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Background: To evaluate outcomes in terms of survival and toxicity in a series of intermediate-risk prostate cancer (PCa) patients treated with hypofractionated radiotherapy (HyRT) + hormonal therapy (HT) with or without image guidance (IGRT) and to investigate the impact of different variables. Methods: This is a multi-centric study. From January 2005 to December 2019, we treated 313 intermediate-risk PCa patients (T2b−T2c, Gleason score 7, or pre-treatment PSA 10 to 20 ng/mL) with HyRT. Patients received 54.75 Gy in 15 fractions in 5 weeks plus 9 months of neo-adjuvant, concomitant, and adjuvant HT with or without IGRT. Results: Median follow-up was 91.6 months (range 5.1−167.8 months). Median OS was not reached, and the 8- and 10-year OS was 81.9% and 72.4%, respectively. Median CSS was not reached, and the 8- and 10-year CSS was 97.9% and 94.5%, respectively. PSA at first follow-up <0.8 ng/mL was significantly related to better oncological outcomes (CSS, bRFS, LRFS, cPFS, and MFS) in both univariate and multivariate analysis. After Propensity Score matching, grade 2−3 acute and cumulative late GU (p = 0.153 and p = 0.581, respectively) and GI (p = 0.196 and p = 0.925, respectively) toxicity were not statistically different in patients treated with or without IGRT. Conclusions: HyRT is effective and safe regardless of the use of IGRT. PSA at first follow-up is an easily accessible prognostic factor that may help the clinicians to identify patients who require a treatment intensification.
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PURPOSE: The aim of the study was to report survival outcomes and toxicities incidence by using one-week vaginal brachytherapy (VBT) schedule in intermediate- and high-intermediate-risk endometrial cancer patients. MATERIAL AND METHODS: One hundred and eight patients were treated with exclusive high-dose-rate (HDR) brachytherapy short schedule (7 Gy/fraction/every other day/1 week). Acute and late rectal, urinary, and vaginal toxicities were recorded according to radiation therapy oncology group (RTOG) scores and late effects normal tissue task force - subjective, objective, management, analytic (LENT-SOMA) scores, respectively. Overall survival (OS), cause specific survival (CSS), and disease-free survival (DFS) were evaluated. RESULTS: Median follow-up was 44 months (range, 6-117 months). The 5-year OS, CSS, and DFS rates were 92.7%, 96.4%, and 89.5%, respectively. Seven of 108 (6.5%) patients relapsed after a median time of 31 months (range, 5-56 months). Death occurred in 6 patients. Four patients died for intercurrent causes without an evidence of disease. Acute bladder toxicity G1-G2 was reported in 11 of 108 (10%) patients, vaginal toxicity G1-G2 in 6 of 108 (5.5%), and gastrointestinal toxicity was observed in 3 of 108 (3%) patients. Late bladder and gastrointestinal G1 toxicities were reported in 4 of 108 (4%) and 1 of 108 (1%) patients, respectively. Late vaginal toxicity (G1-G2) was recorded in 3 of 108 (3%) cases. No grade 3-4 bladder, vaginal, and gastrointestinal toxicities were noted. CONCLUSIONS: Exclusive short course adjuvant VBT is an effective treatment in patients with early-stage endometrial cancer and provides good outcomes in terms of disease local control and DFS, with low rates of toxicity profile.
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The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with 'luminal-like' disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A 'real life' analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had 'luminal-like' disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous 'luminal-like' disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a 'bone-related' risk conditions for developing bone metastases must be considered with caution and surely needs further validations.
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INTRODUCTION: Proper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform two-drugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC). This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity. METHODS: Schedule: oxaliplatin dose-levels, 35-40 mg/m2/week; capecitabine 825 mg/m2/ twice daily, radiotherapy on rectum/nodes, 50/45 Gy, 45 and 9 boost/45 Gy, in first 5 and subsequent patients, 5 days/week, respectively; for 5 weeks. Pathologic complete response (pCR) 10% was projected in order to positively affect clinical outcome. RESULTS: Seventeen fit <75 years patients enrolled: median age 60; young-elderly 4 (23%); T3/T4, 15/2, N0/N1/N2, 7/9/1. At first dose-level, no dose-limiting toxicity (DLT). At second, 2 DLT, G3 mucositis, G3 thrombocytopenia, in 2/6 patients (33%). Oxaliplatin recommended dose, 40 mg/m2/week. Cumulative G3-4 toxicities: mucositis 6%, thrombocytopenia 6%. Limiting toxicity syndromes 18%, 25% in young-elderly, all single site. Objective response rate intent-to-treat 94%. Sphinter preservation 87%, pCR 6%. After 17 months follow-up, progression-free survival and overall survival were not reached. CONCLUSIONS: Oxaliplatin can be safely added to preoperative capecitabine-based chemoradiotherapy at the recommended dose 40 mg/m2/week, in LARC, with promising pCR and high activity.
