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1.
Cell Rep Med ; 5(6): 101610, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38897168

RESUMO

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Microambiente Tumoral , Humanos , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Feminino , Masculino , Prognóstico
2.
JAMA Oncol ; 9(12): 1669-1677, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37824137

RESUMO

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Carcinoma de Pequenas Células do Pulmão/patologia , Topotecan/efeitos adversos , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva
3.
Cancer Discov ; 13(4): 928-949, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36715552

RESUMO

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions. ecDNAs bring to proximity enhancer elements and oncogenes, creating SCLC transcription-amplifying units, driving exceptionally high MYC gene dosage. We demonstrate that cell-free nucleosome profiling can noninvasively detect ecDNA amplifications in plasma, facilitating its genome-wide interrogation in SCLC and other cancers. Altogether, our work provides the first comprehensive map of SCLC ecDNA and describes a new mechanism that governs MYC-driven SCLC heterogeneity. ecDNA-enabled transcriptional flexibility may explain the significantly worse survival outcomes of SCLC harboring complex ecDNA amplifications. SIGNIFICANCE: MYC drives SCLC progression, but the genetic basis of MYC-driven SCLC evolution is unknown. Using SCLC as a paradigm, we report how ecDNA amplifications function as MYC-amplifying units, fostering tumor plasticity and a high degree of tumor heterogeneity. This article is highlighted in the In This Issue feature, p. 799.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Oncogenes , DNA , Amplificação de Genes
4.
Clin Cancer Res ; 29(18): 3603-3611, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37227187

RESUMO

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Masculino , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Camptotecina/efeitos adversos , Camptotecina/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/administração & dosagem
5.
Breast Cancer Res Treat ; 132(1): 197-203, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22113254

RESUMO

Breast conservation therapy (BCT) consisting of lumpectomy and postoperative radiation has become an accepted alternative to mastectomy (MRM) for the treatment of early stage breast cancer. We currently report the 25 year outcomes of a single institution, prospective, randomized clinical trial at the National Cancer Institute. 237 women with pathologically confirmed invasive breast tumors 5 cm or less were accrued between 1979 and 1987 and randomized to receive either BCT or MRM. Overall survival was the primary endpoint. Patients with node positive disease were included and treated with doxorubicin and cyclophosphamide. Both arms received axillary dissection. BCT patients had radiation to the whole breast followed by a boost. At a median follow-up of 25.7 years, overall survival was 43.8% for the MRM group and 37.9% for BCT (P = 0.38). Although the cumulative incidence of a disease-free survival event was higher in BCT patients (29.0% MRM vs. 56.4% BCT, P = 0.0017), the additional treatment failures were primarily isolated ipsilateral breast tumor recurrences (IBTR's) requiring salvage mastectomy. 22.3% of BCT patients experienced an IBTR. Distant disease and second cancers were similar in both arms. After 25 years, long term survival between BCT and MRM continues to be similar in patients treated for early stage breast cancer. Patients receiving BCT may be at risk for additional treatment-related morbidity, which may occur as a late event. Further studies are required to delineate patients at higher risk for these events, and prolonged follow up should be encouraged after treatment for all women.


Assuntos
Neoplasias da Mama/cirurgia , Recidiva Local de Neoplasia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Mastectomia Radical Modificada , Mastectomia Segmentar , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Modelos de Riscos Proporcionais , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos
6.
Mol Cancer Ther ; 21(11): 1722-1728, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-35999657

RESUMO

Alterations in the ATM gene are among the most common somatic and hereditary cancer mutations, and ATM-deficient tumors are hypersensitive to DNA-damaging agents. A synthetic lethal combination of DNA-damaging agents and DNA repair inhibitors could have widespread utility in ATM-deficient cancers. However, overlapping normal tissue toxicities from these drug classes have precluded their clinical translation. We investigated PLX038, a releasable polyethylene glycol-conjugate of the topoisomerase I inhibitor SN-38, in ATM wild-type and null isogenic xenografts and in a BRCA1-deficient xenograft. PLX038 monotherapy and combination with PARP inhibition potently inhibited the growth of both BRCA1- and ATM-deficient tumors. A patient with an ATM-mutated breast cancer treated with PLX038 and the PARP inhibitor rucaparib achieved rapid, symptomatic, and radiographic complete response lasting 12 months. Single-agent PLX038 or PLX038 in combination with DNA damage response inhibitors are novel therapeutic paradigms for patients with ATM-loss cancers.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Inibidores da Topoisomerase I , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Reparo do DNA
7.
Nat Commun ; 13(1): 2023, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440132

RESUMO

Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.


Assuntos
Neoplasias Pulmonares , Tumores Neuroendócrinos , Carcinoma de Pequenas Células do Pulmão , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismo
8.
Sci Transl Med ; 13(578)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504652

RESUMO

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.


