Determination of dihydropyrimidine dehydrogenase (DPYD) gene single-nucleotide polymorphism (SNP) in Mexican patients with locally advanced esophageal carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 93-93
Author(s):  
Erika Ruiz-Garcia ◽  
Alicia Lopez-Yañez ◽  
German Caderillo-Ruiz ◽  
Connie Zuratzi Deneken ◽  
Consuelo Diaz ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Locally Advanced ◽  
Allelic Frequency ◽  
Single Nucleotide ◽  
Dehydrogenase Enzyme ◽  
Race 2 ◽  
Grade 3 ◽  
Locally Advanced Esophageal Cancer ◽  
Mexican Patients

93 Background: Fluoropyrimidines as 5-fluorouracil (5-FU) and its prodrug capecitabine are chemotherapeutic drugs commonly used in the treatment of gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because 80-90% of the administered 5-FU is catabolized by DPD. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 72 Mexican patients with locally advanced esophageal cancer, DPD activity was evaluated through the detection of the seven most relevant DPYD SNPs (IVS14 + 1G>A; 85T>C/85T>T; 2657G>A; 2921A>T; 1679T>G; 2846A>T; and 496A>G). Results: We found that 20.83% (15/72) of our patients had three different polymorphisms: 9.72% (7/72) were positive for SNP 496A>G in heterozygous patients and 4.16% (3/72) in homozygous patients; 4.16% (3/72) were positive for SNP 2657G>A in heterozygous patients; 2.77% (2/72) were positive for SNPs 85T>C and 85T>T in heterozygous patients. The rest of patients 79.10% (57/72) were negative to these SNPs. Conclusions: This is the first study in Mexican population, determining DPYD SNPs. We found that frequency of SNP 85T>C and 85T>T is similar as Oriental race (2-3%), but contrast with Caucasians (0.19%). The SNP 2657G>A whose allelic frequency is unknown, in Mexicans is about 4%; meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). None of our patients even those with toxicity grade 3-4, were positive to the SNP associated to high toxicity (IVS14 + 1G>A). Because of this heterogeneity, know we are sequencing the complete gen.

Neoadjuvant and combined chemoradiotherapy followed by surgery in locally advanced esophageal cancer: A single-centre experience

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15086-15086
Author(s):  
R. Diaz ◽  
G. Reynes ◽  
A. Tormo ◽  
A. Segura ◽  
A. Santaballa ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Response Rate ◽  
Locally Advanced ◽  
Prospective Trial ◽  
High Response Rate ◽  
Long Term Results ◽  
Advanced Esophageal Cancer ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Locally Advanced Esophageal Cancer

15086 Background: Concomitant chemoradiotherapy (CT-RT) with CDDP-5FU CT is a standard treatment in locally advanced esophageal cancer (EC). Long-term results are poor. The role of neoadjuvant CT (nCT) and of radical surgery after CT-RT is unclear. Methods: Single-institution, prospective trial in pts with stage II-IVA EC (TNM). PS 0–1. Staging: CT scan, barium x-ray, esophagoscopy and endoscopic ultrasound. Treatment schema: 1 cycle of neoadjuvant CT (CDDP 100 mg/m2 d1 and 5-FU 1,000 mg/m2/24 h d1–5); after 21 days, 50 Gy of RT (1.8 cGy/day, M to F) and 2 cycles of reduced-dose CT (CDDP 15 mg/m2 d1–5 and 5-FU 800 mg/m2/24 h d1–5, q21 days). In pts deemed resectable, surgery was done after 4–6 weeks. In the remainder, a 10 Gy boost was given with 1 cycle of modified CT. Primary endpoint: clinical and pathological response rate (RR) after 1st phase. Secondary endpoints: OS and toxicity rates. Results: 71 pts accrued between 1998 and 2006. Median age 61 yrs (r 44–80). 96% males. 85% squamous cell carcinomas. Middle third: 51%; upper third: 27%; lower third 22%. Gastric involvement: 11%. cT3: 46%, cT4: 28%. cN positive: 48%. Grade 3–4 toxicity with nCT and CT-RT: mucositis (9 and 19.5%), emesis (9 and 9%) and infection (6 and 9%). Full dose CT-RT: 87%. Clinical RR after 1st phase: CR 50%, PR 25%, SD 9%, PD 7%. Confirmation (CT- biopsy): 69%. Surgery: 30%. Reasons for no surgery: comorbidity (11%) and age (10%). Pathologic RR: CR 39%, microscopic rest 39% and macroscopic rest 22%. Downstaging 50%. No pN positive. 3 pts had unresectable disease. 62% received 2nd phase RT boost, 31% with CT. Clinical RR: CR 69%, PR 6%, PD 25%. Median follow-up 50 m (r 6–129 m). Median OS 10.5 m (r 7.4–12.8 m). 4-year OS of 18%. 47% deaths due to progression, 5% treatment-related deaths and 10% in the postoperative period. Only a clinical CR after 1st phase was found to improve OS (13.5 vs 7 m, p 0.0141). Conclusions: This regimen is well tolerated and offers a high response rate. Clinical response evaluation overestimates the pathologic response rate. In our series, the possible survival benefit of surgery is offset by the postoperative death rate. No significant financial relationships to disclose.