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BACKGROUND/AIM: To evaluate outcomes in patients with low-risk prostate cancer treated with hypofractionated radiotherapy (HyRT). PATIENTS AND METHODS: Between April 2004 and December 2015, 175 patients with low-risk prostate cancer were treated with HyRT 60 Gy in 20 fractions with or without image guidance and reduction of margin from clinical target volume to planning target volume. RESULTS: The median follow-up was 66 months. The 8-year overall survival for the whole patient cohort was 88.9%. The 8-year biochemical no evidence of disease was higher in patients treated with image-guided HyRT (98.8% vs. 88%, p=0.023). During treatment, patients treated with image-guided HyRT presented a lower rate of grade 1-2 gastrointestinal toxicity (25.3% vs. 42.2%, p=0.001). At the last follow-up, the grade 1 Gastro-intestinal toxicity rate was 4.0% and the grade 1-2 genito-urinary toxicity rate was 25.1%. CONCLUSION: Our study demonstrated the efficacy of the schedule used with a low rate of acute and late toxicities. Therefore, reduction of margins with image-guided HyRT is safe.
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Neoplasias da Próstata/radioterapia , Radioterapia Guiada por Imagem/métodos , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Gastroenteropatias/etiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Hipofracionamento da Dose de Radiação , Radioterapia Guiada por Imagem/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. MATERIALS AND METHODS: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. RESULTS: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. CONCLUSIONS: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials.
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Plaquetas , Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/terapia , Estomatite/etiologia , Estomatite/terapia , Administração Oral , Feminino , Géis/administração & dosagem , Géis/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Radioterapia/efeitos adversos , Resultado do TratamentoRESUMO
The present study aimed to measure the improvement in pain relief and quality of life in patients with osteolytic solitary painful bone metastasis treated by cryoablation (CA) or radiofrequency ablation (RFA). Fifty patients with solitary osteolytic painful bone metastases were retrospectively studied and selected by propensity analysis. Twenty-five patients underwent CA and the remaining twenty-five underwent RFA. Pain relief, in terms of complete response (CR), the number of patients requiring analgesia and the changes in self-rated quality of life (QoL) were measured following the two treatments. Thirty-two percent of patients treated by CA experienced a CR at 12 weeks versus 20% of patients treated by RFA. The rate of CR increased significantly with respect to baseline only in the group treated by CA. In both groups there was a significant change in the partial response with respect to baseline (36% in the CA group vs. 44% in the RFA group). The recurrence rate in the CA and RFA groups was 12% and 8%, respectively. The reduction in narcotic medication requirements with respect to baseline was only significant in the group treated by CA. A significant improvement in self-rated QoL was observed in both groups. The present study seems to suggest that CA only significantly improves the rate of CR and decreases the requirement of narcotic medications. Both CA and RFA led to an improvement in the self-rated QoL of patients after the treatments. However, the results of the present study should be considered as preliminary and to serve as a framework around which future trials may be designed.
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PURPOSE: aim of this study was to identify outcomes in pain relief and quality of life in patients with a solitary painful osseous metastasis treated by radiotherapy, cryoablation or the combination using a propensity score matching study design. MATERIALS AND METHODS: 175 patients with painful bone metastases were included in the study. Twenty-five of them underwent a radiation course (20 Gy in five daily fractions) 15 days after the cryoablation. These subjects were retrospectively matched by propensity analysis with a group of subjects treated by radiotherapy (125 subjects) and with a group treated byCryoablation (25 subjects). The pain relief in terms of complete response, rate of subjects requiring analgesics after treatments and the changes in self-rated quality of life were measured. Informed consent was obtained from the subject and the study was approved by the local Ethical Committee. RESULTS: An higher proportion of subjects treated by cryoablation (32%) or cryoablation followed by RT (72%;) experienced a complete response compared with patients treated by radiotherapy alone (11.2%). After Bonferroni correction strategy, the addition of radiotherapy to cryoablation significantly improved the rate of complete response compared with cryoablation alone (p = 0.011) and this paralleled with an improved self-rated quality of life. Seventeen subjects (13.6%) of patients in the radiotherapy group, 9 (36%) in the cryoablation group, and 19 (76)% in the cryoablation- radiotherapy group did not require narcotic medications. CONCLUSIONS: The addition of radiotherapy to cryoablation favorably impacts on perceived pain, with a favorable toxicity profile. However, our data should be interpreted with caution and could serve as a framework around which to design future trials.
