Courses Of Irinotecan Research Articles

The efficacy and safety of irinotecan plus doxorubicin liposome in relapsed/refractory Wilms’ tumors: A retrospective study.

e22007 Background: To evaluate the efficacy of the regimen of combination of irinotecan and doxorubicin hydrochloride liposome in relapsed/refractory pediatric Wilms’ tumor. Life quality and toxicity are seriously considered and assessed. Methods: The project stipulated 5-day course of irinotecan 50 mg/m2 (90-minute infusion) and doxorubicin hydrochloride liposome 40mg/m2 every 3 weeks. Granulocyte colony-stimulating factor was applied when the number of neutrophil count was lower than 1,000/ L. Results: 16 patients received 1to 8 courses (median, 3 courses) of this regimen, including 8 males and 8 females, with a median age of 4.2 years old (range, 0.5-11) . 2 patients were not assessable for response (1were treated in third CR, and 1with refractory WT received only one course as part of complex salvage regimens). Of 14 patients treated for relapsed or refractory Wilms’ tumor and accessed for response, 2 patients had complete responses (CR), 5 patients had partial responses (PR). Of 2 patients had stable diseases (SD), including 1 patient showed objective response on pulmonary lesion. The disease control rate was 64% (2 CR, 5 PR, and 2 SD), and the objective response rate was 50% (2 CR, 5 PR). The median progression-free survival was 3.5 months (range 0.5-12), and the median survival duration was 8 months (range 1-28). Myelosuppressive and gastrointestinal adverse effects were self-limited and clinically controllable with routinely intervention, and this therapeutic regimen was generally continued without delayed therapy. Multiple courses of this regimen had no cumulative toxicity and achieved disease control in relapsed or refractory Wilms’ tumor. Conclusions: The regimen of combination of irinotecan and doxorubicin hydrochloride liposome has positive effect on relapsed/refractory Wilms’ tumor with gentle toxicity without reducing the efficacy, and achieves good quality of life.

Irinotecan-Induced Transient Dysarthria: Case Series and Updated Literature Review

Irinotecan-based regimens are used worldwide for the treatment of several recurrent or advanced gastrointestinal malignancies. In this paper we describe the cases of four patients treated in our institution who developed acute dysarthria while receiving intravenous infusion of irinotecan. In all our cases, dysarthria occurred during the infusion of the first course of irinotecan, and then resolved rapidly without any sequelae. Imaging of the brain was performed, but failed to show any evidence of an acute neurological event. We also reviewed the literature on this very uncommon adverse event. The pathogenesis of irinotecan-induced dysarthria is still unknown and is not completely elucidated by the current pharmacodynamic or kinetic explanations; therefore, we could only hypothesize some assumptions.

Neoadjuvant Chemotherapy for Gastric Cancer: What are we Trying to Accomplish?

Gastric cancer remains the second leading cause of cancer death in the world and is the most common cancer in Japan. Although surgery is the mainstay of curative treatment, even after complete resection, more than half of patients with locally advanced tumors recur, and fewer than 40 % survive beyond 3 years. Accordingly, investigators around the world have explored a variety of adjuvant and neoadjuvant multimodality treatment approaches to this disease. In North America, the standard approach has long been upfront surgery followed by adjuvant chemoradiotherapy based on the findings of the Intergroup 0116 trial, which showed that postoperative 5-fluorouracil (5-FU)/ leucovorin-based chemoradiation increases overall survival compared with surgery alone. However, another standard of care for resectable gastric cancer in North America and Europe emerged with the publication of the MAGIC trial a few years later and the FNCLCC/FFCD multicenter phase III trial a few years after that. The MAGIC trial reported an improvement in overall survival with perioperative epirubicin, cisplatin, and 5-FU (ECF) compared with surgery alone, and the FNCLCC/FFCD trial showed an improved R0 resection rate and survival with perioperative 5-FU and cisplatin. In Japan, the standard approach to patients with T2 N or T3 gastric cancers is upfront surgery with D2 lymphadenectomy followed by 1 year of S-1 chemotherapy, based on the ACTS trial, a large phase III trial demonstrating a significant survival benefit to this approach over surgery alone. Nonetheless, even with adjuvant S-1 chemotherapy, the prognosis of Japanese patients with stage III gastric cancers in particular remains unsatisfactory, and so investigators in Japan recently have been evaluating various regimens of neoadjuvant chemotherapy followed by extended surgery in multiple phase II trials, including one to three courses of S-1 and cisplatin, two to three courses of irinotecan and cisplatin, and two to four courses of paclitaxel and cisplatin. The optimal duration and regimen of neoadjuvant chemotherapy has not yet been established. In this issue, Yoshikawa et al. report the early results of the COMPASS trial, a randomized, multi-institutional phase II trial comparing two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC), followed by surgery and postoperative S-1 chemotherapy, for macroscopically resectable locally advanced gastric cancer. A total of 83 patients were enrolled based on power calculations assuming a 10 % absolute improvement in 3-year overall survival in the four-course PC arm. The primary endpoint of the study is the 3-year overall survival rate, and the secondary endpoints include the clinical and pathologic response rates, chemotherapy-related toxicities, R0 resection rates, and surgical morbidity and mortality. This report summarizes only the early outcomes—that is, these secondary endpoints—because the data are not mature enough to report on the survival outcomes. Unfortunately, the eligibility criteria for this trial included patients with ‘‘resectable minimal peritoneal metastases confirmed by laparoscopy,’’ which is considered M1 (metastatic) disease in all staging systems and not ‘‘locally advanced’’ disease. In fact, 13 (16 %) of the 83 enrolled patients had M1 disease on initial staging as manifested by either gross peritoneal metastases (n = 5) or positive peritoneal cytology (n = 8) and thus did not have a realistic chance for cure at the outset. Accordingly, the 3-year overall survival rates for this trial are likely to be low, and Society of Surgical Oncology 2013

