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Frontiers in Endocrinology 2023Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative... (Meta-Analysis)
Meta-Analysis
Protective effects of exogenous melatonin therapy against oxidative stress to male reproductive tissue caused by anti-cancer chemical and radiation therapy: a systematic review and meta-analysis of animal studies.
BACKGROUND
Male testicular dysfunction is a considerable complication of anti-cancer therapies, including chemotherapy and radiotherapy, partly due to the increased oxidative stress caused by these treatments. Melatonin is an effective antioxidant agent that protects testicles against physical and toxic chemical stressors in animal models. This study aims to systematically review the melatonin's protective effects against anti-cancer stressors on rodential testicular tissue.
MATERIALS AND METHOD
An extensive search was conducted in Web of Science, Scopus, and PubMed for animal studies investigating exogenous melatonin's protective effects on rodent testicles exposed to anti-cancer chemicals and radiotherapeutic agents. Using the DerSimonian and Laird random-effect model, standardized mean differences and 95% confidence intervals were estimated from the pooled data. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022355293).
RESULTS
The meta-analysis included 38 studies from 43 studies that were eligible for the review. Rats and mice were exposed to radiotherapy (ionizing radiations such as gamma- and roentgen radiation and radioactive iodine) or chemotherapy (methotrexate, paclitaxel, busulfan, cisplatin, doxorubicin, vinblastine, bleomycin, cyclophosphamide, etoposide, Taxol, procarbazine, docetaxel, and chlorambucil). According to our meta-analysis, all outcomes were significantly improved by melatonin therapy, including sperm quantity and quality (count, motility, viability, normal morphology, number of spermatogonia, Johnsen's testicular biopsy score, seminiferous tubular diameter, and seminiferous epithelial height), serum level of reproductive hormones (Follicle-Stimulating Hormone and testosterone), tissue markers of oxidative stress (testicular tissue malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase, glutathione, caspase-3, and total antioxidant capacity), and weight-related characteristics (absolute body, epididymis, testis, and relative testis to body weights). Most SYRCLE domains exhibited a high risk of bias in the included studies. Also, significant heterogeneity and small-study effects were detected.
CONCLUSION
In male rodents, melatonin therapy was related to improved testicular histopathology, reproductive hormones, testis and body weights, and reduced levels of oxidative markers in testicular tissues of male rodents. Future meticulous studies are recommended to provide a robust scientific backbone for human applications.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022355293, identifier CRD42022355293.
Topics: Humans; Male; Animals; Rats; Mice; Melatonin; Antioxidants; Iodine Radioisotopes; Semen; Thyroid Neoplasms; Oxidative Stress; Body Weight
PubMed: 37701901
DOI: 10.3389/fendo.2023.1184745 -
American Journal of Hematology Jun 2023There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We...
There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.
Topics: Humans; Aged; Middle Aged; Aged, 80 and over; Rituximab; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Activities of Daily Living; Retrospective Studies; Temozolomide; Lymphoma; Central Nervous System; Central Nervous System Neoplasms
PubMed: 36965007
DOI: 10.1002/ajh.26919 -
JAMA Oncology Apr 2023Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy....
IMPORTANCE
Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear.
OBJECTIVE
To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors.
DESIGN, SETTING, AND PARTICIPANTS
A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022.
EXPOSURES
Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets.
MAIN OUTCOMES AND MEASURES
Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored.
RESULTS
The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose.
CONCLUSIONS AND RELEVANCE
This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.
Topics: Male; Humans; Child; Female; Hodgkin Disease; Procarbazine; Case-Control Studies; Survivors; Colorectal Neoplasms
PubMed: 36729438
DOI: 10.1001/jamaoncol.2022.7153 -
Journal of Korean Medical Science Jun 2018While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the... (Clinical Trial)
Clinical Trial
BACKGROUND
While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation.
METHODS
Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m) on day 1 and procarbazine (60 mg/m) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2-6).
RESULTS
One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5-73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7-12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities.
CONCLUSION
The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM. Trial registry at ClinicalTrials.gov, NCT017337346.
Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Dacarbazine; Disease-Free Survival; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Lomustine; Male; Middle Aged; Neoplasm Recurrence, Local; Procarbazine; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins; Young Adult
PubMed: 29892208
DOI: 10.3346/jkms.2018.33.e167 -
Current Opinion in Oncology Nov 2015Genetic, epigenetic, and expression analyses have refined the traditional, histopathology-based classification of diffusely infiltrating gliomas. This review summarizes... (Review)
Review
PURPOSE OF REVIEW
Genetic, epigenetic, and expression analyses have refined the traditional, histopathology-based classification of diffusely infiltrating gliomas. This review summarizes these trends and implications for elderly patients.
