RESUMEN
Biliary tract cancers (BTC) are rare and often diagnosed in late stages with advanced, nonresectable disease. The targeted agents panitumumab and bevacizumab have shown promising outcomes in combination with chemotherapy in other gastrointestinal (GI) cancers. We wanted to investigate if panitumumab or bevacizumab was the most promising drug to add to chemotherapy. Eighty-eight patients were randomized to combination chemotherapy supplemented by either panitumumab 6 mg/kg or bevacizumab 10 mg/kg on Day 1 in Arm A and Arm B, respectively. All patients received gemcitabine 1000 mg/m2 on Day 1, oxaliplatin 60 mg/m2 on Day 1 and capecitabine 1000 mg/m2 twice daily from Days 1 to 7. Treatment was repeated every 2 weeks until progression or for a maximum of 6 months. At progression, crossover was made to the other treatment arm. The primary endpoint was progression-free survival (PFS) at 6 months. With 19 of 45 in Arm A and 23 of 43 in Arm B PFS at 6 months, the primary endpoint was not met. The overall response rate (ORR) was 45% vs 20% (P = .03), median PFS was 6.1 months vs 8.2 months (P = .13) and median overall survival (OS) was 9.5 months vs 12.3 months (P = .47) in Arm A and Arm B, respectively. Our study showed no consistent differences between adding panitumumab or bevacizumab to chemotherapy in nonresectable BTC and none of the two regimens qualify for testing in Phase III. However, we found a higher response rate in the panitumumab arm with potential implication for future trials in the neoadjuvant setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Exones , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Panitumumab/administración & dosificación , Pronóstico , Tasa de SupervivenciaRESUMEN
AIM: The aim was to study anorectal function in long-term survivors after combined, curatively intended, chemoradiotherapy and endorectal brachytherapy for low rectal cancer. METHODS: This was a case-control design. We compared anorectal function by anal manometry, anal functional lumen imaging probe (EndoFLIP) and rectal bag distension in rectal cancer patients (RCPs) and healthy, normal subjects (NSs). Symptoms were assessed by the low anterior resection syndrome (LARS) and Wexner faecal incontinence scores. RESULTS: Thirteen RCPs (12 men, median age 68 years, range 52-92) after 60 Gy radiotherapy, 5 Gy endorectal brachytherapy and oral tegafur-uracil with complete clinical response (median time since treatment 2.8 years, range 2.2-5.6) were compared to 15 NSs (14 men, median age 64 years, range 47-75). RCPs had lower than normal anal resting pressure, 38.6 mmHg (range 8.8-67.7) versus 58.8 mmHg (25.7-105.2) (P < 0.003), and squeeze pressure, 117 mmHg (55.2-203) versus 188 mmHg (103-248) (P < 0.01). Squeeze-induced pressure increase recorded by EndoFLIP was also lower in RCPs (q > 7.56, P < 0.001) as was the anal canal resistance to increasing distension (q = 3.13, P < 0.05). No differences in median rectal volume at first sensation (72 [22-158] vs. 82 [36-190] ml, P = 0.4) or at urge to defaecate (107 [42-227] vs. 132 [59-334] ml, P = 0.2) were found. However, maximum tolerable rectal volume was lower in RCPs (145 [59-319] vs. 222 [106-447] ml, P < 0.02). The median (range) low anterior resection syndrome score was 27 (0-39) for RCPs and 7 (0-23) for NSs (P < 0.001), while the Wexner score was 0 (0-5) versus 0 (0-4) (P = 0.56). CONCLUSION: Radiotherapy combined with endorectal brachytherapy for rectal cancer causes long-term anorectal symptoms, impaired anal sphincter function and reduced rectal capacity.
