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1.
Artigo em Inglês | MEDLINE | ID: mdl-32353390

RESUMO

PURPOSE: To develop robust normal tissue complication probability (NTCP) models for hepatocellular carcinoma (HCC) patients treated with radiation therapy (RT) using Child-Pugh (CP) score and Albumin-Bilirubin (ALBI) grade increase as endpoints for hepatic toxicity. METHODS AND MATERIALS: Data from 108 HCC patients treated with RT between 2008 and 2017 were evaluated, 47 (44%) of which were treated with proton RT. Of these patients, 29 received stereotactic body RT and 79 received moderately hypofractionated RT to median physical tumor doses of 43 Gy in 5 fractions and 59 Gy in 15 fractions, respectively. A generalized Lyman-Kutcher-Berman (LKB) model was used to model the NTCP using two clinical endpoints, both evaluated at 3 months post-RT: CP score increase of two or more and ALBI grade increase of one or more from pre-RT baseline. Confidence intervals on LKB fit parameters were determined using bootstrap resampling. RESULTS: Compared to previous NTCP models, this study found a stronger correlation between normal liver volume receiving low doses of radiation (5-10 Gy) and CP/ALBI increase. CP score increase exhibited a stronger correlation to normal liver volume irradiated than ALBI grade increase. LKB models for CP increase found values for the volume-effect parameter of a=0.06 for all patients and 0.02/0.09 when fit to photon/proton patients separately. Subset analyses for patients with superior initial liver function showed consistent dose-volume effects (a=0.1) and consistent dose-response relationships. CONCLUSIONS: This study presents an update of liver NTCP models in the era of modern RT techniques using relevant endpoints of hepatic toxicity, CP score and ALBI grade increase. Results show a stronger influence of low-dose bath on hepatic toxicity than those found in previous studies, indicating that RT techniques which minimize the low-dose bath may be beneficial for patients.

3.
Am J Clin Oncol ; 43(5): 311-318, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32235162

RESUMO

OBJECTIVES: Although current guidelines continue to recommend trimodality therapy for stage II to III rectal cancers, a lower incidence of local recurrence has been observed in patients with upper rectal tumors, including those in the rectosigmoid. In practice, patients with upper rectal tumors may not be receiving all 3 modalities of therapy. Patterns of care for patients with rectosigmoid cancers have not previously been described. METHODS: The National Cancer Database (NCDB) was used to identify patients diagnosed with stage II to III rectosigmoid cancer who underwent definitive surgery between 2004 and 2015. Multivariable logistic regression defined adjusted odds ratio and associated 95% confidence intervals of receipt of any pelvic radiotherapy and preoperative and postoperative pelvic radiotherapy. Multivariable logistic regression also assessed odds of treatment with any chemotherapy and multiagent chemotherapy. RESULTS: Among 8410 patients, 3566 (42.4%) received any pelvic radiotherapy, of which 2516 (70.6%) were treated with preoperative radiotherapy. Factors associated with receipt of radiotherapy included male sex, white race, younger age, positive clinical nodes and positive margins (P<0.001). Among patients with clinically positive nodes, 1980 (48.6%) received any radiotherapy and among those with pathologically positive nodes, 1532 (37.9%) received radiotherapy. A total of 5708 patients (67.9%) received any chemotherapy including 3020 (52.9%) with multiagent chemotherapy. A total of 2579 (30.7%) of the cohort was treated with surgery alone and among patients who were T3N0, this proportion rose to 42.5%. CONCLUSIONS: Less than half of patients with stage II to III rectosigmoid cancers are treated with radiation therapy and approximately one third do not receive chemotherapy. Ongoing and future studies may help to better tailor treatment for rectosigmoid tumors to optimize the therapeutic ratio. Our work may serve as a benchmark on which to compare future practice patterns.

