Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 study

SIMPLE SUMMARY: A medulloblastoma recurrence is usually associated with an unfavorable prognosis. The German P-HIT-REZ 2005 Study gathered data from patients with relapsed medulloblastomas treated in different, non-randomized therapy arms dependent on preconditions of the patients (previous treatment, comorbidities, relapse pattern), the decision of treating physicians, and the patients’/parents’ choice. A total of 93 evaluable patients with refractory or relapsed medulloblastoma were enrolled. The main aim of this study was to analyze the impact of patient and disease characteristics as well as local and systemic therapies on post-relapse progression-free (PFS) and overall survival (OS). In multivariate analysis, a short time until the first recurrence (<18 months) was the strongest predictor for a worse PFS and OS, which was mainly associated with molecular subgroup 3. Metastatic disease, at relapse, only had a significant impact on OS. Re-biopsy, at relapse, is highly recommended to investigate the histopathological and molecular genetic tumor characteristics and to exclude a secondary malignancy. ABSTRACT: Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival

Radiotherapy for recurrent medulloblastoma in children and adolescents: survival after re-irradiation and first-time irradiation

Background: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. Methods: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. Results: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7–28.7) vs. 12.0 (CI: 8.1–21.0) months] and OS [31.5 (CI: 27.6–64.8) vs. 20.0 (CI: 14.0–36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4–45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7–41.5) vs. 8.0 (CI: 6.6–12.2)/OS: 31.5 (CI: 27.6–NA) vs. 13.3 (CI: 8.1–20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8–60.6) vs. 6.6 (CI: 1.5–NA) months] and OS [40.2 (CI: 18.7–NA) vs. 12.4 (CI: 4.4–NA) months]. Conclusions: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system

BACKGROUND: This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. DISCUSSION: The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create “top-down” nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism’s allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. SUMMARY: Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine

Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies

Purpose!#!Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.!##!Methods!#!Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.!##!Results!#!Median age at first recurrence was 7.6 years (IQR: 4.0-13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3-20.0) and 36.9 months (CI 29.7-53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74-1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival &amp;gt; 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.!##!Conclusion!#!No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation

MEDB-17. Re-irradiation for recurrent medulloblastoma in a matched cohort: Advantageous especially in patients without resection

Abstract INTRODUCTION: Radiotherapy with craniospinal irradiation (CSI) is an important part of initial treatment for medulloblastoma in most children. Radiotherapy after recurrence is currently not widely used. This analysis aims to evaluate whether re-irradiation (RT2) may show survival benefits. METHODS: Data for patients with recurrent medulloblastomas from the German HIT-REZ studies was gathered. Patients with RT2 at 1st recurrence were matched by propensity score to an equal number of patients without radiotherapy. Matching variables were sex, initial therapy, time to recurrence, metastatic stage and therapy at 1st recurrence and radiotherapy at subsequent recurrences. The matched cohort was analysed regarding PFS and OS after 1st recurrence. RESULTS: From a cohort of 240 pre-irradiated patients, 106 patients were matched. Patients with RT2 showed improved median PFS [21.0 months (95%-CI: 17.5 – 27.6)] and OS [37.5 months (CI: 30.0 – 59.4)] compared to control patients [(PFS: 12.0 months (CI: 8.1 – 17.7) / OS: 20.1 months (CI: 14.5 – 44.8)]. When stratifying by resection at recurrence (36.8% resected), a survival advantage for RT2 was found in patients without resection in PFS [19.6 (CI: 14.9 – 31.5) vs. 8.0 months (CI: 5.4 – 14.4)] and OS [41.9 (CI: 30.0 – 59.4) vs. 13.3 months (CI: 8.1 – 36.7)]. However, no advantage was found after resection [PFS: 22.5 (CI: 17.5 – 50.4) vs. 19.1 months (CI: 14.1 – 34.3) / OS: 32.3 (CI: 27.6 – NA) vs. 48 months (CI: 23.4 – NA)]. CSI was used in 6 patients without differences in survival to focal RT2. Median PFS after first irradiation was 32.5 months, after RT2 20.9 months. No patients with RT2 were alive past 10 years after 1st recurrence.CONCLUSION: Patients with recurrent medulloblastoma show benefits from RT2 in median PFS and OS. However, no advantage for RT2 was found when resection was also applied at recurrence. Cure after treatment with RT2 was not found in our cohort.</jats:p

Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies

Abstract Purpose Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN. Methods Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated. Results Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival &gt; 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found. Conclusion No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation. </jats:sec

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Recurrent medulloblastomas are associated with survival rates &lt;10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (&lt;18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival.</jats:p

MEDB-38. Significance of CSF cytology and neurologic deterioration in relapsed medulloblastomas in the German HIT-REZ-97/-2005 Studies and the HIT-REZ-Register

Abstract BACKGROUND: Follow-up examinations are an essential part of the aftercare of patients with brain tumours. We investigated survival in relation to neurological impairment and positive CSF findings at first relapse/progression of medulloblastomas. METHODS: We collected data from patients with relapsed medulloblastoma from the German HIT-REZ studies (HIT-REZ-1997, HIT-REZ-2005, HIT-REZ-Register, n=342). Survival differences dependent on tumour cell-positive and -negative CSF cytology as well as on new onset or worsening of neurological impairment (i.e. headache, nausea/vomiting, ataxia, seizures and others) were analysed. RESULTS: 247 patients with a recurrent medulloblastoma were evaluable for CSF cytology at first relapse/progression (positive n=97, negative n=150). Patients with tumour cell-positive CSF results showed a significantly shorter median PFS and OS time compared to patients with negative CSF cytology [PFS: 9.1 (CI: 5.3-12.9) vs. 16.8 (CI: 13.8-19.8) months, plog rank test=0.001; OS: 14.4 (CI: 12.3-16.4) vs. 41.8 (CI: 33.3–50.4) months, plog rank test&amp;lt;0.001]. The shortest PFS and OS were observed in SHH-activated (n=18) and group 3 medulloblastomas (n=23) independently of CSF cytology result [median PFSSHH: 4.3 (CI:1.1-12.2), OSSHH: 6.3 (CI:1.1-18.7); PFSgroup3: 4.2 (CI:2.3-13.1), OSgroup3: 13.2 (CI:7.1-18.5) months]. For analysis of the impact of neurological deterioration on survival at first relapse, 249 Patients were evaluable. 105 patients with new or severely worsened neurological impairment at first relapse/progression displayed a significantly poorer PFS and OS time in comparison to 144 patients with unchanged or improved neurological symptoms [PFS: 8.2 (CI: 6.0-10.3) vs. 14.9 (CI: 12.0-17.9) months, plog rank test=0.001; OS: 15.1 (CI: 9.5-20.6) vs. 32.6 (CI: 26.2-38.4) months, plog rank test&amp;lt;0.001]. CONCLUSIONS: Patients with relapsed medulloblastoma show significantly worse survival (PFS and OS) in presence of positive CSF cytology or neurologic deterioration at relapse. These findings could be relevant for patient/parents counselling and treatment recommendations at relapse. Funded by the German Children Cancer Foundation</jats:p

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study

Abstract Background Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results. Methods Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas. Results Fifty-three patients with a median age of 6.9 years (1.25–25.4) at first recurrence and a median follow-up time of 36 months (2–115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9–120.1) vs. 95 (CI: 20.7–169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7–31.3) vs. 7 (CI: 0–15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%. Conclusion The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (&amp;gt;6 months) mediated by TMZ occurred in a small number of cases (14.3%). </jats:sec

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term result of the E-HIT-REZ 2005 study

BACKGROUND: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results. METHODS: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas. RESULTS: Fifty-three patients with a median age of 6.9 years (1.25–25.4) at first recurrence and a median follow-up time of 36 months (2–115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9–120.1) vs. 95 (CI: 20.7–169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7–31.3) vs. 7 (CI: 0–15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%. CONCLUSION: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%)