Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR)

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.BackgroundRandomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC).Patients and methodsPatients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m²/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points.ResultsA total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4–10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4–27.6 resp. 26.0–36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia.ConclusionThe combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.     

Phase I and pharmacologic study of sequential topotecan-carboplatin-etoposide in patients with extensive stage small cell lung cancer

The inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II associated with increased in vitro sensitivity of tumors to etoposide. Maximal synergy has been observed for the sequence of topotecan followed by etoposide. Carboplatin has clinical activity when combined with either of these two agents. These interactions were the pharmacologic rationale for topotecan p.o. days 1-5, carboplatin i.v. day 6, and etoposide p.o. days 6-10. Three successive dose levels were explored: (1) topotecan 2mg/day, carboplatin AUC 5, etoposide 150 mg/day; (2) topotecan 3mg/day, carboplatin AUC 5, etoposide 150 mg/day; and (3) topotecan 3mg/day, carboplatin AUC 5, etoposide 200mg/day. Filgrastim 5 microg/kg/day was injected s.c. days 11-18. Up to 6 cycles were administered every 21 days. Eligible patients had measurable or evaluable, extensive disease, small lung cell lung cancer, no prior chemotherapy, ECOG performance status 0-2, and adequate hematologic, renal, and hepatic function. Follow-up was weekly for CBC. Tumor response was assessed after 2 and 6 cycles. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: grade 3 or 4 non-hematologic toxicity other than nausea and vomiting, grade 4 neutropenia lasting more than 3 days, neutropenic fever or sepsis, grade 4 thrombocytopenia, or failure to recover neutrophils >or=1500/microl or platelets >or=100,000/microl by day 28. Ten patients were enrolled: median age 62 (range, 50-79); female/male 4/6; and performance status 0/1/2 in 2/7/1. Three patients each were treated on dose levels 1 and 2 without DLT. The first 2 patients entered on dose level 3 had no DLT. The third patient on dose level 3 developed grade 4 neutropenia lasting more than 3 days, neutropenic fever, and grade 4 thrombocytopenia on day 15 of cycle 1. The fourth patient on dose level 3 developed grade 4 thrombocytopenia on day 18 of cycle 1. One patient received only 1 cycle and was not evaluable for response. Seven patients completed 6 cycles: 1 had a complete response and 6 achieved a partial response. The third patient on dose level 3 received 2 cycles and had stable disease, but had to be removed from protocol treatment because of grade 4 neutropenia despite dose reduction in cycle 2. The fourth patient on dose level 3 achieved a partial response, but had to be removed from protocol therapy after cycle 5 because of recurrent grade 4 thrombocytopenia. In conclusion, neutropenia and thrombocytopenia were dose-limiting. The maximum tolerated dose (MTD) is topotecan 3mg/day p.o. days 1-5, carboplatin AUC 5i.v. day 6, and etoposide 150 mg/day p.o. days 6-10 with filgrastim.     

Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study.

BACKGROUND: The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. PATIENTS AND METHODS: Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). RESULTS: Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. CONCLUSIONS: Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.     

Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small cell lung cancer-a Danish Oncological Lung Cancer Group (DOLG) phase II trial

INTRODUCTION: The longest survival time reported in randomised trials of limited disease (LD) SCLC has been achieved with early twice-daily concurrent chemoradiation. Topotecan is active in recurrent SCLC and in extensive disease as first line treatment. AIM: To incorporate and assess the effect of topotecan with concurrent twice-daily radiochemotherapy in LD SCLC. PATIENT AND METHODS: Multicentre phase II study of three cycles of regimen A (topotecan i.v., 1.5mg/m(2), day 1-5; cisplatin 50mg/m(2), day 1) and three cycles of regimen B (etoposide i.v., 120mg/m(2), day 1-3; carboplatin, AUC=5, day 1; vincristine, 1.3mg/m(2), day 1) given in the following sequence: A-B-B-A-B-A every 21 days. Twice-daily radiotherapy (1.5Gyx30, 10fr/wk, 45Gy) was delivered concurrently with the first cycle B. Prophylactic cranial irradiation was offered to patients (pts) in complete remission. Eligible were pts with LD SCLC with no prior treatment for SCLC, adequate organ functions, and WHO performance status (PS) < or =2. Pts older than 64 years with PS=2 and LDH>two times the upper limit were excluded. RESULT: Fourty-five pts were included in four centres. Five patients did not meet the inclusion criteria. The median age of the eligible pts was 60 years, range 43-75. PS was < or =1 in 90% of pts. Non-haematological toxicity was mild except grade 3 esophagitis, which was observed in 26.5% of pts. One pt developed an esophageal stricture. Grade 3/4 leucopenia and thrombocytopenia were observed in 82.5% and 75.0 of pts, respectively. One patient died due to neutropenic sepsis. The overall response rate was 77.5% with 30.0% achieving a complete response. Median progression-free survival was 11.8 months (95% CI: 1.3-22.2). Median overall survival was 22.9 months (95% CI: 13.4-31.5) and 5-year survival was 21%. CONCLUSION: The combination of topotecan and cisplatin with concurrent twice-daily chemoradiation results in long-term survivors. As expected the incidence of severe esophagitis is high.     

