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Blood Feb 2015High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose...
High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.
Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Central Nervous System Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Neoplasm Grading; Neoplasm Staging; Procarbazine; Prognosis; Rituximab; Survival Rate; Thiotepa; Transplantation, Autologous; Vincristine; Young Adult
PubMed: 25568347
DOI: 10.1182/blood-2014-10-604561 -
Continuum (Minneapolis, Minn.) Dec 2017This article reviews the standard treatment for high-grade gliomas, with a focus on promising new strategies and response assessment. (Review)
Review
PURPOSE OF REVIEW
This article reviews the standard treatment for high-grade gliomas, with a focus on promising new strategies and response assessment.
RECENT FINDINGS
The new World Health Organization (WHO) classification of central nervous system tumors classifies high-grade gliomas based on molecular markers that are of prognostic and therapeutic significance. The addition of chemotherapy, specifically procarbazine, CCNU (lomustine), and vincristine, to radiation in newly diagnosed 1p/19q codeleted anaplastic oligodendrogliomas doubled overall survival. The US Food and Drug Administration (FDA) recently approved the addition of tumor treating fields to adjuvant temozolomide after radiation with concurrent temozolomide in newly diagnosed glioblastoma. A phase3 trial for recurrent glioblastoma did not show an overall survival benefit for the addition of bevacizumab to lomustine compared to lomustine alone. Current efforts are focused on the development of novel treatment approaches, including molecular targeted agents and immunotherapies.
SUMMARY
Surgery, radiation, and chemotherapy remain the standard treatment options for patients with high-grade gliomas. Despite aggressive treatment, these tumors progress, and overall outcomes have not changed much in the past decade. However, our understanding of the disease is improving, and newer therapies appear promising.
Topics: Antineoplastic Agents; Combined Modality Therapy; Glioma; Humans; Prognosis; Treatment Outcome
PubMed: 29200110
DOI: 10.1212/CON.0000000000000554 -
The Lancet. Oncology Jan 2022Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment... (Comparative Study)
Comparative Study Randomized Controlled Trial
Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised...
BACKGROUND
Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity.
METHODS
Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m etoposide taken intravenously on days 1-5; 60 mg/m prednisone taken orally on days 1-15; and 40 mg/m doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m prednisone taken orally on days 1 to 15; and 100 mg/m procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment.
FINDINGS
Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred.
INTERPRETATION
Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased.
FUNDING
Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Female; Follicle Stimulating Hormone; Hodgkin Disease; Humans; Male; Neoplasm Staging; Prednisone; Procarbazine; Vincristine
PubMed: 34895479
DOI: 10.1016/S1470-2045(21)00470-8 -
Continuum (Minneapolis, Minn.) Dec 2017Low-grade gliomas present vexing management issues for neuro-oncologists. The relatively long survival compared to other brain tumors makes consideration of treatment... (Review)
Review
PURPOSE OF REVIEW
Low-grade gliomas present vexing management issues for neuro-oncologists. The relatively long survival compared to other brain tumors makes consideration of treatment toxicity, and thus timing of potentially damaging interventions such as surgery, radiation, and chemotherapy, crucial. Moreover, the rarity of these tumors makes clinical trials to ascertain optimal care challenging.
RECENT FINDINGS
The discovery that most low-grade gliomas harbor isocitrate dehydrogenase (IDH) mutations that confer a favorable prognosis has improved diagnosis and risk stratification of these tumors. Although Level 1 evidence is still lacking, increasing data support the concept of maximal safe tumor debulking as a first step in tumor management. Preliminary results from a large randomized trial suggest chemotherapy is of comparable effectiveness to radiation therapy for one molecular subtype of low-grade glioma. Importantly, however, the final results of a phase 3 trial comparing radiation with or without procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy indicate a large survival advantage to combined chemotherapy and radiation, raising questions about using chemotherapy alone as an initial treatment strategy.
SUMMARY
While the combination of radiation and PCV provides the best proven overall survival with low-grade gliomas, important questions remain. These include whether the better-tolerated temozolomide is as effective as PCV in conjunction with radiation therapy and whether the use of initial chemotherapy as a strategy to defer the potential delayed cognitive toxicity associated with radiation will yield acceptable survival results with a favorable toxicity profile.
