Shifting cancer care towards Multidisciplinarity: the cancer center certification program of the German cancer society

Background: Over the last decades numerous initiatives have been set up that aim at translating the best available medical knowledge and treatment into clinical practice. The inherent complexity of the programs and discrepancies in the terminology used make it difficult to appreciate each of them distinctly and compare their specific strengths and weaknesses. To allow comparison and stimulate dialogue between different programs, we in this paper provide an overview of the German Cancer Society certification program for multidisciplinary cancer centers that was established in 2003. Main body: In the early 2000s the German Cancer Society assessed the available information on quality of cancer care in Germany and concluded that there was a definite need for a comprehensive, transparent and evidence-based system of quality assessment and control. This prompted the development and implementation of a voluntary cancer center certification program that was promoted by scientific societies, health-care providers, and patient advocacy groups and based on guidelines of the highest quality level (S3). The certification system structures the entire process of care from prevention to screening and multidisciplinary treatment of cancer and places multidisciplinary teams at the heart of this program. Within each network of providers, the quality of care is documented using tumor-specific quality indicators. The system started with breast cancer centers in 2003 and colorectal cancer centers in 2006. In 2017, certification systems are established for the majority of cancers. Here we describe the rationale behind the certification program, its history, the development of the certification requirements, the process of data collection, and the certification process as an example for the successful implementation of a voluntary but powerful system to ensure and improve quality of cancer care. Conclusion: Since 2003, over 1 million patients had their primary tumors treated in a certified center. There are now over 1200 sites for different tumor entities in four countries that have been certified in accordance with the program and transparently report their results from multidisciplinary treatment for a substantial proportion of cancers. This led to a fundamental change in the structure of cancer care in Germany and neighboring countries within one decade

a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24)

Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110)

Background: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. Patients and methods: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. Results: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS ¼ 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS ¼ 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS ¼ 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P ¼ 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P ¼ 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P ¼ 0.022). Conclusion: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy

Chemotherapy-free combination of ibrutinib and obinutuzumab for untreated advanced follicular lymphoma: results of a phase II study from the German Lymphoma Alliance

Immunochemotherapy induces long-term response in patients with follicular lymphoma. However, toxicity of chemotherapy remains a relevant challenge. The Bruton’s tyrosine kinase inhibitor ibrutinib has shown significant activity in patients with indolent B-cell lymphoma. Combining ibrutinib with obinutuzumab may therefore be an attractive chemotherapy free option. We conducted a prospective, single-arm, multicenter phase 2 trial to evaluate the chemotherapy-free regimen of obinutuzumab plus ibrutinib in patients with previously untreated advanced-stage follicular lymphoma. Patients received six 21-days cycles of ibrutinib and obinutuzumab for induction and 12 additional two-month cycles for maintenance. Primary endpoint was one-year progression-free survival (PFS). The study was powered to detect an improvement of 10 percent over the one-year PFS of 85%. A total of 98 patients was enrolled in the trial. Median follow-up was 5.5 years. After induction, 5 patients (5%) had a complete response (CR) and 82 (85%) a partial response (PR). The one-year PFS was 80%, missing the prospected improvement of a one-year PFS of 85% (p=0.93). Median PFS was 4.5 years, median duration of response and overall survival were not reached. The most common adverse events of grade 3/4 were neutropenia, lung infection, hypertension, fatigue, rash and thrombocytopenia. The trial failed the primary efficacy endpoint of the chemotherapyfree regimen of obinutuzumab and ibrutinib in follicular lymphoma patients. However, the combination achieved durable and deep responses and revealed an acceptable safety profile

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

A single nucleotide polymorphism in the gene for FGFR4 (−Arg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P=0.023 and AJCC, P=0.046), presence of microulceration (P=0.009), tumour vascularity (P=0.001), metastases (P=0.025), number of primary tumours (P=0.022), overall survival (P=0.047) and disease-free survival (P=0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P=0.004) and by Breslow in mm (P=0.02)) and the tumour subtype nodular melanoma (P=0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma

Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented. Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. Trial registration: NCT02495922 on June 24th, 2015