RESUMEN
BACKGROUND: We report on a series of consecutive patients with localized radiation-associated angiosarcoma (RAAS) of the breast region (BR) treated at two Italian sarcoma reference centers. MATERIALS AND METHODS: We retrospectively reviewed all cases of primary, localized, resectable RAAS of the BR, treated at one of the two participating institutions from 2000 to 2019. Relapse-free survival (RFS) and overall survival (OS) were calculated. The prognostic role of several variables was investigated. A propensity score matched (PSM) analysis was carried out. RESULTS: Eighty-four patients were retrospectively identified. Nineteen out of 84 patients (22.6%) were pretreated with an anthracycline-based regimen for previous cancer. All patients but one underwent surgery, with 37/84 (44.1%) receiving surgery alone and 46/84 (54.8%) a multimodal approach: 18/84 (21.4%) received radiation therapy (RT) and 46/84 (54.9%) received chemotherapy. An anthracycline-based regimen was used in 10/84 patients (11.9%), while a gemcitabine-based regimen was used in 33/84 (39.3%). With a median follow-up of 51 months (interquartile range: 30-126 months), 36/84 patients (42.9%) relapsed and 35/84 patients (41.7%) died (8/84, 9.5% in the lack of metastatic disease). Five-year OS and 5-year RFS were 57% [95% confidence interval (CI) 43% to 68%] and 52% (95% CI 39% to 63%), respectively. Both (neo)adjuvant RT and chemotherapy were associated with better RFS [hazard ratio (HR) 0.25, 95% CI 0.08-0.83; HR 0.45, 95% CI 0.23-0.89] with a trend towards a better OS (HR 0.51, 95% CI 0.18-1.46; HR 0.60, 95% CI 0.29-1.24). Gemcitabine-based regimens seemed to perform better (HR 4.28, 95% CI 1.29-14.14). PSM analysis retained the above results. CONCLUSIONS: This retrospective study supports the use of (neo)adjuvant RT and chemotherapy, in primary, localized resectable RAAS of the BR. An effort to prospectively validate the role of (neo)adjuvant RT and chemotherapy is warranted.
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Neoplasias de la Mama , Hemangiosarcoma , Neoplasias Inducidas por Radiación , Humanos , Hemangiosarcoma/etiología , Hemangiosarcoma/terapia , Hemangiosarcoma/tratamiento farmacológico , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Anciano , Neoplasias Inducidas por Radiación/etiología , Adulto , Resultado del Tratamiento , Anciano de 80 o más AñosRESUMEN
BACKGROUND: We aimed at investigating outcome of systemic treatments in advanced breast PT. METHODS: All cases of advanced breast PT treated with systemic treatments from 1999 to 2019, in one of the referral sarcoma centers involved in the study, were retrospectively reviewed. RESULTS: 56 female patients were identified. Median age was 52 (range of 25-76) years. Patients received a median number of 2 systemic treatments (range of 1-4). Best responses according to RECIST were 1 (3.7%) CR, 11 (40.7%) PR, 6 (22.2%) SD, 9 (33.3%) PD with anthracyclines plus ifosfamide (AI); 2 (16.7%) PR, 4 (33.3%) SD, 6 (50.0%) PD with anthracycline alone; 3 (18.8%) PR, 4 (25.0%) SD, 9 (56.3%) PD with high-dose ifosfamide given as a continuous infusion (HD-IFX); 3 (20.0%) SD, 12 (80.0%) PD with a gemcitabine-based regimen (with 2 patients not evaluable); 1 (8.3%) PR, 2 (16.7%) SD, 9 (75.0%) PD with trabectedin (with 1 patient not evaluable); 1 (16.7%) PR, 1 (16.7%) SD, 4 (66.7%) PD with tyrosine-kinase inhibitors (TKI). The median PFS were 5.7 (IQR 2.5-9.1) months with AI; 3.2 (IQR 2.2-5.0) months with anthracycline alone; 3.4 (IQR 1.4-6.7) months with HD-IFX; 2.1 (IQR 1.4-5.2) months with gemcitabine-based chemotherapy; 1.8 (IQR 0.7-6.6) months with trabectedin; 3.4 (IQR 3.1-3.8) months with TKI. With a median follow-up of 35.3 (IQR 17.6-66.9) months, OS from the start of first-line systemic treatment was 15.2 (IQR 7.6-39.6) months. CONCLUSION: In this series of advanced PT (to our knowledge, the largest reported so far), AI was associated with a high rate of responses, however, with a median PFS of 5.7 months. Other systemic treatments were poorly active.
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Neoplasias de la Mama , Sarcoma , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Sarcoma/patologíaRESUMEN
BACKGROUND: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS). METHODS: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. RESULTS: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively. CONCLUSIONS: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).
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Quimioterapia Adyuvante , Leiomiosarcoma/tratamiento farmacológico , Pronóstico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leiomiosarcoma/patología , Leiomiosarcoma/radioterapia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Sarcoma/patología , Sarcoma/radioterapia , Resultado del TratamientoRESUMEN
BACKGROUND: To analyse the natural history of extra-abdominal wall desmoid-type fibromatosis (DF) and compare outcome in patients who underwent initial surgery with those who did not. PATIENTS AND METHODS: All consecutive patients affected by primary sporadic extra-abdominal wall DF observed between January 1992 and December 2012 were included. Patients were divided into surgical (SG) or non-surgical groups (NSG) according to initial treatment. Relapse free survival was calculated for SG, and crude cumulative incidence (CCI) of switching to surgery or other treatments for NSG. RESULTS: 216 patients were identified, 94 in SG (43%), 122 in NSG (57%). A shift towards a more systematic use of a conservative approach (78% of all comers) was observed in the latter years (2006-2012), although a small proportion of patients (28%) had been offered the conservative strategy even in the early period (1992-2005). Median follow-up (FU) was 49 mo. (interquartile (IQ), 20-89 mo.), 76 months for SG and 39 months for NSG. 5-year relapse-free survival (RFS) for SG was 80% (95% confidence interval (CI), 72-89%). For the NSG, 5-year CCI of switching to surgery was 5% (95% CI: 1.7%, 14%), and 51% to other treatments (95% CI: 41%, 65%). 27 (20%) NSG patients underwent spontaneous regression. CONCLUSION: A non-surgical approach to extra-abdominal wall DF allowed surgery to be avoided in the majority of patients. This approach can be safely proposed and surgery offered as an option in selected cases.
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Fibromatosis Agresiva/patología , Fibromatosis Agresiva/cirugía , Adulto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , PronósticoRESUMEN
PURPOSE: To explore the value of triazines in solitary fibrous tumor (SFT). EXPERIMENTAL DESIGN: We retrospectively reviewed 8 cases of patients with SFT treated with dacarbazine (1,200 mg/m(2) every 3 weeks) as from January 2012. Then, we studied a dedifferentiated-SFT subcutaneously xenotransplanted into severe combined immunodeficient (SCID) mice. Dacarbazine, temozolomide, sunitinib, bevacizumab, and pazopanib were administered at their reported optimal doses for the mouse model when mean tumor volume (TV) was about 80 mm(3); each experimental groups included 6 mice. Drug activity was assessed as tumor volume inhibition percentage (TVI%). Dacarbazine was tested according to two different schedules of administration. One hunded twenty days after treatment interruption, mouse tumor samples were analyzed. RESULTS: Among the eight patients treated with dacarbazine, best response evaluation criteria in solid tumors responses (RECIST) were three partial responses, 4 stable disease, 1 progression. Two responsive patients had paraneoplastic hypoglycemia that disappeared after 10 days from starting dacarbazine. In the dedifferentiated-SFT xenograft model, dacarbazine and temozolomide showed the highest antitumor activity (about 95% TVI), confirmed pathologically. Sunitinib and pazopanib were only marginally active (52% and 41% TVI, respectively), whereas bevacizumab caused a 78% TVI. No tumor regrowth was observed up to 100 days from end of treatment with temozolomide and dacarbazine, whereas secondary progression followed sunitinib, pazopanib, and bevacizumab interruption. CONCLUSIONS: Dacarbazine as single agent has antitumor activity in SFT. Our preclinical results suggest a cytotoxic effect of temozolomide and dacarbazine, as compared with a cytostatic role for sunitinib, pazopanib, and bevacizumab. A phase II study on dacarbazine in advanced SFT is planned.