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Neoplasias Ósseas/terapia , Crioterapia , Idoso , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Terapia Combinada , Feminino , Humanos , Masculino , Manejo da Dor , Estudos RetrospectivosRESUMO
The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS.
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Adenoma Pleomorfo/terapia , Plaquetas , Neoplasias Parotídeas/terapia , Lesões por Radiação/tratamento farmacológico , Estomatite/tratamento farmacológico , Adenoma Pleomorfo/patologia , Administração Tópica , Idoso , Feminino , Humanos , Neoplasias Parotídeas/patologia , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Estomatite/etiologiaRESUMO
PURPOSE: Chronic radiation cystitis (CRC) is a serious complication that can arise in patients with pelvic malignancies treated with radiotherapy. Polydeoxyribonucleotides (PDRNs) are known to reduce inflammation and improve tissue perfusion and angiogenesis. In this manuscript, we describe our observational experience regarding intravesical instillation of PDRNs in improving symptoms of CRC in subjects unresponsiveness to conventional medical therapy. METHODS: Eight patients with persistent and/or worsening CRC symptoms, despite conventional therapy, received biweekly intravesical instillation of PDRNs for two consecutive months. Symptoms were scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale, before, at the end, and after 4 months following the PDRNs treatment. RESULTS: Four months after instillations, a significant improvement in the subjective perception of CRC symptoms was experienced by participants. The mean LENT-SOMA score was reduced from 1.16+0.26 before to 0.34+0.035 after 4 months from instillations (p<0.001). No adverse effect related to instillations was reported. CONCLUSIONS: Subjective perception of persistent and/or worsening CRC symptoms, despite conventional therapy, is improved after intravesical instillation with PDRNs without adverse events. Even though we deduced suggestive insights, the results need to be collected and verified from a large-scale study.
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Cistite/tratamento farmacológico , Cistite/etiologia , Neoplasias Pélvicas/radioterapia , Polidesoxirribonucleotídeos/administração & dosagem , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/etiologia , Administração Intravesical , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pelve/efeitos da radiação , Projetos PilotoRESUMO
Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.
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Imagem Molecular/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Pesquisa Translacional Biomédica , Antineoplásicos Hormonais/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/uso terapêutico , Transdução de Sinais/genética , Resultado do TratamentoRESUMO
OBJECTIVES: In this article the state of art the of prostate cancer (Pca) imaging and non-surgical salvage treatments (STs) is surveyed in order to explore the impact of imaging findings on the identification of radiorecurrent Pca after external beam radiotherapy (EBRT). METHODS: A computerised search was performed to identify all relevant studies in Medline up to 2012. Additional articles were extracted based on recommendations from an expert panel of authors. RESULTS: Definitive EBRT for Pca is increasingly used as treatment. After radiorecurrent Pca, non-surgical STs are emerging and shifting from investigational status to more established therapeutic options. Therefore, several scientific societies have published guidelines including clinical and imaging recommendations, even if the timing, efficacy and long-term toxicity of these STs have to be established. In some measure, accurately delineating the location and the extent of cancer is critical in selecting target lesions and in identifying patients who are candidates for STs. However, there is increasing awareness that anatomical approaches based on measurements of tumour size have substantial limitations, especially for tumours of unknown activity that persist or recur following irradiation CONCLUSIONS: To date, the main focus for innovations in imaging is the combination of excellence in anatomical resolution with specific biological correlates that depict metabolic processes and hallmarks at the tumour level. The emergence of new molecular markers could favour the development of methods that directly determine their presence, thereby improving tumour detection. KEY POINTS: Imaging may influence therapeutic decisions during non-surgical STs. MRI findings correlate with parametric maps derived from multiple functional techniques. Non-surgical salvage treatments allow local tumour control in patients with radiorecurrent PCa.
