Irinotecan Combination Chemotherapy Research Articles

Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]

CES2 Expression in Pancreatic Adenocarcinoma Is Predictive of Response to Irinotecan and Is Associated With Type 2 Diabetes.

The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC. PDXs were engrafted subcutaneously into nude mice and treated for 4 weeks with either saline control or irinotecan. CES2 and hepatocyte nuclear factor 4 alpha (HNF4A) expression in PDAC tissues was evaluated by immunohistochemical and Western blot analysis. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and hemoglobin A1C (HbA1C) levels in patients who underwent neoadjuvant FOLFIRINOX treatment. High CES2 activity in PDAC PDXs was associated with increased sensitivity to irinotecan. Integrated gene expression, proteomic analyses, and in vitro genetic experiments revealed that nuclear receptor HNF4A, which is upregulated in diabetes, is the upstream transcriptional regulator of CES2 expression. Elevated CES2 protein expression in PDAC tissues was positively associated with a history of type 2 diabetes (odds ratio, 4.84; P = .02). High HbA1C levels were associated with longer overall survival in patients who received neoadjuvant FOLFIRINOX treatment (P = .04). To our knowledge, we provide, for the first time, evidence that CES2 expression is associated with a history of type 2 diabetes in PDAC and that elevated HbA1C, by predicting tumor CES2 expression, may represent a novel marker for stratifying patients most likely to respond to FOLFIRINOX therapy.

Long-term multidisciplinary treatment including proton therapy for a recurrent low-grade endometrial stromal sarcoma and pathologically prominent epithelial differentiation: an autopsy case report

BackgroundLong-term follow-up reports of low-grade endometrial stromal sarcoma (LGESS) including its clinical course and pathological data are rare. We previously reported the case of a Japanese woman diagnosed with LGESS, who was treated with multidisciplinary therapy. She had been suffering from uterine cervical tumor diagnosed as cervical polyps, or fibroid in statu nascendi, since 24 years old. The patient had survived for 25 years with the disease. This report presents her progress and pathological change since the previous report.Case presentationAt age 45, the patient experienced a relapse of the remnant LGESS tumor between the right diaphragm and liver. Although chemotherapy was not effective, the tumor was eliminated by proton therapy. At age 46 years, the remnant tumors outside the irradiated field were resected. The disease was originally diagnosed as “neuroendocrine carcinoma (NEC)” using the surgical specimen. Therefore, cisplatin and irinotecan combination chemotherapy were administered to treat the remnant dissemination. After 4 cycles of chemotherapy, the liver metastases had enlarged and were resected surgically. Consequently, no remnant tumor was visible in the abdominal cavity at the end of the surgery. To determine the origin of NEC, we examined the previously resected specimens obtained from her ileum at age 40 years. A boundary between the LGESS and neuroendocrine tumor grade 2 (NET G2)-like lesion was found in the tumor, indicating that the origin of these tumors was LGESS. After less than 2 years of chemotherapy and undergoing surgery, a relapse of the tumor in the liver induced biliary duct obstruction with jaundice, which was treated with endoscopic retrograde biliary drainage. Although pazopanib prolonged her life for 10 months, she died from sepsis at age 49 years, which was caused by the infection that spread to the liver metastatic tumor via the stented biliary ducts. Autopsy revealed adenocarcinoma-like differentiation of the tumor.ConclusionThis LGESS patient has survived for a long time owing to multidisciplinary treatment including proton therapy. The LGESS tumor differentiated to NET G2-like tissue and then further to adenocarcinoma-like tissue during the long-term follow-up.

