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International Journal of Molecular... Jun 2022(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in... (Review)
Review
(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.
Topics: Bevacizumab; Brain Neoplasms; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 35806212
DOI: 10.3390/ijms23137207 -
The New England Journal of Medicine Jul 2022Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.
METHODS
We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.
RESULTS
A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.
CONCLUSIONS
Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brentuximab Vedotin; Dacarbazine; Disease-Free Survival; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Humans; Neoplasm Staging; Survival Analysis; Treatment Outcome; Vinblastine
PubMed: 35830649
DOI: 10.1056/NEJMoa2206125 -
Biochimica Et Biophysica Acta. Reviews... Dec 2021Temozolomide (TMZ) is a first-choice alkylating agent inducted as a gold standard therapy for glioblastoma multiforme (GBM) and astrocytoma. A majority of patients do... (Review)
Review
Temozolomide (TMZ) is a first-choice alkylating agent inducted as a gold standard therapy for glioblastoma multiforme (GBM) and astrocytoma. A majority of patients do not respond to TMZ during the course of their treatment. Activation of DNA repair pathways is the principal mechanism for this phenomenon that detaches TMZ-induced O-6-methylguanine adducts and restores genomic integrity. Current understanding in the domain of oncology adds several other novel mechanisms of resistance such as the involvement of miRNAs, drug efflux transporters, gap junction's activity, the advent of glioma stem cells as well as upregulation of cell survival autophagy. This review describes a multifaceted account of different mechanisms responsible for the intrinsic and acquired TMZ-resistance. Here, we summarize different strategies that intensify the TMZ effect such as MGMT inhibition, development of novel imidazotetrazine analog, and combination therapy; with an aim to incorporate a successful treatment and increased overall survival in GBM patients.
Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Glioblastoma; Glioma; Humans; Temozolomide
PubMed: 34419533
DOI: 10.1016/j.bbcan.2021.188616 -
Science (New York, N.Y.) Jul 2022Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT)....
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Dacarbazine; Drug Design; Drug Resistance, Neoplasm; Glioblastoma; Humans; Temozolomide; Tumor Suppressor Proteins
PubMed: 35901163
DOI: 10.1126/science.abn7570 -
Journal of Clinical Oncology : Official... Mar 2023Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS).
PATIENTS AND METHODS
E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation.
RESULTS
A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, = .42). MGMT deficiency was associated with response.
CONCLUSION
The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Dacarbazine; Neuroendocrine Tumors; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies; Temozolomide; Treatment Outcome
PubMed: 36260828
DOI: 10.1200/JCO.22.01013 -
Cell Research Oct 2021Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs...
Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
Topics: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Mice; Paracrine Communication; Pericytes; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 34239070
DOI: 10.1038/s41422-021-00528-3 -
The Lancet. Oncology Jun 2021The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q... (Randomized Controlled Trial)
Randomized Controlled Trial
Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.
BACKGROUND
The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.
METHODS
This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.
FINDINGS
Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.
INTERPRETATION
Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.
FUNDING
Merck Sharpe & Dohme.
Topics: Adolescent; Adult; Aged; Australia; Chemotherapy, Adjuvant; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Combined Modality Therapy; Dacarbazine; Europe; Female; Glioma; Humans; Isocitrate Dehydrogenase; Loss of Heterozygosity; Male; Middle Aged; North America; Radiotherapy, Conformal; Temozolomide; Young Adult
PubMed: 34000245
DOI: 10.1016/S1470-2045(21)00090-5 -
Journal of Clinical Oncology : Official... Feb 2023JCO In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of... (Randomized Controlled Trial)
Randomized Controlled Trial
Nivolumab and Doxorubicin, Vinblastine, and Dacarbazine in Early-Stage Unfavorable Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group Phase II NIVAHL Trial.
JCO In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine followed by 30 Gy involved-site radiotherapy resulted in high complete remission rates and an unprecedented 1-year progression-free survival in 109 patients. In this article, we report the preplanned final analysis conducted three years after the registration of the last patient including long-term safety results. No survival events were observed since the primary analysis, and after a median follow-up (FU) of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival was 98% and 100% in the sequential and concomitant nivolumab, doxorubicin, vinblastine, and dacarbazine treatment groups, respectively. At last FU, the mean forced expiratory pressure in one second was 95.5% (standard deviation 12.7%), the mean diffusion capacity for carbon monoxide adjusted for hemoglobin was 82.8% (standard deviation 15.4%), and the left ventricular ejection fraction was in the normal range in 95% of patients. Hypothyroidism requiring long-term medication occurred in 15% of patients, who were nearly exclusively female (87%). No second primary malignancies occurred, and no patient required corticosteroid treatment at last FU. Patient-reported normalized global quality-of-life score measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 improved over time. This preplanned FU analysis of the largest anti-programmed death protein 1 HL first-line trial to date confirms the outstanding efficacy and relatively favorable safety profile of this therapeutic approach.
Topics: Humans; Female; Hodgkin Disease; Vinblastine; Dacarbazine; Nivolumab; Quality of Life; Stroke Volume; Antineoplastic Combined Chemotherapy Protocols; Ventricular Function, Left; Doxorubicin; Bleomycin; Neoplasm Staging; Prednisone
PubMed: 36508302
DOI: 10.1200/JCO.22.02355 -
JCO Oncology Practice Jul 2022The shortage of dacarbazine (DTIC) has created an acute and unprecedented crisis in the management of patients with classical Hodgkin lymphoma, with DTIC being an... (Review)
Review
The shortage of dacarbazine (DTIC) has created an acute and unprecedented crisis in the management of patients with classical Hodgkin lymphoma, with DTIC being an essential component of doxorubicin, bleomycin, vinblastine, and DTIC (ABVD) and prior attempts at omitting DTIC from ABVD leading to substantial loss of efficacy. In this review, we discuss the strategies to manage classical Hodgkin lymphoma during the DTIC shortage and propose a treatment algorithm on the basis of fitness and ability to receive anthracyclines safely.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Hodgkin Disease; Humans; Vinblastine
PubMed: 35254922
DOI: 10.1200/OP.21.00890 -
Cancer Jun 2020The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated...
Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, or doxorubicin alone as a first-line treatment for advanced leiomyosarcoma: A propensity score matching analysis from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
BACKGROUND
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites.
METHODS
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval-censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
RESULTS
Three hundred three patients from 18 EORTC-STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score-matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2-9.7 months), 8.2 months (95% CI, 5.2-10.1 months), and 4.8 months (95% CI, 2.3-6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52-0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9-47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7-33.4 months; HR, 0.65; 95% CI, 0.40-1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0-36.3 months; HR, 0.66; 95% CI, 0.43-0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
CONCLUSIONS
This is the largest retrospective study of first-line treatment for advanced leiomyosarcoma. In the propensity score-matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Leiomyosarcoma; Male; Middle Aged; Propensity Score; Retrospective Studies; Sarcoma
PubMed: 32129883
DOI: 10.1002/cncr.32795