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Frontiers in Oncology 2022Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The...
Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.
PubMed: 35957904
DOI: 10.3389/fonc.2022.934426 -
Cancer Discovery Apr 2023We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5...
UNLABELLED
We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.
SIGNIFICANCE
This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors. See related commentary by Collord and Behjati, p. 811. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Child; Clonal Hematopoiesis; Hematopoiesis; Mutation; Hodgkin Disease; Survivors
PubMed: 36751942
DOI: 10.1158/2159-8290.CD-22-0956 -
Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV.Cancer Medicine Jan 2020The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials... (Review)
Review
PURPOSE
The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high-risk LGG.
METHODS AND MATERIALS
We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high-risk LGG and analyzed the results of these studies.
RESULTS
For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non-1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non-1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status.
CONCLUSIONS
At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high-risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non-1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Chemoradiotherapy, Adjuvant; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioma; Humans; Isocitrate Dehydrogenase; Lomustine; Mutation; Neoplasm Grading; Procarbazine; Progression-Free Survival; Randomized Controlled Trials as Topic; Temozolomide; Vincristine
PubMed: 31701682
DOI: 10.1002/cam4.2686 -
Archives of Toxicology Mar 2021The Organisation for Economic Co-Operation and Development Test Guideline 488 (TG 488) uses transgenic rodent models to generate in vivo mutagenesis data for regulatory...
The Organisation for Economic Co-Operation and Development Test Guideline 488 (TG 488) uses transgenic rodent models to generate in vivo mutagenesis data for regulatory submission. The recommended design in TG 488, 28 consecutive daily exposures with tissue sampling three days later (28 + 3d), is optimized for rapidly proliferating tissues such as bone marrow (BM). A sampling time of 28 days (28 + 28d) is considered more appropriate for slowly proliferating tissues (e.g., liver) and male germ cells. We evaluated the impact of the sampling time on mutant frequencies (MF) in the BM of MutaMouse males exposed for 28 days to benzo[a]pyrene (BaP), procarbazine (PRC), isopropyl methanesulfonate (iPMS), or triethylenemelamine (TEM) in dose-response studies. BM samples were collected + 3d, + 28d, + 42d or + 70d post exposure and MF quantified using the lacZ assay. All chemicals significantly increased MF with maximum fold increases at 28 + 3d of 162.9, 6.6, 4.7 and 2.8 for BaP, PRC, iPMS and TEM, respectively. MF were relatively stable over the time period investigated, although they were significantly increased only at 28 + 3d and 28 + 28d for TEM. Benchmark dose (BMD) modelling generated overlapping BMD confidence intervals among the four sampling times for each chemical. These results demonstrate that the sampling time does not affect the detection of mutations for strong mutagens. However, for mutagens that produce small increases in MF, sampling times greater than 28 days may produce false-negative results. Thus, the 28 + 28d protocol represents a unifying protocol for simultaneously assessing mutations in rapidly and slowly proliferating somatic tissues and male germ cells.
Topics: Animals; Dose-Response Relationship, Drug; Germ Cells; Male; Mice; Mice, Transgenic; Mutagenesis; Mutagenicity Tests; Mutagens; Mutation; Time Factors
PubMed: 33506374
DOI: 10.1007/s00204-021-02977-6 -
Medicine Sep 2020Systematic evaluation of the effectiveness and safety of combined procarbazine, lomustine, and vincristine for treating recurrent high-grade glioma.
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.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Glioma; Humans; Lomustine; Meta-Analysis as Topic; Neoplasm Grading; Neoplasm Recurrence, Local; Procarbazine; Systematic Reviews as Topic; Vincristine; Young Adult
PubMed: 32957367
DOI: 10.1097/MD.0000000000022238 -
Cureus Oct 2020Background The role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This...
