Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Economic burden of clinical trials in lung cancer in a German Comprehensive Cancer Center.

OBJECTIVES: The recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected small patient subgroups. This analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). METHODS: The profit margins between recruiting groups with ≤3 and >3 patients were compared. Clinical and economic data from clinical trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. RESULTS: 161 patients were enrolled in 27 clinical trials. The key economic parameter determining costs and payments was the 'trial visits'. In comparison of the two groups (A≤3; B>3 patients enrolled) we found negative profit margins for the low recruiting group (€ -1444). Concerning the number of visits significant differences were found between PhST and IIT (p=0.009). Additionally, sub-analysis show structural differences in cost composition by conducting PhST and IIT. CONCLUSION: Trials with low patient numbers and IIT, do not cover the cost. To ensure adequate, cost-covering compensation by pharmaceutical companies CCCs have to thoroughly calculate the cost of early proof of concept trials. The findings of this study also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine.

Current antiangiogenic agents in oncology and ophthalmology.

UNLABELLED: Antiangiogenic drugs are approved for many cancer types for longer than a decade. Furthermore, several antiangiogenic agents are approved for local application in ophthalmology for treatment of macular degeneration, venous retinal occlusion and diabetic retinopathy. Knowing that antiangiogenic agents are active in ocular system, we reviewed the current literature, whether antiangiogenic drugs may cause ocular side effects in cancer patients by systemic application. Furthermore, we searched in published papers, if systemic application of antiangiogenic agents in cancer patients may simultaneously treat their ocular disorders, if they have such. Finally, we emphasized cooperation between an oncologist and ophthalmologist when treating patients with antiangiogenic drugs. KEYWORDS: angiogenesis inhibitors, vascular diseases, eye, drug-related side effects and adverse reactions.

Minireview on current antiangiogenic agents in oncology and ophthalmology.

Antiangiogenic drugs are approved for many cancer types for longer than a decade. Furthermore, several antiangiogenic agents are approved for local application in ophthalmology for treatment of macular degeneration, venous retinal occlusion and diabetic retinopathy. Knowing that antiangiogenic agents are active in ocular system, we reviewed the current literature, whether antiangiogenic drugs may cause ocular side effects in cancer patients by systemic application.   Furthermore, we searched in published papers, if systemic application of antiangiogenic agents in cancer patients may simultaneously treat their ocular disorders, if they have such.  Finally, we emphasized cooperation between an oncologist and ophthalmologist when treating patients with antiangiogenic drugs.

Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib.

A 55-year-old Caucasian woman with lung adenocarcinoma stage IV presented with repeated relapse after treatment with cytotoxic chemotherapy (carboplatin, gemcitabine, docetaxel, pemetrexed) and targeted agents (erlotinib, cetuximab, sunitinib). Comprehensive molecular diagnostics (EGFR-, ALK-, RAS-, BRAF-, PIK3CA-, HER2- and DDR2-aberrations) were performed and failed initially to detect any driver mutation. While the patient suffered from rapid deterioration of her general condition, in particular from progressive dyspnea due to lung metastases, we implemented screening for RET- and ROS1 translocations into our molecular diagnostic program based on recent reports of these new molecular subgroups in lung adenocarcinoma. On retesting the patient's tumor sample was found to harbor a ROS1-translocation. The patient was subsequently treated with crizotinib and experienced a pronounced clinical improvement corresponding to a complete metabolic response in (18)F-FDG-PET and a good and confirmed partial response in CT (RECIST 1.1). Our case exemplifies the need for rapid implementation of newly discovered rare genetic lung cancer subtypes in routine molecular diagnostics.

Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors.

BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.

An open-label study of vandetanib with pemetrexed in patients with previously treated non-small-cell lung cancer.

BACKGROUND: Vandetanib (ZACTIMA; ZD6474) is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The safety and tolerability of vandetanib plus pemetrexed was assessed in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously treated NSCLC (stage IIIB/IV) received once-daily oral vandetanib (100 or 300 mg) with pemetrexed (500 mg/m(2) i.v. infusion every 21 days). RESULTS: Patients received vandetanib 100 mg + pemetrexed (n=10) or vandetanib 300 mg + pemetrexed (n=11). The protocol definition of a tolerable dose [vandetanib-related dose-limiting toxicity (DLT) in less than 2 patients] was met in both dose cohorts, with one DLT reported in each: asymptomatic QTc prolongation (>100 ms increase from baseline, but absolute QTc<500 ms) in the 100 mg cohort and interstitial lung disease, which resolved after steroid therapy, in the 300 mg cohort. The most common adverse events were rash, anorexia, fatigue and diarrhea (all n=10). CONCLUSION: Vandetanib and pemetrexed in combination were generally well tolerated in patients with advanced NSCLC.

Assessment of male fertility in patients with Hodgkin's lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials.

BACKGROUND: Infertility is one of the most significant side-effects in long-term survivors of successfully treated Hodgkin's lymphoma (HL). PATIENTS AND METHODS: The fertility status was assessed in male HL patients enrolled into trials of the German Hodgkin Study Group from 1988 to 2003. RESULTS: In pre-treatment analysis (n = 202), 20% of patients had normozoospermia, 11% azoospermia and 69% had other dyspermia. In post-treatment analysis (n = 112), 64% of patients had azoospermia, 30% other dyspermia and 6% normozoospermia (P < 0.001). Azoospermia was observed in 90% of patients treated with chemotherapy alone, 67% of those treated with combined modality and 11% of those treated with radiotherapy alone (P < 0.001). Azoospermia was more frequent after 4x cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8x bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8x BEACOPP escalated (87%) compared with 2x COPP/ABVD (56%; P = 0.003). There was a statistically significant difference in post-treatment follicle-stimulating hormone (FSH) levels between patients with azoospermia and those with preserved spermatogenesis (P = 0.001). CONCLUSIONS: Depending on the treatment received, male HL patients are at high risk of infertility after treatment. FSH might be used as surrogate parameter for male fertility in future studies.

