Irinotecan-containing Chemotherapy Research Articles

ATM or CHEK2 alterations: Potential biomarkers of improved outcomes with irinotecan-containing chemotherapy in advanced pancreatic ductal adenocarcinoma.

754 Background: ATM and CHEK2 mutations are linked to homologous recombination DNA repair deficiency, with the potential for improved therapeutic response to DNA damaging agents. To investigate our clinical observation of improved outcomes with irinotecan (IRI) based chemotherapy in advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) with somatic or germline ATM/ CHEK2 mutations, we examined our institutional real world experience. Methods: Between 2015-2021, 33 pts with ATM or CHEK2 mutations treated with chemotherapy were identified, of which 16 pts had advanced/metastatic disease. Progression-free survival (PFS) was calculated and compared (Kaplan Meier, log-rank test) in several ways to assess the impact of IRI vs platinum or other regimens. The event for PFS was progression (or death), and pts without progression were censored at treatment end, or at last follow up if treatment was ongoing. Results: Among 16 pts with advanced/metastatic PDAC, 8 (50%) had ATM (5 germline, 3 somatic) and 8 (50%), CHEK2 alterations (4 germline, 4 somatic). Overall, pts received 48 lines of chemotherapy (platinum-based-(No-IRI) N=14; IRI-based-(No-Platinum) N=8; both N=4; none N=22). For best-PFS among pts analysis, median line of best-PFS therapy for IRI-Ever (N=9 pts) was 2nd line (range 1-7) and for IRI-Never (N=7 pts) was 1st (range, 1-1); median PFS was 13 vs 3 months (mo) (IRI-Ever vs IRI-Never; p=0.0076). For PFS analysis within lines of treatment of each pt, median therapy line for both IRI-containing and No-IRI lines was 2nd line (range 1-7); median PFS for IRI-containing (N=12 lines of therapy) vs No-IRI (N=36) was 12.1 vs 3 mo (p<0.001). Median PFS for best IRI-based-(No-Platinum) line (N=7) was 13 mo; for best platinum-based-(No-IRI) line (N=9) was 2.8 mo; and for best treatment containing no IRI or platinum (N=13) was 5.1 mo (P= 0.003) (median therapy line for each was 3, 2 and 1.5, respectively). Conclusions: Irinotecan is a topoisomerase 1 inhibitor that induces DNA strand breaks, potentially causing synthetic lethality in tumors with DNA damage repair deficits due to ATM or CHEK2 alterations. IRI-containing therapy out-performed other treatment types, including platinum-containing regimens, in pts with ATM or CHEK2-mutated advanced/metastatic PDAC. Prospective trials are warranted.

Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity.

Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A. A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe. Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n=15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n=23) or modified FOLFIRINOX for pancreatic cancer (n=40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p=0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n=66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n=47). Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

The UGT1A9*22 genotype identifies a high-risk group for irinotecan toxicity among gastric cancer patients.

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3 and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III–IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of toxicity such as severe diarrhea or neutropenia.

Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study.

Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment. All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis. During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50-60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71-8635; p<0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86-1233; p=0.070) in the complete case analysis. Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.

Phase Ib/II open-label, randomized evaluation of efficacy and safety of atezolizumab plus isatuximab versus regorafenib in MORPHEUS-colorectal cancer.