Assuntos
Reparo do DNA , Mutação em Linhagem Germinativa , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Proteína BRCA1/genética , Proteína BRCA2 , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Sequenciamento do Exoma
9.
Cancer Cell ; 39(4): 566-579.e7, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33848478

RESUMO

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Isoxazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirazinas/farmacologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Replicação do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/genética , Instabilidade Genômica/genética , Humanos , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/metabolismo
10.
Cancer Chemother Pharmacol ; 86(4): 475-486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32897402

RESUMO

PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/farmacocinética , Ciclodextrinas/farmacocinética , Modelos Biológicos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacocinética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Camptotecina/administração & dosagem , Ciclodextrinas/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias/patologia , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacocinética , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Inibidores da Topoisomerase I/administração & dosagem
11.
Int J Radiat Oncol Biol Phys ; 70(1): 90-5, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17855015

RESUMO

PURPOSE: To test whether intrarectal amifostine limits symptoms of radiation proctitis, measured by using the Radiation Therapy Oncology Group (RTOG) gastrointestinal (GI) toxicity score and the Expanded Prostate Cancer Index Composite (EPIC) score. METHODS AND MATERIALS: Patients with localized prostate cancer received amifostine as a rectal suspension 30-45 minutes before daily three-dimensional conformal radiation therapy. The first 18 patients received 1 g of amifostine, and the next 12 patients received 2 g. Toxicity was assessed at baseline, during treatment, and at follow-up visits by using RTOG grading and the EPIC Quality of Life (QoL) 50-item questionnaire. The Bowel Function subset of the bowel domain (EPIC-BF), which targets symptom severity, and the Bowel Bother subset of the bowel domain (EPIC-BB), which assesses QoL, were evaluated and compared with the RTOG GI toxicity score. RESULTS: Median follow-up was 30 months (range, 18-36 months). Overall, EPIC-BF and EPIC-BB scores both tracked closely with the RTOG GI toxicity score. Seven weeks after the start of radiation therapy, the incidence of RTOG Grade 2 toxicity was 33% in the 1-g group (6/18 patients) compared with 0% (0/12 patients) in the 2-g group and tended toward statistical significance (p = 0.06). A significant difference between amifostine groups was observed using the EPIC-BF score at 7 weeks (p = 0.04). A difference in EPIC-BB scores between dose groups was evident at 7 weeks (p = 0.07) and was significant at 12 months (p = 0.04). CONCLUSIONS: Higher doses of amifostine produced significant improvements in acute and late bowel QoL (up to 1 year after therapy), measured using the EPIC score.


Assuntos
Amifostina/administração & dosagem , Proctite/prevenção & controle , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Protetores contra Radiação/administração & dosagem , Radioterapia Conformacional/efeitos adversos , Adenocarcinoma/radioterapia , Administração Retal , Idoso , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/prevenção & controle , Reto/efeitos da radiação , Índice de Gravidade de Doença , Inquéritos e Questionários
12.
J Clin Oncol ; 36(16): 1594-1602, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29252124

RESUMO

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isoxazóis/administração & dosagem , Pirazinas/administração & dosagem , Topotecan/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Topotecan/efeitos adversos , Resultado do Tratamento
13.
Int J Radiat Oncol Biol Phys ; 65(4): 1008-13, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16730138

RESUMO

PURPOSE: Our goal was to test the ability of intrarectal amifostine to limit symptoms of radiation proctitis. METHODS AND MATERIALS: The first 18 patients received 1 g of intrarectal amifostine suspension placed 30-45 min before each radiation treatment. The following 12 patients received 2 g of amifostine. Total dose prescribed ranged from 66 to 76 Gy. All patients were treated with three-dimensional conformal radiation therapy. The suspension remained intrarectal during treatment and was expelled after treatment. For gastrointestinal symptoms, during treatment and follow-up, all patients had a Radiation Therapy Oncology Group (RTOG) grade recorded. RESULTS: Median follow-up was 18 months (range, 6-24 months). With 2 g vs. 1 g amifostine, there was a nearly significant decrease in RTOG Grade 2 acute rectal toxicity. Seven weeks after the start of radiation therapy, the incidence of Grade 2 toxicity was 33% in the 1-g group (6/18) compared with 0% (0/12) in the 2-g group (p=0.06). No Grade 3 toxicity or greater occurred in this study. CONCLUSION: This trial suggests greater rectal radioprotection from acute effects with 2 g vs. 1 g amifostine suspension. Further studies should be conducted in populations at higher risk for developing symptomatic acute and late proctitis.