RECENT FINDINGS
The vast majority of diffusely infiltrating gliomas in elderly patients share an unfavorable molecular phenotype, that is, telomerase reverse transcriptase promoter mutation in the absence of isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. Histopathologically, these are mostly astrocytic tumors and treatment is guided by the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. 1p/19q codeletion indicates oligodendroglial histology and benefit from the addition of procarbazine, chlorethyl-cyclohexyl-nitroso-urea/lomustine, and vincristine polychemotherapy to radiotherapy. These tumors are almost exclusively associated with IDH mutations, but their molecular profile is rare in elderly patients. Two large phase III trials, RTOG 0825 and AVAglio, failed to demonstrate an overall survival benefit from antiangiogenic therapy with bevacizumab added to combined chemoradiotherapy (TMZ) in patients with newly diagnosed glioblastoma, but a trend toward improved survival with increasing age can be noted. Ongoing clinical trials in elderly patients with diffusely infiltrating glioma will clarify the role of combined chemoradiotherapy, and of bevacizumab or other antiangiogenic agents as an adjunct to radiotherapy.
SUMMARY
The choice of first-line therapy in elderly patients with diffusely infiltrating glioma is between postoperative hypofractionated radiotherapy and chemotherapy, guided by MGMT methylation in most patients.
Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Central Nervous System Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; DNA Methylation; DNA Modification Methylases; Epigenomics; Gene Expression Regulation, Neoplastic; Glioma; Humans; Isocitrate Dehydrogenase; Molecular Targeted Therapy; Telomerase
PubMed: 26397765
DOI: 10.1097/CCO.0000000000000236 -
Frontiers in Pharmacology 2021Hodgkin Lymphoma (HL) has become one of the most treatable cancers, with more than 80% patients in the advanced stage being cured through improvement of therapeutic... (Review)
Review
Hodgkin Lymphoma (HL) has become one of the most treatable cancers, with more than 80% patients in the advanced stage being cured through improvement of therapeutic regimens. Nevertheless, some treatments were accompanied with toxicities. In the current study, a network meta-analysis (NMA) was conducted to compare the efficacies and toxicities of different chemotherapy regimens for advanced Hodgkin lymphoma (HL). We reviewed PubMed and EMBASE databases from inception to May 2018, and identified randomized controlled trials (RCTs) in which advanced HL patients received chemotherapy. Fourteen eligible RCTs published between 1992 and 2017 were enrolled in this NMA. These studies included a total of 5,964 HL patients, and assessed at least one of seven different chemotherapy regimens. Direct and indirect evidence was combined to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs), and to establish a surface under the cumulative ranking (SUCRA) curve. A cluster analysis was performed to evaluate efficacies and toxicities of different regimens. The COPP + ABVD (cyclophosphamide + vincristine + procarbazine + prednisone + doxorubicin + bleomycin + vinblastine + dacarbazine) regimen had the highest SUCRA partial response and overall remission rate values, while the ABVD regimen resulted in the lowest incidences of anemia, thrombocytopenia, neutropenia, and leucopenia. Cluster analysis revealed that COPP + ABVD had the best efficacy against advanced HL among the seven regimens, and ABVD had the lowest toxicity.
PubMed: 34867316
DOI: 10.3389/fphar.2021.694545 -
Seminars in Radiation Oncology Jul 2015The treatment of newly diagnosed low-grade gliomas remains controversial. Recently published results from the long-term follow-up of Radiation Therapy Oncology Group... (Review)
Review
The treatment of newly diagnosed low-grade gliomas remains controversial. Recently published results from the long-term follow-up of Radiation Therapy Oncology Group (RTOG) trial 9802 demonstrated medically meaningful and statistically significant survival prolongation by adding chemotherapy with procarbazine, lomustine (CCNU), and vincristine after radiotherapy (RT) vs RT alone for "high"-risk patients (median 13.3 vs 7.8 years, hazard ratio = 0.59, P = 0.03). However, in the 17 years since that trial was launched, there have been advances in the understanding of low-grade gliomas biology and patient heterogeneity, an increased recognition of late neurocognitive injury from early RT, and the emergence of temozolomide as an alternative chemotherapy to procarbazine, lomustine (CCNU), and vincristine. These and other changes in the treatment landscape make the applicability of results from RTOG 9802 to all patients less clear. Moreover, in some patients, especially those at the lowest risk for early disease progression, deferred RT in favor of active surveillance or chemotherapy alone may remain a reasonable treatment approach.
Topics: Brain Neoplasms; Chemotherapy, Adjuvant; Glioma; Humans; Observation
PubMed: 26050591
DOI: 10.1016/j.semradonc.2015.02.008 -
Journal of Clinical Oncology : Official... Aug 2022JCO Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization...
JCO 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; = .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; = .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; = .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; = .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.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials, Phase III as Topic; Humans; Lomustine; Neoplasm Recurrence, Local; Oligodendroglioma; Procarbazine; Vincristine
PubMed: 35731991
DOI: 10.1200/JCO.21.02543 -
Acta Neuropathologica Communications Mar 2017Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors....
Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.
Topics: Adult; Aged; Biomarkers, Tumor; Brain Neoplasms; Cohort Studies; DNA Methylation; Epigenesis, Genetic; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local; Oligodendroglioma; Young Adult
PubMed: 28270234
DOI: 10.1186/s40478-017-0422-z -
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