T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

BACKGROUND: Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. METHODS: We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. RESULTS: We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. CONCLUSIONS: Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

Evaluation of mechlorethamine, vinblastine, procarbazine, and prednisone for the treatment of resistant multicentric canine lymphoma.

Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.

Primary Central Nervous System Lymphoma in an Immunocompetent Young Adult Patient: A Rare Case.

Primary CNS Lymphoma (PCNSL) is a rare form aggressive extra nodal     non-Hodgkin Lymphoma (NHL) that comprising 1-2% of the primary brain tumors that develops in the brain, spinal cord, eye or leptomeningeal area without evidence of systemic involvement. The overall incidence of PCNSL with immunocompetent patients is only 0,47/100.000 year in PCNSL. Approximately 10-20% of patients have ocular involvement and around one third have multifocal neurological disease. Overall long-term survival rate only 20-40%, this is because the management of PCNSL is limited to ability of the drug due to cross the blood brain barrier (BBB). We present a B-cell central nervous system lymphoma in an immunocompetent patient who treat responses with chemotherapy.          A 35-year-old man presented to our hospital with suddenly unconscious 4 hours before admission. He was experiencing headache and blurred of vision withing 3 months and have episode seizure. On Examination, GCS E2 M3 Aphasia, Hemiparesis dextra, papil edema, VOD/VOS: NLP. The other physical exam was normal. Laboratory tests  Hb 10,7 g/dl, LDH 446 U/L, and D-dimer 3,21ug/ml.  Rubella IgG 76,9, CMV Ig G 245,6 and, HSV IgG and IgM negative, HIV test non-reactive, Toxoplasma IgG and Toxoplasma IgM negative, HbsAg and HCV test negative. Brain MRI and MRI Spectroscopy: Lobulated mass size 7,08 cm x 4,75 cm at caudates nucleus sinistra-periventricular lateralis sinistra, Cholin/NAA ratio: 5-9, Cholin/Creatin ration 6-11 suspect malignancy dd/Lymphoma. MRI whole spine: Bulging discus intervertebral C4-C5. Chest and Abdomen CT-Scan are normal. Bone Survey normal, EEG: Epileproform left temporal. Cerebrospinal Fluid: Gliosis reaction sup malignancy.The patient underwent craniotomy and biopsy Pathology Anatomy and IHC Basal Ganglia revealed a Diffuse Large B Cell Lymphoma (NHL) Non-Germinal Center, CD 20 +, Ki 67 95% (High Grade), CD 45 +, CD 3 -, BCL6 +, Mum 1+. The patient we give induction therapy with RMP Regimens (Rituximab 375 mg/m2, day 1, 15 and 29, High Dose Methotrexate (HDMTX) 3000mg/m2 day 2, 16 and 30, and Procarbazine 60mg/m2 day 3-12) because Procarbazine in not available in Palembang we change to Dacarbazine 375mg/m2 days 3,17 and 31), Dexamethasone 5mg/6 hours, and has finished  Low Dose Whole Brain Radiotherapy for consolation therapy. PCNSL is rare form aggressive extra nodal NHL, especially in Immunocompetent patient. In this particular case of patients High Dose Methotrexate Chemotherapy has achieved high respond especially for this patient that showed GCS E4M5V6 and recovery neurological deficit after 2 cycle chemotherapy.

Treatment Options for Recurrent Primary CNS Lymphoma.

OPINION STATEMENT: Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

[Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives].

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy.

BACKGROUND: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. METHODS: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 µg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). RESULTS: Overall, the optimal surveillance strategy was annual FIT (47 µg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 µg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 µg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). CONCLUSIONS: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. IMPACT: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Early Postoperative Treatment versus Initial Observation in CNS WHO Grade 2 and 3 Oligodendroglioma: Clinical Outcomes and DNA Methylation Patterns.

PURPOSE: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. EXPERIMENTAL DESIGN: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score-weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. RESULTS: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33-1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52-8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. CONCLUSIONS: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

Procarbazine, prednisolone and cyclophosphamide oral combination chemotherapy protocol for canine lymphoma.

Orally administered daily chemotherapy offers a novel treatment approach for canine lymphoma in a population of dogs that have failed or not tolerated maximum tolerable dose chemotherapy. A multidrug oral chemotherapy protocol was designed and implemented for the treatment of 50 dogs with multicentric lymphoma with minimal side effects. The protocol consisted of oral procarbazine, prednisolone and cyclophosphamide (PPC) administered daily. Efficacy and toxicity were evaluated by clinical and laboratory evaluation. An overall response rate of 70% was achieved, with 24% and 46% of dogs having a partial and complete response, respectively, to treatment with the PPC protocol. Response to the PPC protocol (complete or partial) and age were the only factors identified as prognostic for time from initiation of the PPC chemotherapy until death. Overall, the protocol was very well tolerated with only one dog requiring protocol discontinuation due to grade 4 thrombocytopenia. Eight dogs recorded gastrointestinal toxicities, seven grade I and one grade II toxicity. These findings demonstrate that the administration of a continuous oral combination chemotherapy can provide comparable survival times in the rescue setting in dogs with multicentric lymphoma with minimal side effects.

Prognostic indicators for naïve canine non-indolent T-cell lymphoma treated with combination lomustine, vincristine, procarbazine and prednisolone chemotherapy.

