RESUMO
BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Adenocarcinoma/tratamento farmacológico , Neoplasias PancreáticasRESUMO
BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Trastuzumab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Receptores ErbB/genética , Cloridrato de Erlotinib/efeitos adversos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Receptor ErbB-2/genética , Análise de Sobrevida , Trastuzumab/efeitos adversos , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/efeitos adversos , Oxaliplatina , Modelos de Riscos Proporcionais , Estudos Prospectivos , GencitabinaRESUMO
BACKGROUND: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. METHODS: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, ß = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. DISCUSSION: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. TRIAL REGISTRATION: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Estudos Multicêntricos como Assunto , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Piridinas/efeitos adversos , Adulto Jovem , Proteínas ras/genéticaRESUMO
BACKGROUND: Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. METHODS: Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. RESULTS: Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18). CONCLUSIONS: Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/administração & dosagem , GencitabinaRESUMO
BACKGROUND: In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. METHODS: This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. RESULTS: In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in <1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand-foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3-4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6-2.7). CONCLUSION: In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. IMPLICATIONS FOR PRACTICE: Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/farmacologia , Estudos Prospectivos , Piridinas/farmacologiaRESUMO
OBJECTIVE: The purpose was to validate the prognostic value of an early optimal morphological response on CT in patients treated with bevacizumab-containing chemotherapy for unresectable colorectal cancer liver metastases (CLM). It also evaluated the prognostic value of size-based criteria and the association of optimal morphological response with the receipt of bevacizumab. DESIGN: 141 patients treated first using bevacizumab and 142 patients from a randomised study evaluating the addition of bevacizumab to oxaliplatin-based chemotherapy were retrospectively analysed. Radiologists evaluated pretreatment and restaging CT scans using morphological response criteria. Responses were also assessed with size-based criteria: Response Evaluation Criteria in Solid Tumors (RECIST), early tumour shrinkage (ETS) and deepness of response (DpR). The ability of each criterion to predict progression-free survival (PFS), overall survival (OS) and postprogression survival (PPS) was determined using a univariate Cox proportional hazards model. RESULTS: In both populations, median PFS was significantly longer for patients achieving an optimal morphological response (10.4 vs 6.8 months, p=0.03; and 8.3 vs 4.9 months, p<00001, respectively). Neither RECIST nor ETS responses were associated with a prolonged PFS. Median OS was longer for those with an optimal morphological response but only at second restaging in the first population (n=141, 20.8 vs 12.3 months, p=0.002). DpR but not optimal morphological response was associated with PPS. In the randomised study, an optimal morphological response was 6.2 times more likely among patients receiving bevacizumab (p<0.0001). CONCLUSION: In patients with unresectable CLM, early morphological response may be a better predictor of PFS than size-based response. The addition of bevacizumab improves morphological response rate.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Progress in the liquid biopsy field, combined with the development of droplet digital PCR (ddPCR), has enabled noninvasive monitoring of mutations with high detection accuracy. However, current assays detect a restricted number of mutations per reaction. ddPCR is a recognized method for detecting alterations previously characterized in tumor tissues, but its use as a discovery tool when the mutation is unknown a priori remains limited. METHODS: We established 2 ddPCR assays detecting all genomic alterations within KRAS exon 2 and EGFR exon 19 mutation hotspots, which are of clinical importance in colorectal and lung cancer, with use of a unique pair of TaqMan® oligoprobes. The KRAS assay scanned for the 7 most common mutations in codons 12/13 but also all other mutations found in that region. The EGFR assay screened for all in-frame deletions of exon 19, which are frequent EGFR-activating events. RESULTS: The KRAS and EGFR assays were highly specific and both reached a limit of detection of <0.1% in mutant allele frequency. We further validated their performance on multiple plasma and formalin-fixed and paraffin-embedded tumor samples harboring a panel of different KRAS or EGFR mutations. CONCLUSIONS: This method presents the advantage of detecting a higher number of mutations with single-reaction ddPCRs while consuming a minimum of patient sample. This is particularly useful in the context of liquid biopsy because the amount of circulating tumor DNA is often low. This method should be useful as a discovery tool when the tumor tissue is unavailable or to monitor disease during therapy.
