Martin Heubner

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING Boehringer Ingelheim.

Molecular profiling and prognostic relevance of circulating tumor cells in the blood of ovarian cancer patients at primary diagnosis and after platinum-based chemotherapy.

Objectives: Disseminated tumor cells (DTCs) in the bone marrow (BM) were shown to be of prognostic significance in gynecological cancers. Bone marrow aspiration is less accepted by patients compared with blood drawing. In this pilot study, we applied the AdnaTest BreastCancer based on immunomagnetic enrichment, targeting common antigens on epithelial gynecological cancers, followed by multiplex reverse transcriptase-polymerase chain reaction for selection and detection of circulating tumor cells (CTCs) in the blood of 122 ovarian cancer patients at primary diagnosis and/or after platinum-based chemotherapy. Results were compared with detection of DTC in BM. Methods: Ten-milliliter blood was obtained before surgery (n = 86) and/or after chemotherapy (n = 70) and analyzed for CTC with the AdnaTest BreastCancer for the detection of EpCAM-, MUC-1-, and HER-2-transcripts. CA 125 was assessed in an additional single-plex reverse transcriptase-polymerase chain reaction. Bone marrow aspirates were analyzed in duplicate by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Results: Before surgery, CTCs were detected in 19% of patients, expressing EpCAM (31%), MUC-1 (50%), HER-2 (31%), and CA 125 (50%), respectively. After chemotherapy, the overall detection rate for CTC was 27%, thereof EpCAM (68%), MUC-1 (47%), HER2 (21%), and CA 125 (37%). The overall detection rate for DTC in the BM was 35% before surgery and 31% after therapy. A comparison between DTC and CTC resulted in a concordance rate of 59% before surgery and 56% after chemotherapy. CTC positivity significantly correlated with shorter overall survival before surgery (P = 0.0054) and after chemotherapy (P = 0.047). Conclusions: This methodological approach might help to identify molecular targets for specific biological therapies. Blood analysis could give additional information complimentary to that obtained by DTC.

Implementation of FAST-PET/MRI for whole-body staging of female patients with recurrent pelvic malignancies: A comparison to PET/CT

OBJECTIVES To compare the diagnostic competence of FAST-PET/MRI and PET/CT for whole-body staging of female patients suspect for a recurrence of a pelvic malignancy. METHODS 24 female patients with a suspected tumor recurrence underwent a PET/CT and subsequent PET/MRI examination. For PET/MRI readings a whole-body FAST-protocol was implemented. Two readers separately evaluated the PET/CT and FAST PET/MRI datasets regarding identification of all tumor lesions and qualitative assessment of visual lesion-to-background contrast (4-point ordinal scale). RESULTS Tumor relapse was present in 21 of the 24 patients. Both, PET/CT and PET/MRI allowed for correct identification of tumor recurrence in 20 of 21 cases. Lesion-based sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for the detection of malignant lesions were 82%, 91%, 97%, 58% and 84% for PET/CT and 85%, 87%, 96%, 63% and 86% for PET/MRI, lacking significant differences. Furthermore, no significant difference for lesion-to-background contrast of malignant and benign lesions was found. CONCLUSION FAST-PET/MRI provides a comparably high diagnostic performance for restaging gynecological cancer patients compared to PET/CT with slightly prolonged scan duration, yet enabling a markedly reduced radiation exposure.

Simultaneous positron emission tomography/magnetic resonance imaging for whole-body staging in patients with recurrent gynecological malignancies of the pelvis: a comparison to whole-body magnetic resonance imaging alone.

ObjectivesThe objective of this study was to assess the diagnostic value of integrated positron emission tomography/magnetic resonance imaging (PET/MRI) for whole-body staging of patients with recurrent gynecological pelvic malignancies, in comparison to whole-body MRI alone. Materials and MethodsThe study was approved by the local institutional ethics committee. Written informed consent was obtained before each examination. Thirty-four consecutive patients with a suspected recurrence of cervical (n = 18) or ovarian (n = 16) cancer were prospectively enrolled for an integrated PET/MRI examination, which comprised a diagnostic, contrast-enhanced whole-body MRI protocol including dedicated sagittal dynamic imaging of the pelvis. Two radiologists separately evaluated the data sets regarding lesion count, lesion detection, lesion characterization, and diagnostic confidence. Mean and median values were calculated for each rating. Statistical analyses were performed both per-patient and per-lesion bases using a Wilcoxon signed-rank test to indicate potential significant differences among PET/MRI and MRI (alone) data sets. ResultsMalignant lesions were present in 25 of the 34 patients. Positron emission tomography/magnetic resonance imaging offered correct and superior identification of all 25 patients with cancer recurrence, compared with MRI alone (23/25). A total of 118 lesions (malignant, 89; benign, 29) were detected. Positron emission tomography/magnetic resonance imaging correctly identified 88 (98.9%) of 89 malignant lesions, whereas MRI alone allowed for correct identification of 79 (88.8%) of the 89 malignant lesions. In addition, PET/MRI provided significantly higher lesion contrast and diagnostic confidence in the detection of malignant lesions (P < 0.001) compared with MRI alone. ConclusionsThese first results demonstrate the high diagnostic potential of integrated PET/MRI for the assessment of recurrence of female pelvic malignancies compared with MRI alone.

The prognostic impact of circulating proteasome concentrations in patients with epithelial ovarian cancer.