4.
Pancreatology ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32222340

RESUMO

BACKGROUND: There is limited data on the efficacy of adjuvant therapy (AT) in patients with invasive intraductal papillary mucinous neoplasms of the pancreas (IPMN). This single center retrospective cohort study aims to assess the impact of AT on survival in these patients. METHODS: Patients undergoing surgery for invasive IPMN between 1993 and 2018 were included in the study. We compared the clinicopathologic features and evaluated overall survival (OS) using multivariate Cox regression adjusting for adjuvant therapy, age, T and N stage, perineural and lymphovascular invasion. We also assessed survival differences between surgery alone and AT in node negative (N0) and node positive (N+) subgroups. RESULTS: 103 patients were included in the study; 69 underwent surgery alone while 34 also received AT. Patients in the AT group were significantly younger, presented at higher T and N stages and had more perineural and lymphovascular invasion. Median OS in the surgery alone group was 134 months and 65 months in the AT group, p = 0.052. On multivariate analysis, AT was not associated with improved OS; hazard ratio (HR) = 1.03 (0.52-2.05). In N0 patients, compared to surgery alone, AT was associated with a worse median OS (65 vs 167 months, p = 0.03), whereas in N+ patients there was a non-significant improvement (50.5 vs 20.4 months, p = 0.315). CONCLUSION: AT did not improve survival in the overall cohort even after multivariate analysis. N0 patients have excellent survival, and AT should probably be avoided in them, whereas it may be considered in patients with N+ disease.

5.
J Am Coll Surg ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32035978

RESUMO

BACKGROUND: Postoperative complication (POC) adversely impacts long-term survival in patients with gastric cancer, perhaps due in part to lower rates for receipt of multimodality therapy (MMT). We sought to determine the impact of POC on MMT completion rates and overall survival (OS) in patients with locally advanced gastric cancer. STUDY DESIGN: We analyzed 206 patients with locally advanced gastric cancer undergoing curative-intent resection from 2001 to 2015. POCs were graded using Clavien-Dindo classification and survival outcomes were compared between groups. RESULTS: One hundred and twenty patients underwent operation followed by chemoradiation therapy, 58 received perioperative chemotherapy, and 28 received total neoadjuvant therapy (TNT). Minor (Clavien-Dindo grade I to II) and major (Clavien-Dindo grade III to IV) POC occurred in 72 (35.0%) and 39 (18.9%) patients, respectively. At median follow-up of 37 months, the 3-year OS of patients experiencing a major, minor, or no POC were 33.3%, 56.9%, and 62.1% (p = 0.023), respectively. In contrast, there was no difference in 3-year OS rates in patients experiencing POC if they completed all intended MMT. Non-TNT patients who experienced a major POC were less likely to complete MMT (hazard ratio 0.36, p = 0.017), and a major POC in these patients had a significant impact on OS (hazard ratio 2.76, p = 0.011), and it did not in patients who completed MMT (hazard ratio 1.58, p = 0.336). CONCLUSIONS: Major POC adversely affects long-term survival after gastrectomy for gastric cancer, at least in part via lower completion rates of MMT. Treatment strategy designed to ensure the completion of MMT, such as TNT, might be preferable, particularly for patients at high risk for POCs.

6.
Clin Cancer Res ; 26(8): 1877-1885, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941831

RESUMO

PURPOSE: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. EXPERIMENTAL DESIGN: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. RESULTS: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). CONCLUSIONS: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

