RESUMEN
BACKGROUND: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available. METHODS: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively. RESULTS: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor (EGFR) resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). CONCLUSION: Baseline liquid biopsy-based CGP is feasible, it has high concordance with tumor tissue-based CGP, it could better recapitulate tumor heterogeneity, and it is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAFV600E WT mCRC patients.
RESUMEN
BACKGROUND: Oncologists tend to under-report subjective symptoms during cancer treatment. This study describes the under-reporting rate of selected symptoms and explores its association with overall survival (OS). A secondary aim is to test the association of patient-reported symptoms with OS. PATIENTS AND METHODS: This is a post hoc analysis on data pooled from 12 randomized trials, promoted by the National Cancer Institute of Naples (Italy), enrolling patients between 2002 and 2019, with published primary analyses. Occurrence and grade of six side-effects (anorexia, nausea, vomiting, constipation, diarrhea and fatigue) reported by physicians were compared with corresponding symptoms reported by patients in quality-of-life (QoL) questionnaires. Under-reporting was defined as the rate of cases reported grade 0 by the physician while grade ≥1 by the patient. Prognostic value was tested in a multivariable model stratified by trial, including age, sex and performance status as confounders. A landmark threshold was defined for OS analyses. RESULTS: 3792 patients with advanced lung, ovarian, pancreatic, breast or colorectal cancer were pooled; 2603 (68.6%) were eligible having at least one toxicity assessment and one QoL questionnaire, before the first planned disease restaging. Concordance between physicians' and patients' reporting was low with Cohen's k coefficients ranging from 0.03 (fatigue) to 0.33 (vomiting). Under-reporting ranged from 52.7% (nausea) to 80.5% (anorexia), and was not associated with OS. Patient-reported anorexia, vomiting and fatigue ('a little' or more) were significantly associated with shorter OS. CONCLUSIONS: Under-reporting of treatment side-effects is frequent, but it does not affect OS. Patients' reported symptoms should be used for prognostic evaluation.
Asunto(s)
Neoplasias , Calidad de Vida , Humanos , Anorexia/complicaciones , Fatiga/etiología , Náusea/etiología , Neoplasias/terapia , Neoplasias/complicaciones , Pronóstico , Vómitos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MutaciónRESUMEN
The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.
Asunto(s)
ADN Tumoral Circulante , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Cetuximab , Irinotecán , Proteínas Proto-Oncogénicas B-raf/genética , ADN Tumoral Circulante/genética , Estudios Prospectivos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Colon/etiología , Neoplasias del Recto/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Fluorodesoxiglucosa F18/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Piridinas/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Irinotecán/farmacología , Irinotecán/uso terapéutico , Estudios Retrospectivos , Fluorouracilo/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
OBJECTIVE: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. MATERIALS AND METHODS: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate. RESULTS: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations. CONCLUSION: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives.
Asunto(s)
Adenocarcinoma , Proteína BRCA1 , Proteína BRCA2 , Neoplasias Pancreáticas , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2/genética , Femenino , Mutación de Línea Germinal , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genéticaRESUMEN
The assessment of tumor response, after neoadjuvant radiochemotherapy (nCRT), allows stratifying the patient in order to consider the proper therapeutical management. Histopathology analysis of the surgical specimen is considered the gold standard to assess tumour response and the definition of a complete cancer response is related to the clinical and endoscopic features, by direct evaluation of the rectal wall. However, imaging studies, especially Magnetic Resonance Imaging (MRI) have provided additional parameters, as the evaluation of nodal or mesorectal status. MRI provides a radiological tumour regression grade (mrTRG) that is correlated with the pathologic tumor regression grade (pTRG). Functional MRI parameters have additional impending in early prediction of the efficacy of therapy and can be valuable in drug development processes. Some of functional methodologies are already part of clinical practice: diffusion-weighted MRI (DW-MRI) and perfusion imaging (dynamic contrast enhanced MRI [DCE-MRI]). Other technologies, such as radiomics with MRI are still in the experimental phase. An adequate radiological report describing the restaging of rectal cancer after nCRT should be a "structured report" to improve communication in a multidisciplinary team.
