RESUMO
BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Pele/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Biópsia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasia Residual , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Pele/efeitos dos fármacos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.
Assuntos
Antineoplásicos/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Dacarbazina/uso terapêutico , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirimidinas/efeitos adversos , Análise de SobrevidaRESUMO
We conducted a phase II randomized trial of recombinant granculocyte-macrophage colony-stimulating factor (GM-CSF) administered before topotecan chemotherapy to determine whether it could prevent myelosuppression and to determine the antitumor activity of this topoisomerase I inhibitor in 53 patients with metastatic malignant melanoma and renal cell cancer. All patients received GM-CSF after topotecan at a dose of 250 microg/m(2) daily for at least 8 days. Patients randomly assigned to receive GM-CSF priming were treated with GM-CSF at 250 microg/m(2) twice daily for 5 days before treatment. Twenty-five patients were randomly assigned to receive GM-CSF priming and 28 to receive topotecan without priming. The primary analysis was restricted to the protective effects seen during the first cycle of therapy. Grade 4 neutropenia occurred in 8 of 23 patients (35%) and grade 3 neutropenia in 5 of 23 patients (22%) randomized to GM-CSF priming, whereas 18 of 26 (69%) and 5 of 26 (19%) patients experienced grade 4 or 3 neutropenia, respectively, without GM-CSF priming (P =.0074). The mean duration of neutropenia was reduced by GM-CSF priming: grade 3 neutropenia from 5.2 +/- 0.7 to 2.8 +/- 0.7 days (P =.0232) and grade 4 neutropenia from 2.7 +/- 0.6 to 1.1 +/- 0.4 days (P = 0.0332). The protective effects of GM-CSF extended to the second cycle of treatment. The incidence of febrile neutropenia was also reduced. Chemotherapy-induced anemia and thrombocytopenia were similar in both groups. One partial response was seen in a patient with melanoma, and one patient with renal cell cancer had complete regression of pulmonary metastases and was rendered disease-free by nephrectomy. (Blood. 2001;97:1942-1946)
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Neutropenia/prevenção & controle , Neoplasias Cutâneas/tratamento farmacológico , Topotecan/efeitos adversos , Anemia/induzido quimicamente , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/sangue , Diabetes Mellitus Tipo 1/complicações , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Hipotensão/induzido quimicamente , Neoplasias Renais/sangue , Melanoma/sangue , Neutropenia/induzido quimicamente , Pré-Medicação , Estudos Prospectivos , Indução de Remissão , Índice de Gravidade de Doença , Neoplasias Cutâneas/sangue , Acidente Vascular Cerebral/etiologia , Trombocitopenia/induzido quimicamente , Topotecan/uso terapêutico , Resultado do TratamentoRESUMO
We determined whether a classical conditioning paradigm may be used to condition immunologic responses in normal human subjects receiving an optimal immunostimulating dose of recombinant human interferon-gamma (rhIFN-gamma). We conducted a placebo-controlled, double-blind study of 31 normal volunteers in order to determine whether an initially immune-neutral stimulus, oral propylene glycol (PG), could eventually elicit an immune response as a consequence of its being paired with a known immunostimulatory dose and schedule of rhIFN-gamma. Subjects were randomly assigned to one of three groups: (A) rhIFN-gamma injections paired with PG; (B) normal saline injections paired with PG; (C) rhIFN-gamma injections alone. During the 4-week study, subjects received progressively fewer injections so that, by the final week of the study, no injections were given and groups A and B received only PG. The principal outcome measures were serum concentrations of quinolinic acid (QUIN) and neopterin, two nonspecific but sensitive markers of immune activation, and expression of Fc receptors (CD64) on peripheral blood mononuclear cells. RhIFN-gamma injections produced significant and predictable alterations in each of the measured immune parameters. No group B subject made an immune response. Mean serum QUIN levels were significantly higher at the end of week three for subjects in the experimental condition (group A) than for subjects receiving rhIFN-gamma alone (group C) despite receiving identical doses of rhIFN-gamma. Similarly, the predicted decay in mean serum neopterin levels from the end of week 1 to the end of week 2 was seen in group C but not in group A. The exposure of group A to PG blunted the decline of CD64 expression in week four. The data suggest that the pairing of an unconditioned stimulus (rhIFN-gamma) and a conditioned stimulus (PG) permits the conditioned stimulus alone to prolong a cytokine-induced response in normal humans.