BACKGROUND Intracellularly, the ubiquitin-proteasome system participates in crucial functions such as cell cycling, differentiation, proliferation, gene transcription, and apoptosis. However, in malignancies including ovarian cancer increased extracellular concentrations of circulating 20S proteasomes (c-proteasomes) have been detected in blood. We tested the hypothesis that the c-proteasome plasma concentration is a biomarker associated with the clinical course of ovarian cancer patients. METHODS 20S-proteasome venous plasma concentration was measured by ELISA in patients presenting with ovarian cancer before (n=120) and after (n=68) primary treatment, and in healthy volunteers (n=55). The median follow-up time was 19 months. To assess the relation of proteasome expression with c-proteasome concentration, tumor specimens from 27 patients were immunohistochemically stained for 20S proteasome using an antibody directed against the core subunits of the catalytic domain of the 20S proteasome. RESULTS Median c-proteasome concentration was higher (p<0.0001) in untreated ovarian cancer patients (457.5 ng/ml, range: 200-12540 ng/ml) than in healthy controls 290 ng/ml, range: 140-425 ng/ml). Following completion of primary treatment, the median c-proteasome concentration increased (p=0.003) relative to baseline (595 ng/ml, range: 200-20000 ng/ml) and concentrations positively correlated (p=0.031) with residual disease left at primary surgery. Patients with post-treatment c-proteasome concentrations exceeding the cohorts median showed a diminished survival (p=0.045). We found no correlation between c-proteasome concentration and strength of proteasomal staining in tumor specimens. CONCLUSIONS Circulating proteasome concentrations correlate with residual tumor mass and might be a prognostic variable in ovarian cancer following primary therapy.

Definition of compartment-based radical surgery in uterine cancer: radical hysterectomy in cervical cancer as 'total mesometrial resection (TMMR)' by M Höckel translated to robotic surgery (rTMMR).

BackgroundRadical hysterectomy has been developed as a standard treatment in Stage I and II cervical cancers with and without adjuvant therapy. However, there have been several attempts to standardize the technique of radical hysterectomy required for different tumor extension with variable success. Total mesometrial resection as ontogenetic compartment-based oncologic surgery - developed by open surgery - can be standardized identically for all patients with locally defined tumors. It appears to be promising for patients in terms of radicalness as well as complication rates. Robotic surgery may additionally reduce morbidity compared to open surgery. We describe robotically assisted total mesometrial resection (rTMMR) step by step in cervical cancer and present feasibility data from 26 patients.MethodsPatients (n = 26) with the diagnosis of cervical cancer were included. Patients were treated by robotic total mesometrial resection (rTMMR) and pelvic or pelvic/periaortic robotic therapeutic lymphadenectomy (rtLNE) for FIGO stage IA-IIB cervical cancer.ResultsNo transition to open surgery was necessary. No intraoperative complications were noted. The postoperative complication rate was 23%. Within follow-up time (mean: 18 months) we noted one distant but no locoregional recurrence of cervical cancer. There were no deaths from cervical cancer during the observation period.ConclusionsWe conclude that rTMMR and rtLNE is a feasible and safe technique for the treatment of compartment-defined cervical cancer.

Definition of Compartment Based Radical Surgery in Uterine Cancer—Part I: Therapeutic Pelvic and Periaortic Lymphadenectomy by Michael Höckel Translated to Robotic Surgery

Objective. To define compartment based therapeutic pelvic and periaortic lymphadenectomy in cervical and endometrial cancer. Compartment based oncologic surgery appears to be favorable for patients in terms of radicality as well as complication rates, and the same appears to be true for robotic surgery. We describe a method of robotically assisted compartment based lymphadenectomy step by step in uterine cancer and demonstrate feasibility data from 35 patients. Methods. Patients with the diagnosis of endometrial (n = 16) or cervical (n = 19) cancer were included. Patients were treated by rTMMR (robotic total mesometrial resection) or rPMMR (robotic peritoneal mesometrial resection) and pelvic or pelvic/periaortic rtLNE (robotic therapeutic lymphadenectomy) with cervical cancer FIGO IB-IIA or endometrial cancer FIGO I-III. Results. No transition to open surgery was necessary. Complication rates were 13% for endometrial cancer and 21% for cervical cancer. Within follow-up time median (22/20) month we noted 1 recurrence of cervical cancer and 2 endometrial cancer recurrences. Conclusions. We conclude that compartment based rtLNE is a feasible and safe technique for the treatment of uterine cancers and is favorable in aspects of radicality and complication rates. It should be analyzed in multicenter studies with extended followup on the basis of the described technique.

Morbidity of Inguinofemoral Lymphadenectomy in Vulval Cancer

Background. The aim of this study is to detect possible risk factors for development of short- and long-term local complications after inguinofemoral lymphadenectomy for vulval cancer. Methods. This retrospective cohort study included 34 vulval cancer patients that received inguinofemoral lymphadenectomy. The detected complications were wound cellulitis, wound seroma formation, wound breakdown, wound infection, and limb lymphoedema. Followup of the patient ran up to 84 months after surgery. Results. Within a total of 64 inguinofemoral lymphadenectomies, 24% of the inguinal wounds were affected with cellulitis, 13% developed a seroma, 10% suffered wound breakdown, 5% showed lower limb edema within a month of the operation, and 21.4% showed lower limb edema during the long-term followup. No significant correlation could be found between saphenous vein ligation and the development of any of the local complications. The 3-year survival rate in our cohort was 89.3%. Conclusions. Local complications after inguino-femoral lymphadenectomy are still very high, with no single pre-, intra-, or postoperative factor that could be incriminated. Saphenous vein sparing provided no significant difference in decreasing the rate of local complications. More trials should be done to study the sentinel lymph node detection technique.

Intraoperative navigation in robotically assisted compartmental surgery of uterine cancer by visualisation of embryologically derived lymphatic networks with indocyanine-green (ICG)

To evaluate feasibility of intraoperative visualization of embryologically defined organ compartments and their drainage by ICG in uterine cancer.

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8)

OBJECTIVES To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). METHODS Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. RESULTS Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. CONCLUSIONS Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations.