RESUMO
BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genéticaRESUMO
Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Dosagem de Genes , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients. METHODS: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ⩾60 and ⩾70 years as cut points. RESULTS: Among patients aged ⩾60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2-2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ⩾70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL. CONCLUSION: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Análise de Sobrevida , Idoso , Idoso de 80 Anos ou mais , Paclitaxel Ligado a Albumina , Albuminas/efeitos adversos , Albuminas/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Feminino , Humanos , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: This analysis evaluates safety and efficacy in elderly (≥ 70 years old) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer (NSCLC) trial. PATIENTS AND METHODS: Untreated stage IIIB/IV patients with PS 0/1 were randomly assigned (1:1) to carboplatin AUC6, day 1 every 3 weeks, and either nab-paclitaxel (Abraxane) 100 mg/m(2) weekly (nab-P/C) or solvent-based paclitaxel (Taxol) 200 mg/m(2) day 1 every 3 weeks (sb-P/C). The primary end-point was overall response rate (ORR). RESULTS: Fifteen percent of 1052 enrolled patients were elderly: nab-P/C, n = 74; sb-P/C, n = 82. In both age cohorts, the ORR was higher with nab-P/C versus sb-P/C (age ≥ 70: 34% versus 24%, P = 0.196; age <70: 32% versus 25%, P = 0.013). In elderly patients, progression-free survival (PFS) trended in favor of nab-P/C (median 8.0 versus 6.8 months, hazard ratio (HR) 0.687, P = 0.134), and overall survival (OS) was significantly improved (median 19.9 versus 10.4 months, HR 0.583, P = 0.009). In younger patients, PFS (median 6.0 versus 5.8 months, HR 0.903, P = 0.256) and OS (median 11.4 versus 11.3 months, HR 0.999, P = 0.988) were similar in both arms. Adverse events were similar in both age groups, with less neutropenia (P = 0.015), neuropathy (P = 0.001), and arthralgia (P = 0.029), and increased anemia (P = 0.007) with nab-P/C versus sb-P/C. CONCLUSIONS: In elderly NSCLC patients, nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS, with substantially longer OS versus sb-PC.
Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Paclitaxel/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Phase III trials of the anti-insulin-like growth factor type 1 receptor (IGF-IR) antibody figitumumab (F) in unselected non-small-cell lung cancer (NSCLC) patients were recently discontinued owing to futility. Here, we investigated a role of free IGF-1 (fIGF-1) as a potential predictive biomarker of clinical benefit from F treatment. MATERIALS AND METHOD: Pre-treatment circulating levels of fIGF-1 were tested in 110 advanced NSCLC patients enrolled in a phase II study of paclitaxel and carboplatin given alone (PC) or in combination with F at doses of 10 or 20 mg kg(-1) (PCF10, PCF20). RESULTS: Cox proportional hazards model interactions were between 2.5 and 3.5 for fIGF-1 criteria in the 0.5-0.9 ng ml(-1) range. Patients above each criterion had a substantial improvement in progression-free survival on PCF20 related to PC alone. Free IGF-1 correlated inversely with IGF binding protein 1 (IGFBP-1, ρ=-0.295, P=0.005), and the pre-treatment ratio of insulin to IGFBP-1 was also predictive of F clinical benefit. In addition, fIGF-1 levels correlated with tumour vimentin expression (ρ=0.594, P=0.021) and inversely with E-cadherin (ρ=-0.389, P=0.152), suggesting a role for fIGF-1 in tumour de-differentiation. CONCLUSION: Free IGF-1 may contribute to the identification of a subset of NSCLC patients who benefit from F therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Biomarcadores Tumorais/sangue , Caderinas/sangue , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase II como Assunto , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Imunoglobulinas Intravenosas , Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the demographics, differential risk profile, and treatment outcome in patients with squamous cell carcinomas (SCCs) of the oral tongue according to age at diagnosis. PATIENTS AND METHODS: Patients with invasive SCC of the oral tongue who presented during the years 1985 to 1996 were identified using institutional tumor registry data. Demographics and clinical and pathologic characteristics were abstracted from the medical charts. RESULTS: Eighty-eight patients were identified; 87 were included for analysis. Thirty patients were diagnosed at < or = 45 years of age and 57 at > or = 46 years. The groups showed comparable American Joint Committee on Cancer (AJCC) staging and male predominance. Prior exposure to tobacco and/or alcohol was noted in 40% and 82% of younger and older patients, respectively (P < .001); multiple smoking-related cancers occurred only in older patients (24.5% of older patients, P < .001). With median follow-up time of 29 months (younger group) and 21 months (older group), there were no significant differences in relapse rates, cancer-free survival (CFS), and overall survival (OS) rates (actuarial 5-year CFS rate, 48% and 54% in the younger and older patients, respectively; P = .91). Grouping patients according to smoking and/or alcohol history showed a trend toward better CFS in those with prior exposure to tobacco or alcohol compared with those with neither (5-year CFS rate, 60% and 38%, respectively, P = .11). In a multivariate analysis of all patients, with age used as a continuous parameter, only stage predicted CFS (P = .0019); for patients treated surgically with curative intent, only risk group predicted CFS (P = .0369). CONCLUSION: Prognosis of oral tongue SCC was not affected by age at diagnosis. CFS rates tended to be worse in cases not related to prior tobacco or alcohol exposure. Multiple smoking-related cancers occurred only in older patients.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias da Língua/diagnóstico , Adulto , Fatores Etários , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Neoplasias da Língua/mortalidade , Neoplasias da Língua/terapiaRESUMO
PURPOSE: To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS: From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION: The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Agranulocitose/induzido quimicamente , Agranulocitose/terapia , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Indução de Remissão , Taxa de Sobrevida , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: A number of reports have documented the relationship between pretreatment hemoglobin level and local control and/or survival in the treatment of cervix, bladder, and advanced head and neck tumors. Consideration of correcting anemia before initiation of radiation therapy may prove increasingly important as clinical trials use intensive induction chemotherapy in the treatment of head and neck carcinomas. Neoadjuvant chemotherapy may produce anemia, which in turn may reduce the effectiveness of subsequent irradiation. MATERIALS AND METHODS: One hundred nine patients with T1-2N0 squamous cell carcinoma of the glottic larynx were treated with definitive radiotherapy at the Fox Chase Cancer Center between June 1980 and November 1990. Follow-up times ranged from 26 to 165 months (median, 82). RESULTS: The 2-year local control rate for patients who presented with a hemoglobin level < or = 13 g/dL was 66%, compared with 95% for patients with a hemoglobin level more than 13 g/dL (P = .0018). The 2-year survival rate for patients with a hemoglobin level < or = 13 g/dL was 46%, compared with 88% for patients with a hemoglobin level more than 13 g/dL (P < .001). Cox proportional hazards regression analysis showed that hemoglobin level (P = .0016) was the only variable that significantly influenced local control (P = .0016) and survival (P < .0001). CONCLUSION: Patients who presented with hemoglobin levels more than 13 g/dL had significantly higher local control and survival rates. The strong apparent correlation between hemoglobin level, local control, and survival supports consideration of correcting anemia before initiation of radiation therapy.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Glote , Hemoglobinas/metabolismo , Neoplasias Laríngeas/radioterapia , Análise Atuarial , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/mortalidade , Feminino , Seguimentos , Humanos , Neoplasias Laríngeas/sangue , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Taxa de SobrevidaRESUMO
Relatively little is known about p53 changes in far-advanced head and neck cancer for several reasons: (a) most patients respond well to initial treatment; (b) most institutions do not encounter large numbers of these patients; (c) recurrent or metastatic disease is often within body cavities inaccessible for analysis; and (d) the variety of treatment regimens and disease sites makes meaningful conclusions difficult to draw in such a heterogeneous group. The purpose of this study was to evaluate the clinical significance of p53 mutations and overexpression in a homogeneous group of patients with end-stage squamous cell carcinoma of the head and neck. Pretreatment tumor specimens from a homogeneous group of 16 patients with end-stage squamous cell carcinoma of the head and neck were obtained. All patients had recurred after surgery and radiation +/- induction chemotherapy, and all met the criteria for enrollment in a Phase II chemotherapy trial consisting of 5-fluorouracil, N-phosphoacetyl-L-aspartate, and recombinant IFN-alpha. Each was analyzed for mutations in exons 5-8 of the p53 gene and protein expression using the p53 polyclonal antibody CM-1. No relationship was found between p53 immunostain or p53 mutations and age, gender, site of primary tumor, or site of disease recurrence. p53 alterations also did not correlate with response to Phase II chemotherapy. p53 immunostain (but not p53 mutations) correlated with a shorter survival (P = 0.0124) after diagnosis with end-stage disease. This suggests that mechanisms other than p53 mutations which alter the half-life of p53 protein may contribute to the outcome of these patients.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Proteínas de Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Feminino , Genes p53/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Mutação , PrognósticoRESUMO
Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor beta pathway and/or inhibition of p21ras signaling, leading to differentiation or apoptosis. In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 28-day cycle. The starting dose of POH was 1600 mg/m2/dose, with escalations to 2100 and 2800 mg/m2/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m2. Grade 1-2 hypokalemia was common at 2100 and 2800 mg/m2. Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentration versus time curve and peak plasma concentration (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. One patient treated at the 2800 mg/m2/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21ras, rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600-2100 mg/m2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Monoterpenos , Neoplasias/metabolismo , Terpenos/efeitos adversos , Terpenos/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Cicloexenos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/sangue , Terpenos/sangue , Terpenos/uso terapêutico , Terpenos/urina , Células Tumorais CultivadasRESUMO
The combination of weekly irinotecan (CPT-11) and monthly cisplatin has shown promising activity in advanced non-small cell lung cancer (NSCLC) in previous Phase I and II studies. However, same-day administration of these agents may better exploit their therapeutic synergy and minimize toxicities. This multicenter Phase II study was undertaken to evaluate the efficacy and safety of a combination of weekly CPT-11 and weekly cisplatin in patients with advanced NSCLC. Patients with chemotherapy-naive stage IIIB or IV NSCLC were treated with repeated cycles of therapy comprising weekly treatment with both cisplatin and CPT-11 for 4 weeks, followed by a 2-week rest. The starting doses of CPT-11 and cisplatin were 65 and 30 mg/m2, respectively. Treatment was continued until the occurrence of disease progression, unacceptable toxicity, or a maximum of six cycles. Fifty patients were enrolled. The median age was 59 years (range, 44-79 years). Eastern Cooperative Oncology Group performance status was 0 in 22 patients, 1 in 19 patients, and 2 in 9 patients. Seven and 43 patients had stages IIIB and IV disease, respectively. Five patients had brain metastasis. Patients received a median of three 6-week cycles (range, 1-6). The objective response rate was 36% (18 of 50; 95% confidence interval, 24-54%) and included 18 partial responses. Median time to tumor progression was 6.9 months (range, 0.6-15.2). The median survival was 11.6 months (range, 0.16-21.9 months), and the 1-year survival rate was 46%. Grade 3/4 nonhematological toxicities included vomiting (12%) and diarrhea (26%). Grade 3/4 hematological toxicities included anemia (14%), neutropenia (26%), and thrombocytopenia (14%). Relative dose intensities for CPT-11 and cisplatin were 89 and 62%, respectively. Weekly combined administration of CPT-11 and cisplatin achieved a promising overall response rate, median time to tumor progression, and median survival in patients with stage IIIB/IV NSCLC. The regimen was well tolerated, and the planned dose intensity was well maintained. Further evaluation of this combination in NSCLC is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Camptotecina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Cisplatino/administração & dosagem , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do TratamentoRESUMO
Evidence suggests that locally advanced non-small cell lung cancer may be more effectively treated with induction chemotherapy followed by radiation or concurrent chemoradiation compared with radiation alone. The majority of combined modality regimens evaluated in mature clinical trials incorporated cisplatin-based combinations, but none has incorporated newer active systemic agents or fully examined the potential role of induction chemotherapy followed by concurrent chemoradiation. The Fox Chase Cancer Center and its affiliate network have evaluated induction chemotherapy with paclitaxel plus carboplatin with or without granulocyte colony-stimulating factor priming followed by concurrent systemic chemotherapy and radiation therapy in patients with locally advanced non-small cell lung cancer. The regimen has been well-tolerated and paclitaxel dose escalation continues. The major response to combined therapy was 55% in the first 38 evaluable patients, and the 1-year survival rate is 72%. Median survival is 15 months. The primary toxicity following induction therapy has been myelotoxicity, which has been mild in severity. During concurrent therapy, the major toxicity has been esophagitis; only limited nonhematologic toxicity has been observed. Other studies evaluating different chemoradiation regimens have reported varying results. Paclitaxel/carboplatin-based combinations, administered cyclically at or near full systemic dose in combination with radiation, are feasible. Randomized studies are needed to determine the proper sequencing, potential survival benefits, and relative safety profiles of these combined modality regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Terapia Combinada , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de SobrevidaRESUMO