Effective dosing of topotecan with carboplatin in relapsed ovarian cancer: a phase I/II study.

PURPOSE: This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin. PATIENTS AND METHODS: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m(2)/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m(2)/d and carboplatin AUC of 5, topotecan 0.75 mg/m(2)/d and carboplatin AUC of 5, and topotecan 1.0 mg/m(2)/d and carboplatin AUC of 5. RESULTS: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m(2)/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m(2)/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule. CONCLUSION: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m(2)/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m(2)/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.     

Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/- taxane-pretreated ovarian cancer patients.

BACKGROUND: This multicentre phase II open-label study evaluated safety and antitumour activity of oxaliplatin in cisplatin or carboplatin (cis/carboplatin) +/- taxane-pretreated advanced ovarian cancer (AOC) patients. PATIENTS AND METHODS: Forty-eight patients received oxaliplatin 130 mg/M2 intravenously every 3 weeks, 94% having a performance status (PS) 0-1. All were pretreated with cis/carboplatin and 21 (44%) with paclitaxel. The median number of involved organs was two, 18 (38%) had liver metastasis, 23 (48%) were platinum-resistant and 14 (29%) were taxane-resistant. Forty-two patients were evaluable for a response, 18 (43%) were platinum-resistant and 11 (26%) were taxane-resistant. RESULTS: A total of 253 cycles was administered (median: 5.5/patient). Median cumulative oxaliplatin dose was 666 mg/m2. National Cancer Institute-Common Toxicity Criteria toxicity analysis showed that seven patients (15%) had grade 3/4 thrombocytopenia, two patients (4%) had grade 3 neutropenia, and one patient had grade 3 anaemia. Eleven patients (23%) experienced grade 3 neurosensory toxicity. Of the 29 patients with peripheral neuropathy at the end of treatment, 55% had recovered or improved 1 month later. Eleven objective responses (two complete) were obtained in the 42 evaluable patients [ORR 26%, 95% confidence interval (CI) 14% to 42%], with 10/24 (42%, 95% CI 22% to 63%) in platinum-sensitive, and 1 of 18 (5.6%, 95% CI 0% to 27%) in platinum-resistant patients. Median response duration was 9.2 months (95% CI 6.6% to 11.8%), and median progression-free and overall survival in all treated patients were 4.3 months (95% CI 3.0% to 5.7%) and 15.0 months (95% CI 11.1% to 18.8%), respectively. CONCLUSION: Oxaliplatin has a good safety profile and is active in cis/carboplatin +/- paclitaxel-pretreated AOC patients.     

Phase I trial of gemcitabine and carboplatin in metastatic non-small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie Study

BACKGROUND: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). METHODS: At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m(2) on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5-7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m(2) (level 7). Twenty-nine patients were entered into this phase I study. RESULTS: At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). CONCLUSION: The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m(2), the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m(2).     

Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer. an EORTC phase II study (EORTC 08958)

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-na?ve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.     

A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m(-2)) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (>/=6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2-41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8-6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1-14.2%). Median PFS was 2.0 months (95% CI: 1.7-3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (>/=2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.     

Randomised phase II study comparing topotecan/carboplatin administration for 5 versus 3 days in the treatment of extensive-stage small-cell lung cancer.