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neovascularización Patológica/prevención & control , Tumores Fibrosos Solitarios/tratamiento farmacológico , Tumores Fibrosos Solitarios/patología , Adulto , Anciano , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Indoles/administración & dosificación , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Estudios Retrospectivos , Tumores Fibrosos Solitarios/irrigación sanguínea , Sulfonamidas/administración & dosificación , Sunitinib , Temozolomida , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: To report on a prospective, investigator-driven, phase II study on lapatinib in epidermal growth factor receptor (EGFR)-positive advanced chordoma patients. PATIENTS AND METHODS: From December 2009 to January 2012, 18 advanced progressing chordoma patients entered this study (median age: 61 years; disease extent: metastatic 72% and locally advanced 28%). Epidermal growth factor receptor (EGFR) expression and activation were evaluated by immunohistochemistry and/or phospho-arrays, real-time polimerase chain reaction, fluorescence immunostaining. Fluorescence in situ hybridization analysis was also carried out. Patients received lapatinib 1500 mg/day (mean dose intensity = 1282 mg/day), until progression or toxicity. The primary study end point was response rate (RR) as per Choi criteria. Secondary end points were RR by Response Evaluation Criteria in Solid Tumor (RECIST), overall survival, progression-free survival (PFS) and clinical benefit rate (CBR; RECIST complete response + partial response (PR) + stable disease (SD) ≥ 6 months). RESULTS: All patients were evaluable for response. Six (33.3%) patients had PR and 7 (38.9%) SD, as their best Choi responses, corresponding to RECIST SD in all cases. Median PFS by Choi was 6 [interquartile (IQ) range 3-8] months. Median PFS by RECIST was 8 (IQ range 4-12) months, with a 22% CBR. CONCLUSIONS: This phase II study showed a modest antitumor activity of lapatinib in chordoma. The clinical exploitation of EGFR targeting in chordoma needs to be further investigated, both clinically and preclinically. Clinical trial Registration No: EU Clinical Trials Register trial no. 2009-014456-29.
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Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Cordoma/tratamiento farmacológico , Receptores ErbB/metabolismo , Quinazolinas/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Cordoma/mortalidad , Cordoma/secundario , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Lapatinib , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Sacro/patología , Base del Cráneo/patología , Resultado del TratamientoRESUMEN
BACKGROUND: To report on anthracycline-based chemotherapy in a retrospective case-series analysis of solitary fibrous tumour (SFT) patients treated within the Italian Rare Cancer Network. PATIENTS AND METHODS: We reviewed a set of SFT treated with chemotherapy since 2002, focusing on anthracycline, administered alone or in combination with ifosfamide. Responses to ifosfamide as a single agent were also evaluated. Pathologic diagnosis was centrally reviewed, distinguishing typical, malignant (MSFT) and dedifferentiated (DSFT) subtypes. RESULTS: Among 42 SFT patients treated with chemotherapy, we selected 31 cases (mean age: 62 years; locally advanced/metastatic: 13/18; front-line/further line: 25/6; typical/MSFT/DSFT/not assessable: 1/17/12/1) who received anthracycline-based chemotherapy (anthracycline monotherapy: eight; anthracycline+ifosfamide: 23). 30 patients are evaluable for response. Best response by Response Evaluation Criteria in Solid Tumours (RECIST) was: partial response (PR): 6 (20%), stable disease (SD): eight (27%), progressive disease (PD): 16 (53%) cases. Responses were confirmed after 3 months. Median progression-free survival (PFS) was 4 (range 2-15) months, with 20% of patients being progression-free at 6 months. PR was found in 2/18 (11%) MSFT and 4/12 (30%) DSFT, with a median PFS of 3.5 and 5 months in MSFT and DSFT, respectively. 19 patients received high-dose prolonged-infusion ifosfamide (front-line/further line: 11/8; typical/MSFT/DSFT: 0/15/4) with two (10%) PR, five (26%) SD, 12 (63%) PD. CONCLUSIONS: This retrospective series suggests that in SFT anthracyclines have a degree of antitumour activity in the range of soft tissue sarcoma chemotherapy. Ifosfamide monotherapy seemed to have lower activity. A higher response rate was observed in DSFT in comparison to MSFT. Studies on targeted therapies are ongoing.