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Braquiterapia , Incontinencia Fecal , Neoplasias del Recto , Anciano , Anciano de 80 o más Años , Canal Anal , Braquiterapia/efectos adversos , Quimioradioterapia/efectos adversos , Incontinencia Fecal/etiología , Humanos , Masculino , Manometría , Persona de Mediana Edad , Complicaciones Posoperatorias , Neoplasias del Recto/tratamiento farmacológico , Recto , SíndromeRESUMEN
Background: Molecular markers may identify subgroups of patients with clinically distinct behavior and response to treatment. In some gastrointestinal tumors, KRAS has prognostic value and negative predictive value. This is the first prospective study to report the outcome of combination chemotherapy in biliary tract cancer patients with KRAS mutation.Methods: From 2009 to 2015, 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, ECOG performance status 0-2 and tumor KRAS mutation. A bi-weekly cycle of chemotherapy was administered as gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1, followed by 7 days of oral capecitabine 1000 mg/m2. Response evaluation was done every six treatment and the primary endpoint was the fraction with progression free survival (PFS) at 6 months. The study also included a non-preplanned analysis of circulating tumor specific DNA.Results: Chemotherapy was given for a median of 5 months (range 0-14) and among 17 patients evaluable for response, best responses were complete response (1), partial response (2), and stable disease (14). Eighteen patients had CT-verified progression, six died between evaluations and one patient is still progression-free. Median PFS was 6.8 months (95% CI 3.1-11.0) and median overall survival (OS) was 11.2 months (95% CI 6.6-14.3). The fraction with PFS at 6 months was 52% (95% CI 31-69%). Exploratory analyses found an improved survival in patients with a low level of plasma DNA.Conclusion: Pretreatment molecular characterization was feasible in BTC, but the rate of KRAS mutations was low. The study met its primary endpoint with a fraction of PFS at six months of 52%. The effect of combination chemotherapy with gemcitabine, oxaliplatin and capecitabine in this selected population was comparable to results from unselected groups with PFS and OS of 6.8 and 11.2 months, respectively. ClinicalTrials.gov NCT00779454.
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Neoplasias del Sistema Biliar/tratamiento farmacológico , Capecitabina/farmacología , Desoxicitidina/análogos & derivados , Oxaliplatino/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/metabolismo , Capecitabina/uso terapéutico , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Mutación , Oxaliplatino/uso terapéutico , GemcitabinaRESUMEN
PURPOSE/OBJECTIVE: Chemo-radiotherapy is an established primary curative treatment for anal cancer, but clinically equal rationale for different target doses exists. If joint preferences (physician and patient) are used to determine acceptable tradeoffs in radiotherapy treatment planning, multiple dose plans must be simultaneously explored. We quantified the degree to which different toxicity priorities might be incorporated into treatment plan selection, to elucidate the feasible decision space for shared decision making in anal cancer radiotherapy. MATERIAL AND METHODS: Retrospective plans were generated for 22 anal cancer patients. Multi-criteria optimization handles dynamically changing priorities between clinical objectives while meeting fixed clinical constraints. Four unique dose distributions were designed to represent a wide span of clinically relevant objectives: high-dose preference (60.2 Gy tumor boost and 50.4 Gy to elective nodes with physician-defined order of priorities), low-dose preference (53.75 Gy tumor boost, 45 Gy to elective nodes, physician-defined priorities), bowel sparing preference (lower dose levels and priority for bowel avoidance) and bladder sparing preference (lower dose levels and priority for bladder avoidance). RESULTS: Plans satisfied constraints for target coverage. A senior oncologist approved a random subset of plans for quality assurance. Compared to a high-dose preference, bowel sparing was clinically meaningful at the lower prescribed dose [median change in V45Gy: 234 cm3; inter-quartile range (66; 247); p < .01] and for a bowel sparing preference [median change in V45Gy: 281 cm3; (73; 488); p < .01]. Compared to a high-dose preference, bladder sparing was clinically meaningful at the lower prescribed dose [median change in V35Gy: 13.7%-points; (0.3; 30.6); p < .01] and for a bladder sparing preference [median change in V35Gy: 30.3%-points; (12.4; 43.1); p < .01]. CONCLUSIONS: There is decision space available in anal cancer radiotherapy to incorporate preferences, although tradeoffs are highly patient-dependent. This study demonstrates that preference-informed dose planning is feasible for clinical studies utilizing shared decision making.