BACKGROUND: Topotecan is an active drug in small-cell lung cancer (SCLC). In our previous study, a combination of topotecan with cisplatin was associated with a median overall survival of 7.6 or 8.7 months, depending on the duration of treatment. We have replaced cisplatin by carboplatin in this trial, with the objective of creating a more convenient schedule for our patients. Furthermore, we have also compared the standard 5-day schedule with an experimental 3-day schedule. PATIENTS AND METHODS: A total of 100 patients with metastatic disease were included. Patients were randomly assigned to receive either topotecan 0.75 mg/m2, days 1-5, and carboplatin AUC 5, day 5 (arm A) or topotecan 1.25 mg/m2, days 1-3, and carboplatin AUC 5, day 3 (arm B). Six cycles were given at a 3-week interval. RESULTS: A total of 91 patients were assessable for response. The response during therapy was 86.9% in arm A and 80.0% in arm B. Median survival in arm A was 11.8 months and in arm B 11.6 months (P=0.37). CONCLUSIONS: The combination of topotecan and carboplatin is active in extensive-disease SCLC. Toxicity and median survival were comparable in both arms. Three days of treatment seems to be similar to the 5-day regimen.     

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.     

A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.     

三药联合化疗和单药拓扑替康二线治疗小细胞肺癌的疗效和安全性比较

  目的  比较顺铂、依托泊苷、伊立替康联合化疗方案和单药拓扑替康二线治疗敏感复发型小细胞肺癌(smalll cell lung cancer, SCLC)的疗效和安全性。  方法  收集2014年9月至2017年9月吉林省肿瘤医院就诊78例患者资料, 筛选敏感复发型小细胞肺癌患者, 其中36例患者给予顺铂、依托泊苷、伊立替康联合化疗方案, 42例患者给予单药拓扑替康化疗。联合化疗组药物用法:顺铂25 mg/m2, 第1天、第8天静脉滴注; 依托泊苷60 mg/m2, 第1、2、3天静脉滴注; 伊立替康90 mg/m2, 第8天静脉滴注, 连续给予5个2周方案的化疗。单药拓扑替康组药物用法:拓扑替康1.5 mg/m2, 第1~5天静脉滴注, 每3周1个周期。评价两组治疗方案的无进展生存时间(progressionfree survival, PFS)、总生存时间(overall survival, OS)及安全性。  结果  联合化疗组中位无进展生存时间(mPFS)5.3个月(95% CI:4.3~ 5.8), 拓扑替康组mPFS 3.2个月(95% CI:2.7~4.0), 差异具有统计学意义(P=0.003 0);联合化疗组中位总生存时间(mOS)16.3个月(95% CI:13.8~19.1), 拓扑替康组mOS 13.1个月, 差异具有统计学意义(P=0.009 7)。联合化疗组和单药拓扑替康组常见的3/4级不良事件主要有中性粒细胞下降[31例(86.1%) vs.28例(66.7%)]、白细胞下降[29例(80.6%) vs.21例(50.0%)]、贫血[26例(72.2%) vs.10例(23.8%)]、血小板下降[13(36.1%) vs.11(26.2%)]。联合化疗组发生1例治疗相关死亡(发热性中性粒细胞下降合并肺部感染), 拓扑替康组无治疗相关的死亡发生。  结论  顺铂、依托泊苷、伊立替康联合化疗方案比单药拓扑替康疗效更好, 可考虑作为敏感复发型SCLC患者二线化疗的备选方案之一。两种化疗方案毒性均可耐受, 但联合化疗组不良事件发生率更高, 应进一步探索更为合适的化疗剂量。      

A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with Carboplatin and Etoposide in extensive stage small cell lung cancer

PURPOSE: Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. METHODS: Thirty-four chemotherapy-na?ve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. RESULTS: The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. CONCLUSION: It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.     

Addition of topotecan to standard cisplatin/etoposide combination in patients with extended stage small cell lung carcinoma

BACKGROUND: Topotecan is an active agent for the management of untreated and recurrent extensive-disease small cell lung cancer (ED-SCLC). This study was designed to evaluate the efficacy and safety of a triplet combination with topotecan added to the standard PE regimen in previously untreated patients with ED-SCLC. MATERIALS AND METHODS: Twenty-one patients (median age 55 years, and 18 male) with chemotherapy-naive ED-SCLC were enrolled into the study. PET treatment consisted of etoposide 80mg/m(2), cisplatin 20mg/m(2) and topotecan 0.75mg/m(2) and all were given intravenously on days 1 to 3 for every 3 weeks. RESULTS: Leucopoenia and/or neutropenia and to a lesser extent thrombocytopenia were the main dose-limiting toxicities. Severe leucopenia/neutropenia were observed in 14 (67%)/12 (57%) patients, and only two (10%) developed febrile neutropenia. Severe thrombocytopenia was observed in 6 (29%) patients and one patient died due to orbital and cerebral haemorrhage. Dose reductions were required in 13 (62%) patients, delays in 8 (38%) patients and early treatment discontinuation in 3 (14%) patients. The overall response rate was 52.6% (95% CI: 28, 9-75.6) with 2 (10.5%) complete and 8 (42.1%) partial responses. The overall median survival time was 6.6 months (range 0.5-16.5 months) and the 6-month overall survival was 65.3%+/-11.7. The overall median survival time of responders was 9.7 months compared to 5.7 months in non-responders (p=0.026). CONCLUSION: Topotecan combined with PE regimen with this schedule and dosage does not seem to provide any benefit in terms of response and survival in ED-SCLC patients and does not deserve further studies.     

Phase I study of weekly topotecan combined to concurrent external cranial irradiation in adults with glioblastoma multiforme of the brain

Although the standard of care for patients with glioblastoma multiforme (GM) remains postoperative radiotherapy (RT) in combination with chemotherapy (CT), the optimal regimen awaits verification. A phase I study was performed to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of topotecan (Hycamptin), given concurrently with RT, in patients with previously untreated glioblastoma multiforme (GM) of the brain. Thirty-six patients with histologically confirmed GM were enrolled. After surgery or stereotactic biopsy, patients received conventional external cranial RT (59.4 Gy/33 fractions in 6.6 weeks). Two cycles of topotecan were administered at days 1 and 4 of each week. Each cycle consisted of 30-min intravenous infusion 30-60 min before RT. The dose of topotecan was escalated in three dose increments from 1.0 to 1.25 and 1.5 mg/m(2) on a twice a week schedule among different patient groups. Three dose levels of topotecan were tested. Ten patients accrued to level 1 (topotecan dose 1 mg/m(2)/day, twice a week). No grade 4 toxicities were seen. Grade 2/3 hematologic toxicity was observed in 4 patients. Of the 11 patients included at level 2 (topotecan dose 1.25 mg/m(2)/day twice a week), 3 presented with grade 3 leucopenia and 2 with grade 3 thrombocytopenia. Of the 15 patients accrued to level 3 (topotecan dose 1.5 mg/m(2), twice a week), six had episodes of grade 4 leucopenia and two developed grade 4 thrombocytopenia. No other serious, early non-hematologic or late toxicities were seen at 21 months median follow-up time (range 6-36 months). From the cases included at level 2 and 3, five patients experienced episodes of grade 2/3 asthenia (13.8%), headache 9 (25%), confusion 5 (13.8%), seizure 4 (11%), and cutaneous erythema 3 (8.3%). The DLTs of topotecan given concurrently with RT were mainly hematological and the MTD was determined at the 1.25 mg/m(2)/day, twice a week dose level. A phase II chemoradiation study using the above recommended MTD dose of topotecan is ongoing, to establish the response rates, the local failures and the median survival of the above patients.     

Phase I trial of carboplatin and paclitaxel with escalating doses of oral topotecan in patients with solid tumors

Carboplatin, paclitaxel, and topotecan have activity against a variety of cancers. This phase I study was designed to determine the maximum tolerated dose of oral topotecan when given in combination with carboplatin and paclitaxel. Eligibility criteria were as follows: Karnofsky Performance score greater than or equal to 80; and adequate hepatic, renal, and bone marrow function. Patients received paclitaxel 175 mg/m2 intravenously followed by carboplatin AUC 5 iv on day 1 every 3 weeks for up to 6 cycles. Cohorts of 3 to 5 were treated with escalating doses of oral topotecan on days 1 to 5, initially at 0.75 mg/m2 then 1 mg/m2 and 1.25 mg/m2 in subsequent cohorts. Thirteen patients were treated. Three of three patients in cohort 1 had grade IV neutropenia, with one neutropenic fever and one patient requiring a platelet transfusion. In cohort 2, three of five patients had grade III/IV neutropenia including two with neutropenic fever. Four patients required blood transfusions and one required platelet transfusions. In cohort 3, three of five had grade III/IV neutropenia, one of five had grade IV thrombocytopenia, and one patient required blood transfusions. In conclusion, this three-drug regimen resulted in significant cumulative myelosuppression in the doses and schedule tested in this phase I trial. Subsequent combinations of these drugs should focus on alternate doses or schedules.     

Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site

BACKGROUND: The purposes of this study were to evaluate efficacy and toxicity of the combination of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site (CUP). METHODS: Patients with CUP received carboplatin AUC 5 mg/mL a minute intravenously Day 1, gemcitabine 1000 mg/m(2) intravenously Days 1 and 8, and capecitabine 1600 mg/m(2) orally in divided doses, Days 1-14 of a 21-day cycle for up to 8 cycles. The primary endpoint of the study was objective response rate by intent-to-treat analysis. RESULTS: Thirty-three patients were treated (median age, 58 years; men:women ratio, 19:14). Most patients had a baseline performance status of 1. The objective response rate was 39.4% (95% CI, 22.9%-57.9%) in all patients, 36.4% in 22 patients with well to moderately differentiated adenocarcinoma, and 40.0% in 20 patients with liver metastases. Median progression-free survival time was 6.2 months (95% CI, 5.4%-8.0%), and median survival time was 7.6 months (95% CI, 6.3-14.1). One and 2-year survival rates were 35.6% and 14.2%, respectively. The most frequent grade > or =3 adverse events were neutropenia (67%), thrombocytopenia (48%), and anemia (33%). CONCLUSIONS: The combination of carboplatin, gemcitabine, and capecitabine is active in CUP, especially in patients with liver metastases. This regimen may be a potential therapy for CUP patients with good performance status, particularly those with a suspected origin below the diaphragm.     

Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial

This phase II trial was designed to investigate the efficacy and tolerability of gemcitabine combined with carboplatin in patients with advanced or metastatic NSCLC. Patients were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and carboplatin AUC 5 mg/ml/min on day 2 of each cycle. Fifty patients (Zubrod-ECOG-WHO performance status 0/1 in 70/30%, stage IV disease in 64%) entered the study and were evaluable for response and toxicity. There was 1 complete response and 24 partial responses among 50 evaluable patients, for a response rate of 50% (95% CI: 36.0-64.1%). The median survival time was 13 months (range: 6-22 months), and the 1-year survival rate was 54%. Hematologic toxicities included grades 3 and 4 neutropenia in 24 and 8% of patients, respectively, and grades 3 and 4 thrombocytopenia in 48 and 8% of patients, respectively. These were without clinical sequelae. Seven (14%) patients had grade 3 nausea and vomiting. The combination of gemcitabine and carboplatin is highly active and well tolerated in patients with advanced or metastatic NSCLC.     

Chemotherapy with pegylated liposomal doxorubicin and cisplatin in recurrent platinum-sensitive epithelial ovarian cancer

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is the only nonplatinum agent to significantly improve survival in patients with platinum-sensitive recurrent ovarian cancer. The present study was designed to assess the efficacy and safety of PLD plus cisplatin combination therapy in these patients. METHODS: Twenty-two women (median age, 57 years) with ovarian cancer that recurred 6 months or more after standard carboplatin and paclitaxel therapy were eligible for enrollment. Cisplatin was administered intravenously as a 60-min infusion on day 1, at a single dose of 60 mg/m(2), and PLD was given intravenously as a 1-h infusion on day 2, at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. RESULTS: Hematological toxicity was mainly leucopenia/neutropenia, and this was the principal dose-limiting toxicity. Severe (grade III-IV) leucopenia/neutropenia was observed in 7 (32%) and 9 (41%) patients, respectively. Only 2 (9%) patients were complicated by febrile neutropenia. Grade III-IV anemia occurred in only 4 (18%) patients. Severe thrombocytopenia was not noted; only 5 patients (23%) had grade I-II toxicity. NO toxicity in biochemical parameters was noted. Several severe nonhematological adverse effects were managed according to standard protocols and were transient, as well as being well-tolerated. Twenty-one patients were evaluated for response. The overall response rate was 62% (13 of 21; 95% confidence interval [CI], 38%-82%), with four (19%) complete and nine (43%) partial responses. At the time of last follow-up, all of the 22 patients were alive. The median follow-up period was 8.5 months (range, 2 to 22 months). CONCLUSION: PLD combined with cisplatin at the schedule and dosage used in this study is an active and safe second-line chemotherapy regimen with acceptable and easily manageable toxicities in women with platinum-sensitive recurrent ovarian cancer.