A phase II window study of irinotecan (CPT-11) in high risk ewing sarcoma: A Euro-E.W.I.N.G. study

The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II window study of irinotecan in newly diagnosed high risk metastatic patients with Ewing sarcoma. Patients were recruited between April 2004 and December 2007. Two courses of irinotecan were administered at a dose of 600 mg/m(2) as a 1 hour infusion at 21 day intervals. Response evaluation was determined after the second course of treatment by radiological assessment of primary and metastatic sites and, where appropriate bone marrow sampling. Twenty-three patients were recruited. Two patients were deemed inevaluable for response. Five patients (24%) demonstrated a partial response. Grade 3 or 4 diarrhoea was seen in 4/43 course of treatment and was managed with loperamide. This is the first report of single agent irinotecan activity in an untreated population of patients with Ewing sarcoma. In common with other paediatric tumours and other camptothecin analogues such as topotecan, single agent activity is only modest. The exact role for the use of irinotecan in patients with ES, dose schedule and combinations with other agents still requires further investigation.

Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G

To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE). The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients. The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.

P3-047 - Investigation of Gastrointestinal Neuroendocrine Tumors after Prior Chemotherapy

ABSTRACT Background Evidence-based data regarding the role of chemotherapy in the management of gastrointestinal neuroendocrine tumors are scarce, mainly because the results of only small studies are available. Combination chemotherapy with regimens such as cisplatin–etoposide was reported to have activity against gastrointestinal neuroendocrine tumors. However, few studies have documented a good response of gastrointestinal neuroendocrine tumors to second-line chemotherapy. Patients and methods We studied three patients with unresectable gastrointestinal neuroendocrine tumors who received irinotecan or amrubicin after prior chemotherapy with platinum and etoposide. ResultsThe characteristics of the three patients are shown below. All were men, with a median age of 69 years (range, 62–70). The site of the primary tumor was the stomach in two patients and the esophagus in one. One patient with a gastric neuroendocrine tumor received irinotecan as second-line chemotherapy, and the other received amrubicin as second-line chemotherapy followed by irinotecan as third-line therapy. A partial response was obtained in one patient after two courses of irinotecan, and this patient is now receiving the fifth course of irinotecan. The patient with an esophageal neuroendocrine tumor received amrubicin as second-line chemotherapy, followed by irinotecan as third-line therapy. The second course of irinotecan is now being administered, and response will be evaluated after completion of the second course. Both patients who received amrubicin as second-line therapy had progressive disease after two courses of amrubicin. Conclusions We described our experience with a case of gastrointestinal neuroendocrine tumor that responded to irinotecan after prior chemotherapy. Irinotecan might be effective against gastrointestinal neuroendocrine tumor. However, further clinical studies are required to confirm currently available evidence.

A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma

Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma. Two courses of irinotecan [15 mg/m(2)/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought. Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp. Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials.

Preclinical study of treatment response in HCT‐116 cells and xenografts with 1H‐decoupled 31P MRS

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83 ± 5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5 ± 1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39 ± 10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies.