Assuntos
Adjuvantes Imunológicos/farmacologia , Condicionamento Clássico/fisiologia , Interferon gama/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Citocinas/biossíntese , Método Duplo-Cego , Feminino , Humanos , Interferon gama/administração & dosagem , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Propilenoglicol/administração & dosagem , Propilenoglicol/farmacologia , Ácido Quinolínico/sangue , Receptores de IgG/sangue , Proteínas RecombinantesRESUMO
The purpose of this trial was to determine the toxicity and antineoplastic activity of cisplatin, carboplatin, tamoxifen, and interferon-alpha (IFN-alpha) in patients with advanced melanoma. Eleven patients with metastatic melanoma were enrolled. The patients received carboplatin 400 mg/m2 i.v. on day 0; cisplatin 25 mg/m2 i.v. on days 7, 14, and 21; tamoxifen 20 mg p.o. b.i.d. on days 0-27; and interferon-alpha 5 million units/m2 subcutaneously 3 times per week. Cycles were repeated every 28 days. Patients were assessed for tumor response at the end of 2 cycles. Toxicity was severe, with 14 of 24 cycles given requiring some form of dose reduction. Carboplatin dose reductions were related to bone-marrow toxicity, whereas IFN-alpha caused fatigue, arthralgias, myalgias, and fever. The overall response rate was 18% (2 partial responses [PRs]). The combination of cisplatin, carboplatin, tamoxifen, and IFN-alpha is active in advanced melanoma; however, the toxicity is unacceptable.
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/secundário , Adulto , Antineoplásicos/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: To determine the pathologic complete response rate, toxicity, and survival of patients with resectable squamous cell or adenocarcinoma of the esophagus treated with a 30-day preoperative chemoradiation regimen and surgical resection. PATIENTS AND METHODS: Fifty patients (16 squamous, 33 adeno, one undifferentiated) who had carcinoma of the esophagus (limited to the primary tumor and regional or celiac nodes) were treated with cisplatin 26 mg/m2/day continuous infusion days 1 through 5 and 26 through 30, 5-fluorouracil (5-FU) 300 mg/m2/day continuous infusion days 1 through 30, and radiation 44 Gy, 2 Gy/fx in 22 daily fractions, days 1 through 30, followed by esophagectomy. RESULTS: Forty-seven patients underwent esophagectomy (94% operability rate), and 45 had total gross removal of disease and negative margins of resection (90% resectability rate). Nineteen patients (40%) had a pathologic complete response (CR). Forty (80%) received 100% of the planned cisplatin dose, 29 (58%) received 100% of the planned 5-FU dose, and 40 (80%) received > or = 80% of the planned 5-FU dose. Forty-five (90%) received the planned 44-Gy radiation dose. Grade 3 or 4 neutropenia occurred in 60% of patients. The incidence of febrile neutropenia was 34%. There was one septic death during chemoradiation and no operative deaths. Weight loss requiring nutritional support occurred in 50% of patients, secondary to anorexia, dysphagia, and/or esophagitis. The survival of all registered patients at a median follow-up of 43 months was 2-year survival 58%, median 31.3 months. Survival analysis by histology showed no difference between the two histologic types (squamous vs adenocarcinoma). However, survival by pathologic response was significantly different: pathologic CR, 19 patients, 2-year survival 78%, median survival 58 months; and pathology positive, 28 patients, 2-year survival 46%, median survival 22.4 months. A Cox proportional hazards model and logistic regression analysis demonstrated a significant survival advantage for pathologic CRs and stage I disease versus higher-stage disease and a correlation between chemotherapy dose received and pathologic staging. DISCUSSION: This 30-day chemoradiation regimen followed by surgery resulted in a high pathologic complete response rate, 40%, and apparent survival advantage for this group. The median survival rate of 31.3 months and 2-year survival rate of 58% suggest that this regimen may improve survival over surgical treatment alone. Randomized trials with large accrual and statistical power are necessary to confirm our results and to determine optimal treatment.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Esofagectomia , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Análise de Sobrevida , Trombocitopenia/induzido quimicamenteRESUMO
We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/terapia , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Carcinoma de Células Renais/imunologia , Quimioterapia Adjuvante , Humanos , Hipersensibilidade Tardia/imunologia , Imunoterapia Adotiva , Injeções Subcutâneas , Neoplasias Renais/imunologiaRESUMO
PURPOSE: Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis. PATIENTS AND METHODS: Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival. RESULTS: Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients. CONCLUSION: IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.
Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias/terapia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Biopterinas/análogos & derivados , Biopterinas/sangue , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Estudos de Coortes , Feminino , Humanos , Injeções Subcutâneas , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neopterina , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes , Indução de RemissãoRESUMO
The adoptive transfer of anti-CD3-stimulated T killer (T-AK) cells was tested with different bolus and infusional interleukin-2 (IL-2) regimens, and anti-CD3 stimulation procedures to determine immunologic and antitumor effects in patients with a variety of advanced cancers. Indium-111 labeling was used to observe traffic patterns of the infused T-AK. Autologous peripheral blood mononuclear cells were obtained by leukapheresis. Cyclophosphamide (300 mg/m2) was given to most patients immediately after leukapheresis. The harvested cells were activated ex vivo with anti-CD3 overnight or for 4 days, at which time cells were reinfused and an IL-2 regimen was begun. Treatment was repeated 28 days later. This treatment regimen induced significant increases in leukocytes, lymphocytes, and eosinophils in patients in most treatment cohorts. Circulating lymphocytes were predominantly CD3+ T cells with preferential expansion of the CD8+ subset. Patients receiving cells stimulated in vitro for 4 days had significant T-cell lymphocytosis with either infusional or bolus plus infusional IL-2 regimens. T-cell viability was decreased in culture after a second 4-day stimulation with anti-CD3 at day 28; this decrease could be prevented by adding IL-2 to the culture media. Cells stimulated overnight required both bolus and infusional IL-2 to show an atypical lymphocytosis in vivo. Overnight-stimulated T-AK did not show decreases in in vitro viability at the day 28 restimulation. Indium-III-labeled cells trafficked to the liver, spleen, and bone marrow. No increase in uptake was observed in tumor deposits. There were 2 patients with partial responses, 5 with minor responses, 19 with stable disease, and 88 with progressive disease. The length of in vitro anti-CD3 stimulation, and the dose and timing of IL-2 administration in vivo results in different circulating leukocyte populations after adoptive T-AK infusion. Generally, the CD8+ T-cell subset was preferentially expanded by this treatment approach. Repeated ex vivo stimulation with anti-CD3 may cause cell death.
Assuntos
Anticorpos Monoclonais/imunologia , Complexo CD3/imunologia , Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , Subpopulações de Linfócitos T/efeitos dos fármacos , Adolescente , Adulto , Idoso , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Relação Dose-Resposta Imunológica , Vias de Administração de Medicamentos , Esquema de Medicação , Feminino , Humanos , Interleucina-2/efeitos adversos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/transplanteRESUMO
Previous primate and rodent studies suggested that interleukin-1 alpha (IL-1 alpha) caused changes in the secretion of pituitary, adrenal, thyroid, and gonadal hormones, as well as acute-phase reactants. Plasma samples were obtained after IL-1 alpha and beta treatment in cancer patients to document the changes in endocrine function suggested by the animal models. Successive groups of patients were treated at IL-1 alpha doses of 0.01, 0.03, 0.1, 0.3, and 1.0 microgram/kg, given daily as a 15-min intravenous bolus. IL-1 beta was given at 0.1 microgram/kg by the same route and time course. After the first dose of IL-1, statistically significant elevations of a.m. and p.m. cortisol, growth hormone (GH), and prolactin (PRL) occurred. Thyroid-stimulating hormone (TSH) and C-reactive protein (CRP) were elevated by the sixth treatment day. Testosterone decreased significantly in male patients. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were more variable but decreased in most patients. The changes in cortisol, GH, PRL, TSH, CRP, FSH, LH, and testosterone resolved after treatment and did not result in clinically apparent endocrinopathies. Bolus doses of IL-1 alpha and beta cause significant changes in many endocrine laboratory parameters and influence the in vivo activities of multiple homeostatic endocrine functions in human beings.
