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.

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.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA2-LBA2
Author(s):  
Rui-hua Xu ◽  
Hai-Qiang Mai ◽  
Qiu-Yan Chen ◽  
Dongping Chen ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Double Blind ◽  
Grade 3 ◽  
First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

scholarly journals Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer

2014 ◽  
Vol 32 (25) ◽  
pp. 2735-2743 ◽  
Author(s):  
Ezra E.W. Cohen ◽  
Theodore G. Karrison ◽  
Masha Kocherginsky ◽  
Jeffrey Mueller ◽  
Robyn Egan ◽  
...  
Keyword(s):  
Head And Neck ◽  
Induction Chemotherapy ◽  
Locally Advanced ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Distant Failure ◽  
Common Grade ◽  
Treatment Naïve ◽  
Grade 3

Purpose Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. Patients and Methods Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). Results A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. Conclusion IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.

scholarly journals Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581880304 ◽  
Author(s):  
Con Murphy ◽  
Stephen Byrne ◽  
Gul Ahmed ◽  
Andrew Kenny ◽  
James Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cost Savings ◽  
Cost Effective ◽  
Public Hospitals ◽  
Severe Toxicity ◽  
Care Payer ◽  
Input Variables ◽  
Grade 3 ◽  
The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

WP1-21 Maximum safe resection of large medial temporal intrinsic tumours: does the outcome justify the risk?

2019 ◽  
Vol 90 (3) ◽  
pp. e7.1-e7
Author(s):  
A Kumaria ◽  
A Paterson ◽  
M Sitaraman ◽  
S Basu
Keyword(s):  
Case Series ◽  
Csf Leak ◽  
Visual Field Defects ◽  
Long Term Outcomes ◽  
Karnofsky Score ◽  
Female Age ◽  
Grade 3 ◽  
Age Range

ObjectivesTo analyse on the long-term outcomes in patients undergoing maximum safe resection (MSR) for large intrinsic temporal tumours.DesignCase seriesSubjectsAll patients undergoing MSR of large medial temporal intrinsic tumours between May 2006 and February 2012 at a tertiary neurosurgical centre with a minimum follow up of 6 years.MethodsRetrospective review of hospital records.ResultsFifty-one patients underwent MSR (28 male, 23 female); age range 20–80 years (mean age 55.3). There was no difference in laterality, although dysphasia was a feature in 32% of left-sided lesions. Presenting features in general included seizures (46%), headaches (27%), hemiparesis (12%) and visual field defects (6%). Surgery was generally well tolerated (median post-operative Karnofsky score 92.5). No patients developed new dysphasia or weakness, but there was transient worsening of existing hemiparesis (n=4) and dysphasia (n=2). Other complications included CSF leak/pseudomeningocoele (n=2), oculomotor palsy (n=1) and wound infection (n=1). Histopathological casemix was GBM (50%), WHO 3 gliomas (14%), WHO 2 gliomas (10%) and metastases (4%). In total, 57% of patients received radiotherapy and 35% received chemotherapy. Survival correlated with pathology; in glioblastoma patients it ranged from 2–19 months (mean 10.4 months). Survival in grade 3 tumours ranged from 10–38 months (mean 24.4 months). 60% of patients with Grade 2 tumours are surviving symptom free with no histological upscale at 8–10 years follow-up. No patient required a second debulking procedure.ConclusionsMSR did not result in survival benefit in glioblastoma. MSR is justified in lesions with pre-operative radiological features of Grade 2 glioma.

