Topotecan In Patients Research Articles

Topotecan weekly bolus chemotherapy for relapsed platinum-sensitive ovarian and peritoneal cancers

Objective Topotecan at a dose of 1.5 mg/m 2 on days 1 to 5 of a 21-day cycle is an approved therapy for recurrent ovarian cancer. However, heavily pretreated patients may be predisposed to hematologic adverse events. This prospective study, therefore, investigates the safety and efficacy of an alternate weekly schedule of topotecan in patients with recurrent ovarian or peritoneal cancer. Methods Patients with potentially platinum-sensitive recurrent ovarian or peritoneal cancer were treated with 4.0 mg/m 2 weekly topotecan as tolerated until disease progression. Antitumor response and safety were assessed. Dose reductions, delays, or omissions were implemented for grades 3–4 adverse events. Results Of the 41 enrolled patients (median age, 62 years; range, 42 to 82 years), 39 patients had ovarian cancer, and 2 patients had peritoneal cancer. The median platinum-free interval was 11.7 months. A median of 9 topotecan cycles (range, 1 to 45 doses) was administered. Weekly topotecan was well tolerated: 7 (17%) patients had grades 3–4 neutropenia, and 9 (22%) had grades 3–4 fatigue. No grade 4 thrombocytopenia or anemia was reported. Of 38 response-evaluable patients, 1 (3%) had a complete response, 8 (21%) had a partial response, 16 (42%) had stable disease, and 13 (34%) had progressive disease. Conclusions Weekly topotecan was well tolerated in patients with platinum-sensitive ovarian or peritoneal cancer at first relapse, with a hematologic profile that compared favorably with that of the 5-day topotecan regimen. Moreover, antitumor activity was similar to that reported for the 5-day regimen.

A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.

Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia

Resistance to topoisomerase I (TOP1)-targeting drugs such as topotecan often involves upregulation of topoisomerase II (TOP2), with accompanying increased sensitivity to TOP2-targeting drugs such as etoposide. This trial was designed to investigate sequential topoisomerase targeting in the treatment of patients with high-risk acute myelogenous leukemia. An initial cohort of patients received topotecan and cytosine arabinoside daily for 5 days. Serial samples of circulating mononuclear cells were examined to evaluate peak elevations of TOP2-alpha protein expression. In subsequent cohorts, etoposide was administered daily for 3 days, beginning 6 h after initiation of the topotecan infusion. The etoposide dose was escalated to determine a maximum-tolerated dose. Circulating mononuclear cells were analyzed for TOP1 mutations and ABCG2 protein expression. In addition, systemic and intracellular topotecan concentrations were measured. Thirty-one patients were enrolled. On the basis of TOP1-alpha protein levels in three patients with peripheral blast counts greater than 50%, etoposide administration began 6 h after initiation of the topotecan/cytosine arabinoside infusion. Using this schedule of administration, the maximum-tolerated dose of etoposide was 90 mg/m. No TOP1 mutations were identified, but increases in ABCG2 expression during the infusion were observed in mononuclear cells from two of four evaluable patients. Administration of etoposide 6 h after initiation of a topotecan/cytosine arabinoside infusion is feasible and is associated with clinical activity. Analysis of TOP2-alpha protein levels in this small number of patients indicated that peak increases occurred earlier than expected based on earlier publications. Upregulation of ABCG2 was detected in circulating cells and may represent an inducible form of drug resistance that should be investigated further.

Salvage treatment with topotecan in patients with irinotecan-refractory small cell lung cancer

Although the efficacy of topotecan as a second-line chemotherapy for small-cell lung cancer (SCLC) has been consistently demonstrated in phase II/III clinical trials, the choice of irinotecan as the first-line therapy prevented the use of evidence-based option. This pilot study was conducted to determine the activity and safety of topotecan in SCLC patients refractory to first-line therapy with irinotecan and platinum. Patients with primary refractory (no response, or progression during or < or =90 days after last chemotherapy) SCLC after treatment with a combination of irinotecan and platinum, received topotecan 1.5 mg/m(2) per day as a 30-min infusion daily for 5 days, every 3 weeks. Of 17 eligible patients, ten patients were previously treated with irinotecan plus cisplatin and 7 were treated with irinotecan plus carboplatin. The median age was 68 years (range 44-75) and the median interval from the last chemotherapy was 50 days (range 21-89). A total of 33 chemotherapy cycles were delivered (median 2; range 1-5). All 17 patients discontinued therapy due to disease progression and 5 patients had progressive disease before second cycle. Toxic effects were mainly hematologic (grade > or =3 neutropenia in 65% of patients) and fatigue (grade 3 in 47%). In an intent-to-treat analysis, two (12%) patients had a confirmed partial response and two patients achieved stable disease. Median progression-free and overall survivals were 1.7 months (95% CI, 1.5-1.9) and 3.4 months (95% CI, 1.7-5.0), respectively. Topotecan monotherapy for patients with irinotecan-refractory SCLC does not appear highly active but the observation of some responses merits further study in patients with chemosensitive disease.

