vedotin resulted in a comparable overall survival of 15 months.

To our knowledge this is so far the largest cohort for real-world evidence in metastatic cervical cancer patients in Germany, and one of the largest throughout the entire world.

Another strength is the contribution of only highly specialized dedicated cancer centers from the AGO study leading group and the AGO Organ-Committee Uterus.

However, their retrospective nature – even when collected from dedicated gynecological cancer center databases – comes with a potential selection bias and a few missing items in several variables.

In addition, as the study window was from 2018 to 2022, clinical outcome data on recently incorporated first- and second-line immunotherapy and ADCs have led to a management change but may not have been sufficiently matured during the short follow-up period.

It is remarkable that even in specialized cancer centers, a substantial number of patients did only receive what is considered substandard systemic treatment (e.g. chemotherapy without an antibody treatment). This is unlikely to be caused by limited expertise of the treating physicians considering the contributing centers.

One reason might be – despite a median age of only 55 years – the poor performance status of a significant proportion of the patients at presentation (n = 63; 12% with ECOG 2 or worse).

In fact, almost all those patients with an ECOG of 2 or worse (n = 59/63; 94%), were not fit to undergo any form of systemic anticancer treatment.

This in combination with an anticipated toxicity of combination chemotherapy and antibody treatment might have caused some restraint by the patient and the treating physician. In this respect, the rate for severe bevacizumab-specific toxicity like fistula and/or thromboembolism has been reported with 6 and 8% in the GOG 240 trial, and the rate of severe immune-related adverse events with 11% in the KEYNOTE 826 trial.

We can only speculate that the rate of patients receiving optimal treatment nation-wide might be even lower. This underlines even more the need for novel, effective but also tolerable treatment strategies in metastatic cervical cancer patients.

The significant proportion of patients with poor performance status at initial presentation highlights also the need for a better surveillance and early detection program. In this respect, within a recent proof-of-concept study Mittelstadt and co-workers were able to demonstrate the potential of cell-free-HPV-DNA as a biomarker for treatment and follow-up monitoring in patients with primary and recurrent cervical cancer [19].

In addition, as already pointed out, we were able to reveal a relevant number of patients who did not receive any form of tumor-directed systemic treatment, neither at primary diagnosis of metastatic disease (22%), nor at subsequent progression (38%). This observation is in line with a poster report of the prospective randomized ENGOT-cx12/GOG-3057/innovaTV-301 phase-3 trial, comparing tisotumab vedotin versus chemotherapy according to physicians’ choice in patients with progressive disease after a chemotherapy doublet +/− bevacizumab and an anti-PD-(L)1 agent [20]. In this poster presentation the authors report that only 203 of the 502 patients (40%) included in this trial went on to receive a subsequent systemic anticancer therapy following the discontinuation of study treatment.

This reflects further the urgent need of feasible and effective therapeutic options in metastatic cervical cancer.

Conclusion

In conclusion, findings from this quality assurance study demonstrate that only half of disseminated metastatic cervical cancer patients receive first-line guideline recommended standard therapy in Germany. In addition, there remains a significant unmet need for patients who have progressed on prior systemic therapy. In particular, insights from patients receiving subsequent therapy after progression on first-line therapy indicate that those patients will benefit from having additional effective treatment options with differentiated mechanisms of action. Given recent positive trials on immunotherapy in first- and second-line treatment, updated analyses of treatment patterns should be performed in the future to assess the impact of new emerging treatment options in metastatic cervical cancer therapy.