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Diagnóstico por Imagem , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Terapia de Salvação , Humanos , Masculino , Recidiva Local de Neoplasia/radioterapia , Neoplasias da Próstata/radioterapiaRESUMO
Multimodal treatment has improved the outcome of many solid tumors, and in some cases the use of radiosensitizers has significantly contributed to this gain. Activation of the extracellular signaling kinase pathway (MEK/ERK) generally results in stimulation of cell growth and confers a survival advantage playing the major role in human cancer. The potential involvement of this pathway in cellular radiosensitivity remains unclear. We previously reported that the disruption of c-Myc through MEK/ERK inhibition blocks the expression of the transformed phenotype; affects in vitro and in vivo growth and angiogenic signaling; and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). This study was designed to examine whether the ERK pathway affects intrinsic radiosensitivity of rhabdomyosarcoma cancer cells. Exponentially growing human ERMS, RD, xenograft-derived RD-M1, and TE671 cell lines were used. The specific MEK/ERK inhibitor, U0126, reduced the clonogenic potential of the three cell lines, and was affected by radiation. U0126 inhibited phospho-active ERK1/2 and reduced DNA protein kinase catalytic subunit (DNA-PKcs) suggesting that ERKs and DNA-PKcs cooperate in radioprotection of rhabdomyosarcoma cells. The TE671 cell line xenotransplanted in mice showed a reduction in tumor mass and increase in the time of tumor progression with U0126 treatment associated with reduced DNA-PKcs, an effect enhanced by radiotherapy. Thus, our results show that MEK/ERK inhibition enhances radiosensitivity of rhabdomyosarcoma cells suggesting a rational approach in combination with radiotherapy.
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Butadienos/farmacologia , Reparo do DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nitrilas/farmacologia , Radiossensibilizantes/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/radioterapia , Animais , Linhagem Celular Tumoral , Terapia Combinada , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To test the hypothesis that three-dimensional hypofractionated radiotherapy (3D-HFRT) is well tolerated and not worse than 3-D conventional RT (3D-CRT) for oncological outcome. PATIENTS AND METHODS: In all, 162 men with hystologically confirmed prostate adenocarcinoma were included in the analysis. In all, 82 men were treated with 3D-HFRT (15 fractions of 3.62 Gy delivered 3 times/week; a total dose of 54.3 Gy). This group was retrospectively compared with 80 men who met the same inclusion criteria and who were treated with 3D-CRT (39 fractions of 2 Gy delivered daily; a total dose of 78 Gy). A short course of hormone therapy was administered concomitantly with the RT. RESULTS: Only one (1.7%) patient in the 3D-CRT group and two (4.0%) in the 3D-HFRT group had Grade 3 genitourinary toxicity. There was late gastrointestinal morbidity of ≥ grade 3 in only 5.1% of men treated with 3D-HFRT and in 4.0% of men treated with 3D-CRT. In both groups there was no Grade 4 toxicity. At the median (range) follow-up of 45 (39.4-51) months for the 3D-HFRT group and 57.5 (54.9-59.1) months for 3D-CRT group the progression rate was 18/82 (21.9%) and 20/80 (25.0%), respectively, with no significant worsening in the risk of biochemical failure (BCF; log-rank test, P= 0.222). CONCLUSIONS: In the present study, men with clinically localized prostate cancer had similar levels of morbidity irrespective of whether they received HFRT or CRT without any worsening in the early risk of BCF. Thus, the present data provide some clinical evidence to justify trends already emerging toward HF regimens for treating clinically localised prostate cancer.
