Christoph B. Ostertag

High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma

PURPOSE To improve survival and reduce toxicity in primary CNS lymphoma (PCNSL) treatment, we conducted a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiotherapy (WBRT) for newly diagnosed PCNSL patients younger than 65 years of age. PATIENTS AND METHODS Chemotherapy included three steps: three cycles of methotrexate (8 g/m2); cytarabine (AraC; two doses of 3 g/m2) and thiotepa (40 mg/m2) followed by stem-cell harvest; HDT with carmustine (400 mg/m2) and thiotepa (two doses of 5 mg/kg body weight) followed by ASCT. WBRT (45 Gy, two doses of 1 Gy/d) was administered for consolidation. RESULTS Thirty patients with PCNSL younger than 65 years of age (median, 54 years; range, 27 years to 64 years) were enrolled (nine pilot-phase; 21 phase II). Twenty-eight patients responded to methotrexate: six patients with complete remission (CR), 15 patients with partial remission (PR), and seven patients with stable disease (SD) with clinical improvement. Of 26 patients proceeding to AraC and thiotepa, 10 patients achieved CR, 14 patients achieved PR, one patient experienced SD with clinical improvement, and one patient suffered disease progression. Twenty-three patients received HDT plus ASCT, resulting in 15 patients with CRs and eight patients with PRs. After WBRT, 21 of 21 patients had CRs. One patient died from liver failure after methotrexate. HDT was well tolerated apart from WHO grade 3/4 cytopenia. With a median follow-up of 63 months (range, 4 months to 84 months), 5-year overall survival probability is 69% for all patients and 87% for the 23 patients receiving HDT plus ASCT. The 5-year probability of relapse-related death is 21% for all patients (n = 30) and 8.7% for patients treated with HDT plus ASCT (n = 23). CONCLUSION Sequential systemic methotrexate and AraC and thiotepa followed by HDT plus ASCT and hyperfractionated WBRT is very effective with little toxicity as initial therapy for PCNSL.

High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system

Thirteen patients (age 38–67 years) with primary lymphoma of the central nervous system (CNS) were treated with methotrexate and cytarabine/thiotepa induction-chemotherapy followed by high-dose carmustine/thiotepa and autologous stem-cell transplantation. Radiotherapy was restricted to patients who did not respond completely to chemotherapy. With a median follow up of 25 months, 3-year DFS and OS was 77%.

Radiosurgery followed by planned observation in patients with one to three brain metastases.

OBJECTIVE To analyze the role of radiosurgery alone in patients with brain metastases. There were three specific study goals: 1) to determine whether survival of patients selected for this treatment approach can be predicted successfully by use of the recursive partitioning analysis classification defined by the Radiation Therapy Oncology Group; 2) to evaluate local control; and 3) to identify risk factors of cerebral failure. METHODS A total of 101 patients with Karnofsky Performance Scale scores of at least 50 and up to three brain metastases, each 3 cm or less in maximum diameter, were treated with radiosurgery alone. Survival, local control, distant brain freedom from progression (FFP), and overall brain FFP were evaluated according the method of Kaplan and Meier. Risk factors for survival and overall brain FFP were analyzed using the Cox model. RESULTS Median survival was 13.4 months, 9.3 months, and 1.5 months for patients in recursive partitioning analysis Classes 1, 2, and 3, respectively (P < 0.0001). At 1 year, local control, distant brain FFP, and overall brain FFP were 91, 53, and 51%, respectively. An interval greater than 2 years between diagnosis of the primary tumor and diagnosis of brain metastases and the presence of a single brain metastasis were associated with significantly higher overall brain FFP. CONCLUSION Recursive partitioning analysis classification successfully predicted survival. Radiosurgery alone yielded high local control. Overall brain FFP was highest in patients with an interval greater than 2 years between primary diagnosis and diagnosis of a single brain metastasis.

Combined 1p/19q Loss in Oligodendroglial Tumors : Predictive or Prognostic Biomarker?

Purpose: The combined loss of genetic material on chromosomes 1p and 19q is strongly associated with favorable outcome in patients with WHO grade 3 anaplastic oligodendroglial tumors. The prognostic value of 1p/19q loss in WHO grade 2 oligodendroglial tumors is less well defined. Importantly, the possible effect of combined 1p/19q loss has not been studied in patients who were not treated with radiotherapy or chemotherapy. Experimental Design: Seventy-six patients with oligodendroglioma (n = 33), oligoastrocytoma (n = 30), anaplastic oligodendroglioma (n = 6), or anaplastic oligoastrocytoma (n = 7) were identified who had not received radiotherapy or chemotherapy after their first operation until the end of follow-up or until the first progression and had tissue for 1p/19q status available. 1p/19q status was assessed by multiplex ligation–dependent probe amplification. Results: After a median follow-up of 3.8 years, progressive disease was documented in 34 patients. The estimated median progression-free survival was 4.6 years. Fifty-eight of the 76 patients had a combined loss of 1p and 19q. The absence or presence of combined 1p/19q loss was not prognostic for progression-free survival using multivariate adjustment for histology, extent of resection, and gender. Conclusions: Combined 1p/19q loss is not a sensitive prognostic biomarker in patients with oligodendroglial tumors who do not receive radiotherapy or chemotherapy. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress.

