Nonplatinum-based chemotherapy with irinotecan plus docetaxel for advanced or metastatic olfactory neuroblastoma: a retrospective analysis of 12 cases

BACKGROUND: The efficacy and safety of chemotherapy with irinotecan plus docetaxel were retrospectively evaluated for olfactory neuroblastoma. METHODS: Twelve patients with histologically proven advanced or metastatic olfactory neuroblastoma were treated with chemotherapy with irinotecan plus docetaxel at the study institution between 2001 and 2005. Of these, 7 patients with locoregional disease and no prior radiotherapy received irinotecan plus docetaxel followed by definitive radiotherapy, 1 with photon radiotherapy and 6 with proton radiotherapy, whereas 3 patients with distant metastases and 2 with locoregional disease who had received prior radiotherapy received irinotecan plus docetaxel only. RESULTS: The most common toxicities of >or=grade 3 among the 12 patients receiving irinotecan plus docetaxel were leukopenia (33%), neutropenia (50%), febrile neutropenia (8%), and diarrhea (25%), all of which were manageable. Partial response was achieved in 3 patients, giving an overall response rate of 25%. The response rate was higher in patients aged <50 years (3 of 4 patients) compared with those aged >50 years (0 of 8 patients) (P = .018). With a median follow-up period of 22.2 months, the median progression-free survival and overall survival were 13.6 months and 36.6 months, respectively. Of the 7 patients with locoregional disease also receiving definitive radiotherapy, the 2-year survival rate was 100% and 6 patients were alive at the time of last follow-up. CONCLUSIONS: Chemotherapy for olfactory neuroblastoma with irinotecan plus docetaxel is safe and manageable. Patients aged <50 years may be sensitive to chemotherapy. Induction chemotherapy followed by definitive radiotherapy may represent a promising option for patients with locally advanced olfactory neuroblastoma.     

Docetaxel and irinotecan in recurrent or metastatic head and neck cancer

BACKGROUND:

Docetaxel and irinotecan have single‐agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN.

METHODS:

Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m² and irinotecan 60 mg/m², intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase‐2 and VEGF in baseline tumor tissue.

RESULTS:

Fifty‐two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel‐exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression‐free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085).

CONCLUSIONS:

Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum‐based regimens. Cancer 2009. © 2009 American Cancer Society.     

Chemotherapy for gastric cancer that recurs after adjuvant chemotherapy with S-1

We retrospectively analyzed the efficacy of chemotherapy in patients whose gastric cancer recurred after adjuvant chemotherapy with S-1. A total of 51 patients were evaluated. Twenty-one patients received S-1-containing chemotherapy as first-line treatment after recurrence [cohort A: S-1 plus cisplatin (n = 10), S-1 monotherapy (n = 7), S-1 plus irinotecan (n = 3) and S-1 plus docetaxel (n = 1)]. The other 30 patients received a non-S-1-containing regimen [cohort B: paclitaxel or docetaxel (n = 22), irinotecan plus cisplatin (n = 6) and other drugs (n = 2)]. No objective responses occurred in cohort A, while five patients achieved a partial response in cohort B (response rate, 0 versus 16%; P = 0.04). Median progression-free survival was significantly longer in cohort B than in cohort A (4.3 versus 2.3 months, P = 0.02). S-1-containing chemotherapy does not appear to be effective in patients whose gastric cancer recurs after adjuvant S-1 chemotherapy. Other chemotherapeutic agents should be evaluated in this setting.     

Phase II study of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 007)

This study was designed to evaluate the activity and tolerability of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer (NSCLC). Eligibility included recurrent or progressive NSCLC, previous chemotherapy, age > or = 18 years, ECOG PS < or = 2. Treatment consisted of irinotecan (160 mg/m2 i.v.), followed by docetaxel (65 mg/m2 i.v.) on day 1 of a 21-day cycle, for a maximum of 6 cycles. Forty patients were enrolled. Median age was 60 years and median ECOG PS was 1. All patients were evaluable for toxicity and 31 (78%) were evaluable for response. A total of 125 cycles was administered (median, 3; range, 1-6). Most common grade 3-4 toxicities were neutropenia (62%), neutropenic fever (22%), and diarrhea (32%). Response rate was 10%; a further 40% of patients achieved stable disease. All responses were observed in patients with ECOG PS < or = 1, age <70 years, and who had received only one prior chemotherapy regimen. Median time to progression was 2.8 months and median survival was 7.4 months. Because of significant toxicity and limited activity, further investigation of irinotecan plus docetaxel in second line NSCLC is not recommended.     

Front-line treatment of advanced non-small cell lung cancer with irinotecan and docetaxel: a multicentre phase II study

PURPOSE: To evaluate the efficacy and tolerance of the irinotecan plus docetaxel combination in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-nine chemotherapy-na?ve patients with advanced NSCLC were treated with irinotecan 200mg/m2 followed by docetaxel 80 mg/m2 intravenously on day 1 with granulocyte colony-stimulating factor (150 microg/m2) support from day 2 to 9. Treatment was repeated every 3 weeks. RESULTS: A partial response was achieved in 9 (23%; 95% confidence interval 9.85-36.3%) patients; stable and progressive disease were observed in 10 (25.6%) and 20 (51.4%) patients, respectively. The median duration of response was 7.1 months and the median time to tumor progression 3 months. The median survival time was 10.8 months and the 1-year survival 42.2%. Four (10.3%) patients developed grade 4 neutropenia and all but one were complicated with fever; there was no treatment-related death. Nine (23.1%) patients developed grade 3 or 4 diarrhea while grade 2 or 3 fatigue occurred in nine (23.1%), and grade 3 mucositis in two (2.6%). CONCLUSION: The combination of irinotecan/docetaxel is a relatively active non-platinum-based chemotherapy regimen with manageable toxicity, which could be given in an outpatient basis; this regimen merits to be further studied in order to improve its tolerance and evaluate its clinical relevance in patients who can not tolerate platinum-based doublets.     

Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck.

PURPOSE: To assess the antitumor activity and toxicity of docetaxel plus cisplatin chemotherapy in patients with recurrent or incurable squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with recurrent or incurable SCCHN were eligible if they were chemotherapy naive or if they had received one prior regimen as neoadjuvant or concurrent treatment with radiation. Patients who had received chemotherapy for recurrence or prior taxanes were ineligible. Patients received docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1; cycles were repeated every 21 days. RESULTS: Toxic effects and length of survival were assessable in 36 patients and tumor response was assessable in 32, for whom the overall response rate was 40% (13 of 32) (6% complete response and 34% partial response). Median time to response was 5 weeks, and median duration was 4.9 months. In the intent to treat population (n = 36), median time to disease progression was 4 months. Median survival (n = 36) was 9.6 months, and the 12-month survival rate was 27%. Grade 4 neutropenia was observed in 71% of patients. Two patients (6%) experienced serious fever during grade 4 neutropenia (without documented infection) that required intravenous antibiotics, and an additional four patients had grade 3 infection. Other severe (grades 3 and 4) toxic effects were asthenia (25%), nausea (11%), fever (8%), vomiting (8%), severe hypersensitivity reactions (8%), and diarrhea (8%). Severe stomatitis (grade 3) occurred in only one patient. CONCLUSION: Docetaxel plus cisplatin is an effective regimen with an acceptable safety profile for palliation of recurrent SCCHN. Relative to the standard regimen of cisplatin/fluorouracil, this regimen may offer higher tumor response and survival rates with short outpatient administration and a lower incidence of severe mucosal toxicity.     

A phase 2 study of pemetrexed plus gemcitabine every 2 weeks for patients with recurrent or metastatic head and neck squamous cell cancer

BACKGROUND:

Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC).

METHODS:

This was an open‐label, single‐institution, single‐arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m² intravenously plus gemcitabine 1250 mg/m² intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability.

RESULTS:

Twenty‐five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade ≥3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of >20 but <30% did not meet RECIST criteria for a PR. The median overall survival for all treated patients was 8.8 months.

CONCLUSIONS:

Treatment with pemetrexed plus gemcitabine every 2 weeks with vitamin support generally was well tolerated. The results of this study provided further evidence that pemetrexed may have significant palliative activity against advanced HNSCC. Cancer 2011. © 2010 American Cancer Society.     