Phase II window of irinotecan plus carboplatin in newly diagnosed patients with rhabdomyosarcoma: Results of Memorial Sloan-Kettering Cancer Center (MSKCC) Protocol IRB 03-099.

9533 Background: There has been little improvement in outcome for patients (pts) with intermediate (INT)- and high-risk (HR) rhabdomyosarcoma (RMS) in nearly 2 decades. Methods: From November 2003 through December 2009, we enrolled 56 newly diagnosed pts with INT- (28) and HR (28) RMS on IRB 03-099, a 7-drug regimen that commenced with 2 courses of irinotecan + carboplatin (I+C) given 3 weeks apart. I (20 mg/m2 IV over 1 hour) was given on days 1-5 and 8-12; C (560 mg/m2 IV over 1 hour) was given on day 1. Results: Median age at diagnosis was 11.5 yrs (4 months – 42 years); median tumor size was 6 cm. There were 29 males and 27 females; 30 pts (15 HR) had alveolar RMS (ARMS); 24 pts (12 HR) had embryonal RMS (ERMS); one each had sclerosing RMS and pleomorphic RMS (HR RMS). Of 28 pts with INT-RMS, 26 had invasive (T2) and/or 16 large (Tb) tumors, and 15 were N1. 11 of 28 pts with HR RMS had more than 1 site of metastatic disease. Pts were restaged after 2 cycles using RECIST and WHO response criteria. 4 pt...

Irinotecan as maintenance therapy in high‐risk hepatoblastoma

Children with high-risk hepatoblastoma (metastatic disease or a low alpha-fetoprotein at presentation) and those with recurrent disease have an extremely poor prognosis and are in need of novel therapeutic agents and strategies. We describe three patients who were treated with irinotecan (two in combination with vincristine). In two patients, this contributed to a clinical remission. All three patients received a 1- to 2-year course of irinotecan as maintenance therapy and all remain disease free. Treatment was well tolerated with minimal toxicity. Further evaluation of the use of irinotecan as maintenance therapy in high-risk and recurrent HB patients is warranted.

Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer: A multicenter phase II study

Purpose The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer. Patients and methods Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100 mg/m 2 on days 1–3 and cisplatin 80 mg/m 2 on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20 mg/m 2 on day 1 and etoposide 50 mg/m 2 on day 4 within 5–6 weeks, followed by three courses of irinotecan 60 mg/m 2 on days 1, 8, and 15 and cisplatin 60 mg/m 2 on day 1 of a 4-week cycle. Results There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3–4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6–41.2 months), the median survival time was 19 months (95% CI: 14.5–23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively. Conclusions Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC.

9118 Effect of chemotherapy (CT) in patients (pts) with resected small-cell (SCLC) or large-cell neuro endocrine carcinoma (LCNEC)

The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer.Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100 mg/m2 on days 1–3 and cisplatin 80 mg/m2 on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20 mg/m2 on day 1 and etoposide 50 mg/m2 on day 4 within 5–6 weeks, followed by three courses of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 of a 4-week cycle.There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3–4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6–41.2 months), the median survival time was 19 months (95% CI: 14.5–23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively.Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC.

Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC): WJTOG0105

7504 Background: Weekly chemotherapy with concurrent TRT displays acceptable toxicities and dependable efficacy. We conducted a randomized phase III trial to assess the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP with concurrent TRT via a non-inferiority design. Methods: MVP: mitomycin (8 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36), and cisplatin (80 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). Patients (pts) subsequently received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). The primary endpoint was overall survival (OS), with secondary endpoints of progression free survival (PFS), response, and toxicity. Results: From Sep 2001 to Sep 2005, 456 pts were randomized. Pretreatment characteristics were well-balanced among 3 arms. Major toxicity incidences: The incidence of G3–4 neutropenia in the MVP, IC, and PC arms was 95.9, 72.1, and 46.9 % (p<0.001). The G3–4 non-hematologic toxicity incidences in terms of fatigue, febrile neutropenia, and gastrointestinal disorder were 13.0, 6.1, and 4.8 % (p<0.001), 37.0, 8.8, and 10.2 % (p<0.001), and 24.0, 8.2, and 9.5% (p<0.001) in the respective arms. The overall response rates were 66.4, 56.5, and 63.3 %, in the MVP, IC and PC arms, respectively. The median survival times were 20.5, 19.8 and 22.0 months and the median PFS (MPFS), 8.2, 8.0 and 9.5 months in MVP, IC and PC. Non-inferiority of the 2 experimental arms compared with MVP was not achieved, though no significant differences in OS and PFS were apparent among treatments. The PC arm displayed the most favorable MST, MPFS, and hematologic/non-hematologic toxicities. Conclusions: Weekly PC with TRT displays similar efficacy and more favorable toxicity profiles compared to MVP with TRT. Weekly PC with TRT warrants use as the reference regimen in forthcoming studies. [Table: see text]

Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC)

7530 Background: Concurrent chemoradiotherapy plays an important role in the treatment of unresectable stage III NSCLC. Our group demonstrated a superiority of MVP with concurrent TRT over that with sequential TRT (Furuse, JCO, 1999), while weekly chemotherapy with concurrent TRT has acceptable toxicities and expected efficacy. We conducted a randomized phase III trial to compare the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP by a non-inferiority design. Methods: Patients were assigned to 3 regimens; MVP: cisplatin (80 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36) and mitomycin (8 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). After then, pts received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2) / carboplatin(AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan(50 mg/m2) / carboplatin(AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2) / carboplatin (AUC 5). Primary endpoint was overall survival. Results: From Sep 2001 to Sep 2005, 456 pts were randomized; 429 pts had evaluated responses. Pretreatment characteristics were well-balanced between 3 arms (median age 63 years (30–74), PS0/1 41/55%, Ad/Sq/others 43/45/12%). The achievement rates of full treatment in MVP, IC and PC were 39.9, 29.7, and 49.3 %; those of full-dose TRT/2 courses of consolidation chemotherapy were 81.1/41.3%, 41.4/29.7% and 59.7/50.0%, respectively. Major toxicities were as follows; G4 neutropenia in MVP, IC, PC were 76.9, 13.1, 4.2% (p<0.001), and G3–4 non-hematological toxicities (decrease in PS, and febrile neutropenia) were 13.3, 6.2, 4.2% (p=0.01), and 29.4, 6.9, 4.9% (p<0.001), respectively. The overall response rates were 65.7% (95% CI 57.9–73.5), 58.6 % (95% CI 50.5–66.1) and 62.9% (95% CI 55.0–70.8), in MVP, IC and PC, respectively. Complete analysis will be fixed in Oct 2008. Conclusions: Weekly PC with TRT appears good compliance with high achievement rate and MVP appears poor compliance with severe hematological and non-hematological toxicities. No significant financial relationships to disclose.

Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma

To report on an irinotecan and temozolomide regimen for neuroblastoma (NB). Quality of life and minimizing toxicity were major considerations. The plan stipulated 5-day courses of irinotecan 50 mg/m2 (1-hour infusion) and temozolomide 150 mg/m2 (oral) every 3 to 4 weeks, with a pretreatment platelet count more than 30,000/microL. Granulocyte colony-stimulating factor was used when the absolute neutrophil count was less than 1,000/microL. Forty-nine NB patients received 1 to 15 courses (median, 5). Gastrointestinal and myelosuppressive toxicities were readily managed. Lymphocyte responses to phytohemagglutinin after 2 to 10 courses (median, 3.5) were normal in 10 of 10 patients treated after nonimmunosuppressive therapy, and normalized in five of seven patients first treated less than 2 months after high-dose alkylators. Of 19 patients treated for refractory NB and assessable for response, nine showed evidence of disease regression, including two complete responses and seven objective responses. Of 17 patients treated for progressive disease, three showed evidence of disease regression, including one partial response and two objective responses. Multiple courses entailed no cumulative toxicity and controlled disease for prolonged periods in many patients, including some who were unable to complete prior treatments because of hematologic, infectious, cardiac, or renal problems. This regimen has anti-NB activity, spares vital organs, is feasible with poor bone marrow reserve, causes limited immunosuppression, and allows good quality of life.

I-123 MIBG Scan of Metastatic Neuroblastoma Mimicking a Bone Scan

A 21-year-old man presented to an outside institution with longstanding right hip pain. Magnetic resonance imaging revealed diffuse marrow infiltration in the lumbar spine, sacrum, ilium, and right proximal femur. Biopsy of a left upper quadrant mass was consistent with stroma poor neuroblastoma with differentiation. The patient underwent left radical adrenalectomy, left retroperitoneal lymph node dissection with gross resection of residual tumor and 5 cycles of high-dose chemotherapy (cyclophosphamide, doxorubicin, and vincristine) with evidence of disease progression. A short course of irinotecan was given for palliation. A protocol with low-dose 1-131 MIBG was started for symptomatic control.

