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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 -
Journal of Clinical Oncology : Official... Oct 2020NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the...
Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.
PURPOSE
NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.
METHODS
mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.
RESULTS
Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were wild type, 43 (41%) were mutant/non-codeleted, and 37(35%) were mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; = .003; HR, 0.13; < .001) and OS (HR, 0.38; = .013; HR, 0.21; = .029) in the mutant/non-codeleted and mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the wild-type subgroup.
CONCLUSION
This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with -mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials, Phase III as Topic; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Glioma; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Lomustine; Male; Middle Aged; Neoplasm Grading; Procarbazine; Promoter Regions, Genetic; Proportional Hazards Models; Tumor Suppressor Proteins; Vincristine
PubMed: 32706640
DOI: 10.1200/JCO.19.02983 -
Cancers May 2024The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the... (Review)
Review
The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.
PubMed: 38893177
DOI: 10.3390/cancers16112059 -
Lancet (London, England) Dec 2017The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is... (Randomized Controlled Trial)
Randomized Controlled Trial
PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.
BACKGROUND
The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients.
METHODS
In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554.
FINDINGS
Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group).
INTERPRETATION
The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma.
FUNDING
Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Austria; Bleomycin; Cyclophosphamide; Czech Republic; Doxorubicin; Etoposide; Female; Germany; Hodgkin Disease; Humans; Male; Middle Aged; Neoplasm Staging; Netherlands; Positron-Emission Tomography; Prednisone; Procarbazine; Rituximab; Switzerland; Treatment Outcome; Vincristine; Young Adult
PubMed: 29061295
DOI: 10.1016/S0140-6736(17)32134-7 -
Frontiers in Molecular Neuroscience 2021Anaplastic oligodendrogliomas are a type of glioma that occurs primarily in adults but are also found in children. These tumors are genetically defined according to the... (Review)
Review
Anaplastic oligodendrogliomas are a type of glioma that occurs primarily in adults but are also found in children. These tumors are genetically defined according to the mutations they harbor. Grade II and grade III tumors can be differentiated most of the times by the presence of anaplastic features. The earliest regimen used for the treatment of these tumors was procarbazine, lomustine, and vincristine. The treatment modalities have shifted over time, and recent studies are considering immunotherapy as an option as well. This review assesses the latest management modalities along with the pathways involved in the pathogenesis of this malignancies.
PubMed: 34675774
DOI: 10.3389/fnmol.2021.722396 -
Continuum (Minneapolis, Minn.) Apr 2015Low-grade gliomas represent one of the most vexing management issues for neuro-oncologists. The relatively long survival compared to other gliomas makes consideration of... (Review)
Review
PURPOSE OF REVIEW
Low-grade gliomas represent one of the most vexing management issues for neuro-oncologists. The relatively long survival compared to other gliomas 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 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. Most important, 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 radiation and chemotherapy.
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 and whether the use of initial chemotherapy as a strategy to defer the potential delayed cognitive toxicity associated with radiation will yield equivalent survival results with a favorable toxicity profile.
Topics: Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Disease Progression; Glioma; Humans; Isocitrate Dehydrogenase; Lomustine; Mutation; Procarbazine; Temozolomide; Treatment Outcome; Vincristine
PubMed: 25837900
DOI: 10.1212/01.CON.0000464174.88687.79 -
Neurologia Medico-chirurgica 2015Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly... (Review)
Review
Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21-days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed.
Topics: Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Dacarbazine; Disease Progression; Dose-Response Relationship, Drug; Glioblastoma; Humans; Recurrence; Temozolomide
PubMed: 25744349
DOI: 10.2176/nmc.ra.2014-0277 -
Journal of Clinical Oncology : Official... Jul 2017The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined... (Review)
Review
The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined 1p/19q loss. Today, the diagnosis of anaplastic oligodendroglioma requires the presence of both IDH-mt and 1p/19q co-deletion, whereas anaplastic astrocytoma is divided into IDH wild-type ( IDH-wt) and IDH-mt tumors. IDH-mt tumors have a more favorable prognosis, and tumors with low-grade histology especially tend evolve slowly. IDH-wt tumors are not a homogeneous entity and warrant further molecular testing because some have glioblastoma-like molecular features with poor clinical outcome. Treatment consists of a resection that should be as extensive as safely possible, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade II or III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade II or III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy. Low-grade gliomas with favorable characteristics are slow-growing tumors. When deciding on the timing of postsurgical treatment with radiotherapy and chemotherapy, both clinical and molecular factors should be taken into account, but a more conservative approach can be considered initially in some of these patients. The factor that best predicts benefit of chemotherapy in grade II and III glioma remains to be established.
Topics: Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Humans; Neoplasm Grading; Oligodendroglioma; Prognosis
PubMed: 28640702
DOI: 10.1200/JCO.2017.72.6737 -
Journal of Clinical Medicine Nov 2023The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the... (Review)
Review
The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the mechanisms of their cytotoxicity and cytostatic activity through apoptosis, necroptosis, drug-induced senescence, and autophagy, interaction of critical damage with radiation-induced lesions, mechanisms of glioblastoma resistance to alkylating agents, including the alkyltransferase MGMT, mismatch repair, DNA double-strand break repair and DNA damage responses, as well as IDH-1 and PARP-1. Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.
PubMed: 38068493
DOI: 10.3390/jcm12237442 -
Cancer Treatment and Research 2015Anaplastic gliomas have received increasing attention over the past years. As opposed to glioblastoma, where the focus has been on the evaluation of novel compounds... (Review)
Review
Anaplastic gliomas have received increasing attention over the past years. As opposed to glioblastoma, where the focus has been on the evaluation of novel compounds (with mainly disappointing results), in anaplastic gliomas relevant progress was generated with genotoxic therapies and translational work on biomarkers. Anaplastic gliomas are classified using single biomarkers, namely isocitrate dehydrogenase (IDH) or the related CpG island methylator phenotype (CIMP), alpha-thalassemia/mental retardation syndrome X-linked (ATRX), telomerase reverse transcriptase (TERT), p53, 1p/19q, and O(6)-methylguanine DNA-methyltransferase (MGMT). With these molecular biomarkers, three main prognostically distinct groups have been defined: (i) CIMP-negative anaplastic gliomas, which have a similar prognosis as glioblastoma, (ii) CIMP-positive 1p/19q intact, and (iii) CIMP-positive 1p/19q codeleted gliomas. In the CIMP-negative, mainly IDH wild-type group, MGMT promoter methylation may be used to identify patients who benefit from alkylating chemotherapy. The mutually exclusive ATRX losses and 1p/19q codeletions are used to subcategorize anaplastic tumors with a mixed histology according to microscopic features. This eliminates the biological basis and clinical necessity for the diagnosis of mixed gliomas (anaplastic oligoastrocytomas). Retrospective long-term analysis of the EORTC 26951 and RTOG 9402 trials revealed that patients with tumors harboring 1p/19q codeletions benefit from addition of procarbazine, lomustine, and vincristine (PCV) chemotherapy to primary radiotherapy. RTOG 9402 suggests that this may be the case also for patients with 1p/19q intact tumors, but IDH mutation. Future developments in addition to the ongoing CATNON and CODEL trials, will focus on further refinement of the molecular predictors and development of treatments that not only increase survival but also maintain neurological function, cognition, and health-related quality of life.
Topics: Algorithms; Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 25468227
DOI: 10.1007/978-3-319-12048-5_6