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BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.
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Capecitabina , Cardiotoxicidade , Neoplasias Colorretais , Combinação de Medicamentos , Fluoruracila , Ácido Oxônico , Tegafur , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Tegafur/efeitos adversos , Tegafur/administração & dosagem , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Cardiotoxicidade/etiologia , Capecitabina/efeitos adversos , Capecitabina/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Adulto , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The treatment landscape of solid tumors has changed markedly in the last years. Molecularly targeted treatments and immunotherapies have been implemented and have, in many cancers, lowered the risk of relapse and prolonged survival. Patients with tumors harboring specific targetable molecular alterations or mutations are often of a younger age, and hence future fertility and family building can be important concerns in this group. However, there are great uncertainties regarding the effect of the new drugs on reproductive functions, including fertility, pregnancy and lactation and how young patients with cancers, both women and men should be advised. The goal with this review is to gather the current knowledge regarding oncofertility and the different novel therapies, including immune checkpoint inhibitors, antibody-drug conjugates, small molecules and monoclonal antibody targeted therapies. The specific circumstances and reproductive concerns in different patient groups where novel treatments have been broadly introduced are also discussed, including those with melanoma, lung, breast, colorectal and gynecological cancers. It is clear, that more awareness is needed regarding potential drug toxicity on reproductive tissues, and it is of essence that individuals are informed based on current expertise and on available fertility preservation methods.
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Antineoplásicos , Preservação da Fertilidade , Melanoma , Masculino , Gravidez , Humanos , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Fertilidade , Antineoplásicos/efeitos adversos , Melanoma/tratamento farmacológicoRESUMO
Standard treatment for patient with peritoneal metastases from colorectal cancer is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In recent years, the efficacy of oxaliplatin-based HIPEC has been challenged. An intensified HIPEC (oxaliplatin+irinotecan) in combination with early postoperative intraperitoneal chemotherapy (EPIC) has shown increased recurrence-free survival in retrospective studies. The aim of this trial is to develop a new HIPEC/EPIC regimen and evaluate its effect on morbidity, oncological outcome, and quality-of-life (QoL). This study is designed as a combined phase I/III multicenter randomized trial (RCT) of patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. An initial phase I dose escalation study, designed as a 3+3 stepwise escalation, will determine the maximum tolerable dose of 5-Fluorouracil (5-FU) as 1-day EPIC, enrolling a total of 15-30 patients in 5 dose levels. In the phase III efficacy study, patients are randomly assigned intraoperatively to either the standard treatment with oxaliplatin HIPEC (control arm) or oxaliplatin/irinotecan-HIPEC in combination with single dose of 1-day 5-FU EPIC (experimental arm). 5-FU is administered intraoperatively after CRS-HIPEC and closure of the abdomen. The primary endpoint is 12-month recurrence-free survival. Secondary endpoints include 5-year overall survival, 5-year recurrence-free survival (registry based), postoperative complications, and QoL up to 3 years after study treatment. This phase I/III trial aims to identify a more effective treatment of colorectal peritoneal metastases by combination of HIPEC and EPIC.
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Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Ensaios Clínicos Fase I como Assunto , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Quimioterapia Intraperitoneal Hipertérmica , Irinotecano , Estudos Multicêntricos como Assunto , Oxaliplatina/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Estudos Retrospectivos , Ensaios Clínicos Fase III como AssuntoRESUMO
Background and purpose: Neoadjuvant short-course radiotherapy (SCRT) followed by full-dose systemic chemotherapy is an established treatment modality in locally advanced rectal cancer (LARC). Until recently, SCRT has been exclusively delivered with photons. Proton beam therapy (PBT) may minimize acute toxicity, which in turn likely impacts favorably on the tolerability to subsequent chemotherapy. The aim of this study is a dosimetric comparison between SCRT with photons and protons in the randomized phase II trial PRORECT (NCT04525989). Materials and methods: From June 2021 to June 2022, twenty consecutive patients with LARC have been treated according to study protocol. For each patient, both a VMAT and a PBT treatment plans have been generated and compared pairwise. Results: Dose-volume histogram (DVH) analysis revealed that SCRT with protons significantly reduced radiation dose to pelvic organs at risk including bladder, bones, and bowel in comparison to SCRT with photons. Photon and proton treatment plans had equivalent conformity and homogeneity indexes. Conclusion: Preoperative SCRT with protons offers a significant reduction of radiation dose to normal tissues compared with current photon-based radiotherapy technique. Demonstrated dosimetric advantages may translate into measurable clinical benefits in patients with LARC. Clinical implications of the dosimetric superiority of SCRT with protons will be presented in the coming reports from the PRORECT trial.
