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2.
Cancer Discov ; 12(5): 1233-1247, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35135829

RESUMO

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers. SIGNIFICANCE: NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Biespecíficos , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Rearranjo Gênico , Humanos , Imunoglobulina G , Neoplasias Pulmonares/genética , Neuregulina-1/genética , Receptor ErbB-2 , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo
3.
Clin Pharmacokinet ; 59(7): 875-884, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32006223

RESUMO

BACKGROUND AND OBJECTIVES: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate. METHODS: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden. RESULTS: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0-τ), maximum and trough concentrations of MCLA-128, compared to flat dosing. CONCLUSIONS: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.


Assuntos
Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais/farmacocinética , Neoplasias , Humanos , Imunoglobulina G , Modelos Biológicos , Neoplasias/terapia
4.
Lancet Oncol ; 18(4): 435-445, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28284557

RESUMO

BACKGROUND: There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. METHODS: NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. FINDINGS: Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. INTERPRETATION: Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. FUNDING: Array BioPharma and Novartis Pharmaceuticals Corporation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , GTP Fosfo-Hidrolases/genética , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/administração & dosagem , Dacarbazina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
5.
Oncologist ; 21(5): 535-6, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27091421

RESUMO

LESSONS LEARNED: Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels. BACKGROUND: Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity. METHODS: Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. RESULTS: A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected. CONCLUSION: Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores da Prolactina/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores da Prolactina/fisiologia
6.
Clin Cancer Res ; 19(7): 1644-50, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23515410

RESUMO

The prolactin (PRL)-prolactin receptor (PRLR) signaling complex has been implicated in the pathology of breast and prostate carcinoma. A multitude of pro-oncogenic intracellular signaling pathways are activated by PRL in breast and prostate epithelial cells, leading to enhanced cellular proliferation, survival, and tumorigenesis in numerous model systems. Emerging evidence suggests that targeting the PRL-PRLR axis in human cancer may represent an unexploited avenue for therapeutic intervention and, given the extensive cross-talk between PRLR and other signal transduction pathways, a potential means through which other anticancer agents could be rendered more efficacious in the clinic. LFA102 is a potent anti-PRLR neutralizing antibody that efficiently abrogates the function of this receptor in vivo, mediating significant antitumor effects in preclinical models. The clean safety profile of this antibody in animals and in the clinical experiences to date suggests that blocking the PRLR signaling pathway in human tumors may have few significant toxicologic consequences and may be a promising approach to treating cancer. A phase I trial in patients with breast and prostate cancer is underway to better understand the clinical utility of LFA102 and the contribution of PRL to the maintenance and progression of human cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Prolactina/metabolismo , Neoplasias da Próstata/metabolismo , Receptores da Prolactina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Pesquisa Translacional Biomédica
7.
Clin Cancer Res ; 17(10): 3431-42, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21220472

RESUMO

PURPOSE: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m(2)), or with cisplatin (both on D1, q3w, from 3.6 mg/m(2) CBP501, 50 mg/m(2) cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles. RESULTS: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m(2) CBP501 and 75 mg/m(2) cisplatin, with two patients at the highest dose (36.4 mg/m(2) CBP501, 75 mg/m(2) cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G(3) rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease. CONCLUSIONS: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Fosfatases cdc25/administração & dosagem , Fosfatases cdc25/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Progressão da Doença , Feminino , Fase G2/efeitos dos fármacos , Genes cdc/efeitos dos fármacos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Fragmentos de Peptídeos/efeitos adversos , Fosfatases cdc25/efeitos adversos
8.
J Clin Oncol ; 28(33): 4877-83, 2010 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-20921468

RESUMO

PURPOSE: To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). PATIENTS AND METHODS: Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. RESULTS: In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. CONCLUSION: It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.