Response of heavily treated and relapsed hepatoblastoma in the transplanted liver to single‐agent therapy with irinotecan

We describe here a patient with relapsed hepatoblastoma after LDLT who developed heart failure, which was treated with irinotecan hydrochloride (CPT-11). His native liver was replaced by a liver graft from his mother at 26 months from the onset. However, LDLT failed to induce complete remission and he was diagnosed as relapsed hepatoblastoma six months after LDLT. We again administered cisplatin and doxorubicin. After six courses of chemotherapy, he developed congestive heart failure because of anthracycline toxicity. The chemotherapy regimen was therefore switched to irinotecan at 35 mg/m2 daily for three days/wk for two consecutive weeks, and repeated every 28 days. After four courses of irinotecan, metastatic lesions were remarkably reduced in size, and the serum level of AFP decreased from 0.7 million to 927 ng/mL. No severe side effects were documented and congestive heart failure improved. These results suggest that irinotecan may be safely given to a patient with relapsed hepatoblastoma after LDLT without serious side effects and may contribute to prolonging the survival.

Successful Treatment of Chemoresistant Stage 3 Neuroblastoma Using Irinotecan as a Single Agent

The authors describe a 1-year-old boy who was diagnosed with neuroblastoma by mass screening at age 6 months. The tumor originated from the left retroperitoneum and extended over the midline, involving major vessels and invading the spine with compression of the spinal cord. Although seven courses of chemotherapy consisting of vincristine sulfate, cyclophosphamide, pirarubicin hydrochloride, and cisplatin were administered, there was no reduction in tumor size or decrease in tumor markers. The patient received irinotecan 180 mg/m per day for 3 days. Approximately 3 weeks later the tumor had regressed remarkably, and tumor markers normalized after the second course of irinotecan. This therapy was given a total of four courses every 4 weeks, with the tumor shrinking successively in each session. Four years after treatment there is no sign of recurrence and the patient is doing well. This case may be the first report showing the dramatic efficacy of irinotecan in the treatment of chemoresistant neuroblastoma without the use of other antitumor agents. Irinotecan might be a promising drug in the management of patients with high-risk neuroblastoma.

Five‐day courses of irinotecan as palliative therapy for patients with neuroblastoma

The authors describe a large experience using short courses of irinotecan for palliative therapy in patients with neuroblastoma (NB). Quality of life was a major issue in choosing this regimen for patients whose disease was resistant to standard anti-NB therapies. A retrospective review was conducted of all patients who were followed by the Department of Pediatrics at Memorial Sloan-Kettering Cancer Center and treated for resistant NB with irinotecan at 50 mg/m2 per day for 5 days as a 1-hour intravenous infusion. Treatment was outpatient, and there was a minimum 2-week rest period between courses. Granulocyte colony-stimulating factor was used to keep the absolute neutrophil count >500-1000/mL. Forty-four patients had been treated aggressively and/or extensively before they received one or more five-day courses of irinotecan. Emetogenic, diarrheal, and myelosuppressive effects were readily managed. Hospitalizations were limited to three patients with bacteremia. Twenty-three patients had a change in therapy, although they did not have progressive disease (PD) after receiving 1 (n=10), 2 (n=3), 3 (n=1), 4 (n=6), 7 (n=1 patient), 22 (n=1 patient), or 24 (n=1) courses. The most common reasons for changing treatment were to intensify retrieval therapy or to pursue immunotherapy. Of those 23 patients, 15 patients had stable disease, 7 were not evaluable for response because of concurrent radiotherapy, and 1 patient had a major response. Twenty-one patients had PD after 1 (n=3, 2 (n=9), 4 (n=2), 5 (n=1), 6 (n=3), 7 (n=1), 9 (n=1), and 11 (n=1) courses. In heavily treated patients, the regimen studied was well tolerated, allowed patients to continue most normal life activities, and produced anti-NB effects. Its modest toxicity supported use with other antitumor agents.

Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38.

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)(7)TAA (UGT1A1(*)28), UGT1A9 766G>A (D256N; UGT1A9(*)5), and UGT1A9 98T>C (M33T; UGT1A9(*)3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 +/- 6466 ng x h/mL and 629 +/- 370 ng x h/mL, respectively, which is in line with earlier findings. For UGT1A9(*)5,novariant alleles were observed, whereas for UGT1A9(*)3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1(*)28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1(*)28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p =.022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1(*)28 polymorphism may identify patients with altered SN-38 pharmacokinetics.