Assuntos
Receptores ErbB/genética , Genes ras , Mutação , Neoplasias/genética , Reação em Cadeia da Polimerase/métodos , Biópsia , DNA Tumoral Circulante/sangue , Humanos , Limite de Detecção , Biópsia Líquida , Sondas Moleculares , Neoplasias/sangue , Neoplasias/patologiaRESUMO
OBJECTIVES: Carbohydrate antigen 19-9 (CA19-9) is a sensitive and specific serum marker in pancreatic cancer. Our retrospective analysis aims to evaluate CA19-9 decrease in patients with metastatic pancreatic cancer treated in ACCORD11/PRODIGE4 (FOLFIRINOX vs. gemcitabine). METHODS: A total of 342 patients were treated. CA19-9 was measured at 8 weeks (±2) in 160 patients from a total of 282 with abnormal CA19-9 values at baseline (gemcitabine arm, n = 75; FOLFIRINOX arm, n = 85). In the present study, 8-week CA19-9 decrease or greater CA19-9 decrease according to the 20 and 90% thresholds were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated in each subgroup. RESULTS: In the FOLFIRINOX arm, patients with an 8-week CA19-9 decrease or greater CA19-9 decrease ≥20% showed improved median OS, PFS, and objective response rate. In the overall study population, median OS and PFS were significantly improved in patients with an 8-week CA19-9 decrease ≥20% (vs. <20%). The 8-week CA19-9 decrease was predictive of PFS (interaction test significant according to treatment arm; p = 0.006). CONCLUSION: An 8-week CA19-9 decrease ≥20% is a prognostic factor for OS and PFS. The 8-week CA19-9 decrease (20% threshold) is predictive of PFS. It could help to evaluate the efficacy of FOLFIRINOX and gemcitabine regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CA-19-9/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Compostos Organoplatínicos/administração & dosagem , Prognóstico , Estudos Retrospectivos , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND: Motion management is a major challenge in abdominal SBRT. We present our study of SBRT for liver tumors using intrafraction motion review (IMR) allowing simultaneous KV information and MV delivery to synchronize the beam during gated RapidArc treatment. MATERIALS AND METHODS: Between May 2012 and March 2015, 41 patients were treated by liver SBRT using gated RapidArc technique in a Varian Novalis Truebeam STx linear accelerator. PTV was created by expanding 5 mm from the ITV. Dose prescription ranged from 40 to 50 Gy in 5-10 fractions. The prescribed dose and fractionation were chosen depending on hepatic function and dosimetric results. Thirty-four patients with a minimal follow-up of six months were analyzed for local control and toxicity. Accuracy for tumor repositioning was evaluated for the first ten patients. RESULTS: With a median follow-up of 13 months, the treatment was well tolerated and no patient presented RILD, perforation or gastrointestinal bleeding. Acute toxicity was found in 3 patients with G1 abdominal pain, 2 with G1 nausea, 10 with G1 asthenia and 1 with G2 asthenia. 6 patients presented asymptomatic transitory perturbation of liver enzymes. In-field local control was 90.3% with 7 complete responses, 14 partial responses and 7 stabilisations. 3 patients evolved "in field". 12 patients had an intrahepatic progression "out of field". Mean intrafraction deviation of fiducials in the craneo-caudal direction was 0.91 mm (0-6 mm). CONCLUSION: The clinical tolerance and oncological outcomes were favorable when using image-guided liver SBRT with real-time adaptive tumor gating.
RESUMO
AIM: To evaluate the different techniques used for liver metastases Stereotactic Body Radiation Therapy (SBRT) planning. We especially focused on immobilization devices, motion management and imaging used for contouring. BACKGROUND: Although some guidelines exist, there is no consensus regarding the minimal requirements for liver SBRT treatments. MATERIALS AND METHODS: We reviewed the main liver metastases SBRT publications and guidelines; and compared the techniques used for immobilization, motion management, margins and imaging. RESULTS: There is a wide variety of techniques used for immobilization, motion management and planning imaging. CONCLUSIONS: We provide a subjective critical analysis of minimal requirements and ideal technique for liver SBRT planning.