Conflict of Interest

Dominik Denschlag: AstraZeneca, Eisai, GSK, Intuitive, KLS Martin, MSD, PharmaMar, Seagen. Bastian Czogalla: AstraZeneca, MSD. Florian Heitz: NovoCure, PharmaMar, AstraZeneca, Roche, TESARO, GSK, Clovis, amedes, ZaiLab, MSD. Markus Kerkmann: Amgen, AstraZeneca, Bristol-Myers Squibb, GSK, Janssen-Cilag, Merck Group, MSD, Pharmacosmos, Pierre Fabre, Roche, Takeda. Laura-Christin Fangmann: none. Philip H. Klecker: none. Frederik Stuebs: none. Linn Wölber: Lumenis, Roche, Eisai, Novartis, MSD, Seagen, GSK, AstraZeneca, Pfizer, medupdate, Regeneron, promedicis, Abbvie. Julia Rados: Pfizer, Eisai, MSD, Roche, Novartis, Gedeon Richter, Lilly, Pierre Fabre, Daiichi Sankyo, Clovis, Stemline, AstraZeneca, Theramex, Seagen, Stemline, Exact Sciences, Medac GmbH, Gilead. Pia C. Lodde: Eisai. Stephan Seitz: AstraZeneca, Daiichi Sankyo, Gilead, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Stemline Menarini. Christian George: AstraZeneca, Celgene, Novartis, Pfizer, Roche Pharma, Lilly, Daiichi Sankyo. Pawel Mach: AstraZeneca, MSD, Roche Pharma, Novartis, Eisai, GSK. Angelina Fink: Novartis, Roche, Pfizer, GSK, Clovis Oncology. Davit Bokhua: none. Nikolaus deGregorio: Roche, Gilead, Novartis, GSK, Abbvie, AstraZeneca, MSD, Myriad, Clovis, Daiichi Sankyo, Eisai. Björn Lampe: none. Franziska Hemptenmacher: Pfizer, Novartis, Daiichi Sankyo, Eisei, AstraZeneca, GSK, ViforPharma, MSD, Roche, Clovis Oncology, Intuitive, Olympus, Gynesonics. Verena Friebe: none. Markus Fleisch: Roche, GSK, Bayer. Pauline Wimberger: Amgen, AstraZeneca, MSD, GlaxoSmithKline, Novartis, Pfizer, Roche Pharma, Clovis, Lilly, Teva, Eisai, Lilly, Gilead, Daiichi Sankyo. Anna Jaeger: none. Andreas Schnelzer: AstraZeneca, MSD, Lilly Pharma, Novartis, Daiichi Sankyo. Suzana Mittelstadt: AstraZeneca, Eisai. Dominik Ratiu: none. Michael Eichbaum: GSK. Adriana Haus: Pfizer. Matthias Kalder: none. Beyhan Ataseven: Roche, GSK, Celgene, Clovis, AstraZeneca, Novartis, MSD, Eisai, Lilly, Medconcept, Medupdate, Eickeler, StreamedUp, ClinSol, Esteve, Pfizer, Amgen, Sanofi-Aventis, PharmaMar, Daiichi Sankyo. Willibald Schröder: none. Holger Bronger: Abbvie, AstraZeneca, Gilead, GlaxoSmithKline, MSD. Jens Kosse: none. Uwe Andreas Ulrich: none. Gabriele Elser: none. Philipp Harter: Amgen, AstraZeneca, GSK, Roche, Immunogen, Sotio, Stryker, Zai Lab, MSD, Clovis, Miltenyi, Eisai, Mersana, Exscientia, Daiichi Sankyo, Karyopharm, Abbvie, Novartis, Corcept, BionTech, Zymeworks, Genmab, Seagen, Immatics.

• References

• 1 Zentrum für Krebsregisterdaten. Krebs in Deutschland – Gebärmutterhals. Accessed December 01, 2024 at: https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2023/kid_2023_c53_gebaermutterhals.pdf?__blob=publicationFile
• 2 OnkoZert. Jahresberichte. Accessed December 01, 2024 at: https://www.onkozert.de/info/jahresberichte/
• 3 Leitlinienprogramm Onkologie. Zervixkarzinom. Accessed December 01, 2024 at: https://www.leitlinienprogramm-onkologie.de/leitlinien/zervixkarzinom
• 4 Long 3rd HJ, Bundy BN, Grendys jr. EC. Gynecologic Oncology Group Study. et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 2005; 23: 4626-4633
• 5 Kitagawa R, Katsumata N, Shibata 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: 2129-2135
• 6 Monk BJ, Sill MW, McMeekin DS. et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2009; 27: 4649-4655
• 7 Tewari KS, Sill MW, Long 3rd HJ. et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014; 370: 734-743
• 8 Tewari KS, Sill MW, Penson RT. et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017; 390: 1654-1663
• 9 Colombo N, Dubot C, Lorusso D. KEYNOTE-826 Investigators. et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med 2021; 385: 1856-1867
• 10 Chung HC, Ros W, Delord JP. et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 2019; 37: 1470-1478
• 11 Tewari KS, Monk BJ, Vergote I. Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med 2022; 386: 544-555
• 12 Coleman RL, Lorusso D, Gennigens C. innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021; 22: 609-619
• 13 Vergote I, González-Martín A, Fujiwara K. innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. et al. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med 2024; 391: 44-55
• 14 Leath 3rd CA, Nysenbaum J, Ting J. et al. Patterns of care and health care resource use among Medicaid-enrolled women with recurrent or metastatic cervical cancer. J Manag Care Spec Pharm 2023; 29: 490-498
• 15 D’Andrea MA, Reddy GK. Immune System Activation in Patients with Metastatic Renal Cell Carcinoma Induced by the Systemic Abscopal Effects of Radiation Therapy. Oncol Res Treat 2023; 46: 33-44
• 16 Craig DJ, Nanavaty NS, Devanaboyina M. et al. The abscopal effect of radiation therapy. Future Oncol 2021; 17: 1683-1694
• 17 Alholm Z, Monk BJ, Ting J. et al. Patient characteristics, treatment patterns, and clinical outcomes among patients with previously treated recurrent or metastatic cervical cancer: A community oncology-based analysis. Gynecol Oncol 2021; 161: 422-428
• 18 Peng C, Li X, Tang W. et al. Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study. Int Immunopharmacol 2024; 129: 111578
• 19 Mittelstadt S, Kelemen O, Admard J. et al. Detection of circulating cell-free HPV DNA of 13 HPV types for patients with cervical cancer as potential biomarker to monitor therapy response and to detect relapse. Br J Cancer 2023; 128: 2097-2103
• 20 Manso L, Vergote I, Fujiwara K. et al. Tisotumab vedotin in 2L/3L recurrent or metastatic cervical cancer: Subsequent therapy data from ENGOT-cx12/GOG-3057/innovaTV 301. Accessed December 01, 2024 at: https://meetings.asco.org/abstracts-presentations/234587

Publication History

Received: 19 December 2024

Accepted: 12 January 2025

Article published online:
15 May 2025