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M. Fukuda
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-045 - Drug Fever After Cancer Chemotherapy Is Most Commonly Observed on Post-Treatment Days 3-4 (ID 466)
09:30 - 09:30 | Author(s): M. Fukuda
- Abstract
Background:
Fever during cancer chemotherapy is require attention using antibiotics to prevention severe infection. On the other hand, it should be avoid using antibiotics to non-infectious fever such as drug and tumor fever with the object of development of resistant bacteria, exacerbation of drug fever, and medical economics.
Methods:
Retrospectively, 1,016 consecutive cycles of cancer chemotherapy were analyzed. Fever was defined as a temperature of ≥37.5°C. Age, sex, tumor histology, the treatment regimen, the timing of fever onset, the number of days for which the fever persisted, the cause of the fever, and the presence or absence of radiotherapy were examined.
Results:
Seventy-four percent of the patients (748 of 1016) were males, the patients’ median age was 68 years (range: from 29 to 88 years), and lung cancer was the most common disease (93%). Fevers occurred in 36% of cycles (367 of 1016) including 37% of those involving males and 32% of those involving females. There was no difference in the frequency of fever among the sexes (p=0.146). The incidence of fever according to age were 33% (≤60), 41% (61-65), 36% (66-70), 33% (71-75), 41% (76-80), and 33% (≥81); it did not differ significantly with age (p=0.424). In incidence of fever according to the drugs administered, gemcitabine was the drug that was most frequently associated with fever (41%; 43/106), followed by irinotecan (40%; 108/272), amrubicin (39%; 29/75), and docetaxel (36%; 47/131). Post-treatment days 4 (8.3%), 3 (6.8%), and 12 (6.7%) were the days on which fever was most common. The distribution of fever exhibited a bimodal distribution; i.e., whilst it peaked on post-treatment days 3 and 4; otherwise, it generally gradually increased until day 12 and then gradually decreased. The peak on post-treatment days 3-4 was considered to be due to adverse drug reactions, and the latter peak was considered to represent neutropenic or infection-based fevers. Fevers occurred on post-treatment days 3-4 in 11% of all cycles (113 of 1016) including 11% (84 of 748) of the cycles involving males and 11% (29 of 268) of those involving females. The incidence of fever on post-treatment days 3-4 according to age were 12% (≤60), 13% (61-65), 10% (66-70), 8% (71-75), 13% (76-80), and 10% (≥81); however, this parameter did not differ significantly with age (p=0.427). The incidence of fever on post-treatment days 3-4, gemcitabine was the drug that was most commonly associated with fever (20%), followed by docetaxel (18%), nedaplatin (12%), and carboplatin (11%). The patients’ fevers were caused by infections (47%), adverse drug reactions (24%), unknown causes (19%), and tumors (7%). The causative infections included febrile neutropenia (50%), pneumonia (18%), unidentified infections (9%), and colitis (7%). The incidence of fever was significantly higher among the patients treated with radiotherapy than among those that did not receive radiotherapy (46% vs. 34%, p=0.001).
Conclusion:
The febrile episodes that occurred on post-treatment days 3-4 were considered to represent adverse drug reactions after cancer chemotherapy. Physicians should be aware of this feature of chemotherapy-associated fever and avoid unnecessary examination and treatments including prescribing antibiotics.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-055 - Prospective Study of UGT1A1*27 Gene Polymorphism for Irinotecan Therapy: Result of Lung Oncology Group in Kyushu (LOGiK1004B) (ID 675)
09:30 - 09:30 | Author(s): M. Fukuda
- Abstract
Background:
UGT1A1*27 is known that exist together with UGT1A1*28 as linkage disequilibrium and impair the effect of UDP-glucuronosyltransferase (UGT) in basic research, however, poor clinical investigation because of the rare frequency. The aim of this study is to evaluate the effect of UGT1A1*27 gene polymorphism for safety and efficacy in irinotecan therapy.
Methods:
Eligibility criteria were: lung cancer patients; scheduled the dose of irinotecan therapy as single ≥ 80 mg/m[2], combination ≥ 50 mg/m[2], radiation with single ≥ 50 mg/m[2], radiation with combination ≥ 40 mg/m[2]; age ≥ 20 years; performance status 0-2. After informed consents, patients were enrolled and collected the blood to examine UGT1A1*28 and UGT1A1*6 polymorphism and received irinotecan therapy. Examination of UGT1A1*27 were added when founding UGT1A1*28 polymorphism. We planned 111 enrollment for an accrual of 10 patients with UGT1A1*27 gene polymorphism.