Assuntos
Glândulas Endócrinas/efeitos dos fármacos , Glândulas Endócrinas/metabolismo , Interleucina-1/efeitos adversos , Neoplasias/terapia , Proteínas de Fase Aguda/efeitos dos fármacos , Hormônio Adrenocorticotrópico/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio do Crescimento Humano/efeitos dos fármacos , Humanos , Hidrocortisona/sangue , Interleucina-1/uso terapêutico , Hormônio Luteinizante/efeitos dos fármacos , Masculino , Neoplasias/fisiopatologia , Prolactina/efeitos dos fármacos , Testosterona/metabolismo , Glândula Tireoide/efeitos dos fármacosRESUMO
BACKGROUND: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed. PURPOSE: Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination. METHODS: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1 alpha (O.1 micrograms/kg per day by intravenous bolus) infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests. RESULTS: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with non-visceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1 alpha-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011). CONCLUSIONS: The combination of IL-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response. IMPLICATIONS: Administration of higher doses of IL-1 alpha alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1 alpha doses alone may be a strategy for attaining better response rates.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Distribuição de Qui-Quadrado , Feminino , Antígenos HLA-B/sangue , Humanos , Indometacina/administração & dosagem , Interleucina-1/administração & dosagem , Masculino , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Fatores Sexuais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
We conducted a phase I/II trial of 5-fluorouracil (5-FU), calcium leucovorin (LV), zidovudine (AZT) and dipyridamole (DP), (FLAP) in patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. AZT and DP were given to enhance the biochemical modulation and antitumor activity of 5-FU and LV. All patients received 5-FU (370 mg/m(2) i.v. bolus day 0-4), LV (50 mg/m(2) p.o. every 4 h day 0-4) and DP (50 mg/m(2) p.o. every 6 h days 0-27). In the phase I portion of the study, AZT was dose escalated in cohorts of 5 patients each, from 50 mg p.o. every 6 h days 0-27 to the MTD of 200 mg p.o. every 6 h days 0-27. Thirty-three patients received 200 mg of AZT in the phase II portion of the trial. Eleven patients developed grade III and 5 patients developed grade IV leukopenia. Four patients developed grade III and 21 patients developed grade IV neutropenia, with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. Fifty-eight percent (19 of 33) of patients required dose reductions of AZT for hematologic toxicity (13 of 19 in the first treatment cycle). At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%), no objective responses in 14 patients with renal cell carcinoma or in 14 patients with melanoma. FLAP does not have significant activity in melanoma, renal cell carcinoma or 5-FU-treated colorectal cancer patients, although it may have activity in untreated colon cancer.
RESUMO
BACKGROUND: Interleukin-2 (IL-2) recently was approved by the Food and Drug Administration for the treatment of renal cell cancer. It is effective in a small minority of patients, but no markers identify individuals likely to respond to treatment. METHODS: Two polycythemic patients with erythropoietin-producing renal cell cancer and three other polycythemic patients with renal cell cancer were treated with the combination of IL-2 and alpha-interferon (alpha-IFN). RESULTS: All five patients achieved a partial or complete remission. In both patients in which it was measured, the erythropoietin level decreased significantly with treatment, and the polycythemia resolved in all patients. Hypothyroidism developed in two patients, and transient hyperthyroidism developed in another. CONCLUSION: These results contrast with those achieved with IL-2 alone or in combination with lymphokine-activated killer cells, for which a 15% response rate was seen in patients with renal cell cancer and polycythemia. Although less than 5% of renal cell tumors produce erythropoietin, its production may identify a subset of individuals with renal cell cancer responsive to IL-2 and alpha-IFN.
Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Eritropoetina/biossíntese , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Adulto , Idoso , Biomarcadores/análise , Carcinoma de Células Renais/complicações , Quimioterapia Combinada , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interleucina-2/administração & dosagem , Neoplasias Renais/complicações , Masculino , Pessoa de Meia-Idade , Policitemia/complicações , Indução de RemissãoRESUMO
BACKGROUND: Thrombocytopenia is a frequent side effect of cancer chemotherapy and commonly limits attempts to escalate drug doses. To determine whether interleukin-1 alpha could ameliorate carboplatin-induced thrombocytopenia, we combined it with high-dose carboplatin in 43 patients with advanced neoplasms. METHODS: High-dose carboplatin (800 mg per square meter of body-surface area) was administered alone to a control group. Subsequent patients were randomly assigned to receive the same dose of carboplatin with interleukin-1 alpha, administered either before or after carboplatin. Interleukin-1 alpha was given intravenously at a dose of 0.03, 0.1, or 0.3 microgram per kilogram of body weight per day for five days. RESULTS: Carboplatin alone consistently produced thrombocytopenia with a median nadir of 19,000 platelets per cubic millimeter and a median of 10 days with less than 100,000 platelets per cubic millimeter. All 15 patients receiving interleukin-1 alpha before carboplatin had similar findings. In contrast, 5 of the 15 patients given one of the two higher doses of interleukin-1 alpha after carboplatin had minimal thrombocytopenia (nadir, 91,000 to 332,000 platelets per cubic millimeter). In the 10 patients given 0.3 microgram of interleukin-1 alpha per kilogram after carboplatin treatment, the platelet count recovered to 100,000 per cubic millimeter significantly earlier than in either the control group (P = 0.002) or the patients who received interleukin-1 alpha before carboplatin (P = 0.003), with the median times to recovery in the three groups being 16, 21, and 23 days, respectively. At the highest dose of interleukin-1 alpha, toxicity was substantial (but reversible), requiring inpatient support for hypotension, supraventricular arrhythmias, and pulmonary-capillary leak. CONCLUSIONS: Interleukin-1 alpha can accelerate the recovery of platelets after high-dose carboplatin therapy and may be clinically useful in preventing or treating thrombocytopenia induced by chemotherapy.
Assuntos
Carboplatina/efeitos adversos , Interleucina-1/uso terapêutico , Trombocitopenia/terapia , Adulto , Idoso , Carboplatina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Interleucina-1/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Projetos Piloto , Contagem de Plaquetas , Trombocitopenia/induzido quimicamente , Fatores de TempoRESUMO
PURPOSE: This phase I study was conducted to determine the maximum-tolerated dose (MTD) and the immunologic properties of levamisole in cancer patients when administered alone and in combination with interferon gamma (IFN-gamma). PATIENTS AND METHODS: Twenty patients with advanced cancer and 36 patients with completely resected melanoma (n = 33) or renal cell cancer (n = 3) received levamisole orally every other day for six doses at 1.0, 2.5, 5.0, or 10.0 mg/kg. Ten days later, patients restarted levamisole and began IFN-gamma 0.1 mg/m2 by subcutaneous injection every other day. Blood samples were collected for measurement of neopterin and soluble interleukin-2 receptor (sIL-2R), and for flow-cytometric analysis. RESULTS: The MTD of levamisole was 5 mg/kg, and this was not changed by the addition of IFN-gamma. Dose-related increases in serum levels of neopterin and sIL-2R were noted. Multiple doses of > or = 5 mg/kg of levamisole were required to elicit immune changes, which were more prominent in patients with minimal tumor burdens. Increased expression of CD64 and class I and class II major histocompatibility antigens on monocytes was also observed. The combination of IFN-gamma and levamisole did not result in greater immunologic effects than those observed in previous trials of IFN-gamma alone. CONCLUSION: Levamisole induces dose-related immunologic changes in patients with large or minimal tumor burdens. These changes may be involved in the beneficial effects noted in recent adjuvant trials of levamisole. Ongoing clinical trials should correlate immune changes with response, and trials exploring different schedules of administration using higher, more immunologically active, doses of levamisole should be performed.
Assuntos
Levamisol/farmacologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biopterinas/análogos & derivados , Biopterinas/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunofenotipagem , Interferon gama/administração & dosagem , Interferon gama/sangue , Células Matadoras Naturais/efeitos dos fármacos , Levamisol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neopterina , Receptores de Interleucina-2/efeitos dos fármacos , Proteínas RecombinantesRESUMO
The authors report four patients whose initial symptom of tumor recurrence or progression was unilateral numbness of the chin. Two patients had Hodgkin lymphoma, one had malignant melanoma, and one had prostate cancer. Physical examination was notable only for unilateral anesthesia of the chin and lower lip. Diagnostic evaluation, including computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain, plain radiographs of the mandible, and cerebrospinal fluid analysis for protein, glucose, and cytology were normal. Bone scans revealed osseous lesions in the axial skeleton of all patients, whereas only two patients had abnormal uptake in the mandible. The authors conclude that in the setting of a negative evaluation for central nervous system (CNS) or local mandibular disease, mental neuropathy is associated with recurrent or progressive skeletal disease. In addition, to document relapsed or progressive cancer, the skeletal system may have to be examined at sites distant from the mandible.
