scholarly journals Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Muhammad Wasif M. Saif ◽  
Ruchi Hamal ◽  
Nauman Siddiqui ◽  
Antonia Maloney ◽  
Melissa Smith
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Anal Carcinoma ◽  
Complete Response ◽  
Genetic Mutations ◽  
Molecular Testing ◽  
Severe Toxicity ◽  
Metabolizing Enzymes ◽  
Radiological Response ◽  
A Prospective Study ◽  
To Receive

Background: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase ( DPYD and thymidylate synthetase ( TYMS), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. Methods: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m2/day via continuous intravenous (IV) infusion 1–4 and 29–32, MMC 10 mg/m2 IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the DPYD and TYMS genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m2 day 1 and 29 with cisplatin 25 mg/m2/week plus RT. Toxicities and responses were collected. Results: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: TYMS 2RG/3RC ( n = 2), 3RG/3RC ( n = 1), 2R/2R ( n = 2), T YMS 3′UTR del/Ins ( n = 2), and DPYD c.2864A > T heterozygous ( n = 1). Two patients received 5-FU at a 50% reduced dose on days 29–32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m2 on day 29 with cisplatin (CDDP) 25 mg/m2/week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have TYMS abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment. Conclusions: Molecular testing for DPYD and TYMS genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC.

Alternative chemoradiotherapy to treat locally advanced (LA) anal carcinoma (AC) in patients (pts) with mutations in thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) genes: A case series.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 605-605
Author(s):  
Wasif M. Saif ◽  
Ruchi Hamal ◽  
Nauman Saleem Siddiqui ◽  
Antonia Maloney ◽  
Lilian Chen ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Locally Advanced ◽  
Anal Carcinoma ◽  
Case Series ◽  
Phase Iii ◽  
Genetic Mutations ◽  
Molecular Testing ◽  
Severe Toxicity ◽  
Grade 3 ◽  
Age Range

605 Background: 5-FU and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for pts with LA (T2-4, N0-1, M0 or T1-4, N2-3, M0) AC. Genetic mutations in 2 major metabolizing enzymes for 5-FU; DPYD and TYMS have been associated with clinical response and toxicity. However their place in treatment of AC remains undetermined. Methods: We retrospectively reviewed 21 pts with LA AC treated between 2012 - 2018. All pts were treated with 5-FU 1,000mg/m2/day continuous IV infusion 1–4 and 29–32, MMC 10mg/m2 IV bolus Days 1 and 29 plus RT. Acute toxicity was recorded and discussed during weekly multidisciplinary meetings. The worst grade was scored from start of treatment until 30 days after the last fraction of radiotherapy according to the NCI-CTCAE, v4.03. Tumor response was evaluated by DRE and palpation of inguinal nodes during treatment, at the end of treatment, and radiological imaging 4–6 weeks after completion of treatment. Pts who developed ≥3 toxicities were tested for DPYD and TYMS genes (2 major polymorphisms has been associated with altered TYMS: polymorphic 28bp tandem repeat polymorphism in 5’-untranslated region (5’UTR) into TYMS sequence enhancer region (TSER) and TYMS 1494del, is a 6-base pair (bp) deletion polymorphism in 3’-UTR. Results: 6/21 ptsdeveloped severe toxicities (Caucasians; 5 females, 1 male; age range: 42 -68 yrs) consisting of grade ≥3 pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash and nephritis. The most common genetic mutations found in these pts included TYMS 2RG/3RC (2), 3RG/3RC (1), 2R/2R (2), TYMS 3 ' UTR del/Ins (2) and DPYD c.2864A>T heterozygous (1). Treatment was changed in 2 pts to MMC 10 mg/m2 Day 1 and 29 with cisplatin 25 mg/m2/week plus RT. These 2 pts reached pCR at 70 days and other 4 pts at 140 days. Conclusions: Molecular testing for DPYD and TYMS genes can allow us to identify pts who are most likely to respond or face severe toxicity to 5-FU. Combining radiation with MMC and cisplatin in pts with LA AC is feasible and EORTC is currently comparing this combination with MMC/5-FU in a large phase III trial.