Asunto(s)
Quimioradioterapia Adyuvante , Recurrencia Local de Neoplasia/terapia , Neoplasias del Recto/terapia , Humanos , Imagen por Resonancia Magnética , Recurrencia Local de Neoplasia/diagnóstico por imagen , Radiólogos , Neoplasias del Recto/diagnóstico por imagenRESUMEN
There are a number of chemotherapy-effects that should be assessed with liver imaging since they have an influence on surgical morbidity. Chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH), and SOS might impair the hepatic parenchyma, thus reducing the functionality and inï¬uencing the outcome following resection. The main role of a radiologist is to provide an accurate diagnosis of the lesion. With constant advances in medicine, a radiologist's role should extend beyond just reporting the data of tumor, providing additional information that may greatly improve patient care. Radiologists should assess both chemotherapy effects on the hepatic metastasis itself, as well as chemo-induced focal and diffuse modifications of non-tumor hepatic parenchyma, since it is important to avoid impaired hepatic function after hepatic resection.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Colorrectales/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundario , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.
Asunto(s)
Neoplasias del Colon/patología , Detección Precoz del Cáncer/estadística & datos numéricos , Escisión del Ganglio Linfático/estadística & datos numéricos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Adulto , Anciano , Neoplasias del Colon/etiología , Neoplasias del Colon/cirugía , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Modelos Logísticos , Ganglios Linfáticos/cirugía , Masculino , Auditoría Médica , Uso Excesivo de los Servicios de Salud/estadística & datos numéricos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Potentiation of anticancer activity of capecitabine is required to improve its therapeutic index. In colorectal cancer (CRC) cells, we evaluated whether the histone deacetylase-inhibitor vorinostat may induce synergistic antitumour effects in combination with capecitabine by modulating the expression of thymidine phosphorylase (TP), a key enzyme in the conversion of capecitabine to 5-florouracil (5-FU), and thymidylate synthase (TS), the target of 5-FU. METHODS: Expression of TP and TS was measured by real-time PCR, western blotting and immunohistochemistry. Knockdown of TP was performed by specific small interfering RNA. Antitumour activity of vorinostat was assessed in vitro in combination with the capecitabine active metabolite deoxy-5-fluorouridine (5'-DFUR) according to the Chou and Talay method and by evaluating apoptosis as well as in xenografts-bearing nude mice in combination with capecitabine. RESULTS: Vorinostat induced both in vitro and in vivo upregulation of TP as well as downregulation of TS in cancer cells, but not in ex vivo treated peripheral blood lymphocytes. Combined treatment with vorinostat and 5'-DFUR resulted in a synergistic antiproliferative effect and increased apoptotic cell death in vitro. This latter effect was impaired in cells where TP was knocked. In vivo, vorinostat plus capecitabine potently inhibited tumour growth, increased apoptosis and prolonged survival compared with control or single-agent treatments. CONCLUSIONS: Overall, this study suggests that the combination of vorinostat and capecitabine is an innovative antitumour strategy and warrants further clinical evaluation for the treatment of CRC.
Asunto(s)
Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Timidina Fosforilasa/genética , Animales , Apoptosis/efectos de los fármacos , Capecitabina , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Floxuridina/farmacología , Fluorouracilo/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Timidilato Sintasa/genética , Regulación hacia Arriba , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oxaliplatin (OXA), raltitrexed (RTX), 5-fluorouracil (FU) and folinic acid (FA) have shown activity in metastatic colorectal cancer, radioenhancing effect and synergism when combined. We evaluated a chemotherapy (CT) combination of OXA, RTX and FU/FA during preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC) patients. Fifty-one patients with LARC at high risk of recurrence (T4, N+ or T3N0 < or =5 cm from anal verge and/or circumferential resection margin < or =5 mm) received three biweekly courses of CT during pelvic RT (45 Gy). Surgery was planned 8 weeks after CT-RT. Recommended doses (RDs) determined during phase I were utilised in the subsequent phase II trial, where the rate of tumour regression grade (TRG) 1 or 2 was the main end point. No toxic deaths occurred, and severe toxicity was easily managed. In phase II, RDs delivered in 31 patients were OXA 100 mg m(-2) and RTX 2.5 mg m(-2) on day 1, and FU 900 mg m(-2) and LFA 250 mg m(-2) on day 2. Main severe toxicities by patients were grade 4 neutropenia (23%) and grade 3 diarrhoea (19%). In 71% (95% confidence limits, 52-86%) of patients, TRG1 (13) or TRG2 (9) was obtained. All patients are alive and recurrence-free after a median follow-up of 29 months. Combination of OXA, RTX and FU/FA with pelvic RT has an acceptable toxicity and a high clinical activity in LARC and should be studied further in patients at high risk of recurrence.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/terapia , Terapia Neoadyuvante , Cuidados Preoperatorios , Adulto , Anciano , Procedimientos Quirúrgicos del Sistema Digestivo , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Tiofenos/administración & dosificación , Tiofenos/efectos adversosRESUMEN
Locally advanced rectal cancer carries out a dismail prognosis despite optimal surgery in terms of local and distant relapses. Neoadjuvant chemoradiation offers good results with tumor downstaging and downsizing and leads to more radical surgery with conservative intent. Selection of patients and an intensive chemotherapy may improve long term results. Our experience with a combined polichemotherapy and radiotherapy for low advanced rectal cancer is presented.