525P - Retrospective analysis of outcomes of cisplatin and irinotecan combination chemotherapy for unresectable thymic carcinoma

BackgroundThymic carcinoma is a rare, malignant mediastinal tumor originating from thymic epithelial cells. It exhibits a tendency for metastasis and invasive growth. Unresectable thymic carcinoma is treated with systemic chemotherapy. However, a definitive chemotherapeutic regimen for this entity is yet to be established. The objective of this study was to evaluate the efficacy and safety of cisplatin and irinotecan combination as the first-line chemotherapy. MethodsData pertaining to patients with advanced thymic carcinoma who received cisplatin and irinotecan combination chemotherapy between January 1, 2002 and December 31, 2018, were retrospectively analyzed. The end points were disease control rate, progression free survival, and overall survival. The incidence of significant hematological and non-hematological toxicity was also assessed. ResultsWe identified 17 patients with a median age of 56 years (ECOG performance status: 0 or 1). All patients had clinical stage (Masaoka-Koga staging system) IVa or IVb. Disease control was achieved in 15 patients (88.2%). Median progression-free survival was 7.3 months [95% confidence interval (CI) 2.7–11.6]; median overall survival was 45.6 months (95% CI 9.49–69.5). The outcomes were similar to those achieved with previously reported chemotherapy regimen, CBDCA plus paclitaxel or Cisplatin combination chemotherapy. No treatment-related deaths occurred in this cohort. Grade 3 or worse hematological toxicity was observed in five patients (neutropenia: three patients; anemia: two patients); grade 3 or worse non-hematological toxicity was observed in three patients. None of the patients developed febrile neutropenia. ConclusionsCisplatin and Irinotecan combination chemotherapy may be a safe and effective first-line chemotherapy regimen for unresectable thymic carcinoma. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureY. Hosomi: Honoraria (self): AstraZeneca. All other authors have declared no conflicts of interest.

Neoadjuvant FOLFIRINOX versus adjuvant gemcitabine in pancreatic cancer.

4123 Background: In the metastatic or adjuvant setting for pancreatic cancer, the combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in longer overall survival (OS) compared to gemcitabine therapy. We conducted an institutional study to compare the efficacy of neoadjuvant modified FOLFIRINOX (neo-mFOLFIRINOX) to adjuvant gemcitabine (adj-gem) for pancreatic cancer patients who completed resection. Methods: The study retrospectively enrolled patients from 2006 to 2017 from Ohio State University. While patients who received adjuvant gemcitabine were considered to be resectable upfront, patients who received neo-mFOLFIRINOX were either staged as borderline resectable (BR) or un-resectable (UR) by the institutional tumor board group. 111 patients received adj-gem (average cycles, 5.5) and 52 patients received neo-mFOLFIRINOX (average cycles, 3.5). The survival rates were determined by the Kaplan-Meier method and analyzed using Cox regression and log-rank test. Results: At a median follow up of 21.3 months, the median OS was 35.4 months in the neo-mFOLFIRINOX group and 21.8 months in the adj-gem group (hazard ratio, 0.56, 95% confidence interval (CI), 0.37-0.84 p = 0.005). The OS rate at 3 years was 46% in the neo-mFOLFIRINOX group and 22% in the adjuvant gemcitabine group (p = 0.001). The median disease free survival (DFS) was 18.6 months in the neo-mFOLFIRINOX group and 12.0 months in the adj-gem group (hazard ratio, 0.63, 95% CI, 0.43-0.93 p = 0.022). The DFS rate at 3 years was 17% in the neo-mFOLFIRINOX group and 11% in the adj-gem group (p = 0.02). On surgical pathological specimen review, the neo-mFOLFIRINOX group had statistically (p < 0.05) lower tumor grade, lower rates of perineural invasion and lymphovascular invasion, lower pathological T stage, lower pathological N stage, and lower number of nodes positive compared to the adj-gem group. Frequencies of obtaining R0 resections were higher in the neo-mFOLFIRINOX versus adj-gem groups but not statistically different (51.9% vs 40.4, p = 0.2). The average age and performance status were similar between the two groups. Conclusions: At our institution, BR and UR pancreatic cancer patients who received neo-mFOLFIRINOX and completed resection had longer OS, DFS, and more favorable pathological indicators compared to those patients who had upfront surgery and adjuvant gemcitabine. Randomized clinical trials comparing neoadjuvant versus adjuvant FOLFIRINOX are needed to validate these findings.

Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro

The bacterial receptor, Toll-like receptor (TLR) 4 mediates inflammatory responses and has been linked to a broad array of diseases. TLR4 agonists are being explored as potential treatments for cancer and other diseases. We have previously shown that activation of TLR4 by lipopolysaccharide (LPS) leads to down-regulation of drug metabolizing enzymes/transporters (DMETs), and altered pharmacokinetics/pharmacodynamics (PK/PD) of drugs. These changes can increase the risk of drug-drug interactions (DDIs) in patients on multiple medications. Clinically, DDI was observed for combination chemotherapy of paclitaxel (TLR4 ligand) and irinotecan. To determine the role of TLR4 in DDI between paclitaxel and irinotecan in vitro, primary hepatocytes from TLR4-wild-type (WT) and mutant mice were pre-treated with paclitaxel, followed by irinotecan. Gene expression of DMETs was determined. Paclitaxel treatment increased the levels of irinotecan metabolites, SN-38 and SN-38 glucuronide (SN-38G) in TLR4-dependent manner. Paclitaxel-mediated induction of genes involved in irinotecan metabolism such as Cyp3a11 and Ugt1a1 was TLR4-dependent, while induction of the transporter Mrp2 was TLR4-independent. These novel findings demonstrate that paclitaxel can affect irinotecan metabolism by a TLR4-dependent mechanism. This provides a new perspective towards evaluation of marketed drugs according to their potential to exert DDIs in TLR4-dependent manner.

Phase II study of irinotecan and bevacizumab plus alternate day S-1 as second-line treatment in patients with metastatic colorectal cancer.

749 Background: The recommended dose of combination chemotherapy of irinotecan, bevacizumab and oral S-1 is 100mg/m2, 5mg/kg and 80-120mg/body respectively. To evaluate whether the dose of irinotecan could be raised to 150mg/m2 with modified administration of S-1, we have conducted a phase II study of irinotecan and bevacizumab plus alternate day S-1 in patients with metastatic colorectal cancer (UMIN000008947). Methods: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatine and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1was administered on alternate days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. Results: A total of 51 patients were evaluated in the first fouur cycles. Grade 3 and 4 neutropenia were 10% (10/51) and 13.7%(7/10), grade 3 and 4 thrombocytopenia were 0%(0/51) and 2.0% (1/51). Grade 2 and 3 mucositis were 13.7% (7/51) and 3.9% (2/51). Grade 2 and 3 nausea were 11.8% (6/51) and 2.0% (1/51). Grade 2 and 3 diarrhea were 17.6% (9/51) and 15.7% (8/51). The relative dose intensities were 84.8% for irinotecan, 87.5% for bevacizumab, and 84.8% for S-1 respectively in the first four cycles. Conclusions: Our data suggest that irinotecan (150 mg/m2) and bevacizumab was administered safely with alternate day S-1 as second-line tratment in patients with metastatic colorectal cancer. Clinical trial information: 000008947.

Genetic polymorphisms in cytochrome P450 and clinical outcomes of FOLFIRI chemotherapy in patients with metastatic colorectal cancer

The purpose of this study is to evaluate the influence of germline polymorphisms of cytochrome P450 (CYP450) on objective response, progression-free survival (PFS) and overall suruvival (OS) in metastatic colorectal cancer (mCRC) receiving the combination chemotherapy of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI). All SNPs in CYP450, whose minor allele frequency were more than 10 %, were genotyped in 82 patients with mCRC who received first-line FOLFIRI regimen. χ (2) test or Fisher's exact test was used to assess the correlation between SNPs and objective response as appropriate and log-rank test between SNPs and PFS or OS. Cox proportional hazards models were used to analyze the association of CYP450 gene polymorphisms and clinical factors for PFS and OS. No SNP showed predictive or prognostic value for clinical outcomes, except for CYP3A5 rs776746 A>G, which was significantly associated with PFS (P = 0.0002). Multivariate analysis confirmed its prognostic value for PFS (P = 0.002). CYP3A5 rs776746 A>G polymorphisms have a prognostic contribution toward FOLFIRI regimen in mCRC. This could represent a further step toward personalized therapy.

TEGAFIRI is an effective alternative regimen for the management of recurrent or metastatic colorectal cancer.