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Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Adulto , Anciano , Antraciclinas/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ifosfamida/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tumores Fibrosos Solitarios/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Procedimientos Quirúrgicos Operativos/normas , Adolescente , Adulto , Anciano , Quimioterapia Adyuvante , Epirrubicina/administración & dosificación , Extremidades/patología , Extremidades/cirugía , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Terapia Neoadyuvante , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias Torácicas , Torso/patología , Torso/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor (SFT) treated at a single institution. PATIENTS AND METHODS: From April 2008, 35 patients with progressive advanced SFT (male/female: 20/15; mean age: 58 years; meningeal/extrameningeal: 6/29; locally advanced/metastatic: 15/20; prior chemotherapy: 25) were treated, on an individual use basis, with continuous-dosing sunitinib 37.5 mg/day. Platelet-derived growth factor receptor beta (PDGFRB) and vascular endothelial growth factor receptor 2 (VEGFR2) status were assessed by immunohistochemistry and, in a subgroup of patients, by real time PCR. RESULTS: Thirty-one patients were assessable for response by RECIST (one early death; three early interruptions). Best responses were 2 partial response (PR), 16 stable disease, 13 progressive disease. A <30% decrease in size was observed in three patients. Fourteen of 29 patients assessable by Choi criteria had a PR. Median progression-free survival by RECIST was 6 months (range 1-22). In two of six patients, resistance to sunitinib was overcome by increasing sunitinib to 50 mg/day. PDGFRB and/or VEGFR2 were positive in all cases and not predictive of response; a less aggressive morphology corresponded to an increased response rate (53% PR by Choi in the malignant SFT, 20% PR in the pleomorphic/dedifferentiated SFT). CONCLUSIONS: Sunitinib is active in SFT. Response can be long-lasting.
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Indoles/uso terapéutico , Pirroles/uso terapéutico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Tumores Fibrosos Solitarios/mortalidad , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Antígenos CD34/metabolismo , Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Estudios Retrospectivos , Sunitinib , Resultado del Tratamiento , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Angiosarcoma is a highly aggressive soft tissue sarcoma. Responses to anthracyclines plus/minus ifosfamide, and taxanes alone or in combination with gemcitabine are well documented. Very few data are available on gemcitabine as a single agent. PATIENTS AND METHODS: We retrospectively reviewed all cases of advanced progressive angiosarcoma treated with gemcitabine as a single agent (1000 mg/m(2) i.v. every week for 3 weeks every 4 weeks), at Istituto Nazionale Tumori and within the Italian Rare Cancers Network from January 2008 to November 2010. RESULTS: Twenty-five patients [mean age: 52 years; radiation therapy (RT)-related: 8] received gemcitabine. Best tumor response by RECIST was as follows: complete response = 2, partial response = 14, stable disease = 2, progressive disease = 7 cases, for an overall response rate (PR + CR) of 68%. Six of eight post-RT angiosarcomas responded to treatment. Median overall survival (OS) was 17 months. Median progression-free survival (PFS) was 7 months (range 1-40 months). One patient with a locally advanced thyroid angiosarcoma became resectable after 5 months of gemcitabine, with <10% residual viable tumor cells seen on surgical specimen. Overall, gemcitabine was well tolerated. CONCLUSIONS: Gemcitabine is active in both RT- and non-RT-related angiosarcoma, with dimensional and possibly long-lasting responses. A formal phase II study on gemcitabine as a single agent is warranted.