异环磷酰胺联合卡铂治疗复发和难治性神经母细胞瘤的疗效分析

背景与目的:约30%的神经母细胞瘤患者一线化疗疗效欠佳或在治疗中进展,而且尽管采用综合治疗可使晚期神经母细胞瘤患者获得完全缓解(completeresponse,CR),仍有不少患者最终复发。本研究采用异环磷酰胺/卡铂(IC)方案治疗复发和难治性神经母细胞瘤,探讨复发和难治神经母细胞瘤的挽救化疗方案。方法:9例难治和23例复发性神经母细胞瘤患者接受IC方案化疗:卡铂(carboplatin,CBP)400mg/m2静脉滴注,第1天;异环磷酰胺(ifosfamide,IFO)1.5g/m2,静脉滴注,第1～5天,同时予美斯钠解毒,用法为用IFO后第0、4、8h,各静脉注射1次,每次剂量为IFO剂量的20%。每2～3周重复。结果:部分缓解(partialresponse,PR)19例(59.4%),无CR病例。有效患者中位缓解时间4.2(1～28)个月。8例(25%)患者化疗后获得手术切除肿瘤。主要不良反应有:Ⅲ～Ⅳ度白细胞下降发生率44.7%;Ⅲ～Ⅳ度血小板下降发生率53.1%;粒细胞缺乏合并感染发生率18.8%;Ⅰ度肝功能异常发生率12.5%;出血性膀胱炎发生率9.4%。结论:IC方案治疗复发/难治性神经母细胞瘤近期有效率较高,毒性可耐受。但远期预后较差,仍需探讨一些积极有效的治疗方法以提高其远期生存率。     

Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing,Non-interventional VARGADO Study

AimsTo evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy.Materials and methodsVARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy.ResultsThe median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%).ConclusionsNintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.     

Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients

Background

Recurrent or persistent clear cell carcinoma (CCC) of the ovary is particularly chemotherapy resistant. The purpose of this study was to review our extensive institutional experiences with recurrent or persistent CCC with the aim of finding a more effective chemotherapy regimen.

Methods

The medical records of 67 patients treated for CCC of the ovary were retrospectively reviewed to select patients subsequently treated for recurrence or persistence of the disease.

Results

The review identified 20 patients treated for recurrent or persistent CCC. For these 20 patients, 9 chemotherapeutic regimens, with 125 cycles, were administered. Gemcitabine monotherapy showed the best response rate [1 partial response (20%) and 2 stable diseases out of 5 patients so treated]. A partial response was observed with a combination of docetaxel plus irinotecan in 1 of 11 patients (9%). Stable disease was observed in 1 of 9 cases on a paclitaxel/carboplatin doublet and in 1 case on a docetaxel/carboplatin doublet. The median overall survival time was 8 months (range, 2–52). One group of patients who received gemcitabine therapy showed significantly better survival (n = 5, median 18 months) compared with a group who did not (n = 15, median 7 months) (P = 0.0108, by univariate analysis). In addition, multivariate Cox proportional hazards analysis revealed that gemcitabine administration was a significant factor for survival (hazard ratio: 13.0, 95% CI: 1.4727–115.2255, P = 0.02).

Conclusion

Although most chemotherapeutic regimens for recurrent or persistent CCC have little or no effect, gemcitabine showed modest activity and is the most effective agent we have tested to date.     

Randomized phase II trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV NSCLC.

BACKGROUND: To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients with chemotherapy-na?ve stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel 40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks. RESULTS: Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine-irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine-docetaxel. Median overall survival was 7.95 months (95% CI 5.2-10.2) and 12.8 months (95% CI 7.9-17.1) for gemcitabine-irinotecan and gemcitabine-docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine-irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine-docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. CONCLUSIONS: These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-na?ve advanced NSCLC. The survival data with the combination gemcitabine-docetaxel are promising. Gemcitabine-docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.     