Preoperative radiotherapy and docetaxel in resectable pancreatic adenocarcinoma: A phase II trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4099-4099 ◽  
Author(s):  
F. Viret ◽  
M. Ychou ◽  
V. Moutardier ◽  
V. Magnin ◽  
P. Rouanet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pancreatic Adenocarcinoma ◽  
Median Overall Survival ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Pathological Response ◽  
Phase Iii ◽  
Additional Patient ◽  
Curative Intent ◽  
Grade 3

4099 Background: We previously reported results a phase I trial of weekly docetaxel concurrently with radiation therapy in patients (pts) with locally advanced pancreatic adenocarcinoma (Pancreas, Vol 27, N°3, 2003). We prospectively explored this regimen in 34 pts with biopsy proven potentially resectable pancreatic adenocarcinoma. Methods: Treatment consisted of concomitant radiotherapy (45 Gy within 5 weeks directed at the pancreatic tumor and regional lymphatics) with 5 weekly doses of docetaxel (30 mg/m2/week) by 1-hour infusion, followed by a complete staging evaluation 3–4 weeks after chemo-radiation. Pts without disease progression underwent surgery. Results: From May, 2003 to July, 2005, this study enrolled 34 pts (59% men) with median age 62 years (range 45–72). Median tumor size was 3 cm. Pretreatment Endoscopic Ultrasound (EUS) staging was uT1 (7 pts), uT2 (25 pts), uT3 (2pts), uN0 (26 pts) and uN1 (8 pts). Median pretreatment CA 19.9 levels was 114 (range 1–9432). All pts (97%) but one completed radiation and 91% (31 pts) received the 5 weekly doses of docetaxel. Adverse events included grade 3/4 asthenia (28%), grade 3/4 nausea/vomiting (10%), grade 3/4 anemia (7%) and grade 3/4 neutropenia (7%). Median time between diagnosis and surgery was 3.7 months (range 2.8–8.7). Ten pts (29%) presented progressive disease after chemo-radiation and one additional patient (pt) voluntary stopped treatment procedure. Twenty three pts (68%) underwent surgical procedure, which was with curative intent in 17 pts (50%). One pt died within the 30-day post operative period. Pathological response was observed in 7 pts (30%), including 2 complete response. The median Disease Free Survival (DFS) was 11 months and the 2-year DFS was 21%. The median overall survival (OS) was 14 months. The 2-year DFS for the 17 pts resected with a curative intent was 50.4%. In this subgroup, median overall survival was not reached. Conclusions: Pre-operative combination of radiotherapy and docetaxel is feasible with tolerable toxicity and with promising pathological response. A randomized phase III study comparing this regimen (radiotherapy and docetaxel) and surgery versus surgery alone is starting. Supported in part by Sanofi Aventis, France. No significant financial relationships to disclose.

Randomized phase II trial of concomitant CT/RT versus TPF followed by concomitant CT/RT in locally advanced squamous cell carcinoma of the head and neck (LASCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5518-5518 ◽  
Author(s):  
A. Paccagnella ◽  
A. Buffoli ◽  
H. Koussis ◽  
P. D’Amanzo ◽  
L. Loreggian ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Locally Advanced ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Randomized Phase Ii ◽  
Phase Iii Study ◽  
The Difference ◽  
Grade 3 ◽  
Toxicity Pattern ◽  
Pathological Cr