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Complete pathological response (pCR) is achieved in 10−20% of rectal cancers when treated with short-course radiotherapy (scRT) or long-course chemoradiotherapy (CRT) and in 28% with total neoadjuvant therapy (scRT/CRT + CTX). pCR is associated with better outcomes and a "watch-and-wait" strategy (W&W). The aim of this study was to identify baseline clinical or imaging factors predicting pCR. All patients with preoperative treatment and delays to surgery in Uppsala-Dalarna (n = 359) and Stockholm (n = 635) were included. Comparison of pCR versus non-pCR was performed with binary logistic regression models. Receiver operating characteristics (ROC) models for predicting pCR were built using factors with p < 0.10 in multivariate analyses. A pCR was achieved in 12% of the 994 patients (scRT 8% [33/435], CRT 13% [48/358], scRT/CRT + CTX 21% [43/201]). In univariate and multivariate analyses, choice of CRT (OR 2.62; 95%CI 1.34−5.14, scRT reference) or scRT/CRT + CTX (4.70; 2.23−9.93), cT1−2 (3.37; 1.30−8.78; cT4 reference), tumour length ≤ 3.5 cm (2.27; 1.24−4.18), and CEA ≤ 5 µg/L (1.73; 1.04−2.90) demonstrated significant associations with achievement of pCR. Age < 70 years, time from radiotherapy to surgery > 11 weeks, leucocytes ≤ 109/L, and thrombocytes ≤ 4009/L were significant only in univariate analyses. The associations were not fundamentally different between treatments. A model including T-stage, tumour length, CEA, and leucocytes (with scores of 0, 0.5, or 1 for each factor, maximum 4 points) showed an area under the curve (AUC) of 0.66 (95%CI 0.60−0.71) for all patients, and 0.65−0.73 for the three treatments separately. The choice of neoadjuvant treatment in combination with low CEA, short tumour length, low cT-stage, and normal leucocytes provide support in predicting pCR and, thus, could offer guidance for selecting patients for organ preservation.
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BACKGROUND: Effective patient-physician communication can improve patient understanding, agreement on treatment and adherence. This may, in turn, impact on clinical outcomes and patient quality of life (QoL). One way to improve communication is by using patient-reported outcome measures (PROMs). Heretofore, studies of the impact of using PROMs in clinical practice have mostly evaluated the use of standardized PROMs. However, there is reason to believe that individualized instruments may be more appropriate for this purpose. The aim of this study is to compare the effectiveness of the standardized QoL-instrument, the European Organization for Research and Treatment of Cancer Quality of Life C-30 (EORTC-QOL-C30) and the individualized QoL instrument, the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW), in clinical practice. METHODS: In a prospective, open-label, controlled intervention study at two hospital out-patient clinics, 390 patients with gastrointestinal cancer were randomly assigned either to complete the EORTC-QOL-C30 or the SEIQoL-DW immediately before the consultation, with their responses being shared with their physician. This was repeated in 3-5 consultations over a period of 4-6 months. The primary outcome measure was patients' health-related QoL, as measured by FACIT-G. Patients' satisfaction with the consultation and survival were secondary outcomes. RESULTS: There was no significant difference between the groups with regard to study outcomes. Neither intervention instrument resulted in any significant changes in health-related QoL, or in any of the secondary outcomes, over time. This may reflect either a genuine lack of effect or sub-optimization of the intervention. Since there was no comparison to standard care an effect in terms of lack of deterioration over time cannot be excluded. CONCLUSIONS: Future studies should focus on the implementation process, including the training of physicians to use the instruments and their motivation for doing so. The effects of situational use of standardized or individualized instruments should also be explored. The effectiveness of the different approaches may depend on contextual factors including physician and patient preferences.