BEACOPP and COPP/ABVD as salvage treatment after primary extended field radiation therapy of early stage Hodgkins disease - results of the German Hodgkin Study Group.

Patients with early stage favorable Hodgkin's disease who relapse after extended field radiotherapy have satisfactory results. We retrospectively analysed patients with relapsed HD after initial radiation therapy alone to determine treatment outcome and prognostic factors. Nine-hundred and forty five patients in localized stages without risk factors received either 40 Gy extended field RT or 30 Gy EF RT followed by an additional 10 Gy to involved lymph node regions. 107 patients relapsed and received salvage therapy. Characteristics of the 107 patients at relapse were as follows: median age was 34 years (range 18--75) with relapse occuring at a median of 19 months (range 4--98 months), 31% were female. The majority of patients (93%) were treated with conventional chemotherapy. Sixty-nine percent were treated with COPP/ABVD like regimens, 21% with BEACOPP, and 3% received various other regimens. Seven percent were treated with radiotherapy alone. Complete remission was achieved in 87% of all salvaged patients. The median follow-up after relapse was 45 months. FF2F (freedom from second treatment failure) and OS (overall survival) were 81% and 89%, respectively. In multivariate analysis age was the major prognostic factor for FF2F and OS (p<0.0001, for both). Further independent prognostic factors were B symptoms (p=0.05) and salvage chemotherapy (p=0.03) for FF2F, and B symptoms (p=0.03) and extranodal involvement (p=0.02) for OS. The long-term outcome of patients relapsing after EF RT is excellent. Age, B symptoms, extranodal involvement and salvage chemotherapy were identified as prognostic factors for second relapse and survival.

Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG).

BACKGROUND: Since there are no randomized studies, the treatment of choice for patients with early stage lymphocyte-predominant Hodgkin's lymphoma (LPHL) remains unclear. We thus reviewed all LPHL cases registered in the database of the German Hodgkin Study Group (GHSG) and compared the different treatment approaches, such as extended field (EF), involved field (IF) radiation and combined modality (CM) treatment for LPHL stage IA patients. PATIENTS AND METHODS: One hundred and thirty-one patients with LPHL in clinical stage IA without risk factors were analyzed. Forty-five patients were treated with EF radiotherapy, 45 patients with IF radiation and 41 patients received CM treatment. The median follow-up was 78 months in the EF group, 40 months after CM and 17 months after IF, respectively. RESULTS: A total of 129 patients achieved complete remission (CR and CRu): 98% after EF radiotherapy, 100% after IF radiation and 95% after CM. With a median follow-up of 43 months there were 5% relapses and only three patients died. Toxicity of treatment was generally mild with most events observed after CM. CONCLUSION: In terms of remission induction IF radiotherapy for stage IA LPHL patients is as effective as EF or CM treatment. However, longer follow-up is needed before final conclusion as the optimal therapy.

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

[Ropivacaine, an advantageous anesthetic for subcutaneous infusion anesthesia]. / Ropivacain, ein vorteilhaftes Anästhetikum für die subkutane Infusionsanästhesie (SIA).

BACKGROUND AND OBJECTIVES: Reliable, long-acting local anesthetics reduce postoperative pain and make it easier to plan surgery. This is especially true when slow infusion anesthesia (SIA) is used. The anesthetic agent ropivacaine appears to meet the requirements of SIA especially well. PATIENTS/METHODS: 1. Venous bloodlevels of ropivacaine after subcutaneous infusion of the maximum dose of 300 mg ropivacaine containing adrenaline 1:1,000,000 were measured in 10 volunteers, time not mentioned in German abstract! We agreed they would match. 2. 30 healthy volunteers received 30 ml of three solutions of lidocaine alone, lidocaine mixed with ropivacaine, and ropivacaine alone, all containing adrenaline 1:1,000,000. The local anesthetic effects were studied. 3. Ropivacaine was used clinically both alone and with different mixtures of ropivacaine and prilocaine, each containing adrenaline 1:1,000,000, in a total of 4,670 cutaneous surgical procedures of all kinds in 3,015 patients. No patient was excluded from this kind of anesthesia. Patient ages ranged from 0.5 to 95 years (median: 54.5). No adrenalin was added for nerve blocks of the fingers and penis. RESULTS: The venous blood levels after administration were low. Ropivacaine acted more than twice as long as lidocaine (p > 0.001). Clinical application of the mixtures was completely free of side-effects and complications and involved a very low rate of postoperative bleeding. The patients remained free of pain as a rule for many hours. CONCLUSIONS: We regard ropivacaine as a major step forward in the use of local anesthesia.

[Review of general anesthesia procedures in ophthalmology]. / Prehl'ad postupov celkovej anestézie v oftalmológii.

We review the anaesthetic management of patients undergoing ophthalmic examination or surgery. General anaesthesia is administered in patients demanding immobilisation, since uncontrolled movement may rise intraocular pressure (IOP) and thus endanger the overall outcome of ophthalmic care. We discuss the effects of anaesthetics and anaesthesia related medications on IOP before, during, and after eye surgery. Also, we analyse anaesthetic procedures applied in eye injury management, vitreal and strabismus surgery as well as paediatric ophthalmology. Finally, we review the systemic side effects of topical eye medications, the complications of ophthalmic general anaesthesia as well as their prevention.