Lomustine, vincristine, procarbazine and prednisolone (LOPP) chemotherapy has been suggested to be an effective treatment for dogs with naïve non-indolent T-cell lymphoma (TCL). Studies evaluating prognostic factors for dogs with TCL treated with LOPP chemotherapy are lacking. The aim of this retrospective study was to assess potential prognostic factors for canine naïve non-indolent TCL treated with the LOPP protocol. This was a retrospective cohort study of naïve non-indolent TCL treated with the LOPP chemotherapy protocol at a single specialty veterinary oncology clinic. Sixty-seven dogs met the inclusion criteria. The outcomes assessed included progression free survival (PFS), overall survival time (OST) and duration of complete response (DCR). The overall median PFS was 118 days (range 7-2302 days). The median OST was 202 days (range 8-2302 days). The overall median DCR was 316 days (range 38-2261 days). Number of treatments administered (p < .0001), multicentric disease (p = .044) and the presence of hypercalcaemia (p = .006) were prognostic indicators for PFS. Increasing number of treatments (p < .0001) and age (p = .0088) were prognostic indicators for OST. To our knowledge, this is the first study to describe hypercalcaemia as a positive prognostic indicator of PFS for TCL treated with LOPP chemotherapy. LOPP chemotherapy can be considered as a first-line treatment protocol against naïve hypercalcaemic non-indolent TCL.

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 controlled trial.

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/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 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/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 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.

PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression.

INTRODUCTION: The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. METHODS: Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. RESULTS: PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. CONCLUSIONS: PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.

Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group (GHSG HD14).

BACKGROUND: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. METHODS: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1-3), procarbazine 100 mg/m2 (days 1-7), prednisone 40 mg/m2 (days 1-14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. FINDINGS: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group. INTERPRETATION: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. FUNDING: Deutsche Krebshilfe eV and Swiss Federal Government.

Radiotherapy Plus Procarbazine, Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort.

BACKGROUND: IDH-mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear. METHODS: In a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression-free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity. RESULTS: The 4-year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38-0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41-0.97; p = .0348) in multivariable analysis. The 4-year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30-1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001). CONCLUSION: RT + PCV significantly improved PFS compared with RT + TMZ for IDH-mutant AA. However, RT + TMZ was better tolerated. IMPLICATIONS FOR PRACTICE: In the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH-mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH-mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression-free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH-mutant AA.

ABVD and BEACOPP regimens' effects on fertility in young males with Hodgkin lymphoma.

PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.

Evaluation of ovarian reserve before and after chemotherapy.

BACKGROUND: Progress in oncology has improved patient survival. However, cancer chemotherapy can be gonadotoxic and affect their fertility. Recourse to fertility preservation before starting these treatments is therefore necessary in order to allow a better life quality after survival. The aim of this work was to study the impact of chemotherapy on ovarian reserve by AMH measurement. METHODS: This is a descriptive and longitudinal study from 2015 to 2018 carried out at Aziza Othmana hospital ART center in Tunis on patient aged less than 41 years who were candidates for fertility preservation. Patients included had AMH measurement prior to cancer treatment. We called them back to follow up the AMH level after chemotherapy. The AMH assay was performed by electrochemilumiescence technique. At the end, only 66 patients met the inclusion criteria. RESULTS: The most frequent pathologies were Hodgkin's lymphoma and breast cancer. The mean age of patients was 26.7 ± 6.8. The most used chemotherapy protocols were BEACOPP, ABVD or the combination of both in lymphoma and FEC + TXT for breast cancer treatment. A significant difference between AMH before and after chemotherapy was found for BEACOPP and FEC + TXT protocols (p < 10 3). The patient's age was correlated with the AMH decrease after chemotherapy (r = 0.577, p < 10 3). CONCLUSION: Our results showed that the high risk gonadotoxicity protocols were BEACOPP for lymphoma treatment and FEC + TXT for breast cancer treatment. However, studies with a larger sample and more time extended monitoring are necessary for a better gonadotoxicity understanding of the cancer treatments available today.

A comparative study of the effectiveness and safety of combined procarbazine, lomustine, and vincristine as a therapeutic method for recurrent high-grade glioma: A protocol for systematic review and meta-analysis.

BACKGROUND: Systematic evaluation of the effectiveness and safety of combined procarbazine, lomustine, and vincristine for treating recurrent high-grade glioma. METHODS: Electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, WanFang, and China National Knowledge Infrastructure (CNKI) were used to search for studies related to the utilization of combined procarbazine, lomustine, and vincristine as a therapeutic method for recurrent high-grade glioma. Literature screening, extraction of data, and evaluation of high standard studies were conducted by 2 independent researchers. The robustness and strength of the effectiveness and safety of combined procarbazine, lomustine, and vincristine as a therapeutic methodology for recurrent high-grade glioma was assessed based on the odds ratio (OR), mean differences (MDs), and 95% confidence interval (CI). RevMan 5.3 software was used for carrying out the statistical analysis. RESULTS: These results obtained in this study will be published in a peer-reviewed journal. CONCLUSION: Evidently, the conclusion of this study will provide an assessment on whether combined procarbazine, lomustine, and vincristine provides an effective and safe form of treatment for recurrent high-grade glioma. SYSTEMATIC REVIEW REGISTRATION NUMBER: INPLASY202080078.