Asunto(s)
Neoplasias del Recto/terapia , Terapia Combinada , Progresión de la Enfermedad , Humanos , Neoplasias del Recto/patologíaRESUMEN
Composite pelvic resection with sacrectomy may provide good local control in case of locally advanced rectal cancer infiltrating the sacral bone. A combined multidisciplinary approach including chemotherapy and radiotherapy is here presented for a case of rectal tumor invading the sacrum.
Asunto(s)
Neoplasias Óseas/terapia , Neoplasias del Recto/terapia , Sacro , Adulto , Neoplasias Óseas/patología , Terapia Combinada , Humanos , Masculino , Invasividad Neoplásica , Neoplasias del Recto/patologíaRESUMEN
BACKGROUND: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 215) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. PATIENTS AND METHODS: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MSI+ tumour tissues, respectively. RESULTS: The MSI+ phenotype was detected in 75 (24%) patients, with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial [18/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria; (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. CONCLUSIONS: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis.
Asunto(s)
Carcinoma/genética , Neoplasias Colorrectales/genética , Daño del ADN , Reparación del ADN/genética , Repeticiones de Microsatélite/genética , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica , Análisis Mutacional de ADN , Femenino , Mutación de Línea Germinal , Humanos , Italia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND AND PURPOSE: Preoperative chemoradiation allows downstaging of locally advanced rectal cancer and in selected patients also a sufficient downsizing to ensure sphincter preservation. Selection of patients warranting a preoperative approach is improved by magnetic resonance imaging (MRI) which is able to define the involvement of mesorectal circumferential margin. Similarly it would be crucial to define the response to chemoradiation during the treatment but traditional morphologic imaging techniques may fail in differentiating neoplastic tissue from scarring. PET-FDG has been successfully used in the detection of metastatic colorectal cancer allowing imaging of deposits as small as 0.5 cm and may have a role in evaluating early response to chemoradiation. METHODS: In the present study, in patients with T3-T4 rectal cancer undergoing preoperative chemoradiation PET-FDG and flow cytometry analysis on endoscopic biopsy specimen have been performed before, during and after preoperative chemoradiation. RESULTS: Chemoradiation treatment has been successful in terms of downsizing and downstaging of the tumor. PET-FDG was able to demonstrate local response at only ten-fifteen days after the beginning of neoadjuvant therapy, also identifying non responding patients. CONCLUSIONS: FDG-PET may have a role in defining the response to chemoradiation and modulate the treatments strategy in patients with advanced rectal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Fluorodesoxiglucosa F18 , Terapia Neoadyuvante , Radiofármacos , Radioterapia Adyuvante , Neoplasias del Recto/diagnóstico por imagen , Tomografía Computarizada de Emisión , Biopsia , Fraccionamiento de la Dosis de Radiación , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Recurrencia Local de Neoplasia , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Cuidados Preoperatorios , Quinazolinas/administración & dosificación , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Inducción de Remisión , Tiofenos/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Oxaliplatin (OXA) and irinotecan (IRI) are active drugs in first-line as well as second-line treatment of advanced colorectal cancer patients, their toxicity profiles are not overlapping, and both drugs have shown synergism with folinic acid-modulated 5-fluorouracil (5-FU). We planned this phase I study to define the dose-limiting toxicities (DLTs), the maximum tolerated doses (MTDs), and the recommended doses (RDs) for a triplet regimen including OXA plus IRI on day 1, and 6S-folinic acid (LFA) plus 5-FU on day 2, every 2 weeks. PATIENTS AND METHODS: At least three patients had to be treated at each dose level, and the trial proceeded if no more than 33% of patients showed a DLT after the first cycle. Starting from OXA 85 mg/m(2) (over 2 h) and IRI 150 mg/m(2) (over 1 h), an alternated escalation was planned up to 110 mg/m(2) and 200 mg/m(2), respectively. Thereafter, a fixed dose of LFA, 250 mg/m(2) (as 2-h infusion), plus an escalating dose of 5-FU (from 650 to 800 mg/m(2) as an intravenous bolus) was added on day 2 to the previous dose level of OXA and IRI. RESULTS: Forty-six patients, all but four affected by advanced colorectal primaries, entered this study. The MTDs for OXA and IRI given