At present, the global incidence of colorectal cancer is increasing, with numerous individuals succumbing to the disease. The standard treatment strategy for colorectal cancer is curative resection. However, a cure is rarely achieved for metastatic colorectal cancer. Currently, chemotherapy is the main treatment for metastatic and recurrent colorectal cancer. The majority of metastases or recurrences have been found to respond well to chemotherapy. The present study evaluated the response rates of recurrent or metastatic colorectal cancer patients treated with a combination chemotherapy of irinotecan and oral uracil-tegafur (UFUR). In the pilot study, 33 patients with metastatic or recurrent colorectal cancer were treated with different regimens of irinotecan and UFUR with or without leucovorin; however, irinotecan (150 mg/m2 every two weeks) with continuous UFUR and leucovorin without interruption resulted in improved survival compared with the other regimens evaluated and, thus, was employed for the present study of 113 patients. The patients that received irinotecan with UFUR and leucovorin without interruption exhibited similar efficacy in terms of overall survival and response rate to that of the pilot study. In addition, the incidences of diarrhea, alopecia and hematologic toxicity were acceptable, which was in agreement with the results of the pilot study. Therefore, combination chemotherapy with irinotecan, oral UFUR and leucovorin appears to be a satisfactory treatment strategy for recurrent or metastatic colorectal cancer.

The ‘real-life’ impact of adding bevacizumab to first-line therapy in metastatic colorectal cancer patients: A large Israeli retrospective cohort study

Background. After a decade of extensive use, the actual contribution of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC) is still unclear.Objective. To evaluate ‘real-life’ outcomes of patients with mCRC before and after the introduction of bevacizumab to standard mCRC first-line practice.Methods. Using the computerized administrative database of Clalit Health Services’ (CHS), Israel's largest health care provider, we retrospectively compared two cohorts (n = 1739): (A) all CHS’ patients diagnosed with mCRC between January 2000 and December 2004 that received first-line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced) (n = 1052), and (B) all patients that started first-line irinotecan or oxaliplatin combination chemotherapy together with bevacizumab between September 2006 and December 2009 (after bevacizumab was fully reimbursed in Israel for mCRC first-line therapy) (n = 687). The primary endpoint was overall survival (OS) and secondary endpoints were first-line progression-free survival (PFS) and metastatectomy rates.Results. Median OS was longer in Cohort B than in Cohort A [23.0 months vs.15.0, adjusted hazard ratio (HR), 0.75]. Secondary outcomes were also better; PFS of 14.0 months vs. 9.8 in the earlier period (HR, 0.75) and metastatectomy rate of 8.1% versus 3.9%. The longer OS in Cohort B was preserved even after controlling for latter-line epidermal growth factor receptor (EGFR) inhibitor use (HR = 0.77).Conclusion. In this analysis, OS, PFS and metastatectomy rates of first-line treatment of mCRC were significantly higher in the later period of the study. These results, derived from ‘real-life’ practice, suggest that the use of bevacizumab, among other alterations in the clinical management of mCRC between the two periods, might have had a significant contribution to these outcomes, and may therefore support the current practice of adding bevacizumab to first-line treatment of mCRC.

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy.

An association between UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphisms and irinotecan-induced neutropenia has been previously reported. In this study, we assessed the clinical usefulness of testing for UGT1A1 polymorphisms prior to the initiation of irinotecan-based chemotherapy, as this remains a controversial subject. A total of 136 lung cancer patients who were treated with a combination of nedaplatin and irinotecan as initial chemotherapy were assessed. Following exclusion of patients exhibiting low UGT1A1 enzyme activity, 70 patients were treated after UGT1A1 polymorphism testing (test group) and 66 patients were treated without UGT1A1 polymorphism testing (non-test group). We retrospectively analyzed and compared the adverse events between the test and the non-test groups and observed no reduction in hematological or non-hematological toxicities in the test group compared to that in the non-test group. Of the 9 patients with grade 4 or 5 non-hematological toxicity, 6 patients had febrile neutropenia (FN). All the patients with FN were aged >70 years. The incidence of adverse events was significantly higher among patients aged >70 years compared to that among younger patients. In conclusion, in patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing prior to the initiation of chemotherapy did not reduce the incidence of adverse events. Therefore, UGT1A1 polymorphism testing alone may not be sufficient to predict the occurrence of severe adverse events and it may be more important to effectively manage adverse events, particularly in elderly patients.