The scheduling of chemotherapeutic agents may be important in optimising their antitumour actions. This has been explored in non-Hodgkin lymphoma, osteogenic sarcoma and bladder cancer with improved results using intensive, weekly dosing schemas. We began a phase II study of cisplatin, 5-fluorouracil and vinblastine in non-small cell lung cancer (NSCLC) on a weekly schedule. 38 patients with advanced or metastatic NSCLC were entered; 32 are evaluable for response. 11 patients were treated with 5-fluorouracil 1.5 g/m2 and vinblastine 4 mg/m2 by 24-h continuous infusion, and cisplatin 30 mg/m2 over 30 min, 6-8 h after the start of the infusion. Because of prohibitive myelotoxicity, the next 27 patients received 5-fluorouracil 1.2 g/m2 and vinblastine 3 mg/m2. None had had prior chemotherapy while 6 had had previous radiation therapy. Myelosuppression was the predominant toxic effect. Other side-effects included neuropathy, diarrhoea, mucositis, nausea and vomiting. 32 patients are evaluable for response: there have been 14 partial remissions (44%). Responses have occurred chiefly in lung and lymph nodes. The median survival on this study is 7 months, and responders did not live longer than non-responders. While this regimen is well tolerated by the majority of patients and has a response rate comparable to other active regimens identified in single institution studies, survival does not appear to be enhanced. We conclude that the schedule manipulation described here does not enhance the therapeutic index of these drugs in NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Prognóstico , Trombocitopenia/induzido quimicamente , Vimblastina/administração & dosagemRESUMO
In our previous study, FCCC 93-024, paclitaxel by 24-h infusion combined with carboplatin yielded a response rate of 62% and median survival of 54 weeks in advanced non-small cell lung cancer (NSCLC). Myelosuppression proved dose-limiting, requiring the routine use of granulocyte-colony stimulating factor (G-CSF). Based on the reported activity of 1-h paclitaxel infusion in NSCLC and minimal myelosuppression at doses of 135 and 200 mg/m2 every 3 weeks and the suggestion of a dose-response relationship, we launched an intrapatient dose escalation trial of combination carboplatin and 1-h paclitaxel. Chemotherapy-naïve patients with advanced NSCLC received paclitaxel 175 mg/m2 1-h and carboplatin dosed to a fixed targeted area under the concentration-time curve (AUC) of 7.5 at three weekly intervals for six cycles. In the absence of grade 4 myelosuppression, paclitaxel was escalated by 35 mg/m2/cycle on an intrapatient basis to a maximum dose of 280 mg/m2 by cycle 4. G-CSF was not routinely used. 57 patients (pts) were accrued from November 1994 through to April 1996. 44 pts (77%) had Eastern Cooperative Oncology Group (ECOG) performance status 1. Median age was 64 (range: 34-80) years. Cumulative peripheral sensory neuropathy proved dose-limiting and prohibitive in the first 20 evaluable patients (cohort A): grade > or = 1 in 15 patients (75%), grade 3 in 6 (30%), generally occurring at paclitaxel doses > or = 215 mg/m2 and obligating 3 patients to have treatment halted in the absence of disease progression. The protocol, therefore, was revised and the initial paclitaxel dose reduced to 135 mg/m2 with intrapatient dose escalation of 40 mg/m2/cycle to a maximum dose of 215 mg/m2, recapitulating the original dosing schema used in FCCC 93-024. 35 patients were enrolled in this second cohort (B); 33 proved evaluable. Whilst 17 (52%) experienced peripheral sensory neuropathy, grade 3 neurotoxicity developed in only 3 (9%). Myelosuppression also was less pronounced, with 42% exhibiting grade 4 granulocytopenia and 30% grade > or = 3 thrombocytopenia in cohort B compared with 70% and 50%, respectively in cohort A. Of the first 22 patients accrued to cohort A, 12 (55%) had major objective responses. Median survival was 48.5 weeks, 1-year survival rate 45% and 2-year survival rate 18%. Of 33 evaluable patients in cohort B, 9 (27%) had major objective responses. Median survival was 46 weeks, 1-year survival rate 47% and 2-year survival rate 12%. Combination paclitaxel by 1-h infusion and carboplatin at a fixed targeted AUC of 7.5 is active in advanced NSCLC. Neurotoxicity, not myelosuppression, proved dose-limiting at paclitaxel doses exceeding 215 mg/m2. Lower doses may be associated with lower response rates, but do not appear to compromise survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Taxa de SobrevidaRESUMO