Assuntos
Amifostina/administração & dosagem , Proctite/prevenção & controle , Neoplasias da Próstata/radioterapia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Reto/efeitos da radiação , Administração Retal , Idoso , Humanos , Masculino , Projetos Piloto , Proctite/etiologia , Radioterapia Conformacional , Estatísticas não Paramétricas
14.
Int J Radiat Oncol Biol Phys ; 62(5): 1316-21, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16029787

RESUMO

PURPOSE: This study strives to compare early measures of bowel toxicity in patients with prostate cancer receiving definitive or adjuvant 3D conformal external beam radiation therapy and concurrent daily endorectal application of amifostine. METHODS: Eighteen patients were enrolled in the clinical study with a median follow-up of 12 months. Prescription doses ranged from 66 Gy to 76 Gy with a daily fractionation of 2 Gy. Acute bowel toxicity was measured at baseline, at Weeks 5 and 7 of radiotherapy, and at 1 and 3 months after the completion of therapy. Measures of acute bowel toxicity included the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria, Expanded Prostate Cancer Index Composite (EPIC) self-assessment questionnaires, and proctoscopic examinations. RESULTS: The mean EPIC bowel scores changed significantly through the course of therapy and follow-up (p < 0.0001), with a progressive decrease in scores at Weeks 5 and 7 of treatment, a partial recovery at 3 months, and a correlation to the gold standard RTOG grade (p = 0.004). Proctoscopic toxicity scores were low, did not vary over time, and did not correlate with either EPIC or RTOG scores. CONCLUSION: The EPIC questionnaire measurements are most sensitive to changes in acute bowel toxicity through a course of radiotherapy and correlate with RTOG acute toxicity scores. Endoscopic examination of the rectal mucosa at the end and immediate follow-up of a course of therapy does not seem to be informative or reproducible between observers in the acute setting.


Assuntos
Amifostina/uso terapêutico , Neoplasias da Próstata/radioterapia , Lesões por Radiação/patologia , Protetores contra Radiação/uso terapêutico , Reto/efeitos da radiação , Idoso , Distribuição de Qui-Quadrado , Humanos , Masculino , Pessoa de Meia-Idade , Proctoscopia , Qualidade de Vida , Dosagem Radioterapêutica , Radioterapia Conformacional , Estatísticas não Paramétricas , Inquéritos e Questionários
15.
Int J Radiat Oncol Biol Phys ; 62(3): 785-9, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15936560

RESUMO

PURPOSE: To evaluate the effect of an ipsilateral breast tumor recurrence (IBTR) after breast-conservation therapy (BCT) on survival. METHODS AND MATERIALS: One hundred twenty-one women were randomized to BCT. Patients with an IBTR were analyzed to determine survival. Analysis was performed with Kaplan-Meier estimates, log-rank tests, and time-dependent covariate Cox models. RESULTS: At a median follow-up of 18.4 years, 27 patients had an IBTR. The median survival time after IBTR was 13.1 years. The 5-year survival rate was 91.8% (95% confidence interval [CI], 81.5-100%). The 10-year survival rate was 54.3% (95% CI, 35.8-82.6%). According to a Cox model with time-dependent covariates, the hazard ratio or relative risk of dying for those with an IBTR at <5.3 years after BCT relative to patients without an IBTR after BCT is 1.47 (95% CI, 1.02-2.12%; p = 0.04). The hazard ratio for those who relapse after 5.3 years is 0.59 (95% CI, 0.22-1.61%; p = 0.31). Age at randomization, original tumor size, and the presence of positive regional nodes at initial presentation were not found to be associated with decreased survival. CONCLUSIONS: There seems to be a significant association of early IBTR after BCT with decreased survival. Local control should be maximized.


Assuntos
Neoplasias da Mama/mortalidade , Mastectomia Radical Modificada/mortalidade , Mastectomia Segmentar/mortalidade , Adulto , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Terapia de Salvação , Taxa de Sobrevida
16.
Int J Radiat Oncol Biol Phys ; 74(4): 1040-6, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19117692

RESUMO

PURPOSE: To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m(2)/cycle, and the subsequent 19 patients received 120 mg/m(2)/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. RESULTS: The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). CONCLUSION: The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.


Assuntos
Antineoplásicos Fitogênicos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Paclitaxel , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Terapia Combinada/métodos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fibrose , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Prospectivos , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Pele/efeitos da radiação , Taxa de Sobrevida , Resultado do Tratamento
17.
Cancer ; 98(4): 697-702, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12910512

RESUMO

BACKGROUND: Between 1979-1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results. METHODS: After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival. RESULTS: At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70). CONCLUSIONS: After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups.


Assuntos
Neoplasias da Mama/cirurgia , Carcinoma/cirurgia , Mastectomia Segmentar , Mastectomia , Adulto , Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Carcinoma/secundário , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Taxa de Sobrevida
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