A Case of Organizing Pneumonia Associated with FOLFIRI Chemotherapy

The combination chemotherapy of irinotecan with 5-fluorouracil and leucovorin (FOLFIRI regimen) was recently proven to be beneficial in patients with advanced colorectal cancer. Pulmonary toxicity is very rare in adverse effects of irinotecan. No case of organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia) associated with FOLFIRI chemotherapy has been reported. We experienced a case of a 62-year-old man who presented persistent dry cough and progressive dyspnea after receiving chemotherapy with FOLFIRI regimen. After surgical lung biopsy, the patient was diagnosed with FOLFIRI chemotherapy-induced organizing pneumonia which was successfully treated with steroid therapy.

UGT1A1*6,1A7*3, and 1A9*22 genotypes predict severe neutropenia in FOLFIRI‐treated metastatic colorectal cancer in two prospective studies in Japan

Retrospective studies have suggested that UDP-glucuronosyltransferase (UGT)1A1, UGT1A7, and UGT1A9 predict severe toxicity and efficacy of irinotecan-containing regimens. We prospectively evaluated the impact of UGT1A genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first-line FOLFIRI trial, and FLIGHT2 was a FOLFOX-refractory, second-line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for UGT1A polymorphisms, UGT1A1*28 (TA6>TA7), UGT1A1*6 (211G>A), UGT1A1*27 (686C>A), UGT1A1*60 (-3279T>G), UGT1A1*93 (-3156G>A), UGT1A7 (-57T>G), UGT1A7*3 (387T>G, 622T>C), and UGT1A9*22 (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with UGT1A1*6 (211A), UGT1A7 (387G), and UGT1A9*22 reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (P=0.031). In contrast, haplotype II, which contains four high-risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (P=0.010). Six out of seven patients who were homozygous for UGT1A1*28 or *6 experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that UGT1A polymorphisms, especially UGT1A1*6, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. ( UMIN000002388 and UMIN000002476).

Phase I Study of Bevacizumab Plus Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors

Studies have suggested that bevacizumab has shown activity against various pediatric solid tumors. We, therefore, conducted a Phase I study of bevacizumab plus irinotecan in Japanese children with recurrent, progressive or refractory solid tumors. The starting dose was bevacizumab 10 mg/kg over 60-90 min and irinotecan 125 mg/m(2) over 90 min intravenously on Days 1, 15 and 29. The dose of irinotecan was 340 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs. Treatment was repeated every 6 weeks for up to three courses in the absence of disease progression or unacceptable toxicity. Of 11 patients, 9 (median age, 9 years) were fully assessable for toxicity and received 24 courses. Dose-limiting toxicities were Grade 2 diarrhea and Grade 4 neutropenia/thrombocytopenia in two of the five patients at dose level 1. No dose-limiting toxicities were observed in four patients at dose level -1 at bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs). The maximum-tolerated dose was bevacizumab 10 mg/kg and irinotecan 100 mg/m(2). The most frequent non-dose-limiting toxicities were Grade 1 or 2 hypertension, bleeding and hematologic toxicity. One patient with optic nerve glioma had a partial response. Three patients with medulloblastoma, optic nerve glioma and diffuse intrinsic pontine glioma had stable disease. Combination chemotherapy of bevacizumab plus irinotecan was well tolerated in children. We plan Phase II pediatric studies at doses of bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) every 2 weeks (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs).

A phase II study of combination chemotherapy using docetaxel and irinotecan for TC-refractory or TC-resistant ovarian carcinomas (GOGO-OV2 study) and for primary clear or mucinous ovarian carcinomas (GOGO-OV3 Study)