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Desoxicitidina/análogos & derivados , Hemangiosarcoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Desoxicitidina/uso terapéutico , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , GemcitabinaRESUMEN
BACKGROUND: The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof. PATIENTS AND METHODS: From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case. RESULTS: All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand-dependent activation was confirmed. CONCLUSIONS: We confirm the clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture.
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Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Indoles/uso terapéutico , Pirroles/uso terapéutico , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Adulto , Western Blotting , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Estudios Retrospectivos , Sarcoma de Parte Blanda Alveolar/genética , Sarcoma de Parte Blanda Alveolar/metabolismo , Sunitinib , Tasa de Supervivencia , Resultado del Tratamiento , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Pirroles/uso terapéutico , Sarcoma de Células Claras/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Sarcoma de Células Claras/patología , Sarcoma de Células Claras/radioterapia , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/radioterapia , Sunitinib , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma. PATIENTS AND METHODS: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis. RESULTS: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (> or =10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD > or =6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off. CONCLUSION: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cordoma/tratamiento farmacológico , Sirolimus/administración & dosificación , Neoplasias de la Base del Cráneo/tratamiento farmacológico , Neoplasias de la Columna Vertebral/tratamiento farmacológico , Adolescente , Adulto , Anciano , Benzamidas , Western Blotting , Cordoma/patología , Femenino , Humanos , Mesilato de Imatinib , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteína Oncogénica v-akt/biosíntesis , Proteína Oncogénica v-akt/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sacro/patología , Sirolimus/efectos adversos , Neoplasias de la Base del Cráneo/patología , Neoplasias de la Columna Vertebral/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST). METHODS: From January 2003 to January 2008, all patients affected by bulky localized GIST who presented at our institution were considered for preoperative IM with cytoreductive intent. Clinical, pathological and molecular characteristics were assessed and the rate of response recorded. Progression-free survival (PFS) was calculated according to Kaplan-Meier analysis. RESULTS: Fifteen patients (1 esophageal, 7 gastric, 3 duodenal, 4 rectal GISTs) received preoperative IM for a median of 9 months. All patients had tumor shrinkage, with a median size reduction of 34%. One patient had radiological complete response. In all cases an improvement of the originally planned surgical procedure was obtained: 3 patients initially considered unresectable underwent complete surgery; 7 patients with initial indication for extensive surgery were more conservatively operated on; 4 patients initially deemed at high perioperative risk underwent safe surgery. Due to the small sample size, no association between tumor shrinkage and tumor site, size, IM duration, mutational status and pathological response could be formally explored. PFS at 3 years from IM onset was 77%. CONCLUSIONS: In unresectable or locally advanced GISTs, preoperative IM is a useful tool both to improve resectability and reduce surgical morbidity. It should be therefore always be considered before embarking on a major surgical procedure. The long-term impact of IM on PFS and survival is presently under investigation in multicenter prospective randomized trials.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Adulto , Anciano , Benzamidas , Terapia Combinada , Femenino , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Cuidados Preoperatorios , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The present paper is a critical review about the recent development of new agents that have revolutioned the therapeutical approach of solid tumours with a particular focus on colorectal cancer. Until a few years ago, chemotherapy has been considered the only medical treatment for advanced disease. At the moment, new drugs blocking some cell functions, such as monoclonal antibodies or tyrosin kinase inhibitors are available for many oncologists, but their efficacy should be debated for several reasons. Despite having a strong biological and preclinical rationale, the clinical results of these agents are not comparable to the results obtained by imatinib in gastrointestinal stromal tumour or in chronic myeloid leukaemia even though superior to chemotherapy alone. Moreover, the efficacy does not show any correlation with the molecular expressions of the tumours. In this review, we considered different hypotheses in order to explain these results.