Regine Mayer-Steinacker

Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

BACKGROUNDnRadiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma.nnnMETHODSnBetween May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6-7 weeks in 30 fractions of 1·8-2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241.nnnFINDINGSnOf 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3-10·2) in the temozolomide group versus 9·6 months (8·2-10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84-1·42, p(non-inferiority)=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2-4·1] vs 4·7 [4·2-5·2]; HR 1·15, 95% CI 0·92-1·43, p(non-inferiority)=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0-10·0]; HR 0·62, 95% CI 0·42-0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5-11·7] vs 4·6 [4·2-5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0-3·5] vs 4·6 months [3·7-6·3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight).nnnINTERPRETATIONnTemozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.nnnFUNDINGnMerck Sharp & Dohme.

Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group

PURPOSEnTo define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed.nnnPATIENTS AND METHODSnSixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy.nnnRESULTSnLocal failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors.nnnCONCLUSIONnAn operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0–2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted Pxa0=xa00.56). The hazard ratio (HR) (adjusted HRxa0=xa00.93) was not clinically relevant. The median PFS for the combination arm was low at 6xa0weeks and similar to the median PFS in the monotherapy arm (6xa0weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.

Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials

The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes.

Omission of bone scanning according to staging guidelines leads to futile therapy in non-small cell lung cancer.

The leading European and American professional societies recommend that bone scans (BS) should be performed in the staging of lung cancer only in those patients with bone pain. This prospective study investigated the sensitivity of conventional skeletal scintigraphy in detecting osseous metastases in patients with lung cancer and addressed the potential consequences of failure to use this method in the work-up of asymptomatic patients. Subsequent to initial diagnosis of non-small cell lung cancer, 100 patients were examined and questioned regarding skeletal complaints. Two specialists in internal medicine decided whether they would recommend a bone scan on the basis of the clinical evaluation. Skeletal scintigraphy was then performed blinded to the findings of history and physical examination. The combined results of magnetic resonance imaging (MRI) of the vertebral column, positron emission tomography (PET) of skeletal bone and the subsequent clinical course served as the gold standard for the identification of osseous metastases. Bone scintigraphy showed an 87% sensitivity in the detection of bone metastases. Failure to perform skeletal scintigraphy in asymptomatic patients reduced the sensitivity of the method, depending on the interpretation of the symptoms, to 19–39%. Without the findings of skeletal scintigraphy and the gold standard methods, 14–22% of patients would have undergone unnecessary surgery or neoadjuvant therapy. On this basis it is concluded that bone scans should not be omitted in asymptomatic patients.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

PURPOSEnIn patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ.nnnPATIENTS AND METHODSnIn this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6).nnnRESULTSnIn the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms.nnnCONCLUSIONnBEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Phase I/II Study of Sequential Dose-Intensified Ifosfamide, Cisplatin, and Etoposide Plus Paclitaxel As Induction Chemotherapy for Poor Prognosis Germ Cell Tumors by the German Testicular Cancer Study Group

PURPOSEnTo evaluate the feasibility and the toxicity of sequential, dose-intensified chemotherapy combined with paclitaxel plus peripheral blood-derived hematopoietic stem-cell support (PBSC) for patients with untreated metastatic germ cell tumors (GCTs) who have poor International Germ Cell Consensus Cancer Group prognostic features.nnnPATIENTS AND METHODSnPaclitaxel was added to high-dose (HD) etoposide, ifosfamide, and cisplatin (VIP; etoposide 1,500 mg/m2, ifosfamide 10,000 mg/m2, and cisplatin 100 mg/m2; cumulative dose; days -6 through -2 per cycle) at three dose levels (135, 175, and 225 mg/m2) applied on day -6. Cycles were supported by PBSC and granulocyte colony-stimulating factor. One cycle of standard VIP was administered before start of HD-VIP plus paclitaxel cycles to collect autologous PBSC.nnnRESULTSnFifty-two of 53 patients receiving 152 cycles were assessable. As expected, myelosuppression was the major adverse effect. Median durations of leukocytes less than 1,000/microL and thrombocytes less than 25,000/microL were 6 and 4 days, respectively, independently of the dose of paclitaxel applied. WHO grade 2 neurotoxicity and grade 3 encephalopathy were observed in 5% of patients each. Other main adverse effects observed were stomatitis, diarrhea, and obstipation. Seventy-nine percent of patients achieved a favorable response to chemotherapy plus secondary surgery. After a median follow-up time of 41 months in surviving patients, the calculated 2- and 5-year survival rates were 77.6% (95% CI, 65.4% to 89.9%) and 75.2% (95% CI, 62.5% to 87.8%), respectively.nnnCONCLUSIONnDose-intensive, sequential HD-VIP plus paclitaxel up to a dose of 225 mg/m2 in patients with poor prognosis GCT is a feasible approach. The regimen warrants investigation for its therapeutic potential in an expanded cohort of poor prognosis GCT patients.

Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway

Chordomas are tumors that arise at vertebral bodies and the base of the skull. Although rare in incidence, they are deadly owing to slow growth and a lack of effective therapeutic options. In this study, we addressed the need for chordoma cell systems that can be used to identify therapeutic targets and empower testing of candidate pharmacologic drugs. Eight human chordoma cell lines that we established exhibited cytology, genomics, mRNA, and protein profiles that were characteristic of primary chordomas. Candidate responder profiles were identified through an immunohistochemical analysis of a chordoma tissue bank of 43 patients. Genomic, mRNA, and protein expression analyses confirmed that the new cell systems were highly representative of chordoma tissues. Notably, all cells exhibited a loss of CDKN2A and p16, resulting in universal activation of the CDK4/6 and Rb pathways. Therefore, we investigated the CDK4/6 pathway and responses to the CDK4/6-specific inhibitor palbociclib. In the newly validated system, palbociclib treatment efficiently inhibited tumor cell growth in vitro and a drug responder versus nonresponder molecular signature was defined on the basis of immunohistochemical expression of CDK4/6/pRb (S780). Overall, our work offers a valuable new tool for chordoma studies including the development of novel biomarkers and molecular targeting strategies.

In chordoma, metastasis, recurrences, Ki-67 index, and a matrix-poor phenotype are associated with patients’ shorter overall survival

PurposeTo establish a chordoma tissue cohort (nxa0=xa043) and to correlate localization, size, metastasis, residual disease (R-status), recurrences, histological subtype, matrix content, and Ki-67 proliferation index with patients’ overall survival (OS).Methods and resultsWe used routine histopathology supplemented by immunohistochemistry. In our patient cohort (median age 69xa0years, range 17 to 84xa0years) the median OS was 8.25xa0years. 24 chordomas were localized in the sacrum, 6 in lumbar vertebrae, 7 in thoracic and cervical vertebrae, 5 were limited to the clivus, and one was localized in the nasal septum. Ten patients had metastases, with pulmonary, nodal, and hepatic involvement. 23 patients had recurrent disease. 23 chordomas were classified as ‘not otherwise specified’ (NOS). Besides NOS, we found the following differentiation patterns: renal cell cancer like in six cases, chondroid in four cases, hepatoid differentiation in three cases, and anaplastic morphology in six cases. Ki-67 index of ≥10xa0%, presence of metastasis, and the low content of extracellular matrix were statistically linked to poor OS (pxa0<xa00.05). The matrix-poor phenotype had a higher Ki-67 index (pxa0<xa00.05). Furthermore, presence of metastasis was associated with a higher Ki-67 index in the primary lesion, a positive resection margin, and multiple recurrences (pxa0<xa00.05 each).ConclusionWe propose to include these parameters in the final pathologic report of the resected chordoma.

Rare Phenomenon: Liver Metastases From Glioblastoma Multiforme

Introduction We report the case of a 69-year-old man who presented in our department with previously diagnosed glioblastoma multiforme (GBM). He suffered from severe frontal lobe syndrome and rapid progressive failure of the liver and died within a few days. Using ultrasound imaging of the liver, we could detect at least 10 lesions of necrotic and hemorrhagic aspect suspicious for metastases. The autopsy results confirmed massive metastasization of the liver with wide necrotic confluent parts. Also, immunohistopathologic analyses were positive for glial fibrillary acidic protein (GFAP) and S100 protein and met all the morphologic criteria for metastases of GBM. This case demonstrates that GBM can pass through the brain-blood barrier and may present as a generalized disease with poor outcome. Case Report A 69-year-old man was admitted to our department. The reason for admission was severe agitation in the context of the progression of GBM with frontal lobe participation. The frontal lobe syndrome had been known for approximately 1 month. Primary symptoms were treated with a patch of fentanyl and lorazepam orally. Because of inadequate clinical improvement, his private physician suggested hospitalization. Almost 2 years ago, we were able to detect WHO grade 4 GBM and confirm the diagnosis by histopathologic processing. The tumor was located in the left temporal lobe (Fig 1A). Because of the dimension of the tumor, resection was not completely possible (resection level R2). Subsequently, irradiation at a dose of 59.4 Gy followed the surgical intervention, which led to remission confirmed by magnetic resonance imaging (Fig 1B). One month later, the patient relapsed (Fig 1C). The next procedure was a micronester coil–navigated extirpation of the relapsed part.