Assuntos
Perfilação da Expressão Gênica , Neoplasias/terapia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/mortalidade , Projetos Piloto
9.
J Transl Med ; 8: 89, 2010 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-20875102

RESUMO

BACKGROUND: Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. METHODS: The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity. RESULTS: Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays. CONCLUSIONS: The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma. CLINICAL TRIAL REGISTRATION: NCT00107159.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/citologia , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento
10.
Am J Clin Oncol ; 29(1): 45-51, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16462502

RESUMO

OBJECTIVES: Irinotecan or oxaliplatin combined with 5-fluorouracil (5-FU) +/- folinic acid (FA) has changed the treatment standards for metastatic colorectal cancer (CRC). The oxaliplatin and irinotecan combination has reported consistent activity. The purpose of this phase II study was to assess the efficacy and safety of the simultaneous administration of a triple chemotherapy combination of oxaliplatin, irinotecan, 5-FU bolus, and FA. MATERIALS AND METHODS: Eligible patients had metastatic CRC with no prior oxaliplatin or irinotecan-based chemotherapy. Treatment consisted of oxaliplatin 85 mg/m2 followed by irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and FA 20 mg/m2 on days 1, 8, and 15. An early amendment suppressed the day 8 5-FU/FA. RESULTS: Twenty-six eligible treated patients receiving 253 doses were assessed for toxicity. Myelosuppression was the most frequent toxicity; grade 3 to 4 neutropenia and febrile neutropenia occurred in 50% and 15% of patients, respectively. The treatment schedule modification, omitting the 5-FU dosing on day 8, considerably improved treatment compliance, reducing the incidence of febrile neutropenia, diarrhea, and asthenia. Among the 25 patients evaluable for efficacy, 10 had objective responses including 1 complete response (CR) (4%) and 9 partial responses (PR) (36%), giving an overall response rate of 40%. Median time to progression was 6.20 months [95% confidence interval (CI), 5.44-6.96]. Median overall survival was 12.95 months. CONCLUSIONS: The administration of a triple combination produced promising objective responses with acceptable toxicity but does not seem to produce an evident benefit in time-related parameters.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Diarreia/induzido quimicamente , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Injeções Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do Tratamento
11.
Int J Radiat Oncol Biol Phys ; 54(2): 397-402, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12243813

RESUMO

PURPOSE: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in advanced colorectal cancer patients. Chemoradiotherapy with 5-FU + leucovorin (LV) is considered the standard treatment in unresectable rectal cancer patients. The objective was to evaluate OXA with 5-FU + LV and concurrent radiotherapy in unresectable rectal cancer patients. TREATMENT: OXA 25 mg/m(2)/day in 30-min infusions, followed by bolus LV 20 mg/m(2)/day and bolus 5-FU 375 mg/m(2)/day. All drugs were given on 4 days during Weeks 1 and 5 of a standard radiotherapy cycle (50.4 Gy). A single OXA dose (50 mg/m(2)) was also given on the third week of radiotherapy. A cycle of OXA with 5-FU + LV was administered 4 weeks after chemoradiotherapy, with surgery planned 4 weeks later. RESULTS: Between March 1998 and April 2000, 22 patients with T3-T4 unresectable rectal cancer were accrued. Patient characteristics included the following: 11 females, 11 males, median age 58 (range: 18-76). Performance status ECOG (PS) 0: 2 patients, PS 1: 7 patients, and PS 2: 13 patients. The following RTOG Grade 3-4 toxicities were reported: diarrhea, 6 patients; cutaneous, 3 patients; neutropenia-leukopenia, 2 patients; and thrombocytopenia, 1 patient; 1 treatment-related death resulted (febrile neutropenia-sepsis after chemoradiotherapy). Only 1 patient had neurosensory Grade 2 (OXA-specific Levi's scale) toxicity. Nine patients had PS worsening during treatment. Five patients had chemoradiotherapy delay (median: 6 days). Of 22 patients, 16 underwent surgery (without serious surgical complications); 12/16 had a complete resection (5/12 had sphincter preservation). Pathologic examination revealed 3/12 complete remissions, 2/12 minimal microscopic residual disease, 2/12 T2N0, 1/12 T3N0, and 4/12 positive nodes; 4/16 had unresectable disease. Median follow-up was 15 months (range: 3.0-43.4 months), median time to progression was 15.7 months (CI 95%, 0, 31.7), and median overall survival was 19.5 months (CI 95%, 18.0, 21). CONCLUSIONS: Outpatient treatment with low-dose, 30-min daily OXA infusion was feasible and very active, with acceptable toxicity.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Prognóstico , Neoplasias Retais/patologia
12.
Rev. argent. cancerol ; 29(2): 60-64, jul. 2001.
Artigo em Espanhol | BINACIS | ID: bin-8903

Assuntos
Pesquisa
13.
Rev. argent. cancerol ; 29(2): 60-64, jul. 2001.
Artigo em Espanhol | LILACS | ID: lil-305506

Assuntos
Pesquisa
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