82 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across tumor types. Isatuximab (isa; anti-CD38) targets CD38 receptors expressed on immunosuppressive cells in the tumor microenvironment. We hypothesized atezolizumab (atezo; anti–PD-L1) + isa would induce an anti-tumor response beyond that of regorafenib (rego), a multi-kinase inhibitor, in patients (pts) with tx-refractory metastatic colorectal cancer (mCRC). Methods: This randomized Phase Ib/II trial (NCT03555149) enrolled pts with microsatellite stable/mismatched repair proficient mCRC who had received ≤ 2 prior tx lines (fluoropyrimidine-, oxaliplatin- or irinotecan-containing chemotherapy plus a biologic agent). Pts received atezo (1200 mg intravenously [IV] every 3 weeks [q3w]) + isa (10 mg/kg IV q3w) or control tx with rego (160 mg orally days 1–21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: Data cutoff date was March 3, 2020. Fifteen pts received atezo + isa and 13 pts received rego. Fourteen atezo + isa pts (93.3%) and 11 control arm pts (84.6%) had received 2 prior lines of tx; 9 atezo + isa pts (60.0%) and 9 control pts (69.2%) had liver metastases at enrollment. No responses were seen in either arm; 3 pts receiving atezo + isa (20.0%) and 8 control pts (61.5%) had stable disease as their best response. DCR (response and/or stable disease ≥ 12 weeks) was 6.7% with atezo + isa and 15.4% with control. One pt treated with atezo + isa beyond progression had prolonged disease stabilization. Median PFS was 1.4 mo (95% CI: 1.4, 1.8) with atezo + isa and 2.8 mo (95% CI: 1.6, 3.1) in the control arm; median OS was 5.1 mo (95% CI: 3.1, 7.8) with atezo + isa and 10.2 mo (95% CI: 4.8, not reached) with control. Tx-related adverse events (AEs, Grade 1-4) occurred in 13 atezo + isa pts (86.7%), and 12 control pts (92.3%). The most common tx-related AEs with atezo + isa were infusion-related reaction (73.3%), nausea (26.7%) and fatigue (20.0%). No Grade 5 AEs occurred in the atezo + isa arm, 1 (7.7%) was reported in the control arm (sepsis, considered unrelated to study tx). No atezo + isa pts and 1 control-arm pt (7.7%) withdrew from treatment due to a tx-related AE. Biomarker analyses did not identify any significant trends related to efficacy. Conclusions: In this trial, superior efficacy of atezo + isa vs rego was not shown. However, the atezo + isa combination was well tolerated, with a manageable safety profile. Clinical trial information: NCT03555149.

Efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin after progression on conventional irinotecan-containing chemotherapy for metastatic pancreatic adenocarcinoma.

382 Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.

Clinical outcomes of liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic adenocarcinoma in patients previously treated with conventional irinotecan-containing chemotherapy.

Introduction:Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated.Methods:In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment.Results:In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed (R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%).Conclusion:Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

Tumor Response to Irinotecan is Associated with IL-10 Expression Level in Metastatic Colorectal Cancer-Results from mCRC Biomarker Study.

PurposeMetastatic colorectal cancer (mCRC) is a leading cause of cancer-related death. Resistance to chemotherapy is the main reason for the failure of the treatment of mCRC. IL-10 has been reported to decrease after surgery and increase after mCRC reoccurrence. The role of IL-10 in chemotherapy drug resistance of mCRC is not well elucidated.Patients and MethodsThe retrospective study recruited 264 mCRC patients between January 2012 and December 2016 (NCT03532711). All the enrolled patients received an oxaliplatin-containing or irinotecan-containing regimen. The expression level of IL-10 in 232 patients’ plasma and 68 patients’ tumor tissue was examined. The relationships between IL-10 and clinicopathological characteristics were analyzed. Kaplan–Meier method and Cox regression were used to evaluate the prognostic impact of IL-10.ResultsThe median concentration of IL-10 was 7.60 pg/mL before treatment and 11.08 pg/mL after treatment, which suggested that IL-10 level was significantly increased by treatment with a chemotherapeutic regimen (p = 0.000). By utilizing univariate and multivariate Cox proportional hazard analyses, we found that low IL-10 level in plasma was significantly associated with improved overall survival (OS) of mCRC patients treated with irinotecan-containing regimen-with optimal cutoff value of 5.525pg/mL, respectively (p =0.002). In addition, the low IL-10 expression level in tumor tissue was significantly associated with the improved OS for the irinotecan-containing regimen (p = 0.023).ConclusionOur study demonstrated that IL-10 could act as a prognostic biomarker for mCRC patients undergoing irinotecan-containing chemotherapy.

Transarterial Chemoembolisation of Colorectal Liver Metastases with Irinotecan-Loaded Beads: A Bi-institutional Analysis of 125 Treatments in 53 Patients.

To retrospectively review outcomes in patients treated for colorectal liver metastases with DEBIRI. A retrospective analysis of patients with CRLM treated with DEBIRI was performed between 2008 and 2017 between two tertiary centres. Outcome parameters were overall survival and hepatic progression-free survival, as well as safety. Subgroup analyses were performed to assess the impact on outcomes of hepatic tumour burden at time of treatment, the presence of extrahepatic disease, prior systemic chemotherapy and the prior administration of systemic irinotecan-containing chemotherapy. Fifty-three patients received 125 treatments with DEBIRI over the study period. Median age of patients was 71 (range 41-88). Patients previously received a median of 1 line of chemotherapy (range 1-5). Median number of DEBIRI treatments was 2 (range 1-6). The median survival from first treatment was 14.5months (range 1-107). Median hepatic progression-free survival was 5months (0-86.5months). The presence of extrahepatic disease (seen in 45% of patients) correlated with lower OS. Prolonged OS was seen in patients who received previous ablation and systemic chemotherapy. Technical success rate was found to be 99%. Post-procedural complication rate was 6%. Our findings add to the growing body of literature to support the safety profile of DEBIRI in the treatment of CRLM. Further studies will be necessary to help establish the optimum berth of DEBIRI in the treatment algorithm for colorectal liver metastases.

Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity.

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.

2313 Multicenter retrospective analysis of pancreatic acinar cell carcinoma: Overall survival and potential benefit of platinum- or irinotecan-containing chemotherapy

2313 Multicenter retrospective analysis of pancreatic acinar cell carcinoma: Overall survival and potential benefit of platinum- or irinotecan-containing chemotherapy

Is panitumumab monotherapy safe in metastatic colorectal cancer patients over 70 years old?

714 Background: Metastatic Colorectal Cancer (mCRC) often occurs in patients older than 70 years old. Monoclonal antibodies targeting EGFR have improved the outcome of mCRC patients. Panitumumab in monotherapy is indicated in wild-type K-RAS mCRC progressing disease following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. Very few data are available in elderly patients receiving panitumumab. Methods: Based on the cohort of the Observatory of Cancer B PL in France, we studied the efficacy and tolerance of panitumumab. We retrospectively collected data from patients treated between July 2008 and January 2014 and older than age 70 and compared the results between two cohorts: one contained patients ages 70 to 74; the other contained patients age 75 and older. Results: 136 patients were identified. The median age was 77. The median number of course received was 7 infusions. There was no difference in outcomes between the patients of the two cohorts. Median overall survival was 6.16 months. Median PFS was 13 weeks. The older patients received less previous chemotherapy ligns than the younger with a statistical difference (p=0.023). Tolerance was acceptable with a skin toxicity rate of 67% and 11.5% of grade 3-4. No diarrhea or hypomagnesemia were reported. Conclusions: Our study shows that panitumumab is feasible in elderly patients "in the real world" and has comparable efficacy than in younger patients.

Comparison Between Perioperative and Postoperative Chemotherapy After Potentially Curative Hepatic Resection for Metastatic Colorectal Cancer

Additional chemotherapy in patients with resectable colorectal liver metastases (CRLM) likely improves outcomes. Whether to administer chemotherapy as perioperative or adjuvant therapy remains controversial. We analyzed outcomes between these two treatment strategies. Patients were identified from a prospective CRLM database and studied retrospectively. Patients with extrahepatic disease or initially unresectable CRLM were excluded. Only patients receiving oxaliplatin- and/or irinotecan-containing chemotherapy regimens were included. Univariate and Cox regression models were developed for recurrence and death. Between 1998 and 2007, 236 patients (57.4 %) in the adjuvant group and 175 patients (42.6 %) in the perioperative group were compared. The perioperative group was younger and had more tumors, shorter disease-free intervals, and higher clinical risk scores (CRS), but had smaller tumors. The overall survival was similar between the groups (perioperative 72.9 months vs. adjuvant 71.5 months; p = 0.48). When the comparison was adjusted for other clinicopathologic factors and CRS, the differences remained insignificant. On univariate analysis, there was a significant difference in recurrence-free survival between the groups (perioperative 17.2 months vs. adjuvant 27.4 months, p = 0.036). However, when the recurrence-free survival was adjusted for other clinicopathologic factors and the CRS, differences were not significant. The timing of additional chemotherapy for resectable CRLM is not associated with outcomes. Trials comparing adjuvant and perioperative chemotherapy would have to be powered for small differences in outcome.