GT方案与XT方案治疗复发转移性乳腺癌的临床观察

目的:观察吉西他滨联合紫杉醇（GT）及卡培他滨联合多西他赛（XT）方案治疗复发转移性乳腺癌的临床疗效及毒副反应。方法:复发转移性乳腺癌患者36例,采用回顾性研究方法分为两组:GT组18人,第1天紫杉醇175mg/m2静滴3小时,第1、8天吉西他滨1 000mg/m2静滴30分钟,21天为一周期;XT组18人,第1天多西他赛75mg/m2静滴1小时,第1~14天卡培他滨1 000mg/m2口服Bid,周期同为21天。化疗期间观察患者化疗毒副反应,每两周期行影像学检查评价疗效。结果:GT组CR为11.1%,PR为38.9%,SD为 27.8%,DCR为77.8%;XT组CR为5.6%,PR为44.4%,SD为22.2%,DCR为72.2%,两组对比无统计学差异（P>0.05）。GT组中位TTP为8.7个月,XT组中位TTP为7.8个月,两者统计学上无差异（P>0.05）。毒副反应方面GT组血小板减少发生率较XT组高,XT组手足综合征发生率高于GT组,其余各项无显著性差异（P>0.05）。结论:GT方案与XT方案治疗复发转移性乳腺癌疗效确切,毒副反应能耐受。     

Two cases with recurrent non-small cell lung cancer successfully treated with cisplatin and S-1

We report two cases with recurrent non-small cell lung cancer (NSCLC) successfully treated with cisplatin and S-1 after multiple chemotherapy. A 64-year-old woman was diagnosed with adenocarcinoma, yield-T4N2M1, stage IV. She was treated with cisplatin 60 mg/m(2) (day 8) and S-1 80 mg/m(2) (days 1-21) as sixth-line chemotherapy after treatment with paclitaxel and irinotecan, cisplatin and gemcitabine, docetaxel, gefitinib, and vinorelbine. Chest computed tomography (CT) showed partial response of recurrent tumors. Another woman (56 years old) was diagnosed with adenocarcinoma, yield-T0N1M1, stage IV. She was also treated with cisplatin and S-1 as fourth-line chemotherapy after treatment with nedaplatin and gemcitabine, docetaxel and irinotecan, and gefitinib. Chest CT showed a partial response of recurrent tumors. Additionally, we retrospectively reviewed 10 cases with recurrent NSCLC treated with cisplatin and S-1 during the same period. Grade 3 to 4 hematologic toxicity included neutropenia in 30% of these 10 patients, thrombocytopenia in 20%, and anemia in 60%. Grade 3 non-hematologic toxicity included hyperglycemia and hyponatremia in 20% of the 10 patients. All side effects were manageable and there was no case of treatment-related death. Cisplatin combined with S-1 could be an option for recurrent NSCLC.     

Phase II study of docetaxel and irinotecan combination chemotherapy in metastatic gastric carcinoma

The current treatment for metastatic gastric cancer (MGC) consists of cisplatin and/or fluorouracil (5-FU) based combination chemotherapy, but cisplatin-based regimens are associated with considerable toxicity. We evaluated the efficacy and safety of a noncisplatin-, non-5-FU-containing regimen, docetaxel/irinotecan in MGC. Chemo-naive patients with MGC received docetaxel (30 mg m(-2)) and irinotecan (70 mg m(-2)) on days 1 and 8 every 3 weeks. The 48 eligible patients (median age 56 years) received a median of four cycles of docetaxel/irinotecan (range 1-18). Of the 46 patients in whom efficacy could be evaluated, 21 showed a partial response (response rate=45.7%; 95% confidence interval (CI) 31.3-60.1%). At a median follow-up of 15.0 months, the median time to progression was 4.5 months (95% CI 3.8-5.2 months) and overall survival was 8.2 months (95% CI, 5.8-10.6 months). Grade 3/4 neutropenia developed in 57.4% of patients, and febrile neutropenia/neutropenic infection in 19.1%. Nonhaematological toxicities were moderate; grade 3/4 diarrhoea occurred in 19.1% of patients, however, was manageable by a dose reduction. There was one possible treatment-related death. In conclusion, weekly docetaxel/irinotecan is a promising outpatient regimen in MGC, with appropriate dose modification.     

Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors

BACKGROUND: Response rates to second-line chemotherapy in recurrent high-grade glial tumors are low and new effective treatments are needed. The objective of this study was to evaluate response rates and tolerability of chemotherapy with bevacizumab and irinotecan in recurrent high-grade gliomas. METHODS: Twenty patients with recurrent gliomas were treated with bevacizumab 5 mg/kg and irinotecan 125 mg/m(2) every 2 weeks. The response was evaluated by gadolinium-enhanced magnetic resonance imaging performed every 4 cycles of treatment. RESULTS: The patients received 1 to 22 cycles of treatment. Nine of 19 patients available for response evaluation (47.3%) showed an objective radiologic response: 2 patients (10.5%) a complete response (CR), and 7 patients (36.8%) a partial response (PR). Two additional patients showed stable disease (SD) for 2 and 6 months, respectively. Eight patients developed rapid progression after 1 to 4 cycles of treatment. Median time to progression on treatment was 4.7 months. The 6-month progression-free survival (PFS) and overall survival (OS) were 25% and 55%, respectively. The adverse effects were mild and in all but 2 cases were no more than grade 2. There were no thrombotic complications or significant bleeding other than epistaxis. CONCLUSIONS: The preliminary data show a promising high response rate of recurrent high-grade gliomas to chemotherapy with bevacizumab and irinotecan. The regimen is associated with minimal toxicity.     

Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma

BACKGROUND: The optimal chemotherapy regimen for the treatment of olfactory neuroblastoma has not been clearly defined. The purpose of the current study was to evaluate the efficacy of neoadjuvant chemotherapy with the combination of etoposide, ifosfamide, and cisplatin (VIP) for patients with olfactory neuroblastoma. METHODS: Eleven consecutive patients with newly diagnosed olfactory neuroblastoma were treated with etoposide (75 mg/m2), ifosfamide (1000 mg/m2), and cisplatin (20 mg/m2) all administered intravenously on Days 1-5. Cycles were repeated every 21 days. Patients were excluded from analysis if they had previously received surgery or radiotherapy. RESULTS: Nine patients achieved objective responses (objective response rate, 82%; 95% confidence interval, 52-95%), which included 2 complete responses and 7 partial responses. The major side effect was hematologic toxicity, with Grade 3/4 neutropenia observed after the receipt of 37% of all cycles and febrile neutropenia observed after the receipt of 2 cycles. All toxic events were reversible, and no chemotherapy-related deaths were documented. The median survival period was 18 months (range, 3-45 months). CONCLUSIONS: Neoadjuvant VIP chemotherapy was active in the treatment of olfactory neuroblastoma.     

A phase II study of sequential chemotherapy with docetaxel after the weekly PELF regimen in advanced gastric cancer. A report from the Italian group for the study of digestive tract cancer

In advanced gastric cancer, we investigated feasibility and activity of sequential chemotherapy with docetaxel after an intensive weekly regimen consisting of cisplatin, epidoxorubicin, fluorouracil, leucovorin (PELF) plus filgrastim. Chemotherapy-naive patients with relapsed or metastatic gastric cancer received 8 weekly administrations of chemotherapy with cisplatin 40 mg/m(2), fluorouracil 500 mg/m(2), epidoxorubicin 35 mg/m(2), 6S-stereoisomer of leucovorin 250 mg/m(2) and glutathione 1.5 g/m(2). On the other days filgrastim 5 microg kg(-1) was administered by subcutaneous injection. Subsequently, patients with partial response or stable disease received 3 cycles of docetaxel 100 mg/m(2) every 3 weeks. 40 patients have been enrolled and they are evaluable for response and toxicity. After the PELF regimen, 3 patients achieved complete response, 13 patients showed partial response, 21 patients had stable disease and 3 patients progressed (40% response rate; 95% CI 25% to 55%). After docetaxel, 9 out 34 patients improved the outcome (26.5%); 7 patients with stable disease achieved partial response and 2 patients with partial response achieved complete response. The overall response rate in the 40 patients was 57.5% (95% CI, 42.5% to 72.5%). The PELF regimen did not cause any grade IV toxicity, the most frequent grade III acute side-effects were thrombocytopenia and vomiting which occurred in the 10% of 320 PELF cycles. Docetaxel caused grade III-IV neutropenia and thrombocytopenia in the 10% and the 19% of cycles respectively. Fatigue was a frequent side-effect during both PELF and docetaxel chemotherapy. The sequential application of docetaxel after PELF chemotherapy gained major objective responses with manageable toxicity. This strategy is worth of further investigation in the setting of palliative or neoadjuvant chemotherapy.     