Malignant pineal parenchymal tumors in adult patients : Patterns of care and prognostic factors

OBJECTIVE The aim of our study was to analyze patterns of care and to identify prognostic factors in patients at least 18 years of age who received radiotherapy for malignant pineal parenchymal tumors. METHODS In a multicenter, retrospective study, we analyzed data for 37 previously published cases and 64 patients treated at the participating institutions. RESULTS A total of 56 patients received postoperative radiotherapy, and 45 patients received primary radiotherapy. Chemotherapy was administered to 34 patients. The median follow-up period was 38 months, and median overall survival was 100 months. The variables that significantly influenced overall survival were the extent of disease (localized versus disseminated;P = 0.0002), differentiation (pineal parenchymal tumor of intermediate differentiation versus pineoblastoma;P = 0.001), and residual disease (≥50% versus <50% reduction in size;P < 0.0001). In a multivariate analysis, the parameters turned out to be independent risk factors. The median survival in patients with local or spinal failure was 15 months. Local control was better in older patients (≥32 yr versus <32 yr;P = 0.02). Spinal control was more successful in patients with pineal parenchymal tumors of intermediate differentiation than it was in patients with pineoblastomas (P = 0.03). Nine of 45 treatment failures occurred later than 5 years after treatment. CONCLUSION Stage, histological characteristics, and response are independent risk factors in adults with malignant pineal parenchymal tumors. Late relapses are common.

Stereotactic management of lesions of the pineal region.

OBJECTIVE The relevance of the computed tomography-guided stereotactic approach for the management of lesions of the pineal region is analyzed. METHODS In a retrospective analysis conducted between 1985 and 1993, the risk profile, the diagnostic accuracy, and the therapeutic relevance of the stereotactic approach in 106 patients was studied. Survival analysis was used to assess the reliability of the stereotactically obtained diagnosis in terms of follow-up observation. RESULTS A histological diagnosis was obtained in 103 of the 106 patients. In three patients, a conclusive diagnosis could not be established because of intraoperative complications. One lesion was misdiagnosed as a pineocytoma instead of a pineoblastoma. Two of the 106 patients died; 9 patients experienced perioperative morbidity. In 38 patients, the stereotactic approach was also useful for therapy. Cyst aspiration and/or internal drainage was performed in 18 patients with symptomatic cystic lesions, and radiosurgical treatment with use of interstitial 125iodine was performed in 16 patients with low-grade tumors and in 4 patients with solitary metastases. In 12 patients, the obtained tissue diagnosis was the basis for deferring additional therapy. In 43 patients with germ-cell tumors, pineoblastomas, or malignant gliomas, a stereotactic biopsy was the starting point for additional radiotherapy/chemotherapy. Open tumor resection played a minor role (five patients). CONCLUSION The stereotactic approach to the pineal region is a relatively safe procedure in experienced hands. The diagnosis obtained by computed tomography-guided stereotactic biopsy is a valid basis for treatment decisions. Long-term follow-up observation of the benign lesions is necessary for a definite confirmation of diagnostic accuracy.

Validation of intraoperative diagnoses using smear preparations from stereotactic brain biopsies: intraoperative versus final diagnosis--influence of clinical factors.

OBJECTIVE:Despite improvements in imaging techniques, histopathological diagnosis is still an important tool in neuro-oncology. At Freiburg University Hospital in Germany, approximately 450 patients per year undergo a serial stereotactic biopsy to obtain a diagnosis. We analyzed the accuracy of intraoperative diagnosis for rapid establishment of treatment options. Furthermore, we wanted to find out whether the location and histopathology of the tumors as well as the age and sex of the patients affected accuracy. Because of the large number of biopsies performed per year, parameters could also be evaluated for rare cerebral lesions. METHODS:We retrospectively analyzed 5000 consecutive stereotactic brain biopsies from 4589 patients. The digital database comprises the intraoperative and final diagnoses, the location of the tumors, and the sex and age of the patients. Regression analysis was performed to identify parameters that had a significant impact on the results. RESULTS:Intraoperative diagnosis was correct in 90.3% of biopsies. This included complete correlation in 81.3% of the biopsies and partial correlation in 9% of the biopsies. In 5.1% of the biopsies, no correlation between the intraoperative and final diagnosis was obtained. In 4.6% of the biopsies, no diagnosis could be made during or after surgery. A high correlation was found for World Health Organization Type II astrocytomas and, with regression analysis, for World Health Organization Type I astrocytomas, glioblastomas, and metastases. CONCLUSION:Intraoperative diagnosis with stereotactic biopsy has high validity. Immediate treatment based on the intraoperative diagnosis can be justified (e.g., for metastases or glioblastomas). Stereotactic biopsy with an exact histopathological diagnosis is strongly recommended for planning adequate therapy for patients with unidentified brain lesions.