ObjectiveTo analyze the efficacy and safety of combination chemotherapy of docetaxel and irinotecan for paclitaxel and carboplatin (TC) -refractory or -resistant ovarian carcinomas and for first treatment of primary clear cell and mucinous ovarian carcinomas. Study designBetween 2002 and 2009, we conducted a prospective Phase II study of the efficacy and safety of combination chemotherapy using docetaxel and irinotecan in 62 patients with TC-refractory or -resistant ovarian carcinoma cases (GOGO-OV2) and 15 patients with primary clear cell and mucinous ovarian carcinoma cases (GOGO-OV3). The dose of docetaxel and irinotecan was determined during our previous Phase I study. ResultsA docetaxel plus irinotecan regimen provided a 53% response rate, 6 months progression-free survival (PFS), and 12 months overall survival (OS) for primary clear cell and mucinous ovarian carcinomas (similar to TC therapy). The differences of anti-tumor and survival effects between refractory and resistant cases were not statistically significant. The regimen also provided a 15% response rate, 5 months PFS, and 15 months OS for TC-refractory or TC-resistant cases, when used as a second-line chemotherapy. These data are similar to previous reports, however, our study provides the first data exclusively for the cases refractory or resistant to a gold standard TC therapy as a second-line chemotherapy. The regimen was demonstrated to be well tolerable. ConclusionCombination chemotherapy of docetaxel and irinotecan may be a useful option to treat TC-refractory/resistant cases and primary clear cell and mucinous adenocarcinoma cases of ovarian carcinoma.

The usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy.

11055 Background: A few studies have revealed an association between UGT1A1 genotype and irinotecan-induced neutropenia. However, the usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy is controversial, even now. We assessed the clinical usefulness of UGT1A1 polymorphism testing before chemotherapy. Methods: 136 lung cancer patients were treated with nedaplatin and irinotecan combination chemotherapy as initial chemotherapy. Except for the patients with low enzyme activity of UGT1A1, 70 patients were treated after UGT1A1 polymorphism testing. (test group) 66 patients were treated without UGT1A1 polymorphism testing. (non-test group) We retrospectively analyzed adverse events and compared the test group with non-test group. Results: We could not confirm any reduction in hematologic or non-hematologic toxicity statistically in the test group. In 9 patients with non-hematologic toxicity of grade 4 and 5, 6 patients had febrile neutropenia (FN). All patients with FN were older than 70 years old. Adverse events in elderly patients were significantly more frequent than in the non-elderly. Conclusions: In patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing before starting chemotherapy did not reduce adverse events. With UGT1A1 polymorphism testing only, it was difficult to predict the onset of severe adverse events. Therefore, it is more important to manage adverse events carefully, especially in elderly patients.

The "real life" impact of adding bevacizumab to first-line treatment of metastatic colorectal cancer: A retrospective large database study.

e14571 Background: Bevacizumab is included in the Israeli National List of Reimbursed Drugs (NLRD) for 1st line treatment of all metastatic colorectal cancer (mCRC) patients since 7/2006. This study evaluates the "real life" impact of adding bevacizumab to 1st line treatment of mCRC by comparing patients' outcomes before and after the drug's availability in the NLRD. Methods: We conducted a retrospective database study ,using the computerized databases of Clalit Health Services' (CHS), Israel's largest health care provider, to compare two cohorts: (A) all CHS' patients diagnosed with mCRC between 1/2000-12/2004 that received 1st line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced), and (B) all CHS's patients that started 1st line treatment with irinotecan or oxaliplatin-based combination chemotherapy and bevacizumab between 7/2006 and 8/2009 (allowing a minimum follow-up of 3 years). The primary endpoint was overall survival (OS) and the secondary endpoints were 1st line progression free survival (PFS) and metastatectomy rates. Since data on actual progression status was unavailable, PFS was defined as the duration of 1st line treatment. As CHS covers more than 50% of the Israeli population, our study may represent the general care received by Israeli patients with mCRC. Results: The study population included 1,739 patients: 1,052 in cohort A and 687 in cohort B. Patient demographics were similar between the cohorts. Median OS was 15.0 months for cohort A (95% CI: 13.4–16.6) and 23.0 months for cohort B (95% CI: 21.7–24.3), with an unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.64-0.80, p<0.0001). Median PFS was 9.8 months (95% CI: 9.0–10.5) for cohort A and 14.0 months (95% CI: 13.0-15.0) for cohort B, with a HR of 0.80 (95% CI: 0.71-0.87, p<0.0001). The rate of metastatectomies was significantly higher in cohort B (8.1% vs. 3.9%; P = 0.001). Conclusions: In this retrospective database analysis, OS, PFS and metastatectomy rates of 1st line treatment of mCRC were significantly higher in the later period of the study. The addition of bevacizumab to standard treatment of mCRC may have had a major contribution to this improvement.