RESUMO
Reproductive techniques such as prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD), although debated, are legally forbidden in France in case of Lynch syndrome. The preference of mutation carriers about their reproductive options is not systematically considered in France. We aimed to prospectively assess the reproductive preferences of mismatch repair mutation carriers consulting in our institution (2003-2010, n = 100). We also considered the short- and long-term post-disclosure psychological impact using the Impact of Events Scale-Revised questionnaire to measure the prevalence of posttraumatic stress disorder (PTSD) in those patients. Complete data were obtained for 34 respondents (17 males, 17 females, median age of 33.5 years [22-59]). Seventeen respondents (57 %) preferred spontaneous natural conception versus 28 % and 35 % choosing PND and PGD, respectively. At results disclosure, respondents mainly explained their distress by fear of premature death (43 %) and transmitting mutated genes (42 %). One year later, this last fear remained predominant in 55 % of subjects. None of the main socio-demographical, psychological or medical variables (including fear of transmitting mutations) was significantly associated with the reproductive preferences. Results disclosure had a real and time-decreasing psychological impact on mutation carriers. Reproductive techniques, expected to decrease the hereditary risk, were not significantly preferred to natural conception.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/psicologia , Tomada de Decisões , Mutação , Reprodução , Adulto , Reparo de Erro de Pareamento de DNA , Revelação , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Diagnóstico Pré-Implantação , Diagnóstico Pré-Natal/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. METHODS: We used BEAMing technology to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest-angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor-in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. FINDINGS: Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS (KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA (PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35-0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40-0·65 for KRAS mutant [KRAS wild type vs mutant, pinteraction=0·74]; HR 0·50, 95% CI 0·40-0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32-0·89 for PIK3CA mutant [PIK3CA wild-type vs mutant, pinteraction=0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40-0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40-0·70, for high circulating DNA concentrations; low vs high circulating DNA, pinteraction=0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. INTERPRETATION: BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. FUNDING: Bayer HealthCare Pharmaceuticals.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Receptor de TIE-1/sangue , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Classe I de Fosfatidilinositol 3-Quinases , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Fenótipo , Fosfatidilinositol 3-Quinases/sangue , Fosfatidilinositol 3-Quinases/genética , Medicina de Precisão , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Ensaios Clínicos Controlados Aleatórios como Assunto , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Proteínas ras/sangue , Proteínas ras/genéticaRESUMO
BACKGROUND: No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. METHODS: We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. FINDINGS: Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64-0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). INTERPRETATION: Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. FUNDING: Bayer HealthCare Pharmaceuticals.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Taxa de SobrevidaRESUMO
BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , Qualidade de Vida , Índice de Gravidade de Doença , Análise de Sobrevida , GencitabinaRESUMO
BACKGROUND: Docetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC. METHODS: Data were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks. RESULTS: Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %). CONCLUSION: TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Taxoides/administração & dosagemRESUMO
PURPOSE: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. METHODS: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. RESULTS: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. CONCLUSION: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov : NCT03828799.
RESUMO
BACKGROUND: Triplet chemotherapy plus cetuximab showed promising results in phase II trials in unsystematically selected RAS population. We evaluated FOLFIRINOX+cetuximab efficacy as first-line treatment in extended RAS wild-type metastatic colorectal cancer (mCRC) patients. METHODS: We retrospectively analyzed patients treated with FOLFIRINOX+cetuximab, using data from clinical trials and real-life practice. Extended mutation analysis was performed when RAS/BRAF status was unavailable. The primary endpoint was progression-free survival (PFS). RESULTS: Seventy patients (61.4 % male, median age 58.7 years) were analyzed. Eighty percent had left-sided mCRC and 97.1 % had liver metastases. Median PFS and overall survival (OS) were 13.3 and 48.5 months, respectively. The objective response rate was 85.7 %, with 20 % complete response. Primary tumor location did not affect OS and PFS. BRAF wild-type patients (n = 65) had longer PFS (13.3 vs. 6.0 months; p = 0.005) and OS (50.1 vs. 21.2 months; p = 0.007) than BRAF mutated patients (n = 5, including four BRAFV600E). Median OS was significantly longer in resected patients (n = 39, 55.1 vs. 30.7 months; p = 0.030). Main toxicities were diarrhea (31.4 %) and neutropenia (21.4 %). CONCLUSION: FOLFIRINOX+cetuximab provides good PFS, high response rate and prolonged disease control in initially unresectable extended RAS wild-type mCRC. This combination is particularly interesting for selected patients with liver-limited disease eligible to secondary resection.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Neoplasias Colorretais , Fluoruracila , Irinotecano , Leucovorina , Oxaliplatina , Humanos , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Feminino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Idoso , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Adulto , Intervalo Livre de Progressão , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , MutaçãoRESUMO
Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]). Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.