on the same day were 110 and 200 mg/m(2): these doses caused a DLT in three of six patients. The previous dose level (110 and 175 mg/m(2), respectively) on day 1 was safely followed on day 2 by LFA plus 5-FU up to 800 mg/m(2). Indeed, only one of three patients treated at this last level had a DLT. This cohort was then expanded including a total of 14 patients, and on the whole series five cases of DLT occurred: WHO grade 4 neutropenia (two patients), grade 3 or 4 diarrhoea (three patients). Cumulative toxicity was analysed in 43 patients for a total of 347 cycles: grade 4 neutropenia was detected in 13 patients (30%); it was not dose-related, nor was it exacerbated by the addition of modulated 5-FU. Febrile neutropenia occurred in four patients. Grade 3 or 4 diarrhoea was suffered by nine (21%) and five (12%) patients, respectively. Two complete and nine partial responses were reported on 40 evaluable patients (six patients were disease-free at study entry), giving a response rate of 27.5% (95% confidence interval 15% to 44%); nine of 18 (50%) assessable patients of the two last cohorts treated with the triplet regimen achieved a complete response (two patients) or a partial response (seven patients). CONCLUSIONS: The RDs for this biweekly regimen were: OXA 110 mg/m(2) plus IRI 175 mg/m(2) on day 1, and LFA 250 mg/m(2) plus 5-FU 800 mg/m(2) on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Dosis Máxima Tolerada , Adolescente , Adulto , Anciano , Biopsia con Aguja , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias Colorrectales/mortalidad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/mortalidad , Neoplasias Gastrointestinales/patología , Humanos , Infusiones Intravenosas , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Pronóstico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Association between microsatellite instability (MSI) and favorable postoperative survival in patients with colorectal cancer receiving adjuvant chemotherapy has been indicated. To evaluate whether an analogous positive prognostic role of MSI could be present in rectal carcinoma (RC; most RC patients receive adjuvant radiotherapy), PCR-based microsatellite analysis of archival RCs and statistical correlation with clinico-pathological parameters were performed. PATIENTS AND METHODS: DNA from paraffin-embedded paired samples of tumors and corresponding normal tissue from 91 RC patients was analyzed for MSI using five microsatellite markers (tumors were classified as MSI(+) when two or more markers were unstable). RESULTS: Seventeen (19%) RC patients exhibited a MSI(+) phenotype. Prevalence of instability was found in patients with earlier RC onset (28% in cases with diagnosis age < or =55 years versus 15% in cases >55 years), whereas similar MSI frequencies were observed in patients with different disease stage or receiving different adjuvant therapies. While MSI was detected in seven (64%) of 11 familial patients, a remarkably lower MSI incidence was observed in sporadic cases (10/80; 12.5%). A significant association with better disease-free survival (DFS) and overall survival (OS) was found for MSI(+) patients (median DFS/OS, 30/32 months) in comparison to MSI(-) ones (median DFS/OS, 18/21 months) (P <0.001). CONCLUSIONS: MSI was demonstrated to be a strong molecular prognostic marker in rectal carcinoma, independent of the administered treatment (radiotherapy, chemotherapy or both).
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , ADN de Neoplasias/análisis , Repeticiones de Microsatélite/genética , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Biopsia con Aguja , Distribución de Chi-Cuadrado , Técnicas de Cultivo , Femenino , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa/métodos , Valor Predictivo de las Pruebas , Prevalencia , Probabilidad , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/cirugía , Sensibilidad y EspecificidadRESUMEN
The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg x m(-2) (2 h i.v. infusion) and raltitrexed 3.0 mg x m(-2) (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg x m(-2) (2 h i.v. infusion) and 5-fluorouracil 1050 mg x m(-2) i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43-79) years; ECOG performance status was 0 in 26 patients, > or =1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1-12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13-38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10-30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was > or =1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Irinotecán , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Terapia Recuperativa , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Resultado del TratamientoRESUMEN
Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.