8.
Ann Surg Oncol ; 27(4): 1122-1129, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31873931

RESUMO

OBJECTIVE: The aim of this study was to evaluate outcomes for patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT). METHODS: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008 to 2018. Median age at RT was 76 years (range 30-92), including 27 patients (41%) aged ≥ 80 years. Median RT dose was 58.05 Gy (range 37.5-67.5), all delivered in 15 daily fractions. Thirty-two patients received proton RT and 34 patients received photon RT. RESULTS: Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, five patients (7.6%) developed local failure. The 2-year outcomes were 84% local control (LC) and 58% OS. Among the 51 patients treated with definitive intent, the 2-year LC rate was 93% and the OS rate was 62%. On multivariate analysis for LC, older age was associated with a lower risk of local failure [hazard ratio (HR) 0.91; p = 0.02], while prior surgery (HR 16.5; p = 0.04) and macrovascular invasion (HR 123.93; p = 0.02) were independently associated with an increased risk of local failure. On multivariate analysis for OS, female sex (HR 0.33; p = 0.001) and prior chemotherapy (HR 0.38; p = 0.003) remained significantly associated with OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). The rate of overall grade 3 + toxicity was 11%. One patient developed radiation-induced liver disease and was treated with corticosteroids. CONCLUSIONS: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC.

10.
Ann Surg Oncol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758284

RESUMO

OBJECTIVE: To define short-term and long-term outcomes of IORT for the management of BR/LA PDAC in the era of modern neoadjuvant therapy (NAT). BACKGROUND: In the era of neoadjuvant FOLFIRINOX, many patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) become candidates for surgical exploration with curative intent. IORT may be used to consolidate treatment for successfully resected patients with close or positive margins or administered in unresectable patients without distant metastases. METHODS: A retrospective review of 158 patients who received IORT in the setting of biopsy-proven BR/LA PDAC following NAT between 2008 and 2017 was performed. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) of FOLFIRINOX treated patients. RESULTS: Most patients (83%) received FOLFIRINOX, and 95% underwent consolidative chemoradiation therapy (50.4-58.8 Gy). Among FOLFIRINOX-treated patients, 86 underwent combined surgical resection with IORT (10 Gy) while 46 received IORT alone (15-20 Gy). The median PFS and OS were 21.5 and 46.7 months for patients who underwent resection with IORT and 14.7 and 23 months in the IORT alone group. Local progression occurred in 12.7% of patients after resection with IORT, and in 15% of patients who received IORT alone. Major complications occurred in 13% of patients following resection, and 5% of patients after IORT alone, including one death. CONCLUSION: IORT combined with surgical resection appears to be associated with improved survival and minimal morbidity in patients with positive or close margins. IORT is also associated with improved survival in patients with unresectable, non-metastatic disease.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31705172

RESUMO

PURPOSE: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis with surgical resection offering the best chance for long-term survival and potential cure. However, in up to 36% of patients who undergo surgery, more extensive disease is found at time of operation requiring cancellation of surgery. PET/MR is a novel hybrid technology that might improve local and whole-body staging in ICC patients, potentially influencing clinical management. This study was aimed to investigate the possible management implications of PET/MR, relative to conventional imaging, in patients affected by untreated intrahepatic cholangiocarcinoma. METHODS: Retrospective review of the clinicopathologic features of 37 patients with iCCC, who underwent PET/MR between September 2015 and August 2018, was performed to investigate the management implications that PET/MR had exerted on the affected patients, relative to conventional imaging. RESULTS: Of the 37 patients enrolled, median age 63.5 years, 20 (54%) were female. The same day PET/CT was performed in 26 patients. All patients were iCCC-treatment-naïve. Conventional imaging obtained as part of routine clinical care demonstrated early-stage resectable disease for 15 patients and advanced stage disease beyond the scope of surgical resection for 22. PET/MR modified the clinical management of 11/37 (29.7%) patients: for 5 patients (13.5%), the operation was cancelled due to identification of additional disease, while 4 "inoperable" patients (10.8%) underwent an operation. An additional 2 patients (5.4%) had a significant change in their operative plan based on PET/MR. CONCLUSIONS: When compared with standard imaging, PET/MR significantly influenced the treatment plan in 29.7% of patients with iCCC. TRIAL REGISTRATION: 2018P001334.