Phase I Study of Capecitabine With Concomitant Radiotherapy for Patients With Locally Advanced Pancreatic Cancer: Expression Analysis of Genes Related to Outcome

2005 ◽  
Vol 23 (34) ◽  
pp. 8679-8687 ◽  
Author(s):  
M. Wasif Saif ◽  
Mohammaed A. Eloubeidi ◽  
Suzanne Russo ◽  
Adam Steg ◽  
Jennifer Thornton ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Locally Advanced ◽  
Three Dimensional ◽  
Advanced Pancreatic Cancer ◽  
Needle Aspiration ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Grade 3

Purpose To establish the feasibility of capecitabine with concurrent radiotherapy (XRT) in patients with locally advanced (LA) pancreatic cancer and evaluate the effect of XRT on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-alpha (TNF-α). Patients and Methods Fifteen patients with LA pancreatic cancer received three-dimensional conformal XRT to a dose of 50.4 Gy with capecitabine at escalating doses from 600 to 1,250 mg/m2 bid (Monday through Friday). Following chemo-XRT, stable and responding patients were treated with capecitabine 2,000 mg/m2 orally bid for 14 days every 21 days. Tumor specimens were procured with endoscopic ultrasound–guided fine-needle aspiration 1 week before and 2 weeks after chemo-XRT to evaluate TP, DPD, and TNF-α mRNA levels. Results Dose-limiting grade 3 diarrhea was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 with XRT. Three patients (20%) achieved partial response. Mean percent difference in TP pre- and post-XRT was 119.2% (P = .1934). There was no significant differences in mean TNF-α, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF-α levels were not significantly correlated both at pre- and post-XRT (P = .670 and P < .154, respectively). Median value of TP:DPD ratios at baseline was 2.65 (range, 0.36 to 11.08). No association between TP:DPD ratio and efficacy of capecitabine or severity of toxicities was identified. Conclusion The recommended dose for phase II evaluation is capecitabine 800 mg/m2 bid (Monday through Friday) with concurrent XRT. This approach offers an easy alternative to intravenous fluorouracil as a radiosensitizer in these patients. Role of TP and TP:DPD ratio warrants further investigation in a larger clinical trial.

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5 FU) and cisplatin for locally advanced resectable esophageal cancer: A retrospective study.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 119-119
Author(s):  
Khaldoun Almhanna ◽  
Sarah Hoffe ◽  
Ravi Shridhar ◽  
Jonathan R. Strosberg ◽  
William R. Dinwoodie ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Complete Response ◽  
R0 Resection ◽  
Severe Toxicity ◽  
Advanced Esophageal Cancer ◽  
Resectable Esophageal ◽  
Grade 3 ◽  
Locally Advanced Esophageal Cancer