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Neoplasias del Ano/radioterapia , Toma de Decisiones , Estudios de Factibilidad , Humanos , Prioridad del Paciente , Dosificación RadioterapéuticaRESUMEN
BACKGROUND: Abdominoperineal resection is the standard treatment for patients with distal T2 or T3 rectal cancers; however, the procedure is extensive and mutilating, and alternative treatment strategies are being investigated. We did a prospective observational trial to assess whether high-dose radiotherapy with concomitant chemotherapy followed by observation (watchful waiting) was successful for non-surgical management of low rectal cancer. METHODS: Patients with primary, resectable, T2 or T3, N0-N1 adenocarcinoma in the lower 6 cm of the rectum were given chemoradiotherapy (60 Gy in 30 fractions to tumour, 50 Gy in 30 fractions to elective lymph node volumes, 5 Gy endorectal brachytherapy boost, and oral tegafur-uracil 300 mg/m(2)) every weekday for 6 weeks. Endoscopies and biopsies of the tumour were done at baseline, throughout the course of treatment (weeks 2, 4, and 6), and 6 weeks after the end of treatment. We allocated patients with complete clinical tumour regression, negative tumour site biopsies, and no nodal or distant metastases on CT and MRI 6 weeks after treatment to the observation group (watchful waiting). We referred all other patients to standard surgery. Patients under observation were followed up closely with endoscopies and selected-site biopsies, with surgical resection given for local recurrence. The primary endpoint was local tumour recurrence 1 year after allocation to the observation group. This study is registered with ClinicalTrials.gov, number NCT00952926. Enrolment is closed, but follow-up continues for secondary endpoints. FINDINGS: Between Oct 20, 2009, and Dec 23, 2013, we enrolled 55 patients. Patients were recruited from three surgical units throughout Denmark and treated in one tertiary cancer centre (Vejle Hospital, Vejle, Denmark). Of 51 patients who were eligible, 40 had clinical complete response and were allocated to observation. Median follow-up for local recurrence in the observation group was 23·9 months (IQR 15·3-31·0). Local recurrence in the observation group at 1 year was 15·5% (95% CI 3·3-26·3). The most common acute grade 3 adverse event during treatment was diarrhoea, which affected four (8%) of 51 patients. Sphincter function in the observation group was excellent, with 18 (72%) of 25 patients at 1 year and 11 (69%) of 16 patients at 2 years reporting no faecal incontinence at all and a median Jorge-Wexner score of 0 (IQR 0-0) at all timepoints. The most common late toxicity was bleeding from the rectal mucosa; grade 3 bleeding was reported in two (7%) in 30 patients at 1 year and one (6%) of 17 patients at 2 years. There were no unexpected serious adverse reactions or treatment-related deaths. INTERPRETATION: High-dose chemoradiotherapy and watchful waiting might be a safe alternative to abdominoperineal resection for patients with distal rectal cancer. FUNDING: CIRRO-The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research.
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Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/administración & dosificación , Braquiterapia/métodos , Quimioradioterapia/métodos , Neoplasias del Recto/terapia , Tegafur/administración & dosificación , Espera Vigilante , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Biopsia , Braquiterapia/efectos adversos , Braquiterapia/mortalidad , Quimioradioterapia/efectos adversos , Quimioradioterapia/mortalidad , Dinamarca , Procedimientos Quirúrgicos del Sistema Digestivo , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Selección de Paciente , Estudios Prospectivos , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Tegafur/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Neoadjuvant chemotherapy has proven valuable in several tumors, but it has not been elucidated in colon cancer. The present phase II trial addressed the issue in high-risk patients selected by computed tomography (CT) scan. MATERIAL AND METHODS: Patients with resectable colon cancer fulfilling the following criteria were offered inclusion; Histopathological verification of adenocarcinoma, T3 tumor on CT scan with extramural tumor invasion > 5 mm or T4 tumor, age ≥ 18 years, PS ≤ 2, adequate hematology, and informed consent. Patients with KRAS, BRAF or PIK3CA mutation or unknown mutational status received three cycles of capecitabine 2000 mg/m(2) days 1-14 q3w and oxaliplatin 130 mg iv day 1 q3w. Wild-type patients received the same chemotherapy supplemented with panitumumab 9 mg/kg iv q3w. After the operation, patients fulfilling the international criteria for adjuvant chemotherapy, i.e. high-risk stage II and III patients, received five cycles of the same chemotherapy without panitumumab. Patients not fulfilling the criteria were offered follow-up only. The primary endpoint was the fraction of patients not fulfilling the criteria for adjuvant chemotherapy (converted patients). Secondary endpoints were recurrence rate, disease-free survival (DFS), and toxicity. RESULTS: The study included 77 patients. The conversion rate was 42% in the wild-type group compared to 51% in patients with a mutation. The cumulative recurrence rate in converted versus unconverted patients was 6% versus 32% (p = 0.005) translating into a three-year DFS of 94% versus 63% (p = 0.005). CONCLUSION: Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy. Validation in a randomized trial is warranted.