13.
Nat Med ; 25(9): 1415-1421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501609

RESUMO

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias Gastrointestinais/sangue , Biópsia Líquida , Autopsia , Ácidos Nucleicos Livres/genética , Estudos de Coortes , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Exoma
14.
Eur J Nucl Med Mol Imaging ; 46(11): 2260-2269, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359108

RESUMO

PURPOSE: The primary aim of the present study was to evaluate if PET/MR induced management changes versus standard of care imaging (SCI) in treated colorectal cancer patients. The secondary aim was to assess the staging performance of PET/MR and of SCI versus the final oncologic stage. METHODS: Treated CRC patients who underwent PET/MR with 18F-FDG and SCI between January 2016 and October 2018 were enrolled in this retrospective study. Their medical records were evaluated to ascertain if PET/MR had impacted on their clinical management versus SCI. The final oncologic stage, as reported in the electronic medical record, was considered the true stage of disease. RESULTS: A total of 39 patients who underwent 42 PET/MR studies were included, mean age 56.7 years (range 39-75 years), 26 males, and 13 females. PET/MR changed clinical management 15/42 times (35.7%, standard error ± 7.4%); these 15 changes in management were due to upstaging in 9/42 (21.5%) and downstaging in 6/42 (14.2%). The differences in management prompted by SCI versus PET/MR were statistically significant, and PET/MR outperformed SCI (P value < 0.001; odds ratio = 2.8). In relation to the secondary outcome, PET/MR outperformed the SCI in accuracy of oncologic staging (P value = 0.016; odds ratio = 4.6). CONCLUSIONS: PET/MR is a promising imaging tool in the evaluation of treated CRC and might change the management in these patients. However, multicenter prospective studies with larger patient samples are required in order to confirm these preliminary results.

15.
Am J Clin Oncol ; 42(7): 564-572, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31166209

RESUMO

OBJECTIVES: Most localized hepatocellular carcinoma (HCC) patients are not surgically operable or transplantation candidates, increasing the role for nonsurgical therapies. Ablative external beam radiotherapy (XRT) and transarterial radioembolization (TARE) are emerging radiotherapeutic treatments for localized HCC. We sought to evaluate their utilization and efficacy in a large nationwide cohort. MATERIALS AND METHODS: We conducted an observational study of 2685 patients from the National Cancer Database (NCDB) diagnosed with American Joint Committee on Cancer 7th edition clinical stage I to III HCC between 2004 and 2015, treated with definitive-intent XRT delivered in 1 to 15 fractions or TARE. The association between treatment modality (XRT vs. TARE) and overall survival (OS) was defined using propensity score-weighted Kaplan-Meier estimators and propensity score-weighted multivariable Cox regressions. RESULTS: Among 2685 patients, 2007 (74.7%) received TARE and 678 (25.3%) received XRT, with increasing usage for both from 2004 to 2015 (Ptrend<0.001), but with overall greater uptake and absolute usage of TARE. Patients who received TARE were more likely to have elevated alpha fetoprotein and more advanced stage (P<0.05 for all). Median OS was 14.5 months for the entire cohort. XRT was associated with an OS advantage compared with TARE on propensity score-unadjusted analysis (adjusted hazard ratio [AHR], 0.89; 95% confidence interval, 0.79-1.00; P=0.049), but not on propensity score-adjusted analysis (AHR, 0.99; 95% confidence interval, 0.86-1.13; P=0.829). CONCLUSIONS: Our study demonstrates that while both XRT and TARE usage have increased with time, there was greater uptake and absolute use of TARE. We found no difference in survival between XRT and TARE after propensity score adjustment.

16.
Clin Cancer Res ; 25(18): 5561-5571, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31253631

RESUMO

PURPOSE: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized.Experimental Design: We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)]. RESULTS: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer. Concurrent KRAS/TP53 mutations (KP) associated with NR tumors and were enriched for an epithelial-mesenchymal transition transcriptional program. Furthermore, NR was associated with reduced CD4/CD8 T-cell infiltrates and a post-CRT M2 macrophage phenotype. Absence of any local tumor recurrences, KP/NR status predicted worse progression-free survival, suggesting that local immune escape during or after CRT with specific genomic features contributes to distant progression. CONCLUSIONS: Overall, while CRT did not impact genomic profiles, CRT impacted the tumor immune microenvironment, particularly in resistant cases.