Docetaxel monotherapy as a second-line treatment after failure of fluoropyrimidine and platinum in advanced gastric cancer: experience of 154 patients with prognostic factor analysis

OBJECTIVE: To investigate the efficacy and safety of docetaxel monotherapy as salvage chemotherapy for advanced gastric cancer (AGC) in clinical practice and to determine the prognostic factors in these patients. METHODS: We retrospectively reviewed the medical records of patients with AGC for whom fluoropyrimidine and platinum had previously failed and who had received docetaxel salvage monotherapy between December 2000 and March 2006. Docetaxel was administered at a dose of 75 mg/m(2) intravenously every 3 weeks with dexamethasone prophylaxis. RESULTS: A total of 154 patients received 583 cycles of docetaxel with a median of three cycles per patient (range 1-10). The median age was 54 years (range 27-75 years). The objective response rate of 86 patients with measurable lesions was 14%, with 1 complete response and 11 partial responses, with a median response duration of 5.6 months. An additional 25 patients achieved stable disease. The median time to progression (TTP) for all patients was 2.6 months [95% confidence interval (CI), 2.2-2.9] and the median overall survival (OS) from the start of docetaxel chemotherapy was 7.2 months (95% CI, 5.9-8.5). The chemotherapy was generally well tolerated. Multivariate analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) was an independent prognostic factor for both TTP and OS. Disease status indicative of a relatively small tumor burden (resected metastatic or recurrent tumor) was a predictor for better TTP and good differentiation of the tumor was a predictor for better OS. CONCLUSION: Docetaxel 75 mg/m(2) is relatively active and tolerable as a second-line salvage treatment after failure of fluoropyrimidine and platinum in general clinical practice for AGC.     

Pediatric phase 2 trial of a WEE1 inhibitor,adavosertib (AZD1775), and irinotecan for relapsed neuroblastoma,medulloblastoma, and rhabdomyosarcoma

Background

Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib.

Methods

Pediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided.

Results

The 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose.

Conclusion

This is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.     

Salvage chemotherapy with mitomycin, docetaxel, and irinotecan (MDI regimen) in metastatic pancreatic adenocarcinoma: a phase I and II trial

BACKGROUND: This study evaluates the maximum tolerated dose (MTD) and activity of mitomycin, docetaxel, and irinotecan (MDI) regimen on metastatic pancreatic adenocarcinoma, previously treated with gemcitabine-containing chemotherapy. PATIENTS AND METHODS: Patients with less than 76 years, Karnofsky performance status > or = 60, and adequate bone marrow, kidney, and liver function were eligible for this trial. Treatment consisted of mitomycin 6 mg/m2 day 1, docetaxel and irinotecan on days 2 and 8 with escalating doses, every 4 weeks. Dose levels were level 1:30 and 70 mg/m2; level 2:30 and 100 mg/m2; level 3:30 and 85 mg/m2; and level 4:35 and 85 mg/m2. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia > 7 days, febrile neutropenia, grade 4 thrombocytopenia, nausea and vomiting, or diarrhea, grade > or = 3 nonhematological toxicity, or failure to recover to grade < or = 1 toxicity by day 43, occurring during the first cycle of chemotherapy. RESULTS: Between September 2001 and October 2002, 15 eligible patients, three of whom had been previously treated with two lines of chemotherapy, received 33 cycles of MDI. Toxicity consisted of grade 3 to 4 neutropenia in 23% of cycles, fatigue, diarrhea, and vomiting in 10% of cycles, and one toxic death. DLT was observed in 2 of 6 level 2 patients (one toxic death and one grade 3 fatigue), and 2 of 3 level 4 patients (one neutropenic fever and one grade 3 fatigue). Thirteen patients were assessable for response. No objective response was observed among patients treated with MTD or higher doses. Three patients had stable disease; all other patients had progressive disease. The median time to tumor progression and median survival was 1.7 and 6.1 months, respectively. CONCLUSION: The MTD was mitomycin 6 mg/m2 day one, and docetaxel 30 and irinotecan 85 mg/m2 days 2 and 8. This regimen is inactive in metastatic pancreatic cancer.