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Adenocarcinoma/patología , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Recurrencia Local de Neoplasia/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/genética , Anciano , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina/administración & dosificación , Quimioterapia Adyuvante , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Mutación , Terapia Neoadyuvante , Invasividad Neoplásica , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Panitumumab , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Radiografía , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Preoperative staging is essential to plan correct treatment of colon cancer and calls for objective, accurate methods for the introduction of neoadjuvant chemotherapy, which represents a new treatment option. PURPOSE: To evaluate the diagnostic accuracy of multislice computed tomography (CT) in local staging of colon cancer correlated with histopathological parameters, including criteria for adjuvant chemotherapy. MATERIAL AND METHODS: A total of 74 included patients had preoperative CT scans and surgical resection of their colon tumors. Tumor stage (T-stage), extramural tumor invasion (ETI), nodal stage (N-stage), extramural venous invasion (EVI) and the distance from tumor to nearest retroperitoneal fascia (DRF) were retrospectively assessed on the CT scan and compared blindly with the results of the pathological examination, including evaluation of the criteria for adjuvant chemotherapy. Advanced tumors were defined as T3 with ETI ≥5 mm or T4. RESULTS: Sixty-nine percent of the tumors were correctly T-staged by CT, 7% were overstaged and 24% were understaged. As to correct recognition of ETI on the CT scan, the observer was 73% accurate compared with histology (70% sensitivity (95% CI: 53-82%), 78% specificity (95% CI: 60-90%), 81% positive predictive value (PPV) (95% CI: 63-91%) and 66% negative predictive value (NPV) (95% CI: 49-80%). N-stage, EVI and DRF had poor accuracy: 53%, 53% and 64%. All patients with advanced tumors on CT fulfilled the criteria for adjuvant chemotherapy. Positive predictive value: 100% (95% CI: 88-100%). CONCLUSION: CT has a potential in the preoperative selection of advanced tumors suitable for neoadjuvant chemotherapy without overtreatment of low-risk patients.
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Carcinoma/diagnóstico por imagen , Carcinoma/terapia , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/terapia , Tomografía Computarizada Multidetector , Terapia Neoadyuvante , Estadificación de Neoplasias , Selección de Paciente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Quimioterapia Adyuvante , Neoplasias del Colon/patología , Fascia/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Espacio Retroperitoneal , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer and KRAS mutations have no effective treatment option. The present study evaluated the efficacy of temsirolimus in chemotherapy refractory mCRC with KRAS mutations. Furthermore, we wanted to investigate if resistance to temsirolimus could be reversed by the addition of irinotecan. Finally, we analyzed pre-treatment blood samples for KRAS mutations to investigate the association between quantitative measures of KRAS mutated alleles and clinical outcome. MATERIAL AND METHODS: Patients received weekly temsirolimus 25 mg until progression. Thereafter patients were treated with combination therapy comprising biweekly irinotecan 180 mg/m(2) and weekly temsirolimus. A polymerase chain reaction method was used to quantify the KRAS mutated alleles in plasma (pKRAS). RESULTS: Sixty-four patients were included. Treatment was well tolerated. Thirty-eight percent achieved stable disease on monotherapy and 63% on combination therapy. Four and eight patients had a minimal response, respectively. Median overall survival was 160 days. Median time to progression was 45 and 84 days, respectively. The concordance between KRAS status in tumor and plasma was 82%. All patients with tumor reduction had low levels of pKRAS. Patients with high pKRAS had a 77% risk of early progression on monotherapy compared to 43% in patients with lower levels. Multivariate survival analysis confirmed that pKRAS was a strong prognostic factor. CONCLUSION: Temsirolimus has limited efficacy in chemotherapy resistant KRAS mutant disease, but plasma KRAS quantification is a strong predictor of outcome.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Mutación , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras) , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Resultado del TratamientoRESUMEN
BACKGROUND: Cutaneous metastases can cause distressing symptoms and be challenging to treat. Local therapies are essential in management. Calcium electroporation uses calcium and electrical pulses to selectively kill cancer cells. This multicentre study aimed to define response in cutaneous metastases across different cancer types. METHODS: Patients with tumours ≤3 cm of any histology were included (stable or progressing on current therapy ≥2 months), at three centres. Tumours were treated with 220 mM calcium chloride injection and manual application of eight 0.1 ms pulses with 1 kV/cm and 1Hz with a handheld electrode, in local or general anaesthesia. Clinical response was evaluated after 1, 2, 3, 4, 5, 6, and 12 months. Primary endpoint was response at two months. The overall response rate (ORR) was partial- and complete responses of treated tumours. MR-imaging and qualitative interviews were performed in respective subsets. RESULTS: Nineteen patients with disseminated cancer (breast n = 4, lung n = 5, pancreatic n = 1, colorectal n = 2, gastric n = 1, and endometrial cancer n = 1) were enrolled, and 58 metastases were treated (50 once, 8 retreated). The ORR was 36% (95% CI 22-53) after two months. Best ORR was 51% (CR 42%; PR 9%). Previous irradiation improved outcomes (p = 0.0004). Adverse events were minimal. Median pain score was reduced after two months (p = 0.017). Treatment may relieve symptoms according to qualitative interviews. MRI showed restriction in treated tissue. CONCLUSION: The majority of tumours were treated only once with calcium electroporation, achieving an ORR of 36% after two months and best ORR of 51%. Efficacy, symptom-relief and safety support calcium electroporation as a palliative treatment option for cutaneous metastases.