Associations between UGT1A1*6/*28 polymorphisms and irinotecan-induced severe toxicity in Chinese gastric or esophageal cancer patients

The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced gastric or esophageal cancer patients. The genotypes of UGT1A1*6 and UGT1A1*28 were analyzed by PCR amplification and Sanger sequencing in 42 gastric and 91 esophageal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1*6/*28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1*6/*28 variants in gastric cancer and esophageal cancer was 38.1 % (GA: 31.0 %; AA: 6.9 %), 28.6 % (TA6/TA7: 26.2 %; TA7/TA7: 2.4 %) and 33.0 % (GA: 28.6 %; AA: 4.4 %), 25.3 % (TA6/TA7: 23.1 %; TA7/TA7: 2.2 %) in our cohort, respectively. A total of 10 patients (gastric cancer: 9.5 %, 4/42; esophageal cancer: 6.6 %, 6/91) had severe diarrhea and 35 patients (gastric cancer: 35.7 %, 15/42; esophageal cancer: 22.0 %, 20/91) had severe neutropenia. Statistic analysis between UGT1A1 genotyping and severe diarrhea was not conducted due to the limited number of patients. For gastric cancer, it seemed that only UGT1A1*6 variant was associated with severe neutropenia (P = 0.042), while among esophageal cancer patients, UGT1A1*6 (P = 0.011) or UGT1A1*28 (P = 0.026) variants were significantly associated with severe neutropenia. UGT1A1*6 variant was closely associated with severe neutropenia both in gastric cancer and in esophageal cancer, but the association between UGT1A1*28 variant and severe neutropenia in gastric and esophageal cancer was not consistent in this study, which would be validated in the future large samples.

Sequential salvage chemotherapy for CDDP-refractory advanced testicular cancer: Japanese high-volume center experience.

e15526 Background: Chemotherapy- refractory or resistant GCTs, so called ‘difficult-to-treat’ GCTs would remain continuously disease-free with salvage chemotherapy or surgery. The optimal salvage chemotherapy remains unclear. The aim of this study was to assess the efficacy of ‘sequential’ chemotherapy for advanced testicular cancer. Methods: Salvage chemotherapy was required in 129 patients out of 233 advanced GCTs treated at Kyoto Prefectural University of Medicine from June, 1998 to December, 2011. Clinical outcomes were retrospectively assessed. Results: Median age was 31 year-old (range:17-65y.o.). Non-seminoma was in 111 cases (86.0%). IGCCC showed good in 37 cases (28.9%), intermediate 33 (25.6%), poor 47 (36.4%), and unknown 12 (9.1%). As the 2nd line therapy, VIP/VeIP and TIP/N therapy were done in 43 (33.3%) and 49 cases (38.0%), respectively. With regard to the patients requiring 3rd line or more chemotherapy, 95, 67, 40, 26 cases had 3rd, 4th, 5th and 6th line or more chemotherapy, respectively. TIN therapy was performed in 48 patients as 3rd line and in 24 patients as 4th line. Irinotecan-containing chemotherapy was done in 24 and 36 cased as 2nd +3rd line therapy and 4th line or more, respectively. Gemcitabine-containing therapy was done in 33 cases with 3rdline or more chemotherapy. Overall survival rate at median follow-up period was 71.0%at median follow-up of 48m. Overall survival stratified by IGCCC was shown in the figure. There was no significant difference between any two groups. Clinical outcomes showed no evidence of disease (NED) was obtained in 86.1% with second line therapy. Noteworthy mentioned, about 40% patients had NED even in the 4thline or more chemotherapy group. Conclusions: Relatively good prognosis was obtained in the patients with salvage chemotherapy at Japanese high volume center. Sequential continuous chemotherapy would be very important to manage ‘difficult-to-treat’ advanced germ cell tumors.

A phase II, randomized, double blind comparison of calcium aluminosilicate clay (CASAD) versus placebo (dibasic calcium carbonate) for the prevention of diarrhea in patients (pts) with metastatic colorectal cancer (mCRC) treated with irinotecan (I).