Final results of a phase II multicenter study of neoadjuvant S-1 and irinotecan in patients with locally advanced gastric cancer.

65 Background: Combination chemotherapy involving S-1 and irinotecan (IRI-S) has failed to demonstrate a survival benefit over S-1 alone in metastatic gastric cancer. However, the tumor response rate was significantly higher with I-RIS. Therefore, we evaluated the effect of I-RIS as neoadjuvant chemotherapy for locally advanced gastric cancer. Methods: Patients with locally advanced gastric adenocarcinoma, T3-4, N0-3, M0, for whom curative surgery was planned after neoadjuvant chemotherapy, PS 0-1, with adequate organ function were enrolled in this study. Patients received irinotecan 80 mg/m2 on days 1 and 15 and oral S-1 80 mg/m2/day on days 1 to 21. Treatment was repeated every 28 days for 2 courses. Patients then underwent gastrectomy with lymphadenectomy. After surgery, patients resumed treatment with S-1 alone for 1 year. Results: Of the 39 patients enrolled, 37 were eligible. Two cycles of chemotherapy were completed in 34 patients, and surgery was performed in 33 patients. Of 27 RECIST-evaluable patients, 16 (59%) had a partial response and 9 (33%) had stable disease. Major grade 3 toxicities were neutropenia in 6, anorexia in 4, nausea in 3, diarrhea in 2, and fatigue in 2. Resection was performed in 32 (86%) patients and R0 resection was possible in 20 (54%) patients. The reason for R1/R2 were cy+ in 6, M1(LYM) in 5, M1(PER) in 4, M1(HEP) in 1 and PM+ in 2. Postoperative complications were observed in 13 (39%) patients. There were no treatment-related deaths. Pathological response was observed in 13 of 32 patients (41%); 2 patients had pathological CR. Median survival time was 15.9M and median progression-free survival (PFS) was 5.9M. Overall survival and PFS were significantly better in patients underwent R0 resection (p < 0.0001). Neither objective tumor response nor pathologic response predicted the survival. Conclusions: These results show that neoadjuvant S-1 and irinotecan combination chemotherapy was active and feasible for treating locally advanced gastric cancer. R0 resection is essential to achieve long-term survival. Therefore, careful diagnosis with staging laparoscopy before surgery is mandatory to avoid non-curative operation. Clinical trial information: NCT00134095.

Phase II trial of irinotecan, S-1, and bevacizumab (IRIS/Bev) combination chemotherapy as second line for advanced colorectal cancer (NCCSG04).

496 Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853-860) previously demonstrated the non-inferiority of Irinotecan plus S-1 (IRIS) to FOLFIRI for metastatic colorectal cancer (mCRC), with progression-free survival as the primary endpoint. IRIS plus bevacizumab (IRIS/Bev) was reported an active and generally well-tolerated first-line treatment for mCRC (Yuki et al. ASCO 2012 #3593). We planned a Phase II trial to evaluate the efficacy and safety of IRIS/Bev as second-line therapy for patients with mCRC. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2 and Bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety. Results: From 08/12 until 11/06, 35 patients were enrolled. One patient did not start therapy. Thirty-four patients were investigated. Median age was 63 years (range, 38 to 82). Twenty-five patients were male. The mean of relative dose intensity of TS-1/Irinotecan/Bev were respectively 92.1%/87.0%/86.2%. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 9.3 months, median TTF was 8.2 month and median survival time 23.1 month. On safety analysis, the incidence of grade 3 or 4 adverse reactions were as follows: neutropenia, 14.7%; fatigue, 14.7%; white blood cell decreased, 11.8%; anorexia, 8.8%; anemia, 8.8%; diarrhea, 2.9%; proteinuria, 5.9%; thromboembolic event, 2.9%. Conclusions: IRIS/Bev is an active and well-tollarated second-line treatment for patients with mCRC. Clinical trial information: UMIN000001631.

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.