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Calcio , Neoplasias Cutáneas , Humanos , Calcio/uso terapéutico , Neoplasias Cutáneas/patología , Electroporación , Terapia de ElectroporaciónRESUMEN
AIMS: High-dose chemoradiation is now considered the standard treatment of locally advanced rectal cancer. To provide feedback on the effect of this treatment, several regression grading systems have been proposed. For a grading system to be useful it has to be reproducible. The aim of this study was to test the reproducibility of a five-point grading system, proposed originally by Mandard, and to describe the sources of disagreement. METHODS AND RESULTS: Tumour regression was assessed independently by two observers on 100 consecutive chemoradiated rectal cancer specimens. The grading system was extremely reproducible, with weighted and unweighted kappa values of 0.89 and 0.82, respectively. The most frequent source of disagreement was assessment of the relative amount of fibrosis. Displacement of epithelium was a minor source of disagreement. CONCLUSIONS: The five-point grading system of Mandard is extremely reproducible.
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Quimioradioterapia , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Fibrosis , Humanos , Clasificación del Tumor/métodos , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
INTRODUCTION: Skin malignancy is a distressing problem for many patients, and clinical management is challenging. This article describes the protocol for the Calcium Electroporation Response Study (CaEP-R) designed to investigate tumour response to calcium electroporation and is a descriptive guide to calcium electroporation treatment of malignant tumours in the skin. Calcium electroporation is a local treatment that induces supraphysiological intracellular calcium levels by intratumoural calcium administration and application of electrical pulses. The pulses create transient membrane pores allowing diffusion of non-permeant calcium ions into target cells. High calcium levels can kill cancer cells, while normal cells can restore homeostasis. Prior trials with smaller cohorts have found calcium electroporation to be safe and efficient. This trial aims to include a larger multiregional cohort of patients with different cancer diagnoses and also to investigate treatment areas using MRI as well as assess impact on quality of life. METHODS AND ANALYSIS: This non-randomised phase II multicentre study will investigate response to calcium electroporation in 30 patients with cutaneous or subcutaneous malignancy. Enrolment of 10 patients is planned at three centres: Zealand University Hospital, University Hospital of Southern Denmark and University Hospital Schleswig-Holstein. Response after 2 months was chosen as the primary endpoint based on short-term response rates observed in a prior clinical study. Secondary endpoints include response to treatment using MRI and change in quality of life assessed by questionnaires and qualitative interviews. ETHICS AND DISSEMINATION: The trial is approved by the Danish Medicines Agency and The Danish Regional Committee on Health Research Ethics. All included patients will receive active treatment (calcium electroporation). Patients can continue systemic treatment during the study, and side effects are expected to be limited. Data will be published in a peer-reviewed journal and made available to the public. TRIAL REGISTRATION NUMBERS: NCT04225767 and EudraCT no: 2019-004314-34.
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Calcio , Neoplasias Cutáneas , Calcio de la Dieta , Ensayos Clínicos Fase II como Asunto , Electroporación , Humanos , Estudios Multicéntricos como Asunto , Calidad de Vida , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
PURPOSE: Surgery is standard treatment for rectal cancer, but neoadjuvant chemoradiation therapy (CRT) may result in clinical complete response (cCR) in select patients, allowing for nonsurgical management (NSM). Prospective studies of NSM strategies are sparse, however, and long-term data on quality of life (QoL) are limited. We conducted a single-arm phase 2 trial of high-dose CRT for NSM of distal rectal cancer; we report secondary long-term patient-reported outcomes (PROs), local regrowth, and overall survival in patients managed nonsurgically. METHODS AND MATERIALS: Fifty-one patients with resectable, T2 or T3, N0-N1, low adenocarcinoma received 65 Gy (intensity modulated radiation therapy, brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, magnetic resonance imaging, biopsy) were referred for observation and followed closely with clinical examination, endoscopy, positron emission tomography/computed tomography, and PROs for 5 years. Overall colorectal cancer-specific QoL and specific symptom scores were evaluated at baseline and in follow-up and compared between time points. Local regrowth was estimated using cumulative incidence and overall survival using Kaplan-Meier estimates. RESULTS: Forty patients achieved cCR after treatment; 29 were in follow-up at 24 months, 21 at 36 months, and 20 at 60 months. PRO questionnaire completion rates were 90% at 24 months, 100% at 36 months, and 85% at 60 months for patients still in follow-up. Average QoL score did not differ between baseline (median 11.1) and 24 months (13.7), 48 months (11.1), or 60 months (6.9). Only rectal bleeding deteriorated from baseline, with bowel- and bladder-related symptom scores otherwise unchanged in follow-up. At median follow-up of 5.0 years, local regrowth rate and overall survival were 31% (95% confidence interval, 15%-47%) and 85% (95% confidence interval, 75%-97%), respectively. CONCLUSIONS: Long-term follow-up after NSM of distal rectal cancer showed excellent general colorectal cancer QoL and local symptom scores. Our study results indicate that high-dose CRT followed by organ preservation might be an alternative to standard treatment.