3600 Background: CASAD is a naturally occurring calcium montmorrilonite clay that serves as a cation exchange absorbent. One of the active metabolites of Irinotecan is SN-38, which is adsorbed by CASAD in vitro. The study hypothesis was that oral CASAD would reduce the rate of grade 3/4 diarrhea in mCRC patients treated with irinotecan. Methods: The study is a multicenter, prospective, randomized, double blinded placebo-controlled phase II trial. One hundred patients receiving I-based chemotherapy were randomized equally between CASAD (1000 mg po 4x daily) and placebo in order to have 75% power to detect a difference in the proportions of patients with grade 3/4 diarrhea within 6 weeks at a 1-sided 5% significance level. We also compared symptom burden using the MDASI questionnaire summed over the 13 symptom items for weeks 0, 3, 5, and 6. Results: Between 5/2009 and 5/2012, 100 patients were randomized in a 1:1 ratio between study arms. Median age 57 yrs, 54% male, 74% Non-Hispanic White, 93% performance status 0 or 1. Serious diarrhea was less frequent than expected based upon prior studies with Irinotecan. In evaluable patients, no significant difference in the rate of G3/4 diarrhea was seen (the primary endpoint): CASAD arm: 7/43 pts (16%), Placebo arm: 3/32 pts (9%), p=0.70. The rate of any diarrhea among all pts was also similar: CASAD arm 64% vs. Placebo arm 70%. The rate of study dropout was 14% in CASAD and 38% for placebo (p=0.01; 2-sided). No differences were found in symptom burden or individual symptom items or serious adverse events. Conclusions: Compared with placebo, CASAD use was safe but ineffective in preventing diarrhea in mCRC patients treated with irinotecan-containing chemotherapy regimens. There were no favorable or unfavorable signals in terms of the patient experience related to symptoms, but there were significantly more dropouts in the placebo arm. Future CASAD trials are focused on active treatment of diarrhea. Clinical trial information: NCT00748215.

UGT1A1*6/*28 polymorphisms could predict irinotecan-induced severe neutropenia not diarrhea in Chinese colorectal cancer patients

The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced colorectal cancer patients. The genotypes of UGT1A1 6 and UGT1A1 28 were analyzed by PCR amplification and Sanger sequencing in 276 advanced colorectal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1 6/28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1 6 and UGT1A1 28 variants was 35.5 % (GA: 28.6 %; AA: 6.9 %) and 21.0 % (TA6/TA7: 19.9 %; TA7/TA7: 1.1 %) in our cohort, respectively. A total of 16 patients (5.8 %, 16/276) had severe diarrhea and 56 patients (20.3 %, 56/276) had severe neutropenia. Neither UGT1A1 6 nor UGT1A1 28 variants were associated with severe diarrhea; however, either UGT1A1 6 (P = 0.001) or UGT1A1 28 (P = 0.029) variants were significantly associated with severe neutropenia. No differences were found between severe toxicities and clinical response in this study. Compared to western countries, Chinese patients had a distinct frequency of UGT1A1 6 or UGT1A1 28 genotypes. Both UGT1A1 6 and UGT1A1 28 variants were closely associated with irinotecan-induced severe neutropenia, but not diarrhea.

Antiemetic prophylaxis and frequency of chemotherapy-induced nausea and vomiting in palliative first-line treatment of colorectal cancer patients: the Northern Bavarian IVOPAK I Project

This study aims to evaluate adherence to guidelines of antiemetic prophylaxis and frequency of chemotherapy-induced nausea and vomiting (CINV) in the palliative first-line treatment of colorectal cancer (CRC) patients in Northern Bavaria. We collected detailed information on chemotherapy and supportive drugs in 103 patients within a prospective observational study. The study was conducted to determine quality of care within an interdisciplinary context (first endpoint) and direct costs of palliative treatment for patients with CRC between 2006 and 2010 (second endpoint, Emmert et al. (Eur J Health Econ, 2012) [1]). In this paper, we evaluate adherence to Multinational Association of Supportive Care in Cancer (MASCC) 2006 recommendations for prophylaxis of CINV during the first administration of chemotherapy as well as incidence and grade of CINV within 120 h thereafter. Of the patients studied, 95 patients (92%) received moderately emetogenic (oxaliplatin- and/or irinotecan-containing combined chemotherapy treatment) and eight (8%) received low emetogenic chemotherapy (either 5-fluorouracil (5-FU) or capecitabine monotherapy). Antiemetic prophylaxis could be assessed in 101 out of 103 (98%) of patients. MASCC-recommended antiemetic prophylaxis was prescribed in three patients (3%). Nonadherence was mainly caused by omission of dexamethasone. Nausea and/or vomiting occurred in 18 patients (18%) within a 120-h period. All documented episodes were grade 1 or 2 according to the Common Toxicity Criteria of the National Cancer Institute. None of these patients received the recommended prophylaxis for CINV. In only one patient, antiemetic prophylaxis was intensified during the next chemotherapy application. In the Integrated Health Care in the Palliative Treatment of Colorectal Carcinoma (IVOPAK) I Project, adherence to the MASCC clinical recommendations was very poor. Extent of CINV in this patient population seems to be underestimated. There is an urgent need to improve clinicians' awareness of this patient-relevant side effect.

Panitumumab (pmab) in patients (pts) with chemorefractory metastatic colorectal cancer (mCRC): Final analysis from a community-based, observational study (VECTOR) in Germany.