Topics: Combined Modality Therapy; Glioma; Humans
PubMed: 29200111
DOI: 10.1212/CON.0000000000000537 -
The New England Journal of Medicine Jun 2016We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma.
METHODS
Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.
RESULTS
A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.
CONCLUSIONS
Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Disease-Free Survival; Doxorubicin; Female; Hodgkin Disease; Humans; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome; Vinblastine; Young Adult
PubMed: 27332902
DOI: 10.1056/NEJMoa1510093 -
International Journal of Molecular... May 2022One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable... (Review)
Review
One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.
Topics: Glioma; Humans; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 35628161
DOI: 10.3390/ijms23105351 -
CNS Oncology 2015The treatment of glial brain tumors begins with surgery, and standard adjuvant treatment at the end of the past millennium for high-grade glioma and high-risk low-grade... (Review)
Review
The treatment of glial brain tumors begins with surgery, and standard adjuvant treatment at the end of the past millennium for high-grade glioma and high-risk low-grade glioma was radiotherapy and chemotherapy was given at recurrence. However, over the past 10 years much has changed regarding the role of chemotherapy in gliomas and it is now clear that chemotherapy has a role in the treatment of almost all newly diagnosed diffuse gliomas (WHO grade II-IV). This is the result of several prospective studies that showed survival benefit after combined chemoradiotherapy with temozolomide in glioblastoma (WHO grade IV) or after procarbazine, CCNU (lomustine) and vincristine chemotherapy in diffuse low-grade (WHO grade II) and anaplastic (WHO grade III) glioma. The current standard of treatment for diffuse gliomas is described in this overview and in addition some attention is given to targeted therapies.
Topics: Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Glioma; Humans
PubMed: 25906059
DOI: 10.2217/cns.15.2 -
The Lancet. Oncology Dec 2017A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well... (Randomized Controlled Trial)
Randomized Controlled Trial
Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group.
BACKGROUND
A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy.
METHODS
We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m on days 2-4, doxorubicin 35 mg/m on day 2, cyclophosphamide 1250 mg/m on day 2, procarbazine 100 mg/m on days 2-8, and prednisone 40 mg/m on days 2-15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m on days 2-4, doxorubicin 40 mg/m on day 2, cyclophosphamide 1250 mg/m on day 2, dacarbazine 250 mg/m on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2-21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204.
FINDINGS
Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period.
INTERPRETATION
Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity.
FUNDING
Takeda Pharmaceuticals.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brentuximab Vedotin; Confidence Intervals; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Germany; Hodgkin Disease; Humans; Immunoconjugates; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Predictive Value of Tests; Prednisone; Procarbazine; Prognosis; Prospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome; Vincristine
PubMed: 29133014
DOI: 10.1016/S1470-2045(17)30696-4 -
Pediatric Blood & Cancer May 2021Over the past century, classical Hodgkin lymphoma (HL) has been transformed from a uniformly fatal disease to one of the most curable cancers. Given the high cure rate,... (Review)
Review
Over the past century, classical Hodgkin lymphoma (HL) has been transformed from a uniformly fatal disease to one of the most curable cancers. Given the high cure rate, a major focus of classical HL management is reducing the use of radiation therapy (RT) and chemotherapy agents such as procarbazine and doxorubicin to minimize long-term toxicities. In both North America and Europe, an important philosophy in the management of classical HL is to guide the intensity of treatment according to the risk category of the disease. The main factors used for risk classification are tumor stage, bulk of disease, and the presence of B symptoms. Response to chemotherapy is an important factor guiding the utilization of RT in ongoing Children's Oncology Group (COG) and European Network Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials. Both trial groups have transitioned to reduced RT volumes that target the highest risk sites using highly conformal techniques, along with standard or intensified chemotherapy regimens to improve outcomes in higher risk patients. However, given the potential acute toxicities of intensified chemotherapy, immunoregulatory drugs are being investigated in upcoming trials. The purpose of this review is to summarize current approaches to treating pediatric classical HL according to the COG and EuroNet-PHL.
Topics: Antineoplastic Agents; Chemoradiotherapy; Child; Hodgkin Disease; Humans
PubMed: 33818890
DOI: 10.1002/pbc.28562