A phase II, multicenter trial of weekly topotecan in patients with recurrent platinum-sensitive epithelial cancers of the ovary and peritoneum

The purpose of this study was to evaluate the response rate and toxicity of weekly topotecan in patients with recurrent platinum-sensitive epithelial cancers of the ovary and peritoneum. Thirty-nine platinum-sensitive recurrent ovarian cancer patients received topotecan (4 mg/m(2)) intravenously day 1, day 8, day 15, every 28 days. Colony-stimulating factors were excluded from the study. Clinical response was assessed by clinical, serologic, and radiographic measures at the conclusion of cycle four. Patients received 136 cycles of topotecan (median = 3; range 1-6) and were evaluated for response and toxicity. Median number of prior regimens was one. Grade 3/4 neutropenia developed in 3 (7.7%) patients. Grade 3 thrombocytopenia was seen in one (2.6%) patient, with no incidence of grade 4 thrombocytopenia. There was no evidence of grade 3 anemia, but one patient (2.6%) was associated with grade 4 anemia. There was no grade 3 or 4 neuropathy. We encountered 18 dose reductions following less than or equal to grade 2 myelosuppression, necessitating the removal of eight (20.5%) patients prior to cycle four. Twenty-one (53.8%) patients were removed from the study due to disease progression. Following the completion of cycle four, four (10.3%) patients demonstrated stable disease and four (10.3%) patients exhibited a partial response. There were no complete responses. Median disease-free survival was 12 weeks. Weekly topotecan (4 mg/m(2)) demonstrated modest activity and was moderately well tolerated. However, the significant number of dose reductions and high incidence of patients who demonstrated disease progression suggests additional modifications with this specific regimen are necessary.

Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer

Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer

A feasibility study of low-dose, prolonged oral topotecan in patients with advanced ovarian, fallopian tube, or primary peritoneal serous cancer who have attained a complete clinical response following platinum-based chemotherapy

A feasibility study of low-dose, prolonged oral topotecan in patients with advanced ovarian, fallopian tube, or primary peritoneal serous cancer who have attained a complete clinical response following platinum-based chemotherapy

Primary central nervous system lymphomas: Salvage treatment after failure to high-dose methotrexate

This review analyzes the major methodological caveats related to the design and conduction of trials addressing new active drugs in patients with failed primary CNS lymphoma (PCNSL) and provides some recommendations for their therapeutic management. The enrolment of patients in well-designed prospective trials is the best option at failure. In the clinical practice, radiotherapy is an option for unirradiated patients and re-treatment with high-dose methotrexate (HD-MTX) can be suggested to relapsing patients who experienced a prolonged lymphoma remission after first-line chemotherapy containing HD-MTX. Salvage monochemotherapy with temozolomide or topotecan in patients previously managed with a radiotherapy-containing approach is supported by prospective trials, while the combination chemotherapy remains investigational. High-dose chemotherapy supported by stem cell autotransplant and intrathecal chemotherapy in meningeal failure have to be further investigated in prospective trials.

6601 POSTER A pilot study of topotecan in patients with irinotecan-refractory small cell lung cancer

The purpose of this study was to evaluate the activity and toxicity of carboplatin, paclitaxel and pegylated liposomal doxorubicin combination in advanced or recurrent of the uterine carcinosarcoma.Twenty-nine eligible patients with measurable disease were treated with carboplatin [area under the curve (AUC) 5], paclitaxel 175mg/m2 and pegylated liposomal doxorubicin 25 mg/m2 every 3 weeks for 6–8 cycles.There were 10 complete responses (CRs) (34%) and 8 partial responses (PRs) (28%) for an overall response rate (RR) of 62% (95% confidence interval [CI], 43–81%). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.1–12.2 months) and the median overall survival (OS) was 16.4 months (95% CI, 14.7–18.0 months). There was no statistically significant difference between histology and response to therapy. Patients with PS of 0 or 1 had a higher RR than those with worst PS. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 52% of patients and 10% experienced febrile neutropenia. Anemia grade 3 or 4 developed in 27% of patients and thrombocytopenia grade 3 or 4 in 31% of patients. Three patients (10%) developed grade 3 sensory neuropathy and only 2 patients (8%) grade 3 palmar-plantar erythrodysesthesias. No treatment-related deaths were recorded in our series.The combination of carboplatin, paclitaxel and pegylated liposomal doxorubicin appears to have activity in advanced, persistent or recurrent endometrial carcinosarcoma with an acceptable toxicity profile.