550 Background: Pmab monotherapy significantly improves progression-free survival versus best supportive care in pts with chemorefractory KRAS wild-type (WT) mCRC. This study evaluated the efficacy and safety of pmab in routine clinical practice in Germany. Methods: To ensure a representative sample, eligibility criteria were largely unrestricted. Consenting pts were &gt;18 years old, had histologically confirmed KRAS WT mCRC, &gt;4 weeks pmab therapy, failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy (CTx) regimens, and women of child-bearing age received contraception. Predefined endpoints were overall response rate (ORR; investigator`s assessment) and skin toxicity (NCI Common Terminology Criteria for Adverse Events v3.0). Results: A total of 428 pts were included in the full analysis set. At the start of pmab therapy, median age was 69 (range 22-89) years, 268 pts (63%) were male and 343 (80%) had an ECOG performance status of 0-1. Overall, 400 pts (93%) had undergone prior surgery and 154 (36%) had received ≥1 cycle of adjuvant CTx. Pts had received a median of 3 cycles (range: 1‑12) of prior CTx for mCRC. The most common regimens were FOLFOX/FOLFIRI ±antibody therapy; 65% of regimens were given with palliative, 32% with curative/palliative and 3% with curative intent. The median pmab dose was 6 mg/kg (range 2.4-7.2) q2w for a median of 8 (range 2‑45) cycles, with 143 pts (33%) receiving &gt;10 cycles. The ORR during pmab therapy was 20% (complete response: n=7 [2%]; partial response: n=77 [18%]); disease control (including stable disease) was achieved in 261 pts (61%). Skin reactions occurred in 324 pts (67%) with 52% experiencing a maximum grade ≥2. Most pts had some type of rash (48% acne, 5% desquamation, 4% hand-foot skin reaction, 1% erythema multiforme). Overall, 21% of pts had other toxicities. Three serious adverse drug reactions (infection/fever; thrombosis/embolism; erythema multiforme) and two grade 1 infusion reactions were reported. Conclusions: In this observational study, pmab monotherapy had efficacy at least as good as was seen in the randomised pmab trial and safety was also similar.

WS14-5 - Management of Advanced Testicular Cancer

ABSTRACT Introduction Though eighty percent of advanced germ cell tumors (GCTs) could be cured to date, only 20–30% of patients with chemotherapy refractory or resistant GCTs, so called ‘difficult-to-treat’ GCTs would remain continuously disease-free with salvage chemotherapy or surgery. International classification gave us to the information about induction and second-line chemotherapy, however, the optimal salvage chemotherapy remains unclear. In this session, we will review literatures and present our sequential chemotherapy strategy for advanced GCTs. Patients and methods Two hundred sixteen patients with advanced GCTs treated at Kyoto Prefectural University of Medicine from June 1998 to December 2011 were retrospectively assessed. Results Median age was 32 years (range: 17–68 years). Non-seminoma was in 181 cases (83.8%), regarding primary histology. IGCCC showed good in 94 cases (45.2%), intermediate 58 (27.9%), poor 56 (26.9%). As the induction therapy, BEP therapy was carried out in 190 cases (88.0%). Salvage chemotherapy was done for 121 cases. As the second-line therapy, VIP/VeIP and TIP/N therapy were done in 42 (34.7%) and 41 cases (33.8%), respectively. Regarding the patients requiring third line or more chemotherapy, 90, 61, 39, 23 cases had third, fourth, fifth and sixth line or more chemotherapy, respectively. Irinotecan-containing chemotherapy was done in 22 cases and 35 cased as second- + third-line therapy and fourth line or more, respectively. Gemcitabine-containing therapy was done in 35 cases with fourth line or more chemotherapy. The overall survival rate at median follow-up period was 95.7% in induction chemotherapy group (median follow-up; 53 months) and 69.2% in salvage chemotherapy group (median follow-up; 47 months). Clinical outcomes showed no evidence of disease (NED) was obtained in 91.5% and 90.3% with induction and second-line therapy, respectively. Noteworthy mentioned, about 40% patients had NED even in the fourth line or more chemotherapy group. Conclusion Very good and relatively good prognosis were obtained in the patients with induction and salvage chemotherapy at high volume center, respectively. Sequential continuous chemotherapy would be very important to manage ‘difficult-to-treat’ advanced germ cell tumors.