Chronic High-Frequency Deep Brain Stimulation of the STN/SNr for Progressive Myoclonic Epilepsy

Summary:  Chronic high‐frequency deep brain stimulation (DBS) may also be effective in patients with refractory epilepsy. A possible benefit has been postulated because of the connections that exist between the subthalamic nucleus (STN) and the superior colliculus. Individual case reports and pilot studies of successful DBS in different types of epilepsy have already been presented. Here, the case of a 39‐year‐old male with progressive myoclonic epilepsy is reported who remained severely impaired despite VNS and combined antiepileptic drug therapy. Bilateral DBS electrodes were implanted into the STN, followed by implantation of a neurostimulation system under general anesthesia. Adjustment and testing of the remaining contacts was done over several months postoperatively. Bilateral monopolar DBS reduced the intensity and frequency of seizures by 50%. The patient has so far been followed for 12 months. This is the first report of positive effects of DBS in progressive myoclonic epilepsy in an adult patient. A subsequent prospective study will have to investigate whether the STN or other target nuclei are most suitable for DBS in these types of epilepsy and which long‐term results can be obtained.

Subthalamic nucleus deep brain stimulation in elderly patients – analysis of outcome and complications

BackgroundThere is an ongoing discussion about age limits for deep brain stimulation (DBS). Current indications for DBS are tremor-dominant disorders, Parkinsons disease, and dystonia. Electrode implantation for DBS with analgesia and sedation makes surgery more comfortable, especially for elderly patients. However, the value of DBS in terms of benefit-risk ratio in this patient population is still uncertain.MethodsBilateral electrode implantation into the subthalamic nucleus (STN) was performed in a total of 73 patients suffering from Parkinsons disease. Patients were analyzed retrospectively. For this study they were divided into two age groups: group I (age <65 years, n = 37) and group II (age ≥ 65 years, n = 36). Examinations were performed preoperatively and at 6-month follow-up intervals for 24 months postoperatively. Age, UPDRS motor score (part III) on/off, Hoehn & Yahr score, Activity of Daily Living (ADL), L-dopa medication, and complications were determined.ResultsSignificant differences were found in overall performance determined as ADL scores (group I: 48/71 points, group II: 41/62 points [preoperatively/6-month postoperatively]) and in the rate of complications (group I: 4 transient psychosis, 4 infections in a total of 8 patients, group II: 2 deaths [unrelated to surgery], 1 intracerebral hemorrhage, 7 transient psychosis, 3 infections, 2 pneumonia in a total of 13 patients), (p < 0.05). Interestingly, changes in UPDRS scores, Hoehn & Yahr scores, and L-dopa medication were not statistically different between the two groups.ConclusionDBS of the STN is clinically as effective in elderly patients as it is in younger ones. However, a more careful selection and follow-up of the elderly patients are required because elderly patients have a higher risk of surgery-related complications and a higher morbidity rate.

The Brain Tumor Board: Lessons to Be Learned from an Interdisciplinary Conference

Background: The aim of this study is to analyze the work of the interdisciplinary Brain Tumor Board (BTB) which was established at Freiburg University Hospital in 1998. Patients and Methods: From January 1998 to December 2003, a total of 1,516 patients were discussed in 259 meetings of the BTB. The protocols of the BTB were analyzed retrospectively. Results: In 79% of the patients, the diagnosis was based on histological findings or a typical radiological appearance of a lesion, or both. This group was composed of 4 subgroups: 28% benign skull base tumors (19% meningiomas, 4% pituitary adenomas, 3% acoustic schwannomas, 2% others), 24% primary brain tumors of glial origin (8% glioblastomas, 12% gliomas other than glioblastomas, 5% oligoastrocytomas or oligodendrogliomas), 19% brain metastases, and 8% other brain or skull base tumors. In 13% of the cases, the exact diagnosis was still unknown when the patient was presented. 8% of the presentations were motivated by nontumorous interdisciplinary problems (e.g. arterio-venous malformations). The recommendations given by the BTB included: 23% further diagnostic procedures (11% non-invasive examinations, 12% stereotactic biopsies), 57% active antitumoral therapy (22% resection, 17% fractionated radiotherapy, 13% radiosurgery, 5% chemotherapy, <1% embolization), 20% no treatment (14% watchful waiting, 6% supportive care). 91% of the BTB recommendations were realized within 3 months. Conclusion: Interdisciplinary care seems to be particularly necessary in patients with benign skull base tumors, gliomas and brain metastases. Decisions made in a small interdisciplinary group of experts have a high potential of subsequently being realized.