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BACKGROUND: The Stockholm III trial randomly assigned 840 patients to short-course radiotherapy of 5 × 5 Gy with surgery within 1 week (SRT), short-course radiotherapy of 5 × 5 Gy with surgery after 4-8 weeks (SRT-delay), or long-course radiotherapy of 25 × 2 Gy with surgery after 4-8 weeks (LRT-delay). This study details the long-term oncological outcomes and health-related quality of life (HRQoL). METHODS: Patients with biopsy-proven resectable adenocarcinoma of the rectum were included. Primary outcome was time to local recurrence (LR), and secondary endpoints were distant metastases (DMs), overall survival (OS), recurrence-free survival (RFS), and HRQoL. Patients were analysed in a three-arm randomization and a short-course radiotherapy comparison. RESULTS: From 1998 to 2013, 357, 355, and 128 patients were randomized to the SRT, SRT-delay, and LRT-delay groups respectively. Median follow-up time was 5.7 (range 5.3-7.6) years. Comparing patients in the three-arm randomization, the incidence of LR was three of 129 patients, four of 128, and seven of 128, and DM 31 of 129 patients, 38 of 128, and 38 of 128 in the SRT, SRT-delay, and LRT-delay groups respectively. In the short-course radiotherapy comparison, the incidence of LR was 11 of 357 patients and 13 of 355, and DM 88 of 357 patients and 82 of 355 in the SRT and SRT-delay groups respectively. No comparisons showed statistically significant differences. Median OS was 8.1 (range 6.9-11.2), 10.3 (range 8.2-12.8), and 10.5 (range 7.0-11.3) years after SRT, SRT-delay, and LRT-delay respectively. Median OS was 8.1 (range 7.2-10.0) years after SRT and 10.2 (range 8.5-11.7) years after SRT-delay. There were no statistically significant differences in HRQoL. CONCLUSION: After a follow-up of 5 years, delaying surgery for 4-8 weeks after radiotherapy treatment with 5 × 5 Gy was oncologically safe. Long-term HRQoL was similar among the treatment arms. TRIAL REGISTRATION NUMBER: NTC00904813.
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Adenocarcinoma , Neoplasias Retais , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Qualidade de Vida , Neoplasias Retais/radioterapia , Neoplasias Retais/cirurgia , Reto/patologiaRESUMO
BACKGROUND: Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families. METHODS: Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population. RESULTS: A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations. CONCLUSION: Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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OBJECTIVE: The aim of this study was to assess the acute effect of preoperative RT for rectal cancer on endocrine testicular function. BACKGROUND: Preoperative radiotherapy (RT) enhances local control and cancer-specific survival in patients treated for rectal cancer. In case series, a negative acute effect on Leydig cell function has been reported. METHODS: This prospective cohort study included 168 males with rectal or prostate cancer stage I-III. Males treated with preoperative RT and surgery for rectal cancer formed the exposed group (n = 93). Males treated with surgery alone were assigned to the unexposed group (n = 75). The androgen levels were assessed at baseline and after preoperative RT. The exposure was quantified with the treatment planning system to estimate the cumulative testicular dose (TD). The risk of low T (serum T < below 8ânmol/L) was the primary endpoint. Secondary endpoints were serum testosterone (T), bioavailable T, luteinizing hormone (LH), and the LH-T ratio. RESULTS: The baseline levels of androgens were not related to exposure status or type of cancer. The proportion of low T increased from 14.6% at baseline to 35.4% after RT, relative risk 2.41 (95% CI 1.57 to 3.71, P < 0.001). Preoperative RT resulted in a significant decrease of serum and bioavailable T and a significant increase of LH and LH-T ratio. The decline in serum and bioavailable T was related to the TD. CONCLUSIONS: Preoperative RT for rectal cancer results in dose-dependent primary testicular failure increasing the risk of hypogonadism at the time of surgery by 2.4 times (number needed to harm = 5).
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Adenocarcinoma/radioterapia , Terapia Neoadjuvante/efeitos adversos , Protectomia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/etiologia , Neoplasias Retais/radioterapia , Doenças Testiculares/etiologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/cirurgia , Lesões por Radiação/diagnóstico , Radioterapia Adjuvante , Neoplasias Retais/cirurgia , Fatores de Risco , Doenças Testiculares/diagnóstico , Resultado do TratamentoRESUMO
Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Método Duplo-Cego , Éxons/genética , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Irinotecano , Masculino , Pessoa de Meia-Idade , Receptor IGF Tipo 1/genéticaRESUMO
BACKGROUND: AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naïve patients with inoperable pancreatic carcinoma. PATIENTS AND METHODS: AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of four × four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated. RESULTS: Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 µM. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up. CONCLUSION: Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Genisteína/administração & dosagem , Genisteína/farmacocinética , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Hepáticas/secundário , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. MATERIAL AND METHODS: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. RESULTS AND CONCLUSION: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.