PD6-1-7: A phase II study of UCN-01 in combination with topotecan in patients (pts) with chemosensitive relapsed small cell lung cancer (SCLC): a study of the Princess Margaret Hospital phase II consortium (PMH-C).

PD6-1-7: A phase II study of UCN-01 in combination with topotecan in patients (pts) with chemosensitive relapsed small cell lung cancer (SCLC): a study of the Princess Margaret Hospital phase II consortium (PMH-C).

P2-318: Activity of intravenous Topotecan in patients with advanced non-small cell lung cancer pre-treatred with platinum and taxanes: Results of the first analysis

P2-318: Activity of intravenous Topotecan in patients with advanced non-small cell lung cancer pre-treatred with platinum and taxanes: Results of the first analysis

Proteasome inhibition with bortezomib (BORT) in combination with topotecan : A phase I solid tumor trial

14047 Background: Topoisomerase-I (Topo-I) down-regulation via the ubiquitin/26S proteasome pathway has been associated with drug resistance. We hypothesize that proteasome inhibition by BORT would enhance topotecan sensitivity by preventing down-regulation of topo-I. This phase I trial examined the safety and feasibility of combining weekly BORT with topotecan in patients (pts) with advanced solid tumors. Methods: Pts on 1 of 4 dose levels were treated with topotecan (3–4 mg/m2) IV and BORT (1–1.6 mg/m2) IV on days 1, 8, and 15. BORT was given 3 hours after topotecan based on preclinical studies (Flannery, 2003). Cycles were repeated q28 days. After 6 cycles, pts without progression could remain on BORT alone. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets (plts) (&lt;25K), Gr3 plts (&lt;50K) with bleeding, febrile neutropenia, neutropenia with infection, Gr3 neuropathy, or any=Gr3 non-heme toxicity. Results: 15 pts were accrued. Pt characteristics: Median age 58 years (range 25–73); Male sex:7; Performance status =80%:13. Two DLTs were seen at dose level 4 (Topotecan 4 mg/m2 and BORT 1.6mg/m2): Gr 4 plts (1) and Gr 3 neutropenia with infection (1). Few other toxicities &gt; Gr3 were seen past cycle 1. Of 11 evaluable pts, 1 had a partial response (small cell bladder). 4 had stable disease (lung, brain, adenoid cystic and prostate). Conclusions: Weekly BORT and topotecan is feasible and well tolerated. The recommended phase II dose is topotecan 3mg/m2 and BORT 1.6mg/m2 IV weekly (3 of 4). An expanded cohort at this dose will examine efficacy of this combination in pts with small cell cancers. Correlative studies evaluating serum markers for proteasome inhibition and topo-1 activity are ongoing. No significant financial relationships to disclose.

A phase I study of lapatinib and topotecan in patients with solid tumors

3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic No significant financial relationships to disclose.

UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: A study of the Princess Margaret Hospital Phase II consortium

Background and objective UCN-01 is a staurosporine analogue shown to abrogate the G2 checkpoint through inhibition of cyclin-dependent kinases. Preclinical evidence suggests synergy between UCN-01 and cytotoxic chemotherapy. Topotecan is an active agent in ovarian cancer. This phase II study was conducted to investigate the safety and efficacy of topotecan and UCN-01 in patients with advanced ovarian cancer. Methods A two-stage phase II trial was designed for patients with advanced ovarian cancer with progressive disease despite prior treatment with platinum and paclitaxel. Patients with advanced ovarian cancer were treated with topotecan, 1 mg/m 2 IV, days 1 to 5, and UCN-01 70 mg/m 2 on day 1 of the first cycle, and 35 mg/m 2 on day 1 of all subsequent cycles. Treatment was repeated on a 3-week cycle. The primary objective of this study was objective response rate while secondary objectives included rates of stable disease, duration of response, progression-free and overall survival, as well as toxicity. Tumor biopsy specimens were also collected where possible for molecular correlative studies. Results Twenty-nine patients are evaluable for toxicity and efficacy. Three patients (10%) achieved a partial response. The median time to progression was 3.3 months (95% CI 1.5–NA), and the median overall survival was 9.7 months (95% CI: 7.5–15.3). The most common grade 3–4 toxicities were neutropenia (79%), anemia (41%), thrombocytopenia (14%), hyperglycemia (10%), and pain (10%). Conclusion The combination of UCN-01 and topotecan is generally well tolerated, however, this combination is not considered to have significant antitumor activity against advanced ovarian cancer.