Neoadjuvant gemcitabine-cisplatin (GC) for muscle-invasive bladder cancer (MIBC): Does midway CT staging predict for pathologic complete response (pCR)?

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 306-306
Author(s):  
Jo-An Seah ◽  
Raya Leibowitz-Amit ◽  
Eshetu G. Atenafu ◽  
Nimira Alimohamed ◽  
Anthony Michael Joshua ◽  
...  
Keyword(s):  
Bladder Tumour ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Exact Test ◽  
Disease Characteristics ◽  
Definitive Therapy ◽  
Radiological Response ◽  
Muscle Invasive ◽  
To Receive

306 Background: Neoadjuvant cisplatin-based chemotherapy (NC) improves overall survival in MIBC, with pCR post radical cystectomy (RC) linked to better outcomes. NC is underutilized in part due to concerns over disease progression during NC. Midway radiological CT (post 2 NC cycles) may identify patients (pts) progressing on NC who should proceed to definitive therapy (DT). Methods: We reviewed 39 MIBC pts planned to receive 4 cycles of NC (GC) between Jan2005-April2013. Most pts (70%) had midway CT staging. A radiological response was defined as clear improvement in tumour +/- nodal status on CT compared to baseline, taking into account prior trans-urethral resection of bladder tumour; any other result was considered no response. DT consisted of RC, concurrent chemoradiation (CCR), or radiation alone (R). Descriptive statistics and Fisher’s exact test examined associations between disease characteristics and outcomes. Results: Overall, 28 pts (72%) completed planned NC; 7 pts (18%) stopped early due to no response on midway CT; 4 (10%) discontinued due to death (1), sepsis (2), and fatigue (1). Twenty-six pts (67%) had RC, 3 (8%) had CCR, 6 (15 %) had R and 4 (10%) did not receive DT. Of the 26 RC pts – 6 (23%) had a pCR. There were no pCRs among pts who had no radiological response at midway CT. At time of last follow up, 8 pts (21%) had died, 13 (33%) had recurrence/ metastases, and the remainder are being actively followed. Of pts with pCR, there were no recurrences (median follow up 12.2 mo (range 6.3-20.9 mos). The rate of venothromboembolism (VTE) was 26%, and nearly half occurred during NC, but did not affect treatment. Conclusions: Lack of response on midway CT was associated with a lack of pCR at RC, suggesting midway staging may be of value in MIBC receiving NC. The rates of pCR were consistent with reported literature, but rates of VTE appear higher than expected and requires further investigation. [Table: see text]

scholarly journals In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

2020 ◽  
Vol 9 (8) ◽  
pp. 2342
Author(s):  
Eiji Hishinuma ◽  
Evelyn Gutiérrez Rico ◽  
Masahiro Hiratsuka
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
In Vitro Tests ◽  
Severe Toxicity ◽  
Metabolizing Enzymes ◽  
Underlying Mechanisms ◽  
Enzyme Metabolism

Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.

Distinct cytokines predict response to immunotherapy and targeted therapy in metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 352-352
Author(s):  
Alex Chehrazi-Raffle ◽  
Luis A Meza ◽  
Marice Alcantara ◽  
Nicholas Salgia ◽  
Nazli Dizman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitor ◽  
Complete Response ◽  
Vascular Endothelial ◽  
Protein Assay ◽  
Ongoing Work ◽  
Plasma Cytokines ◽  
A Prospective Study ◽  
Endothelial Growth Factor ◽  
To Receive

352 Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.

scholarly journals Liquid Biopsy Analysis in Clinical Practice: Focus on Lung Cancer

2021 ◽  
Vol 2 (3) ◽  
pp. 241-254
Author(s):  
Pasquale Pisapia ◽  
Francesco Pepe ◽  
Antonino Iaccarino ◽  
Roberta Sgariglia ◽  
Mariantonia Nacchio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Treatment Options ◽  
Molecular Testing ◽  
Specific Information ◽  
Sample Collection ◽  
Timely Manner ◽  
Oncology Practice ◽  
Nsclc Patients ◽  
To Receive