5518 Background: Concomitant CT/RT is the standard treatment for LASCCHN. Induction chemotherapy followed by CT/RT vs CT/RT alone have not yet been compared. The feasibility of TPF followed by CT/RT has been evaluated in a previous study (Int J Rad Oncol Biol Phys 2004, 59:481). Methods: Pts with inoperable stage III-IVa, PS 0–1, were randomized to CT/RT [2 cycles of Cisplatin 20 mg/sqm days 1–4, 5FU 800 mg/sqm 96 hours c.i. weeks 1 and 6 during RT (66–70 Gy)] (Arm A) or 3 cycles of neoadjuvant TPF (Docetaxel 75mg/sqm day1, Cisplatin 80mg/sqm day1, 5FU 800mg/sqm 96 hours c.i) followed by the same CT/RT (Arm B). Pts were stratified according to tumor site, T stage and nodal status. Neck dissection was performed in N2-N3 patients with pathological CR on primary tumor. The planned sample size was 96 pts to detect a difference in CR (primary endpoint) up to 15% in favour of arm B. The radiological responses were evaluated by an internal committee according to RECIST criteria. Results: Preliminary data are available for 84/96 randomized pts (42 arm A, 42 arm B). Pts/tumor characteristics are well balanced in the two arms. Toxicities during induction TPF consisted primarily of G3–4 granulocytopenia 56% (febrile neutropenia: 7.5%). Grade 3–4 toxicities during CT/RT in arm A and B were mucositis (42% and 26%), dysphagia (20% and 9%), skin reaction (12% and 8.6%), asthenia (5% and 3%); G3 weight loss (2% and 3%), G3 dry-mouth (0% and 3%). Duration of CT/RT was equivalent: 6.1 wks (4.2–8.7) in arm A and 6.3 wks (3.8–9.5) in arm B. At the end of CT/RT, in the 82 pts evaluable for efficacy, radiological CR were 20% (95% CI 8–37%) in arm A and 64% (95% CI 45–80%) in arm B. Conclusions: Three cycles of neoadjuvant TPF are feasible and don’t compromise subsequent concomitant CT/RT with comparable toxicity pattern. At the end of the treatment sequence serious adverse events were 31% in arm A and 34% in arm B. The difference in CR of 40% in favour of arm B justifies the following phase III study. Final results including pCR and DFS will be presented at the meeting. [Table: see text]

Updated analysis of SWOG 0023: A randomized phase III trial of gefitinib versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients with locally advanced stage III non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7513-7513 ◽  
Author(s):  
K. Kelly ◽  
K. Chansky ◽  
L. E. Gaspar ◽  
J. R. Jett ◽  
Y. Ung ◽  
...  
Keyword(s):  
Median Survival ◽  
Alternative Hypothesis ◽  
Locally Advanced ◽  
Phase Iii ◽  
Stage Iii ◽  
Definitive Treatment ◽  
Logrank Test ◽  
Ideal Agent ◽  
Thoracic Radiation ◽  
Grade 3

7513 Background: Early clinical studies with gefitinib (G) showed promising efficacy and mild toxicity in patients (pts) with advanced NSCLC. Thus, G was an ideal agent to evaluate in a maintenance setting in stage III disease following definitive treatment. Methods: Untreated pts with stage III NSCLC, a PS of 0–1 and adequate organ function were eligible. Patients received the SWOG 9504 core regimen (cisplatin 50 mg/m2, d1 & 8 plus etoposide 50 mg/m2 day 1–5, every 28 days for 2 cycles with concurrent thoracic radiation, 1.8–2 Gy fractions/day, total dose 61 Gy, followed by 3 cycles of docetaxel 75 mg/m2). Non- progressing pts were randomized to G 250 mg per day or placebo (P) until disease progression, intolerable toxicity or 5 years. The planned sample size was 672, to confer power of 0.89 to detect a 33% increase over the expected median survival of 21 months (one-sided 0.025 level logrank test). Randomization was stratified by stage and histology. Results: Enrollment began in July 2001. An unplanned interim analysis prompted by outside data was conducted in April 2005 and the alternative hypothesis of improved survival was rejected at the 0.0015 level for 243 randomized patients. The study closed and preliminary results were reported (ASCO 2005). Now with a median follow up of 27 months, median survival for the G arm (n=118) was 23 months and was 35 months for the P arm (n=125) (two sided p=0.013). Overall survival for the 571eligible patients was 19 months. ≥ Grade 3 toxicities in the G arm were rash (7%), diarrhea (7%) and pneumonitis (3%). Conclusion: In this unselected population G did not improve survival. Decreased survival was due to cancer not G toxicity. Three year survival estimates will be presented. Molecular studies of the EGFR pathway are underway and will be correlated with outcomes. No significant financial relationships to disclose.

Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
D. L. Nielsen ◽  
S. T. Langkjer ◽  
K. Bjerre ◽  
S. Cold ◽  
L. Stenbygaard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Rank Test ◽  
Hematologic Toxicity ◽  
Phase Iii Study ◽  
Her 2 ◽  
Grade 3

1015 Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented. No significant financial relationships to disclose.

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