17.
JAMA Oncol ; 5(7): 1020-1027, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145418

RESUMO

Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. Main Outcomes and Measures: R0 resection rate. Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. Trial Registration: ClinicalTrials.gov identifier: NCT01821729.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia , Losartan/administração & dosagem , Terapia Neoadjuvante , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Neoplasias Pancreáticas/patologia , Resultado do Tratamento
18.
Int J Radiat Oncol Biol Phys ; 105(1): 90-95, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128146

RESUMO

PURPOSE: Definitive chemoradiation with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) is an effective treatment for localized anal cancer, but it is associated with significant acute long-term treatment-related toxicity. Pencil beam scanning proton beam (PBS-PT) radiation therapy may potentially reduce this toxicity. This is a multi-institutional pilot study evaluating the feasibility of definitive concurrent chemoradiation with PBS-PT in combination with 5-FU and MMC for carcinoma of the anal canal. METHODS AND MATERIALS: Patients were enrolled on a National Cancer Institute-sponsored, prospective, multi-institutional, single-arm pilot study (NCT01858025). Key eligibility criteria included Eastern Cooperative Oncology Group 0 to 2, age ≥18 years, histologically confirmed invasive squamous cell carcinoma of the anal canal, and clinically staged T1-4, N0-3 disease. Patients were treated with PBS-PT per Radiation Therapy Oncology Group 0529 dose schema and concurrent 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with concurrent 5-FU/MMC, defined as grade 3+ dermatologic toxicity less than 48% (reported grade 3+ dermatologic toxicity from Radiation Therapy Oncology Group 98-11). Secondary objectives were to determine the rates of overall grade 3+ toxicities, clinical complete response rate, and disease outcomes. RESULTS: Between February 2014 and April 2017, we enrolled 25 patients into our study, all of whom were analyzed. Twenty-three patients (92%) completed treatment per protocol, and 2 patients died on treatment. Median time to completion of treatment was 42 days (range, 38-49). The grade 3+ radiation dermatitis rate was 24%. Median follow-up is 27 months (range, 21-50) among the 21 patients still alive. The overall rate of clinical complete response was 88%. The 2-year local failure, colostomy-free survival, progression-free survival, and overall survival are 12%, 72%, 80%, and 84%, respectively. CONCLUSIONS: In our prospective, multi-institutional pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. A phase 2 study of proton beam radiation therapy is currently underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/métodos , Terapia com Prótons/métodos , Radiodermatite/patologia , Idoso , Canal Anal , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Colostomia , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Projetos Piloto , Intervalo Livre de Progressão , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Dosagem Radioterapêutica
19.
JAMA Netw Open ; 2(4): e192249, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977859