119 Background: Neoadjuvant CCRT has become the standard treatment for esophageal cancer. Most clinicians use a conventional cisplatin/5 FU combination which is associated with moderate to severe toxicity. For the last 15 years we have used contiuous low-dose 5-FU combined with two doses of cisplatin. Methods: Between July 1997 and June 2012, 155 patients with locally advanced esophageal cancer (T3 or N1 and higher), received CCRT consistent of cisplatin 75 mg/m2 on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m2/day) on the days of radiation. Results: Median age of patients was 63 year (30-76).Seventeen percent of pts were female and 85% had adenocarcinoma. (3, 34, 86 and 31 pts had stage I, II, III and IVa disease respectively. One hundred and twenty seven pts had N1 disease. Radiation dose (RT) ranged from 45-60 Gy (median 56Gy). Median weight loss was 6.5%. All patients completed treatment. 20% of patients had >=grade 3 toxicity, with 29 patients requiring hospital admission. 53% of patients had surgical resection between 37-149 days following CCRT (median 62 days). R0 resection was achieved in 96% of patients. A pathological complete response was achieved in 38 of 83 pts (45%) who underwent surgical resection. With a median follow up of 26 months (1.2 -144 months), 36% of pts recurred and total of 50% died. Conclusions: Compared to conventional chemotherapy regimen, our CCRT regimen for locally advanced esophageal cancer is well tolerated and associated with a high pathological response rate.

Single nucleotide polymorphisms analysis of BRAC and ERCC1 as predictor of recurrence after chemoradiation for cervical cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13540-e13540
Author(s):  
Luis Roberto Féliz ◽  
Verónica Pereira ◽  
Mariano Monzo ◽  
Carmen Munoz ◽  
Pere Fuste ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Single Nucleotide Polymorphisms ◽  
Locally Advanced ◽  
Initial Response ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Number Of Patients ◽  
The Status ◽  
Grade 3

e13540 Background: A number of patients with locally advanced cervical cancer will recur despite presenting initial response to chemoradiation. Single-nucleotide polymorphisms (SNP) of DNA repair genes have been found to be predictors of efficacy of chemotherapy and radiotherapy. Methods: We evaluated the presence of SNP in ERCC1, BRAC 1 and 2 genes. We analysed paraffin-embedded biopsies from patients who had relapsed after receiving treatment with chemoradiation, for SNP of the mentioned genes. The status of the alleles wild type (wt) or at least 1 SNP was compared with time to progression (TTP) and toxicity. Results: 90 patients who experience recurrence of their cervical cancer were included in the analysis. Of those, we only could obtain evaluable tumour from 43 patients. Median age: 52.5 yrs (31-81). Histology: 32 squamous cell, 8 adenocarcinoma, 3 adenosquamous. One SNP in BRAC1 (rs12516) was found to be significantly associated with better TTP for the mutant variant compared to the wild-type (124 m. vs. 14 m.). Furthermore, all six patients who presented with severe (grade 3-4) toxicity had this wild-type SNP (rs12516) in BRAC1 gene. Conclusions: We have identified a SNP which confers better outcome in patients with cervical cancer. Further analysis need to be done to determine its relation to radiation-induced toxicity in this group of patients.

Multimodality therapy for locally advanced esophageal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 211-211
Author(s):  
Nitesh N. Paryani ◽  
Stephen Ko ◽  
Corey James Hobbs ◽  
Kristin Kowalchik ◽  
Elizabeth Johnson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Esophageal Cancer ◽  
Acute Toxicity ◽  
Locally Advanced ◽  
Late Toxicity ◽  
Advanced Esophageal Cancer ◽  
Current Standard ◽  
Grade 3 ◽  
Experienced Grade ◽  
Locally Advanced Esophageal Cancer

211 Background: The current standard of care for locally advanced esophageal cancer includes chemoradiotherapy with or without surgery. Radiation is usually delivered via a 3D technique. IMRT has been utilized in the treatment of multiple tumors and demonstrated similar efficacy while offering the possibility of decreased toxicity. Methods: Thirty-six patients were treated with IMRT and chemotherapy. Twenty-one patients underwent surgical resection. Eleven underwent open surgery and the remainder underwent minimally invasive surgery. Chemotherapy consisted primarily of 5-FU with oxaliplatin or cisplatin. All but two patients received 50.4 Gy; one patient received 41.4 Gy without surgery and one patient discontinued treatment after 25.2 Gy. Eleven patients required a treatment break during radiotherapy. The median age was 69 (range 46-87). Approximately two-thirds of tumors were adenocarcinomas located in the lower thorax. Two thirds of patients were staged as T3 and had positive lymph nodes. The median tumor size was 5 cm (range 2-13). Results: With a median follow-up of 21.3 months (range 2.4-44.8) and 33.9 months for survivors (range 3.7-44.8), overall survival at 24 months was 55%. The 24 month overall survival was 75% vs 24% for surgical and non-surgical patients, respectively. Seven patients had a complete pathologic response. Twenty-four patients experienced grade 3 or higher acute toxicity and there was one grade 5 toxicity. Acute toxicity was similar between surgery and non-surgery patients. Fourteen patients experienced grade 3 or higher late toxicity; 9 surgery and 5 non-surgery patients. The most frequent late toxicity was grade 3 stricture (21%). On multivariate analysis, advanced age (RR [10 year increase] 2.01, p=0.032) and heart maximum dose >55 Gy (RR 3.73, p=0.011) were associated with decreased survival. Conclusions: Patients who undergo surgery after chemoradiotherapy demonstrate improved survival; however, this may be related to underlying comorbidities that preclude surgery. IMRT appears to be a reasonable treatment option that may reduce complications from radiotherapy. Careful attention should be given to heart dose during treatment planning.

Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 521-521
Author(s):  
Moh'd M. Khushman ◽  
Peter Joel Hosein ◽  
Daniel Cameron ◽  
David Roland Clarkson ◽  
Thomas Wayne Butler ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Single Nucleotide ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Dpyd Gene ◽  
Gene Testing ◽  
Grade 3 ◽  
Dose Limiting Toxicity

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.

scholarly journals Toripalimab Used on the Same Day or Third Day With Chemotherapy for Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer—A Phase II Study

2021 ◽  
Author(s):  
Wenqun Xing ◽  
Lingdi Zhao ◽  
Yan Zheng ◽  
Baoxing Liu ◽  
Xianben Liu ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Control Group ◽  
Advanced Esophageal Cancer ◽  
Grade 3 ◽  
Experimental Group ◽  
Locally Advanced Esophageal Cancer

Abstract Background There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored. Methods This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020, 30 patients with locally advanced ESCC (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experiment group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pCR rate, the secondary endpoint were safety and disease-free survival. Results Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was got in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (P = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in control group had a PD-L1 CPS of 10 and pCR was achieved, while the left 13 were all ≤ 1, 11 of the 13 patients received surgery in which two (in the experimental group) got pCR. Two patients endured from ≥ grade 3 adverse events, one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery. CONCLUSIONS Although the primary endpoint was not met, initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on same day, and further large-sample clinical trials are needed to verify this. Trial registration: NCT 03985670, registered 10 June 2019.

scholarly journals Pemetrexed, Carboplatin, and Concomitant Radiation followed by Surgery for Locally Advanced Esophageal Cancer: Results of a Planned Interim Toxicity Analysis of North Central Cancer Treatment Group Study N044E

2008 ◽  
Vol 2 ◽  
pp. CMO.S444
Author(s):  
Rajini Katipamula ◽  
Aminah Jatoi ◽  
Nathan R. Foster ◽  
Francis Nichols ◽  
Joseph Rubin ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Adverse Event ◽  
Treatment Group ◽  
Locally Advanced ◽  
Pathologic Response ◽  
Advanced Esophageal Cancer ◽  
North Central ◽  
Toxicity Analysis ◽  
Grade 3 ◽  
Locally Advanced Esophageal Cancer

Purpose This brief report describes a planned, interim, 6-patient toxicity analysis that confirms the safety of pemetrexed, carboplatin, radiation with subsequent surgery, as prescribed in the North Central Cancer Treatment Group trial N044E, in patients with locally advanced esophageal cancer. Methods Six patients with locally advanced, potentially resectable esophageal cancer received pemetrexed 500 mg/m2 and carboplatin AUC = 6 on days 1 and 22 with 5040 centigray of concomitant radiation in 28 fractions over 5.5 weeks followed by esophagectomy as a prelude to a phase II multi-institutional trial. Results Only 1 of the 6 patients experienced a grade 4 adverse event (neutropenia). This patient also experienced a grade 3 depression. Of the remaining 5 patients, three experienced at least one grade 3 adverse event (neutropenia, nausea/vomiting, and esophagitis). There were no deaths. Incidentally, one patient manifested a complete pathologic response, three a partial pathologic response, and one stable disease. Conclusion These preliminary observations on safety suggest that this regimen can be further studied in this clinical setting.

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