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Adenocarcinoma/terapia , Quimioradioterapia Adyuvante/métodos , Tratamientos Conservadores del Órgano/métodos , Medición de Resultados Informados por el Paciente , Calidad de Vida , Neoplasias del Recto/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/secundario , Anciano , Braquiterapia/métodos , Intervalos de Confianza , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Dosificación Radioterapéutica , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patologíaRESUMEN
INTRODUCTION: Using multidetector computed tomography, we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer. METHODS: Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment. All patients had histologically confirmed colon cancer, a T4 or T3 tumour with extramural invasion ≥ 5 mm and no distant metastases or peritoneal nodules. The patients were treated with oxaliplatin and capecitabine. In addition, those with no mutations in the KRAS, BRAF and PIK3CA genes were also treated with panitumumab. Before and after treatment, we measured the tumour diameter in two different planes, the extension of the extramural tumour invasion, and the number and size of enlarged lymph nodes. RESULTS: The mean tumour length was 7.8 cm (95% confidence interval (CI): 5.3-10.4) at baseline and 4.34 cm (95% CI: 4.0-4.9) after treatment. The mean extramural tumour invasion was 10.6 mm (95% CI: 9.5-11.8) at baseline and 5.7 mm (95% CI: 4.7-6.7) after treatment. The mean number of enlarged lymph nodes was 4.1 (95% CI: 3.4-4.9) at baseline and 2.1 (95% CI: 1.4-2.7) after treatment. According to RECIST 1.1, 45% (95% CI: 34-57) of the patients had a response and 55% (95% CI: 43-67) had stable disease. None of the patients showed progressive disease. CONCLUSION: Using CT, we demonstrated a significant reduction in tumour size, extramural tumour invasion, number and size of enlarged lymph nodes following neoadjuvant treatment. FUNDING: not relevant. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT 01108107).
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Antineoplásicos/administración & dosificación , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/terapia , Tomografía Computarizada Multidetector , Terapia Neoadyuvante , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Capecitabina/administración & dosificación , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/estadística & datos numéricos , Neoplasias del Colon/patología , Progresión de la Enfermedad , Femenino , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Invasividad Neoplásica , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Panitumumab , Resultado del Tratamiento , Carga TumoralRESUMEN
OBJECTIVE: The current literature has described the usefulness of elastography and diffusion-weighted MRI in patients with cancer, but to the best of our knowledge so far none of them has compared the two new methods. The tumour cell density is related to the MRI-measured apparent diffusion-weighted coefficient (ADC). The purpose of the present study was to compare quantitative elastography based on ultrasound shear wave measurements with MRI ADC. METHODS: We prospectively examined 52 patients with histopathologically proven rectal cancer. The mean age was 67 years (range 42-90 years). Males: 39, females: 13. Tumour elasticity was measured transgluteally using the acoustic radiation force impulse (ARFI) to generate information on the mechanical properties of the tissue. The objective quantitative elastography shear wave velocity was blindly compared with the ADC measurements using a 1.5-T MRI system. RESULTS: The mean tumour elasticity was 3.05 m s(-1) [standard deviation (SD): 0.79], and the mean ADC was 0.69 × 10(-3) mm(2) s(-1) (SD: 0.27). Elasticity was inversely strongly correlated with ADC, r = -0.65 (Salkin scale). ARFI = 4.392 - 1.949 × ADC, R(2) = 0.43, p < 0.0001. Intercept = 4.392 (95% CI: 3.92 to 4.86), slope = -1.949 (95% CI: -1.31 to -2.59), p < 0.0001. CONCLUSION: Elasticity correlates with the estimated diffusion restriction by MRI ADC measurements in rectal tumours. The relationship between ARFI and ADC measurement was linear in our study population. ADVANCES IN KNOWLEDGE: This work describes a correlation between tissue elasticity and diffusion in rectal cancer.