RESUMO

Importance: Although both short-course radiotherapy and long-course chemoradiotherapy have been practiced in parallel for more than 15 years, no cost-effectiveness analysis comparing these 2 approaches in patients with locally advanced rectal cancer has been published. Objective: To analyze the cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy for the treatment of patients with locally advanced rectal cancer. Design, Setting, and Participants: This economic evaluation used a cost-effectiveness model simulating 10-year outcomes for 1 million hypothetical patients aged 65 years with locally advanced rectal cancer treated with either short-course radiotherapy or long-course chemoradiotherapy, followed by surgery and chemotherapy. Utilities and probabilities from the literature and costs from the Healthcare Bluebook and Medicare fee schedules were used to determine incremental cost-effectiveness ratios. It was assumed that long-course chemoradiotherapy would result in higher rates of low anterior resection (LAR). To model preference-sensitive care, a 2-way sensitivity analysis was conducted in which the utilities of the no-evidence-of-disease (NED) states with LAR and abdominoperineal resection (APR) were simultaneously varied. The analysis was repeated for patients with distal rectal tumors. Analysis was conducted from January to October 2018. Exposures: Short-course radiotherapy and long-course chemoradiotherapy. Main Outcomes and Measures: Incremental cost-effectiveness ratios. Results: Short-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy (incremental cost-effectiveness ratio, $133 495 per quality-adjusted life-year). Two-way sensitivity analysis revealed that the cost-effective approach for a given patient depended on the utilities for the NED-LAR and NED-APR states. Assuming that a greater proportion of patients with locally advanced distal tumors undergoing long-course chemoradiotherapy (39%) would proceed to LAR compared with those treated with short-course radiotherapy (19%), long-course chemoradiotherapy was the cost-effective approach (incremental cost-effectiveness ratio, $61 123 per quality-adjusted life-year). Conclusions and Relevance: Short-course radiotherapy was the cost-effective strategy compared with long-course chemoradiotherapy for patients with locally advanced rectal cancer. The cost-effectiveness of short-course radiotherapy vs long-course chemoradiotherapy was sensitive to the utilities of the NED-LAR and NED-APR health states, highlighting the importance of care that is sensitive to patient preference. Long-course chemoradiotherapy was the cost-effective approach for patients with distal tumors.


Assuntos
Quimiorradioterapia/economia , Radioterapia/economia , Neoplasias Retais/economia , Neoplasias Retais/terapia , Fatores de Tempo , Idoso , Quimiorradioterapia/métodos , Análise Custo-Benefício , Feminino , Humanos , Masculino , Medicare , Anos de Vida Ajustados por Qualidade de Vida , Radioterapia/métodos , Estados Unidos
20.
Oncologist ; 24(6): e275-e283, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30755500

RESUMO

BACKGROUND: This study characterizes the tumor-immune microenvironment in pretreatment, localized anal squamous cell carcinoma (ASCC), including two markers that have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and human leukocyte antigen (HLA) class I. MATERIALS AND METHODS: Retrospective review identified 63 patients with ASCC receiving definitive chemoradiation between 2005 and 2016 with pretreatment tissue available. Immunohistochemistry was used to quantify cluster of differentiation 8 (CD8), programmed cell death protein 1, programmed death-ligand 1, HLA class I, and IDO1. Cox proportional hazards models evaluated associations between outcomes and immune markers, controlling for clinical characteristics. RESULTS: With a median follow-up of 35 months, 3-year overall survival was 78%. The only marker found to have a robust association with outcome was tumor IDO1. In general, the percentage of tumor cells expressing IDO1 was low (median 1%, interquartile range 0%-20%); however, patients with >50% of tumor cells expressing IDO1 had significantly worse overall survival (hazard ratio [HR] 4.7, p = .007) as well as higher local recurrence (HR 8.6, p = .0005) and distant metastasis (HR 12.7, p = .0002). Tumors with >50% IDO1 were also more likely to have the lowest quartile of CD8 infiltrate (<40 per high-power field, p = .024). CONCLUSION: ASCC has a diverse immune milieu. Although patients generally do well with standard therapy, IDO1 may serve as a prognostic indicator of poor outcome and could help identify a patient population that might benefit from IDO-targeted therapies. IMPLICATIONS FOR PRACTICE: After definitive chemoradiation, patients with locally advanced anal cancer may experience significant treatment morbidity and high risk of recurrence. The goal of the current study is to identify novel prognostic factors in the tumor-immune microenvironment that predict for poor outcomes after definitive chemoradiation. This study characterizes the tumor-immune microenvironment in pre-treatment, localized anal squamous cell carcinoma (ASCC), including two markers which have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and HLA class I. With a median follow-up of 3 years, this study demonstrated that high IDO1 expression is correlated with significantly worse 3-year overall survival (88% vs. 25%). Whereas recent studies of IDO1 inhibitors have shown mixed results, this study suggests that patients with anal cancer with high IDO1 expression have dismal prognosis and may represent a patient population primed for response to targeted IDO1 inhibition.

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