Results:
Fifty patients were enrolled in this trial between October 2011 and December 2013. Two patients judged protocol violation. Remaining 48 were evaluated. UGT1A1 gene polymorphisms *28/*28, *6/*6, *28/*6, *28/-, *6/-, -/- observed 0, 1, 1, 7, 17 and 22, respectively. UGT1A1*27 were analyzed in 9 patients including ineligible one patients with *28/*28, however, no UGT1A1*27 gene polymorphism was found and the study was stopped. A total of 153 times of irinotecan therapy were administered with a median of 3 times per one patient: 1 time in 7 patients (15%), 2 times in 9 (19%), 3 in 19 (40%), 4 in 3 (6%), 5 in 1 (2%), and 6 in 9 (19%). Irinotecan were used as combination chemotherapy in 32 (67%) patients, with cisplatin in 12 (25%), carboplatin in 10 (21%), gemcitabine in 9 (19%), paclitaxel in 1 (2%). In remaining 16 patients (33%), only irinotecan single therapy were administered. Radiotherapies were administered concurrently in 23 (48%) patients with median 60 (range 40-61.4) Gy. Febrile neutropenia were observed higher tendency in patients with UGT1A1*6 (32%) and UGT1A1*28 (25%) gene polymorphism compare with wild type (14%) but had no significant difference. Grade 3/ 4 leukopenia and neutropenia were observed in 6 out of 8 patients with UGT1A1*28 gene polymorphism and significant higher compare with wild type (75% vs. 32%, p=0.049; 75% vs. 36%, p=0.039, respectively). The other toxicities have no difference between UGT1A1 gene polymorphism and wild type. There was no pneumonitis and treatment-related death. Tumor response was not evaluated because not included endpoints. Median PFS of 48 patients was 6.8 months and the 1- and 2-year survival rates were 20.8%. Median PFS separated by UGT1A1 gene polymorphisms were 10.1 months in UGT1A1*28 heterozygous, 8.5 months in UGT1A1*6 heterozygous, and 6.8 months in both wild type, respectively. Median OS of 48 patients was 15.7 months and the 1- and 2-year survival rates were 57.7% and 40.3%, respectively. Median OS separated by UGT1A1 gene polymorphisms were not reached in in UGT1A1*28 heterozygous, 16.4 months in UGT1A1*6 heterozygous, and 12.3 months in wild type, respectively.
Conclusion:
UGT1A1*27 gene polymorphism was not found in our methods. Further investigation might be warranted in patients with UGT1A1*28 wild type.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-069 - Phase II Trial of Paclitaxel, Irinotecan, and Bevacizumab for Patients with Untreated NSCLC Overexpressed ERCC1 MRNA; Evaluated by EBUS-GS (ID 1362)
09:30 - 09:30 | Author(s): M. Fukuda
- Abstract
Background:
We prospectively evaluated the efficacy and toxicity of non-platinum triplet regimen, which consist of paclitaxel, irinotecan, and bevacizumab for patients with advanced non-small cell lung cancer (NSCLC) expected to be platinum resistant.
Methods:
All patients were diagnosed with NSCLC using endobronchial ultrasonography with a guide sheath (EBUS-GS) system. We defined the EBUS-GS as a core biopsy. RNA was immediately isolated from this unfixed biopsy specimens, and quantitative real-time reverse transcriptase PCR assays were performed to determine the excision repair cross-complementing 1 (ERCC1) mRNA expression. Patients with advanced, untreated NSCLC showing high ERCC1 levels (ΔCt≧6.5) were entered the phase II trial of the non-platinum triplet regimen. Paclitaxel of 180mg/m2 on day 1, irinotecan of 50mg/m2 on day 1 and 8, and bevacizumab of 15mg/kg on day 1 were administered every 4 weeks. Primary end point was the objective response rate (ORR), assuming 30% for a standard therapy and 60% for a target therapy (alpha=0.05 and beta=0.1), and the estimated required total number of patients was 28 by Simon’s Optimal Two-stage Design.
Results:
Total 141 untreated patients received EBUS-GS and were evaluated the expression of ERCC1, and 30 patients were entered in this trial. The ORR was 66.7%(95% confidence interval [CI]: 47.2-82.7). Median progression-free survival was 174 days. Grade 4 thrombosis occurred one patient, but other toxicities were mild and controllable. Fifty-three patients were treated with platinum-containing regimens and 22 patients were responded (ORR was 41.5% [95% CI: 28.1-55.9]). Twenty-three of these patients were high ERCC1 levels and 6 patients were responded, and 30 patients were low ERCC1 levels and 16 patients were responded (p=0.0053, by Fisher’s exact test).
Conclusion:
The triplet combination of paclitaxel, irinotecan and bevacizumab might be effective for patients with advanced, untreated NSCLC overexpressing ERCC1. ERCC1 mRNA levels extracted from unfixed lung biopsy specimens obtained by EBUS-GS also might be a predictive factor for platinum-containing regimens.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-008 - Detection of EML4-ALK Fusion Gene by Using Nested Long-Ranged Polymerase Chain Reaction (ID 704)
09:30 - 09:30 | Author(s): M. Fukuda
- Abstract
Background:
The fusion of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein-like 4 (EML4) was identified in Non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors were proved to be superior to standard chemotherapies and it is important to detect EML4-ALK fusion gene accurately. Reverse transcriptase-polymerase chain reaction (RT-PCR), Fluorescence in situ hybridization (FISH) and Immunohistochemical (IHC) stain are performed clinically to detect the fusion gene. However, there are discrepancies among these methods for detection of EML4-ALK fusion gene and the best detection method remain unknown. The purpose of this study was to evaluate the new method for detection of the EML4-ALK fusion gene.
Methods:
The combination of nested polymerase chain reaction (PCR) and ｌong-ranged PCR (Nested long-ranged PCR) was used to detect EML4-ALK fusion gene. Genomic deoxyribonucleic acid (gDNA) was extracted from EML4-ALK positive lung cancer cell lines (NCI-H2228,NCI-H3122,ALKSFA8). It was verified whether the fusion gene was amplified. We evaluated the sensitivity of Nested long-ranged PCR for EML4-ALK fusion gene in various ratios. It was confirmed whether the amplification products were EML4-ALK fusion gene by using PCR direct Sequencing.
Results:
EML4-ALK fusion genes were detectable successfully in each of EML4-ALK positive lung cancer cell lines.NCI-H3122 had EML4-ALK variant 1. ALK-SFA8 and NCI-H2228 had EML4-ALK variant 3a/b. One fusion gene in the presence of 1×10[2] wild type genes was detectable in each cell line. Each PCR product was confirmed by sequencing from both ends.
Conclusion:
In this study, we were able to detect the fusion gene in vitro by Nested long-ranged PCR. This may become a new diagnostic method for EML4-ALK fusion gene.