Assuntos
Neoplasias Ósseas/secundário , Queixo/inervação , Doenças Mandibulares/etiologia , Neoplasias/complicações , Sensação , Nervo Trigêmeo , Adulto , Idoso , Medula Óssea/patologia , Neoplasias Ósseas/complicações , Doenças dos Nervos Cranianos/etiologia , Feminino , Doença de Hodgkin/complicações , Humanos , Masculino , Neoplasias Mandibulares/secundário , Melanoma/complicações , Pessoa de Meia-Idade , Neoplasias da Próstata/complicações , SíndromeRESUMO
OBJECTIVE: Based upon their individual clinical activity and combined effects in animal models or in vitro, we wished to evaluate a regimen of cisplatin, interferon-alpha, and IL-2 in patients with metastatic melanoma. DESIGN: Phase II pilot study. SETTING: Referral-based US Government clinical research unit. PATIENTS: Nine patients with metastatic malignant melanoma. INTERVENTION: Cisplatin 75-100 mg/m2 was administered intravenously over 30 minutes on days 1 and 8. Interferon-alpha 2a 5 Mu/m2 body surface area (BSA) was given subcutaneously for 4 days beginning 1 day before each dose of cisplatin. Beginning on day 15 and day 22, IL-2 was administered by intravenous continuous infusion at 3 Mu/m2 BSA/d for 96 hours and by daily intravenous bolus concurrent with daily subcutaneous doses of interferon-alpha 2a. MAIN OUTCOME MEASURES: Antitumor response and toxicities. RESULTS: The study was stopped due to renal and hematopoietic toxicity and severe, delayed nausea and vomiting associated with the cisplatin-interferon treatment. Three of 9 patients achieved a partial response (duration 2.5, 4, 14+ months), and an additional patient had a 50% reduction in measurable tumor volume before undergoing resection of residual disease. Overall response rate was 45%. CONCLUSION: This regimen was associated with excessive toxicity, and the lack of complete responses in a patient cohort with favorable characteristics for response (good performance status, predominance of skin and lymph node metastatic sites) suggests that it had no advantage over less toxic treatment regimens. REGISTRATION: National Cancer Institute/Cancer Therapy Evaluation Program T89-0137.
Assuntos
Cisplatino/uso terapêutico , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Melanoma/terapia , Adulto , Idoso , Cisplatino/efeitos adversos , Terapia Combinada , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interleucina-2/efeitos adversos , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Proteínas Recombinantes , Vômito/induzido quimicamenteRESUMO
PURPOSE: A phase I trial was undertaken because interleukin-1 alpha (IL-1 alpha) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. PATIENTS AND METHODS: In this phase I trial, IL-1 alpha was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. RESULTS: The maximum-tolerated dose (MTD) of IL-1 alpha alone was 0.3 microgram/kg. A second group of patients received indomethacin plus IL-1 alpha based on preclinical studies, which indicated that indomethacin could abrogate IL-1 alpha-induced hypotension; however, the MTD of IL-1 alpha plus indomethacin was 0.1 microgram/kg lower than IL-1 alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 micrograms/kg IL-1 alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1 alpha treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1 alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. CONCLUSION: We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.
Assuntos
Células Sanguíneas/efeitos dos fármacos , Interleucina-1/farmacologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Medula Óssea/efeitos dos fármacos , Avaliação de Medicamentos , Feminino , Hematopoese/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Indometacina/farmacologia , Interleucina-1/administração & dosagem , Interleucina-1/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangueRESUMO
BACKGROUND: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclophosphamide or doxorubicin or by the biologic agent interferon alpha. PURPOSE: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN alpha-2a) in patients with metastatic melanoma and renal cell carcinoma. METHODS: IL-2 (3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN alpha-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study. RESULTS: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths. CONCLUSIONS: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN alpha-2a as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.