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Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Podofilotoxina/análogos & derivados , Receptor IGF Tipo 1/metabolismo , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neutropenia/induzido quimicamente , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Podofilotoxina/sangue , Podofilotoxina/uso terapêutico , Estudos Prospectivos , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Radiotherapy (RT) for rectal cancer can have adverse effects on testicular function resulting in azoospermia and low testosterone levels. Variability of testicular dose (TD) due to differences in position of testes has been assessed with scrotal dosimeters and resulted in substantial variability of delivered TD. The aim of this study was to estimate planned and delivered TD using a treatment planning system (TPS). METHODS: In 101 men treated with RT for rectal cancer the cumulative mean TD (mTD) was calculated by TPS based on plan-computed tomography (CT) to evaluate the effect of different predictors on planned TD. The delivered TD was estimated by TPS based on repeated cone-beam CTs in 32 of 101 men to assess within-person variability of planned and delivered TD in a longitudinal analysis. RESULTS: The median planned mTD for short course RT was 0.57 Gy (range 0.06-14.37 Gy) and 0.81 Gy (range 0.36-10.80 Gy) for long course RT. The median planned mTD was similar to the median delivered mTD in the 32 men analysed over the entire course of RT (p=0.84). The mTD did not change significantly over time of planning and delivering RT. The variation in proximity between testes and planning target volume (PTV) was related to within-person variability of mTD in men on the 50th and 75th percentile of mTD and as expected the absolute difference between planned and delivered mTD increased with higher mTD. CONCLUSION: Testicular doses calculated based on plan-CT are an accurate estimation of delivered TD based on repeated cone beam (CB)CT. The within-person variability of TD is related to variation in proximity between testes and PTV in men with moderate to high TD.
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Tomografia Computadorizada de Feixe Cônico/métodos , Dosagem Radioterapêutica , Neoplasias Retais/radioterapia , Neoplasias Retais/cirurgia , Testículo/efeitos da radiação , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Período Pré-Operatório , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
BACKGROUND: Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer. METHODS: Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided. RESULTS: The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01). CONCLUSIONS: Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Receptor IGF Tipo 1/metabolismo , Proteínas ras/genética , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Astenia/induzido quimicamente , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Estudos de Viabilidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hiperglicemia/induzido quimicamente , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras) , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Chemotherapy and targeted drugs are important tools in the treatment of malignant diseases. A number of the planned treatments are cancelled late which is a great challenge for the clinic to minimize in order to prevent the risk for misused resources. The aim of this study was to analyze the frequency and reasons for late (<48 hours) cancellations and also to get an overview of all intravenous medical anti-cancer treatment at the clinic. MATERIAL AND METHODS: During four weeks in October 2010 all patients with intravenously administered chemotherapy and/or targeted drugs were registered at the Department of Oncology, Karolinska University Hospital. The survey comprehends the vast majority of all such treatment for solid tumors in adult patients in the Stockholm region with two million inhabitants. All bookings and late cancellations including their reasons were recorded. Diagnoses, treatment indication, line of treatment and survival, in particular short term survival, were analyzed. RESULTS: Almost 3000 bookings for 1460 patients were included and 13% were cancelled late. Patient detoriation was the dominating cause for late cancellation in patients with palliative treatment (59%), while hematological toxicity was most common in the adjuvant group (42%). The most common treatment indication was palliative (62%). Of the palliative treatments, 95% where given in the first to third treatment line. Breast cancer (31.9%) and colorectal cancer (29.9%) were the two most common diagnoses. Seventy-one patients (4.9%) died within two months after the treatment. CONCLUSION: A more careful selection and monitoring of the patients might reduce the number of late cancellations due to patient detoriation. To record performance status (PS) as a routine for all patients might be helpful in that process. If the number of late cancellations could be reduced, resources at the clinic could be used more efficiently.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Hospitais Universitários , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Inquéritos e Questionários , Suécia , Adulto JovemRESUMO
Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a target for active cancer immunotherapy. A study was conducted to investigate safety and immunogenicity in non-resectable pancreatic carcinoma patients using a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D (n=4) was treated with gemcitabine alone. Adverse events (AE) related to vaccination were mild (grades I-II). Grade III AEs were few and transient. An induced GV 1001specific immune response was defined as an increase ≥2 above the baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine secretion assays, respectively). A telomerasespecific immune response was noted in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C. An induced rasspecific immune response (antigenic spreading) was seen in 5 of the 17 patients. The cytokine pattern was that of a Th1-like profile. A treatment induced telomerase or ras response was also noted in group D. All responses were weak and transient. A significant decrease in regulatory T-cells over time was noted in patients in groups A and B (p<0.05). Telomerase vaccination (GV1001) in combination with chemotherapy appeared to be safe but the immune responses were weak and transient. Measures have to be taken to optimize immune responses of GV1001 for it to be considered of clinical interest.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Desoxicitidina/análogos & derivados , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Neoplasias Pancreáticas/terapia , Fragmentos de Peptídeos/administração & dosagem , Telomerase/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Terapia Combinada/efeitos adversos , Citocinas/análise , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/efeitos adversos , Telomerase/efeitos adversos , GencitabinaRESUMO
PURPOSE: Previous clinical studies have indicated that natural IgM antibodies have the ability to induce apoptosis of tumor cells but IgE and IgA may also mediate tumor cell killing (in addition to IgG). The aim of the study was to analyse induction of IgM, IgA and IgE antibodies in patients vaccinated with the tumor associated antigen CEA. METHODS: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with CEA ± GM-CSF. Four different dose schedules were used over a 12-month period. IgM, IgA and IgE antibody responses against recombinant CEA were determined by ELISA. Patients were monitored immunologically for 36 months and clinically for 147 months. RESULTS: GM-CSF significantly augmented the anti-CEA response for all three antibody classes. Low dose of CEA tended to induce a higher IgM, IgA or IgE anti-CEA antibody response than higher. Anti-CEA IgA antibodies could lyse CEA positive tumor cells in antibody dependent cellular cytotoxicity (ADCC) as well as in complement dependent cytotoxicity (CDC). A significant correlation between survival and high IgA anti-CEA titers was noted (p = 0.02) irrespective of GM-CSF treatment. CONCLUSIONS: The observation that IgA anti-CEA antibodies were cytotoxic and associated with improved survival might indicate that also these antibodies may exert a clinical anti-tumor effect.
Assuntos
Vacinas Anticâncer/imunologia , Antígeno Carcinoembrionário/imunologia , Neoplasias Colorretais/imunologia , Imunoglobulina A/biossíntese , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Celular Dependente de Anticorpos , Apoptose , Neoplasias Colorretais/terapia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Vacinação , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: Inhibition of the Insulin-like Growth Factor-1 receptor (IGF-1R) has resulted in extensive anti-tumor effects. Picropdophyllin (PPP, AXL1717) is a small-molecule inhibitor of the IGF-1R without inhibition of closely related receptors including the insulin receptor and has shown extensive effects against a wide range of tumors in animals. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. PATIENTS AND METHODS: The first part (Phase IA) consisted of single day BID dosing every three weeks with consecutive dose escalations. The second part (Phase IB) consists of seven days or longer BID dosing every three weeks, dosing range being 520-700 mg BID. Non-progressing patients could continue treatment within a compassionate use setting. RESULTS AND DISCUSSION: The present report describes our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with PPP. Despite more than seven months of PPP treatment as third or fourth line treatment, the reported patients did not develop any additional metastases. Furthermore, CT scans as well as (18)FDG-Positron Emission Tomography (PET) scans of the patients demonstrated large central necrotic areas, which may suggest tumor response. At the same time, the study drug is so far well tolerated. The phenomenon of necrosis in the tumors suggestive of tumor response has not been reported before in anti-IGF-1R treatment and will be subject to further studies in the present clinical trial.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
The feasibility, safety, and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma (UGIA) are unknown. Seventy-three patients with gastric (GC; n = 22), pancreatic (PC; n = 28) or biliary cancer (BC; n = 23) were randomised to start with 45 mg/m(2) docetaxel or 180 mg/m(2) irinotecan combined with 5-FU/leucovorin every 2nd week. After every 2nd course, the patients were crossed over to the other combination. Treatment was given for a maximum of 12 courses. Quality-of-life (QoL) was evaluated during the first two months using the EORTC QLQ-C30. Eighteen patients (25%; GC 32%, PC 21%, BC 22%) demonstrated partial response (PR) and 21 (29%) had prolonged stable disease. Mean QoL scores were low at baseline. Twenty-three (32%) patients had improved QoL using a summary measure and 13 were stable. Median time to progression was 4.4 months and overall survival 8.2 months. The treatments were reasonably well tolerated. Grade 3-4 toxicities were slightly more common for the docetaxel combination. There were two treatment-related deaths. Planned sequential treatment with docetaxel or irinotecan with 5-FU/leucovorin is feasible, reasonably tolerable and appears active in advanced UGIA.