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CA: a Cancer Journal For Clinicians 2023Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens.... (Review)
Review
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Biological Products
PubMed: 37329269
DOI: 10.3322/caac.21785 -
JAMA Oncology Dec 2023Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
IMPORTANCE
Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
OBJECTIVE
To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).
DESIGN, SETTING, AND PARTICIPANTS
This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.
INTERVENTIONS
Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.
MAIN OUTCOMES AND MEASURES
The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.
RESULTS
Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.
CONCLUSIONS AND RELEVANCE
This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01356290.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Medulloblastoma; Etoposide; Quality of Life; Administration, Metronomic; Brain Neoplasms; Cerebellar Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37883081
DOI: 10.1001/jamaoncol.2023.4437 -
Journal of Clinical Oncology : Official... Jan 2024The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses.
METHODS
Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety.
RESULTS
Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; = .3504; median, 5.4 months tiragolumab 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively.
CONCLUSION
Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Etoposide; Lung Neoplasms; Small Cell Lung Carcinoma
PubMed: 37976444
DOI: 10.1200/JCO.23.01363 -
Blood Advances Nov 2023In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified...
In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
Topics: Humans; Middle Aged; Rituximab; Retrospective Studies; Lymphoma, Large B-Cell, Diffuse; Prednisone; Vincristine; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Cyclophosphamide; Doxorubicin; Etoposide; Lactate Dehydrogenases
PubMed: 37171397
DOI: 10.1182/bloodadvances.2023009731 -
Journal of Clinical Medicine Jun 2023Anogenital warts (AWs) represent a therapeutic challenge, especially in infants, due to sensitive skin and frequent disease recurrence. Though the initial wait-and-see... (Review)
Review
Anogenital warts (AWs) represent a therapeutic challenge, especially in infants, due to sensitive skin and frequent disease recurrence. Though the initial wait-and-see approach is often adopted in asymptomatic immunocompetent children, with spontaneous clearing in almost 90% of cases within two years, persistent or symptomatic lesions can be reasonably treated. However, few studies have been conducted on children. Consequently, most treatments on patients under age 12 are not approved by the Food and Drug Administration. Herein, we review possible therapies for pediatric use in AW and report an illustrative case of a two-year-old boy with atopic skin and symptomatic, persistent AWs who was successfully treated with topical podophyllotoxin, without adverse effects or recurrence. Among available therapies for AWs, topical therapies, such as immunomodulating-agents (topical imiquimod 5% and 3.75% cream, sinecatechins 15% ointment) and cytotoxic agents (podophyllotoxin and cidofovir) are considered manageable in children because of their low aggressiveness. In particular, podofillotoxin gel 5% and imiquimod 5% cream have been reported to be safe and efficacious in children. Currently, HPV vaccination is not recommended as a treatment for established HPV infection and AWs, yet a possible therapeutic role of HPV vaccination was recently suggested in the literature and deserves mention.
PubMed: 37445264
DOI: 10.3390/jcm12134230 -
Lung Cancer (Amsterdam, Netherlands) Dec 2023In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide.
OBJECTIVES
In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival.
MATERIALS AND METHODS
Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS.
RESULTS
More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm.
CONCLUSION
These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.
CLINICALTRIAL
gov Identifier: NCT02763579.
Topics: Humans; Small Cell Lung Carcinoma; Carboplatin; Etoposide; Lung Neoplasms; Survivors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37931445
DOI: 10.1016/j.lungcan.2023.107418 -
Pharmaceutical Biology Dec 2024Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.
CONTEXT
Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.
OBJECTIVE
This study synthesizes PPT derivatives to assess their anticancer activities.
MATERIALS AND METHODS
Compounds E1-E16 antiproliferative activity was tested against four human cancer cell lines (H446, MCF-7, HeLa, A549) and two normal cell lines (L02, BEAS-2B) using the CCK-8 assay. The effects of compound on A549 cell growth were evaluated through molecular docking, assays (flow cytometry, wound healing, Transwell, colony formation, Western blot), and tests in female BALB/c nude mice treated with (2 and 4 mg/kg). (4 mg/kg) significantly reduced xenograft tumor growth compared to the DMSO control group.
RESULTS
Among the 16 PPT derivatives tested for cytotoxicity, exhibited potent effects against A549 cells (IC: 0.35 ± 0.13 µM) and exceeded the reference drugs PPT and etoposide to inhibit the growth of xenograft tumours. -induced cell cycle arrest in the S and G2/M phases accelerated tubulin depolymerization and triggered apoptosis and mitochondrial depolarization while regulating the expression of apoptosis-related proteins and effectively inhibited cell migration and invasion, suggesting a potential to limit metastasis. Molecular docking showed binding of to tubulin at the colchicine site and to Akt, with a consequent down-regulation of PI3K/Akt pathway proteins.
DISCUSSION AND CONCLUSIONS
This research lays the groundwork for advancing cancer treatment through developing and using PPT derivatives. The encouraging results associated with call for extended research and clinical validation, leading to novel and more effective cancer therapies.
Topics: Mice; Animals; Humans; Female; Podophyllotoxin; Tubulin; Molecular Docking Simulation; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Drug Screening Assays, Antitumor; Antineoplastic Agents; Cell Proliferation; Cell Line, Tumor; Apoptosis; Tubulin Modulators
PubMed: 38393642
DOI: 10.1080/13880209.2024.2318350 -
Lung Cancer (Amsterdam, Netherlands) Jul 2023Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in... (Randomized Controlled Trial)
Randomized Controlled Trial
Carboplatin and irinotecan (CI) vs. carboplatin and etoposide (CE) for the treatment of extended-stage small-cell lung cancer in an elderly population: A phase II/III randomized control trial.
OBJECTIVES
Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC.
MATERIALS AND METHODS
This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m on days 1 and 8) intravenously every 3 weeks for 4 cycles.
RESULTS
In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm).
CONCLUSIONS
The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.
Topics: Humans; Aged; Carboplatin; Etoposide; Irinotecan; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Small Cell Lung Carcinoma; Cisplatin
PubMed: 37156212
DOI: 10.1016/j.lungcan.2023.107195