Many patients with stage I-IIIA non-small cell lung cancer (NSCLC) resected for cure will experience distant relapse. Results of adjuvant chemotherapy trials after surgery have generally been negative. Neoadjuvant or induction chemotherapy before surgery offers several theoretical advantages; the results of neoadjuvant chemotherapy or combined chemoradiation therapy followed by surgery in resectable and potentially resectable NSCLC are reviewed in this report. In resectable NSCLC, the results of two small trials have yielded positive trends in favor of neoadjuvant chemotherapy. However, neither of these trials was flawless; therefore, firm conclusions cannot yet be drawn. In selected patients with initially nonresectable NSCLC, several phase II studies have demonstrated the potential utility of induction chemotherapy or combined chemoradiation therapy. A relatively high proportion of these patients were rendered resectable. Pathologic complete remissions were observed in up to 25% of patients and survival rates improved significantly, particularly in patients achieving pathologic complete remission. A current intergroup trial will ultimately assess the utility of surgery after induction chemoradiation in this group of patients. The advent of newer agents with demonstrated activity in advanced NSCLC has led to the design of potentially more effective but also more toxic neoadjuvant regimens. Some of these are under investigation in large randomized phase III trials, which should ultimately elucidate the role of induction therapy with "modern" agents in potentially curable NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Terapia NeoadjuvanteRESUMO
Cumulative experience with single-agent paclitaxel in advanced metastatic non-small cell lung cancer (NSCLC) suggests that it is a highly active cytotoxic agent. The consistent finding of a 35% to 40% 1-year survival rate is notable. The major toxicities include neutropenia, neuropathy, and myalgia/arthralgia syndrome. Paclitaxel has been used in combination with several other nonplatinum agents for the treatment of NSCLC. Order of administration and schedule are clearly relevant in these combinations. For example, in one study, etoposide and paclitaxel given simultaneously proved ineffective, with substantial grade IV neutropenia Another schedule with an identical dose of etoposide, given daily for 3 days, followed by paclitaxel achieved a response rate of 41%, with markedly diminished neutropenia A variety of phase I studies have evaluated gemcitabine/paclitaxel, with response rates ranging from 22% to 30%. Paclitaxel/vinorelbine also has proven feasible in both small cell lung cancer and NSCLC, with a response rate of 17%. Investigators have combined paclitaxel with ifosfamide at full dose with response rates of 21% and 23%. The three-drug nonplatinum combination of paclitaxel/ifosfamide/vinorelbine also has been studied. The maximum tolerated dose for ifosfamide was 1.2 g/m2 on days 1 through 3, for vinorelbine 20 mg/m2 on days 1 through 3, and for paclitaxel 175 mg/m2 on day 1. The response rate of 16% was disappointing. Median survival was 6.1 months and toxicity was substantial. Paclitaxel/non-platinum combinations may prove to be reasonable alternatives for NSCLC patients who cannot tolerate cisplatin and for relapsed patients and patients with compromised performance status.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Ensaios Clínicos como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Etoposídeo/administração & dosagem , Humanos , Ifosfamida/administração & dosagem , Paclitaxel/administração & dosagem , Inibidores da Topoisomerase I , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%, and, in combination with cisplatin, response rates of 30% to 60%. Carboplatin causes much less nonhematologic toxicity than cisplatin, and initial therapy with carboplatin yields equivalent survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Carmichael and colleagues have identified a maximum tolerated dose of carboplatin of area under the curve 5.2 mg/mL/min administered monthly in combination with gemcitabine 1,000 mg/m2 on days 1, 8, and 15. This combination produced a response rate of 31% and a median survival of 45 weeks in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine --> carboplatin day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. At Fox Chase Cancer Center and elsewhere, similar phase I trials will determine the maximum tolerated doses of each agent in combination using a compressed schedule with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Carboplatina/farmacocinética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Humanos , GencitabinaRESUMO