Lung cancer is the leading cause of cancer death worldwide. Despite the emergence of highly effective targeted therapies, up to 30% of advanced stage non-small cell lung cancer (NSCLC) patients do not undergo tissue molecular testing because of scarce tissue availability. Liquid biopsy, on the other hand, offers these patients a valuable opportunity to receive the best treatment options in a timely manner. Indeed, besides being much faster and less invasive than conventional tissue-based analysis, it can also yield specific information about the genetic make-up and evolution of patients’ tumors. However, several issues, including lack of standardized protocols for sample collection, processing, and interpretation, still need to be addressed before liquid biopsy can be fully incorporated into routine oncology practice. Here, we reviewed the most important challenges hindering the implementation of liquid biopsy in oncology practice, as well as the great advantages of this approach for the treatment of NSCLC patients.

scholarly journals NCOG-19. BEVACIZUMAB IN REAL LIFE PATIENTS WITH RECURRENT GLIOBLASTOMA: BENEFIT OR FUTILITY?

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii133-ii133
Author(s):  
Cristina Smolenschi ◽  
Emeline Colomba ◽  
Elie Rassy ◽  
Naima Lezghed ◽  
Mohamed Kettab ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Therapeutic Option ◽  
Performance Status ◽  
Objective Response ◽  
Real Life ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Arterial Bleeding ◽  
Substantial Clinical Benefit ◽  
Radiological Response

Abstract Angiogenesis represents a hallmark of glioblastoma but most trials disappointed and failed to change the poor outcome of this disease. However, Bevacizumab (Bev) is widely used in clinical practice by expert oncologists due to experience or efficacy in real life.We retrospectively reviewed the use of Bev and its benefit in terms of Time to treatment failure (TTF), Overall Survival(OS), Objective Response Rate (ORR) and clinical benefit. METHODS: We analyzed two hundred and two patients treated at Gustave Roussy Cancer Campus with Bev until definitive failure for recurrent glioblastoma between 2006 and 2016. Patients were treated with Bev alone or in association with radiotherapy, temozolomide, lomustine or irinotecan. RESULTS: The median duration of Bev treatment until definitive failure was 6 months. The median TTF was 7.27 months(95%CI 6.30-8.24) and the median OS from diagnosis was 22.43 months(95%CI 19.68-25.18). Two patients were still alive without active treatment at the end of study. A hundred and fourteen (56%) patients experienced symptom amelioration and seventy-five (37%) improved their Performance Status. Fifty percent of patients exhibited Partial and Complete Response on MRI, as best radiological response, within 1.6 months. No patient had anaphylactic reaction. Grade 1-2 hypertension(HT)(17%) and grade 1(10%) proteinuria were most common. Six patients presented lethal toxicity: 4 with GI perforation, 1 p with cerebral hemorrhage and 1 p with arterial bleeding. HT was correlated with treatment response in 67% of patients. A neutrophil count superior to 6000/mm³ was associated with longer TTF(mTTF 8.23m(95%CI 6.64-9.82). CONCLUSION: This retrospective study reports a substantial clinical benefit of Bev in patients with recurrent glioblastoma with an acceptable toxicity profile. As the panel of therapeutic option is still very limited in these tumors, this work supports the maintained use of Bev as a therapeutic option.

Role of 18F-FDG PET-derived parameters for predicting complete response to chemoradiotherapy in squamous cell anal carcinoma

2020 ◽  
Vol 41 (10) ◽  
pp. 1089-1094 ◽  
Author(s):  
Luca Filippi ◽  
Antonella Fontana ◽  
Gian Paolo Spinelli ◽  
Lugi Rossi ◽  
Oreste Bagni
Keyword(s):  
Squamous Cell ◽  
Fdg Pet ◽  
Anal Carcinoma ◽  
Complete Response ◽  
18F Fdg

Role of routine fluid replacement in children undergoing tonsillectomy

1990 ◽  
Vol 104 (10) ◽  
pp. 801-802 ◽  
Author(s):  
P. S. Wilson ◽  
D. G. Snow ◽  
J. O'Connel ◽  
D. W. Proops ◽  
M. Barrow
Keyword(s):  
Blood Loss ◽  
Prospective Study ◽  
Intravenous Infusion ◽  
Intravenous Fluid ◽  
Fluid Replacement ◽  
Control Group ◽  
A Prospective Study ◽  
To Receive

AbstractIt has been suggested that children undergoing tonsillectomy would benefit from an intravenous infusion, to counteract the period of pre-operativefasting combined with the blood loss at operation.A prospective study of 50 children undergoing tonsillectomy was undertaken. The children were randomly allocated into two groups, one to receive an infusion and a control group.There were no significant differences between the two groups, although the children with an infusion had a longer mean post-operative stay.There would seem to be no role for routine intravenous fluid replacement in children undergoing uncomplicated tonsillectomy.

Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)

2004 ◽  
Vol 22 (12) ◽  
pp. 2313-2320 ◽  
Author(s):  
Bent Ejlertsen ◽  
Henning T. Mouridsen ◽  
Sven T. Langkjer ◽  
Jorn Andersen ◽  
Johanna Sjöström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Response Rate ◽  
Complete Response Rate ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Severe Toxicity ◽  
Free Survival

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m2 (950 mg/m2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

Obinutuzumab short-duration infusion (SDI) in previously untreated advanced follicular lymphoma: Results from the end of induction analysis of the phase IV GAZELLE study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7545-7545
Author(s):  
Miguel Angel A. Canales Albendea ◽  
Thomas A. Buchholz ◽  
Koji Izutsu ◽  
Takayuki Ishikawa ◽  
Laura Maria Fogliatto ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
Primary Analysis ◽  
Open Label ◽  
Secondary Endpoints ◽  
To Receive ◽  
Phase Iv

7545 Background: Obinutuzumab (G)-chemotherapy (chemo) has demonstrated improved progression-free survival compared with rituximab (R)-chemo in previously untreated advanced follicular lymphoma (FL). G is currently administered by IV infusion over ̃3–4 hours. A shorter duration of infusion in Cycle (C) 2 and subsequent cycles, as is standard practice with R, could improve convenience for patients (pts) and efficiency for infusion facilities. We report the primary analysis of the prospective, open-label, multicenter, single-arm, Phase IV, GAZELLE study (NCT03817853), which evaluated the safety of G administered as a 90-minute (min) SDI from C2 onwards in pts with FL. Methods: Pts with previously untreated FL received G (1000mg) intravenously on Day (D) 1, 8, and 15 of C1, and on D1 thereafter, plus chemo (bendamustine, CHOP, or CVP) for 6–8 cycles. In C1, pts received G at the standard infusion rate. Pts without a Grade (Gr) ≥3 infusion-related reaction (IRR) in C1 were eligible to receive G as a 90-min SDI from C2. Pts with a Gr 3 IRR in C1 received the standard G infusion in C2, and were eligible for G SDI in subsequent cycles if no Gr ≥3 IRRs occurred. Pts with a second Gr 3/4 IRR discontinued G. At the end of induction (EOI), responding pts received maintenance G (1000mg) as SDI for 2 years or until disease progression (PD). The primary endpoint was incidence of Gr ≥3 IRRs during C2. IRRs were defined as any event occurring ≤24 hours from infusion judged to be related to treatment. Secondary endpoints included adverse events (AEs) and investigator-assessed overall response rate at EOI. Results: As of December 3, 2020, 113 pts had received study treatment. Median age was 62.0 years, 50.4% were male, 61.9% had stage IV FL, and 45.1% were classified as high-risk FLIPI. Of the 110 pts who were eligible for G SDI from C2, no pt experienced a Gr ≥3 IRR with SDI in C2 (Table). One pt experienced a Gr 3 IRR with SDI in C5, presenting hypertension. All other IRRs with SDI were Gr 1/2. No Gr 4/5 IRRs were reported. Other AEs were similar to those observed in previous studies. At the clinical cut-off date, 104 pts had a CT imaging-based response assessment at EOI and 9 pts had no response assessment; 76/113 (67.3%) had a complete response, 22 (19.5%) had a partial response, and six (5.8%) had PD. Conclusions: In GAZELLE, G SDI in C2 and beyond appeared to be safe. No Gr 3 IRRs were observed in C2 and only one Gr 3 IRR was reported in subsequent cycles. The safety profile of G SDI was comparable with the established profile of G in advanced FL. Clinical trial information: NCT03817853. [Table: see text]

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