Asunto(s)
Imagen de Difusión por Resonancia Magnética , Diagnóstico por Imagen de Elasticidad , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recto/diagnóstico por imagen , Recto/patología , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
AIM: We investigated the efficacy and safety of capecitabine and gemcitabin (GemCap) in heavily pre-treated, therapy-resistant metastatic colorectal cancer (mCRC) patients and the clinical importance of cell-free DNA (cfDNA) measurement. PATIENTS AND METHODS: Patients' inclusion criteria included histopathologically-verified mCRC refractory to standard chemotherapy, adequate organ function and performance status. Treatment included capecitabine (2,000 mg/m(2) day on days 1-7 q2w) and gemcitabine (1,000 mg/m(2) on day 1). The number of DNA alleles was measured in pre-treatment plasma samples using an in-house developed qPCR. RESULTS: Forty-nine patients were included in the study. GemCap was well-tolerated in the majority of patients. Disease control rate was 30%, median progression-free survival (PFS) and overall survival (OS) by intention-to-treat were 2.7 (95%CI=2.6-2.8) and 6.8 (95%CI=5.0-7.7) months. Median OS in patients with cfDNA concentrations above the median (13,200 alleles/ml) was 4.7 (3.7-9.6) months compared to 7.8 months in the remaining patients (HR=2.22; 1.07-3.9; p=0.0186). The prognostic value of the cell-free DNA (cfDNA) was confirmed by multivariate analysis. CONCLUSION: GemCap was well-tolerated with encouraging efficacy, and cfDNA was shown to hold a strong prognostic value.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Investigación Biomédica Traslacional , GemcitabinaRESUMEN
PURPOSE/OBJECTIVE(S): Mature data on tumor control and survival are presented from a randomized trial of the addition of a brachytherapy boost to long-course neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer. METHODS AND MATERIALS: Between March 2005 and November 2008, 248 patients with T3-4N0-2M0 rectal cancer were prospectively randomized to either long-course preoperative CRT (50.4 Gy in 28 fractions, per oral tegafur-uracil and L-leucovorin) alone or the same CRT schedule plus a brachytherapy boost (10 Gy in 2 fractions). The primary trial endpoint was pathologic complete response (pCR) at the time of surgery; secondary endpoints included overall survival (OS), progression-free survival (PFS), and freedom from locoregional failure. RESULTS: Results for the primary endpoint have previously been reported. This analysis presents survival data for the 224 patients in the Danish part of the trial. In all, 221 patients (111 control arm, 110 brachytherapy boost arm) had data available for analysis, with a median follow-up time of 5.4 years. Despite a significant increase in tumor response at the time of surgery, no differences in 5-year OS (70.6% vs 63.6%, hazard ratio [HR] = 1.24, P=.34) and PFS (63.9% vs 52.0%, HR=1.22, P=.32) were observed. Freedom from locoregional failure at 5 years were 93.9% and 85.7% (HR=2.60, P=.06) in the standard and in the brachytherapy arms, respectively. There was no difference in the prevalence of stoma. Explorative analysis based on stratification for tumor regression grade and resection margin status indicated the presence of response migration. CONCLUSIONS: Despite increased pathologic tumor regression at the time of surgery, we observed no benefit on late outcome. Improved tumor regression does not necessarily lead to a relevant clinical benefit when the neoadjuvant treatment is followed by high-quality surgery.
Asunto(s)
Braquiterapia , Quimioradioterapia Adyuvante/métodos , Neoplasias del Recto/terapia , Adulto , Anciano , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dinamarca , Supervivencia sin Enfermedad , Femenino , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Radioterapia Conformacional , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Tegafur/administración & dosificación , Uracilo/administración & dosificaciónRESUMEN
PURPOSE: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. METHODS AND MATERIALS: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D50,i, and the normalized dose-response gradient, γ50,i. RESULTS: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D50,TRG1=92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), γ50,TRG1=0.982 (CI 0.533-1.429), and for major response (TRG1-2) D50,TRG1&2=72.1 Gy (CI 65.3-94.0 Gy), γ50,TRG1&2=0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. CONCLUSIONS: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.