Based on the superior response rates (21% to 24%) of patients treated with single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in Eastern Cooperative Oncology Group and M.D. Anderson Cancer Center trials in non-small cell lung cancer (NSCLC) and on the superior 1-year survival rates of NSCLC patients treated with carboplatin in a randomized study of cisplatin combination and analogues, we initiated a phase II trial of paclitaxel/carboplatin in patients with stage IV or effusion-positive stage III NSCLC. Eligibility stipulated chemotherapy-naive patients with measurable disease, good performance status, and adequate hematologic, hepatic, and renal function. Previous radiotherapy was restricted to < or = 30% of marrow-bearing bone. Paclitaxel was initially given at 135 mg/m2 over 24 hours followed by carboplatin dosed to a targeted area under the concentration versus time curve (AUC) of 7.5, with treatment repeated at 3-week intervals for six cycles. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, with the paclitaxel dose sequentially escalated in 40 mg/m2 increments to a maximum dose of 215 mg/m2 in patients with less than grade 4 granulocytopenia and less than grade 3 thrombocytopenia. Of 54 patients enrolled, 30 currently are evaluable for response, 23 for toxicity. Myelosuppression has been the principal toxicity, with grade 3 or 4 granulocytopenia occurring in 70% of patients after the first cycle. After the introduction of granulocyte colony-stimulating factor, granulocytopenia decreased to 37% during the second cycle and then consistently to 20% or lower during subsequent cycles. Only 22% of cycles have been delayed for 1 week or more. Neutropenic fever has occurred in five (5%) of 100 evaluable cycles. Other grade 3 or 4 toxicities include thrombocytopenia (13%), anemia (9%), fatigue (9%), and hemorrhagic cystitis (1%). The paclitaxel dose was boosted to 215 mg/m2 in 12 (70%) of 17 patients by cycle 3 or 4. At an AUC of 7.5, the median first-cycle carboplatin dose was 434 mg/m2 (range, 293 to 709 mg/m2). The objective response rate is 50%, with three complete, 12 partial, and five minor responses. We conclude that the paclitaxel/carboplatin combination is active in advanced NSCLC and, with AUC-based dosing of carboplatin, can be given at 3-week intervals. Although dose limiting at a paclitaxel dose of 135 mg/m2, granulocytopenia can be reduced substantially with granulocyte colony-stimulating factor, allowing sequential dose escalation of paclitaxel to 175 mg/m2 and 215 mg/m2 in 70% of patients receiving three or more cycles.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Agranulocitose/induzido quimicamente , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/secundário , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Trombocitopenia/induzido quimicamenteRESUMO
Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%. In combination with cisplatin, response rates of 30% to 60% and encouraging survival have been observed. Carboplatin causes much less nonhematologic toxicity than cisplatin. In a phase III Eastern Cooperative Oncology Group trial, initial therapy with carboplatin yielded superior survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Thus, studies designed to identify optimal dose schedules for a combination of gemcitabine plus carboplatin are clearly warranted. Carmichael et al from the United Kingdom have identified a maximum tolerated dose of carboplatin of area under the curve of 5.2 mg/mL/min administered on day I followed by gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. This combination produced a response rate of 31% and a median survival of 10.5 months in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine preceding carboplatin on day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. Other investigators have identified similar promising results with this regimen, although one North American investigator has observed untoward toxicity in a small number of patients using a standard 28-day dose schedule with gemcitabine administered on days, 1, 8, and 15. Day-15 gemcitabine dosing is problematic and may contribute to excessive thrombocytopenia when gemcitabine is combined with carboplatin. The ongoing phase I/II trials reviewed here have focused on a compressed 21-day schedule, with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Esquema de Medicação , Humanos , GencitabinaRESUMO
Lung cancer is the leading cause of cancer-related death in North America and Europe. Approximately 75% of lung cancer is non-small cell lung cancer, and approximately 70% of these patients present with unresectable disease. In the past, these patients were treated with either palliative radiotherapy or other best supportive care measures. The survival of patients with stage IV disease was extremely poor. Median survival was between 16 and 17 weeks, and only 10% to 15% of patients were alive at 1 year. Cisplatin-based chemotherapy was the first therapy to show that survival could be improved. Randomized trials that compared best supportive care, including palliative radiotherapy, with cisplatin-based combination therapy showed modest improvement in the survival of these patients. On average, the median survival of patients improved by 10 weeks (from 16 to 26 weeks) and the 1-year survival rate improved by 10% (from 15% to 25%). These cisplatin-based therapies also relieved symptoms and improved quality of life at acceptable costs, which were sometimes less than those associated with best supportive care. More recently, a number of new chemotherapeutic agents (gemcitabine, paclitaxel, docetaxel, vinorelbine, and irinotecan) with high, single-agent activities and novel mechanisms of action have shown superior activity and improved quality of life when used in combination with conventional agents and with each other.