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Neoplasias da Próstata/radioterapia , Lesões por Radiação/etiologia , Sistema Urogenital/efeitos da radiação , Idoso , Fracionamento da Dose de Radiação , Métodos Epidemiológicos , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Radioterapia/efeitos adversosRESUMO
BACKGROUND: Epigenetic modifications play a key role in the in prostate cancer (Pca) progression to a hormone refractory state (HRPC) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. In this regard, 5-Azacitine (5-Aza) represents a promising epigenetic modulator. This study tested the hypothesis that 5-Aza may restore and enhance the responsiveness of HRPC cells to anti-hormonal therapy on Androgen receptor (AR) expressing (22rv1) and AR-deficient (PC3) cells. METHODS: The effects were studied in vitro and in vivo models. This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines. RESULTS: This combined treatment up-regulated the expression of FasL, phospho-FADD, p16(INKA), Bax, Bak, and p21(WAF1), and inhibited FLIP, Bcl-2, and Bcl-XL expression. The re-activation of hormonal response of AR-negative PC3 cell line was partially due to the AR re-expression mediated by 5-Aza treatment. In contrast, the increase in the response to anti-androgenic therapy in 22rv1 did not correlate with AR expression levels. Furthermore, xenograft studies revealed that the combined treatment of 5-Aza with AR-antagonist Bicalutamide had additive/synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis. CONCLUSIONS: So, this study strongly suggests a therapeutic potential of 5-Aza in combination with anti-androgen therapy in patients with in AR expressing and AR-deficient HRPC.
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Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azacitidina/farmacologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Nitrilas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/biossíntese , Compostos de Tosil/farmacologia , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Receptores de Andrógenos , Anilidas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Azacitidina/administração & dosagem , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Nitrilas/administração & dosagem , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Distribuição Aleatória , Compostos de Tosil/administração & dosagemRESUMO
We described the results of a hypofractionated regimen (HFRT) in a cohort of elderly patients (36 subjects) with stage I-II non-small-cell-lung cancer (NSCLC), tumor size> or =3 cm and ineligible for surgery. HFRT was delivered in 20 daily fractions of 3 Gy per fraction with a total dose of 60 Gy. The median PTV was 145 cm(3). The primary purpose of study was to estimate the local tumor control at 2 years as well as the modifications in the lung function parameters at 6 and 12 months. The local tumor control was 63.9% at 2 years. The incidence of distant recurrence rate at 2 years was 50%. The overall-survival (OS), the cause-specific-survival (CSS) and the disease-free-survival (DSF) at 2 years were 55.6, 57.1, and 38.9%, respectively. The median OS, CSS, and DFS was 25.4 (CI 95% 21.7-32.9), 26.7 (CI 95% 22.5-33.5) and 23.4 months (CI 95% 18.6-30.1), respectively. The two clinical parameters with a positive influence on OS were a KPS> or =90 (HR 1.16; p=0.013) and tumor size< or =4 cm (HR 0.763; p=0.011). No grade 3-4 acute toxicity was reported. No significant change in lung function parameters was measured at 6 and 12 months. For patients with larger or centrally located tumors as well as for subjects with lymph nodes involvement SBRT may be of limited valiance. Although the performances of our regimen were lower than the ones achieved by SBRT, our therapeutic option may offer a lower incidence of complications against a satisfactory local tumor control.
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Carcinoma Pulmonar de Células não Pequenas/radioterapia , Fracionamento da Dose de Radiação , Neoplasias Pulmonares/radioterapia , Recidiva Local de Neoplasia/radioterapia , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de NeoplasiasRESUMO
OBJECTIVES: The antitumor activity and toxicity of a multi-step treatment were evaluated in patients with locally advanced, inoperable, or incompletely resected pancreatic (Pa) and biliary tree (Bt) adenocarcinomas (ADKs). METHODS: Fifty-four patients, 63% with Pa and 37% with Bt ADK, received 3 courses of cisplatin-gemcitabine induction chemotherapy. Progression-free (PF) patients were given consolidation radiotherapy with concurrent capecitabine. PF patients had, as maintenance immunotherapy (MI), interleukin 2 (1.8x10 IU) and 13-cis-retinoic acid (0.5 mg/kg) [DOSAGE ERROR CORRECTED]. RESULTS: Thirty-eight patients, 27 with Pa and 11 with Bt ADKs, PF after cisplatin/gemcitabine, were treated with consolidation radiotherapy with concurrent capecitabine. Fourteen PF patients, 7 with Pa and 7 with Bt ADK, received MI. Median PF and overall survivals (OS) for all 54 patients were 6.8 and 12.1 months, respectively. Patients treated with MI had a median PF survival of 16.2 months, whereas median OS had not been reached yet, after a median follow-up of 27.5 months. TOXICITY: Grades 3 and 4 hematological and gastrointestinal in 30% and 37% of patients, respectively; grades 1 and 2 autoimmune reactions in 28% of patients. CONCLUSIONS: These results support the efficacy and safety of a multi-step sequential treatment in patients with locally advanced, inoperable or incompletely resected Pa and Bt ADKs.