Phase III Study of Oral Compared With Intravenous Topotecan As Second-Line Therapy in Small-Cell Lung Cancer

Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV topotecan in patients with SCLC sensitive to initial chemotherapy. Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status < or = 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of > or = 90 days were assigned to treatment with either oral topotecan 2.3 mg/m2/d on days 1 through 5 or IV topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral topotecan (n = 153) and 21.9% with IV topotecan (n = 151), with a difference (oral -IV) of -3.6% (95% CI, -12.6% to 5.5%). Median survival time was 33.0 weeks for oral and 35.0 weeks for IV topotecan; 1- and 2-year survival rates were 32.6% and 12.4% for oral topotecan, respectively, and 29.2% and 7.1% for IV topotecan, respectively. Third-line chemotherapy was similar for both groups (33% for oral; 35% for IV). Incidence of grade 4 toxicity in patients who received oral and IV topotecan was as follows: neutropenia in 47% and 64%, thrombocytopenia in 29% and 18%, grade 3 or 4 anemia in 23% and 31%, and sepsis in 3% and 3%, respectively. The most frequent nonhematologic adverse events (all grades) included nausea (43% oral; 42% IV), alopecia (26% oral; 30% IV), fatigue (31% oral; 36% IV), and diarrhea (36% oral; 20% IV). Oral topotecan demonstrates activity and tolerability similar to IV topotecan in chemotherapy-sensitive SCLC patients and offers patients a convenient alternative to IV therapy.

A feasibility study of low-dose, prolonged oral topotecan in patients with advanced ovarian, fallopian tube, or primary peritoneal serous cancer who have attained a complete clinical response following platinum-based chemotherapy

To determine the tolerability of oral maintenance topotecan when administered to patients with advanced ovarian, fallopian tube, and primary peritoneal serous cancers who have achieved a complete clinical response after first-line platinum-based therapy. Oral topotecan was given at a starting dose of 0.4 mg/m(2)/dose, twice a day (BID) for 21 consecutive days out of 28 days. The dose was subsequently increased to 0.5 mg/m(2)/dose, twice a day as tolerated. If the patient experienced toxicities during cycle 1 or subsequent cycles, doses were delayed and/or reduced. The lowest dose allowed on protocol was 0.3 mg/m(2)/dose twice daily. Thirteen patients were enrolled in the study, representing a total of fifty-nine cycles of oral topotecan. The starting dose of 0.4 mg/m(2) by mouth (PO) BID for 21 days was generally difficult for patients to tolerate, usually due to progressive anemia and fatigue, and a dose reduction to 0.3 mg/m(2) was necessary in 10/13 patients. A median of six cycles was administered, although 6 of 13 patients could not tolerate the planned 6 cycles due to toxicity. Hematologic toxicity was the most common side effect, although there were no episodes of febrile neutropenia. Diarrhea was the most common nonhematologic side effect, occurring in 8 of 13 patients. Six patients were removed from the study prior to completing the planned six cycles of therapy, after receiving a median number of 2.5 cycles of treatment. This dose and schedule of oral topotecan does not appear to be feasible in this patient population.

A multi-center phase II study of weekly topotecan as second-line therapy for small cell lung cancer

To determine the response rate, toxicity, failure free and overall survival of weekly topotecan in patients with relapsed small cell lung cancer who received one prior platinum based chemotherapy. Twenty two patients with relapsed disease after response to one prior chemotherapy with or without radiotherapy and patients with relapse more than 90 days after their last therapy received topotecan 4mg/m(2) intravenous over 30min on days 1,8,15; every 4 weeks (3 weeks on and 1 weeks off). Chemotherapy was given until disease progression or unacceptable toxicity. Of 22 patients, none of the patients responded to weekly topotecan therapy. Four patients had stable disease. After a median follow up of 1 year, median time to progression was 6 weeks and median survival was 5 months. The common toxicities associated with this regimen were anemia, thrombocytopenia, fatigue, GI side effects and alopecia. Weekly topotecan was well tolerated but ineffective in this trial. Although commonly used, weekly regimen of topotecan should be used with caution in relapsed SCLC.

Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer

The objective of this study was to investigate the effectiveness and toxicity of weekly topotecan in patients with recurrent epithelial ovarian cancer. Twenty patients were treated with topotecan at a dose of 4 mg/m(2) weekly. Efficacy was determined according to the Response Criteria in Solid Tumors (RECIST) Gynecologic Cancer Inter Group criteria. Median age was 62 years (45-78). Patients had received 1-7 (median 3) prior chemotherapy lines. A total of 203 weekly treatments were administered. In 13 patients (65%) treatment delay was necessary due to bone marrow toxicity. Grade 3/4 neutropenia occurred in 11 patients (55%) and grade 3/4 thrombocytopenia in four patients (20%). Six patients (30%) needed a dose reduction, and 42 cycles (21%) were given with dose reduction. No neutropenia, fever, or sepsis was observed. There was one complete response and one partial response (response rate 10%). All patients with response had platin-sensitive disease (three out of eight). Six patients needed blood transfusion. None of the patients required granulocyte/granulocyte-macrophage colony-stimulating factor. The median duration of response was 13 months. In addition, there were four patients (20%) with a stable disease lasting at least for 4 months. Based on the results of this Phase II study, the toxicity of weekly topotecan seems to be lower than with the 3-weekly topotecan. The response rate of 10% is low but was not expected to be higher as these patients were heavily pretreated.

Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer

For patients with small-cell lung cancer (SCLC), further chemotherapy is routinely considered at relapse after first-line therapy. However, proof of clinical benefit has not been documented. This study randomly assigned patients with relapsed SCLC not considered as candidates for standard intravenous therapy to best supportive care (BSC) alone (n = 70) or oral topotecan (2.3 mg/m2/d, days 1 through 5, every 21 days) plus BSC (topotecan; n = 71). In the intent-to-treat population, survival (primary end point) was prolonged in the topotecan group (log-rank P = .0104). Median survival with BSC was 13.9 weeks (95% CI, 11.1 to 18.6) and with topotecan, 25.9 weeks (95% CI, 18.3 to 31.6). Statistical significance for survival was maintained in a subgroup of patients with a short treatment-free interval (< or = 60 days). Response to topotecan was 7% partial and 44% stable disease. Patients on topotecan had slower quality of life deterioration and greater symptom control. Principal toxicities with topotecan were hematological: grade 4 neutropenia, 33%; grade 4 thrombocytopenia, 7%; and grade 3/4 anemia, 25%. Comparing topotecan with BSC, infection grade 2 was 14% versus 12% and sepsis 4% versus 1%; other grade 3/4 events included vomiting 3% versus 0, diarrhea 6% versus 0, dyspnea 3% versus 9%, and pain 3% versus 6%. Toxic deaths occurred in four patients (6%) in the topotecan arm. All cause mortality within 30 days of random assignment was 13% on BSC and 7% on topotecan. Chemotherapy with oral topotecan is associated with prolongation of survival and quality of life benefit in patients with relapsed SCLC.

Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

Purpose: To assess hypofractionated stereotactic radiotherapy (H-SRT) with concurrent topotecan in patients with recurrent malignant glioma. Methods and Materials: Between February 1998 and December 2001, 25 patients with recurrent malignant glioma were treated in a phase I-II study (8 females and 17 males; median age, 45 years; range, 11–66 years; median Karnofsky performance status, 80%, range, 50–100%; median Mini Mental Standard Examination score, 25 points; range, 10–30 points). Of the 25 patients, 20% had World Health Organization Grade III and 80% World Health Organization Grade IV glioma. All patients had been treated previously by external beam radiotherapy with 54.4 Gy in 34 fractions twice daily, at least 6 h apart, within 3.5 weeks or 60 Gy in 30 fractions within 6 weeks. In addition, 84% had already received at least one chemotherapy regimen for recurrence. The median H-SRT dose at the 80% isodose was 25 Gy, and the maximal dose was 30 Gy delivered in five to six fractions on consecutive days. Topotecan (1.1 mg/m 2 /d) was given as a continuous i.v. infusion during H-SRT. Depending on the toxicity and compliance, patients received an additional 48 topotecan courses. Results: For all patients, the actuarial median progression-free survival was 10.5 months (range, 1.4–47.8 months), the median functional survival was 12.6 months (range, 1.6–49.5 months), and the median overall survival was 14.5 months (range, 3–56.4 months). Twelve percent of patients developed presumed adverse radiation effects (Radiation Therapy Oncology Group Grade 2). According to the Common Toxicity Criteria, version 2.0, no topotecan-related Grade 4 toxicity was noted. Grade 3 neutropenia was documented after 14 and Grade 3 thrombopenia after 12 courses. Conclusion: H-SRT with topotecan is feasible and well-tolerated in patients with recurrent high-grade glioma and results in similar survival compared with other repeat treatment modalities.