Background The role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This improved survival has led to the increasing administration of PCV to LGG patients over the past years. However, like other chemotherapies, serious hematological and non-hematological toxicities may occur. The purpose of this study was to evaluate the toxicity profile of PCV and its clinical relevance in our practice. Materials and Methods We reviewed 63 patients of LGG retrospectively who received chemotherapy PCV between January 2015 and January 2018 at Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore. Results Significant hematological toxicity as grade 3 anemia, thrombocytopenia, and neutropenia occurred in 19%, 27%, and 46% respectively with PCV. Other toxicities such as neurotoxicity, vomiting and derangement of liver enzymes occurred in 3.2%, 19%, and 19% respectively. Patients who were on concurrent anticonvulsants had no increase in PCV toxicity. Survival was not impacted by hematological toxicities up to grade 3. Conclusion PCV chemotherapy is associated with major hematological, hepatic, and clinical toxicities (vomiting, constipation, and neuropathy). Hematological toxicities influenced the course of treatment in terms of delays and interruptions.
PubMed: 33224664
DOI: 10.7759/cureus.11070 -
Frontiers in Veterinary Science 2024Canine gastrointestinal (GI) and hepatosplenic (HS) high-grade (large cell) lymphomas are uncommon forms of canine lymphomas, with a very poor response to chemotherapy...
Canine gastrointestinal (GI) and hepatosplenic (HS) high-grade (large cell) lymphomas are uncommon forms of canine lymphomas, with a very poor response to chemotherapy and a very poor prognosis. Currently, there are no established effective chemotherapy protocols for canine GI/HS lymphomas. This case series aimed to retrospectively evaluate the efficacy of lomustine-based protocols L-LOP (L-asparaginase, lomustine, vincristine, and prednisolone) and L-LOPP (with the addition of procarbazine) for treatment of canine GI/HS lymphomas. Medical records of dogs with cytologically or histologically diagnosed lymphoma at CityU Veterinary Medical Centre from 2019 to 2022 were retrospectively reviewed. The L-LOP/LOPP treatment protocol was well tolerated with rare severe adverse events. Median progression-free survival for GI and HS lymphoma was 56 days (range, 10-274 days) and 57 days (range 8-135 days) respectively; while median survival time for GI and HS lymphoma was 93 days (range 10-325 days) and 210 days (range 8-240 days) respectively.
PubMed: 38846784
DOI: 10.3389/fvets.2024.1373180 -
BMJ Open Apr 2023Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central...
Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.
INTRODUCTION
Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL.
METHODS AND ANALYSIS
Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility.
ETHICS AND DISSEMINATION
This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications.
TRIAL REGISTRATION
jRCTs061180093.
Topics: Aged; Humans; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System; Central Nervous System Neoplasms; Clinical Trials, Phase II as Topic; Cytarabine; Lymphoma; Methotrexate; Multicenter Studies as Topic; Prospective Studies; Rituximab; Treatment Outcome; Vincristine
PubMed: 37094899
DOI: 10.1136/bmjopen-2022-071350 -
Cancer Medicine Sep 2020We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and... (Comparative Study)
Comparative Study Review
PURPOSE
We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials.
PATIENTS AND METHODS
Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression-free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT).
RESULTS
About 1227 patients were included. The 7-year OS was 84.3% (95% CI 80.8-87.2) for ABVD vs 87.7% (95% CI 84.5-90.2) for BEACOPP. Two follow-up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HR = 1.59; 95% CI 1.09-2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7-year PFS was 71.1% (95% CI 67.1-74.6) for ABVD vs 81.1% (95% CI 77.5-84.2) for BEACOPP (P < .001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP.
CONCLUSIONS
This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials, Phase III as Topic; Cyclophosphamide; Dacarbazine; Disease Progression; Doxorubicin; Etoposide; Female; Hodgkin Disease; Humans; Male; Middle Aged; Neoplasms, Second Primary; Prednisone; Procarbazine; Progression-Free Survival; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Vinblastine; Vincristine; Young Adult
PubMed: 32710498
DOI: 10.1002/cam4.3298 -
Journal of Clinical Oncology : Official... Jan 2024JCO The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; value for noninferiority = .9735; difference test < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; value for noninferiority = .8577; difference test = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Disease-Free Survival; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Neoplasm Recurrence, Local; Prednisone; Procarbazine; Vinblastine; Vincristine
PubMed: 37967311
DOI: 10.1200/JCO.23.01745