Asunto(s)
Adenocarcinoma/terapia , Quimioradioterapia/métodos , Neoplasias del Recto/terapia , Espera Vigilante , Adenocarcinoma/patología , Adulto , Anciano , Braquiterapia/métodos , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estadificación de Neoplasias , Selección de Paciente , Cuidados Preoperatorios/métodos , Dosificación Radioterapéutica , Neoplasias del Recto/patología , Inducción de Remisión/métodos , Tegafur/administración & dosificación , Carga Tumoral , Uracilo/administración & dosificaciónRESUMEN
The aim of this study was to describe the dynamics of HIF-1α, GLUT-1, Bcl-2 and Ki-67 during chemoradiotherapy (CRT) of rectal cancer, and to investigate the fluctuation of these biomarkers in relation to pathological response to CRT. The study included 86 patients with rectal adenocarcinoma receiving preoperative CRT (>50.4 Gy and Uracil/Tegafur). Immunohistological expressions of HIF-1α, GLUT-1, Bcl-2 and Ki-67 were investigated in biopsies taken before treatment, after 2, 4 and 6 weeks of CRT and in specimens from the operation. Decreasing expressions of HIF-1α, Bcl-2 and Ki-67 were observed during CRT, whereas GLUT-1 overall was unchanged. No significant changes of the markers were observed in the interval between CRT and surgery. A significant association was observed between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT, but no association was seen between the fluctuations of any of the markers and response to CRT. This unique material containing specimens before, after and during CRT for rectal cancer demonstrated biological dynamics in HIF-1α, Bcl-2 and Ki-67, but not GLUT-1, expression during CRT, and a significant association was seen between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT.
Asunto(s)
Transportador de Glucosa de Tipo 1/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Antígeno Ki-67/genética , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Proteína X Asociada a bcl-2/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Quimioradioterapia , Femenino , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Manejo de Especímenes , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to investigate the feasibility of F-fluoroazomycinarabinofuranoside (F-FAZA) positron emission tomography (PET)/computed tomography (CT) in patients with locally advanced rectal cancer. MATERIALS AND METHODS: The study included 14 patients with locally advanced rectal cancer. Before chemoradiotherapy, PET/CT with F-FAZA was performed with static 15 min images 2 h after injection of F-FAZA. Attenuation correction was obtained with a low-dose CT, and a contrast-enhanced CT was performed immediately after the PET scan. RESULTS: F-FAZA uptake [mean and maximum standardized uptake value (SUVmean) and (SUVmax)] was significantly higher in rectal tumours than in both muscles (P<0.003) and normal intestinal walls (P<5×10). The tumour to muscle (T/M) ratios ranged from 1.19 to 3.05 with a mean of 1.97, whereas the tumour to intestinal wall (T/I) ratios had values of 1.73-5.81 with a mean of 2.83. Intense activity accumulating in the bladder produced obvious scattered activity, which spread into the surrounding tissue. Tumour volumes excluding scatter were therefore determined, in which the SUVmax and SUVmean were also significantly higher than in both muscles (P<0.004) and normal intestinal walls (P<2×10) and had T/M ratios of 1.19-2.72 with a mean of 1.85 and T/I ratios of 1.71-5.40 with a mean of 2.67. The individual SUVmax, SUVmean, T/M and T/I values were significantly higher in the entire tumour volume compared with the tumour volume adjusted for scatter from the urinary bladder (P<0.005), although the absolute differences were small. CONCLUSION: F-FAZA PET/CT is feasible for visualization of hypoxia in patients with rectal cancer, but scattered activity from the urinary bladder should be taken into consideration.
Asunto(s)
Imagen Multimodal , Nitroimidazoles , Tomografía de Emisión de Positrones , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Tomografía Computarizada por Rayos X , Anciano , Transporte Biológico , Hipoxia de la Célula , Estudios de Factibilidad , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nitroimidazoles/metabolismo , Neoplasias del Recto/metabolismo , Carga Tumoral , Vejiga Urinaria/diagnóstico por imagen , Vejiga Urinaria/metabolismoRESUMEN
The aim of this study was to investigate the predictive impact of polymorphisms in the HIF-1α gene on the response to chemoradiotherapy (CRT) in rectal cancer. This study included two cohorts of patients with locally advanced rectal cancer receiving long-course CRT. The HIF-1α C1772T (rs11549465), G1790A (rs11549467) and c(*)191T>C (rs2057482) polymorphisms were investigated in the test cohort (n=65), and HIF-1α c(*)191T>C was analysed in the validation cohort (n=198). No correlations were identified between the polymorphisms and clinicopathological factors. The HIF-1α C1772T and HIF-1α G1790A polymorphisms demonstrated no correlation with tumour response to CRT in the test cohort. The HIF-1α c(*)191T>C CC genotype was marginally associated with a higher rate of complete tumour response (P=0.05) in the test cohort, while the HIF-1α c(*)191T>C CC genotype was associated with a poor tumour response (P=0.03) in the validation cohort. In conclusion, these results suggest that HIF-1α polymorphisms have no value as predictors of response to neoadjuvant CRT in rectal cancer. The results of the HIF-1α c(*)191T>C in two cohorts differ and emphasise the importance of biomarker validation.