Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors

Purpose

This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.

Methods

Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m²/d IV, administered as a 72 h continuous infusion on days 1–3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.

Results

Seventeen patients received 39 cycles of treatment: median 2, (range 1–5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60–90%) and age: 52 (range 24–75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m²/d, the median CSF/plasma ratio was 19.4% (range 15.1–59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02–3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2–5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.

Conclusions

The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m²/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.     

FDG-PET as a Prognostic Factor in High-grade Astrocytoma

Background: The prognostic value of the metabolic status of cerebral gliomas determined by positron emission tomography with [¹⁸F]-fluoro-deoxy-D-glucose (FDG-PET) has been established in populations with a mixture of grades 2, 3 and 4 gliomas, but remains uncertain when only malignant gliomas are considered (grade 3 and 4). Methods: FDG-PET performed in 30 patients with anaplastic astrocytoma (grade III) and 61 patients with glioblastoma (grade 4) were classified according to a metabolic grading. The uptake of FDG was lower in the tumor compared to white matter (WM) in grade 1 (4 glioblastoma, 4 anaplastic astrocytoma), it was intermediate between WM and cortex in grade 2 (20 glioblastoma, 22 anaplastic astrocytoma), and it was superior to cortex in grade 3 (38 glioblastoma, 4 anaplastic astrocytoma). Results: Kaplan–Meier survival curves were similar in patient with grades 1 and 2, but were significantly worse (p = 0.007) in grade 3. In multivariate analysis considering age, pathological grade (anaplastic astrocytoma versus glioblastoma), and metabolic grades, the metabolic grade did not appear to be an independent prognostic factor. When anaplastic astrocytomas and glioblastomas were considered separately, metabolic grade is of predictive value only in the group of glioblastomas. Conclusion: In malignant gliomas, metabolic grading determined by FDG-PET was not superior to the pathological grading for survival prediction. Still, it remains of predictive value when applied to malignant gliomas histologically classified as glioblastoma.     

NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94).

Purpose:We conducted a phase II multicentre study of gemcitabinein patients with anaplastic astrocytoma and glioblastoma multiforme at firstrelapse. Patients and methods:Patients with anaplastic astrocytoma orglioblastoma multiforme receiving a stable dose of steroids and ECOGperformance status 3 were eligible for this study at the time of firstrelapse. One adjuvant chemotherapy regimen was permissible. Patients receivedgemcitabine 1000 mg/m² i.v. weekly × 3, repeated on afour-weekly cycle. Results:Of 20 patients enrolled, 15 were evaluable for response,19 for non-hematological toxicity and 18 for hematological toxicity. Sevenpatients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme(GBM). Age ranged from 28–71 years (median 50). Fifteen patientsdiscontinued therapy due to disease progression. The median number of cyclesadministered was 1 (range 1–11); only two patients received more thanthree cycles. Hematologic toxicity was acceptable and no grade 4 toxicity wasseen. One patient developed Pneumocystispneumonia and eventualpulmonary embolism; one died of gastric hemorrhage related to steroid therapy.No objective responses were seen. Nine patients had stable disease (medianduration 2.7 months, range 0.9–11.2). Conclusions:Gemcitabine given in this dose and schedule seemswell tolerated but is not active in patients with recurrent high-gradegliomas.     

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. Methods: The treatment schedule was 150–200 mg/m² per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas. Received: 24 October 1996 / Accepted 5 February 1997     

Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors

Background:Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. Patients and methods:Patients with advanced cancer and performance status ECOG 2. The starting dose was paclitaxel 175 mg/m² day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m² daily day 1–5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. Results:Fifty-one patients were entered; men : women ratio 30 : 21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m²/carboplatin AUC 5/topotecan mg/m² (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/1.0 for four days. G-CSF 5 µg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. Conclusions:The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.     

Bevacizumab and irinotecan in recurrent malignant glioma,a single institution experience

Background

Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial.

Patients and methods.

The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m² or 125 mg/m²) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated.

Results

Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0–2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3–8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6–8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1–2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed.

Conclusions

In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.     

Thiotepa and etoposide treatment of recurrent malignant gliomas: phase I study

 Purpose: To determine: (1) the maximum tolerable dose (MTD) of thiotepa (TT) that can be administered with etoposide without stem cell support; (2) whether this regimen is active against recurrent malignant gliomas. Background: Although several chemotherapeutic agents show minor activity against recurrent brain tumors, there is no consensus about the most effective regimen. The alkylating agent TT has excellent central nervous system (CNS) penetration and is synergistic with the topoisomerase II inhibitor etoposide. Design/Methods: Fifteen patients with recurrent malignant gliomas (14 glioblastomas, 1 anaplastic astrocytoma) received intravenous etoposide 100 mg/m² on days 1, 2, and 3, and intravenous TT (40, 50, 60, or 70 mg/m²) on day 2. All had received irradiation, and eight BCNU. Chemotherapy was repeated every 3 – 4 weeks, with stepwise TT dose increments of 10 mg/m², provided toxicity was less than grade III. Results: The major toxicity was dose-limiting leukopenia. The MTD of TT in cycle 1 was 60 mg/m². All patients died of progressive disease and none died of chemotherapy-related complications. Conclusions: The MTD of TT in this regimen for recurrent malignant gliomas is 60 mg/m². Higher doses of TT would require colony-stimulating factors or stem cell support. Received: 14 March 1995 / Accepted: 5 September 1996     

Clinical significance of the 2016 WHO classification in Japanese patients with gliomas

In this study, we retrospectively compared the prognostic value of the 2016 WHO classification with the former classification in 387 patients with glioma treated at our institution. According to the new classification, diagnoses included oligodendroglioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion (5.4%), anaplastic oligodendroglioma with IDH mutation and 1p/19q co-deletion (3.4%), diffuse astrocytoma IDH-mutated (3.9%), anaplastic astrocytoma IDH-mutated (2.8%), glioblastoma IDH-mutated (7.8%), glioblastoma IDH-wildtype (58.4%), diffuse midline glioma H3 K27M mutation (2.6%), oligodendroglioma NOS (1.3%), anaplastic oligodendroglioma NOS (0.8%), diffuse astrocytoma IDH-wildtype (2.8%), and anaplastic astrocytoma IDH-wildtype (10.9%). The prognoses of IDH-mutated astrocytomas clearly varied according to tumor grade. However, we identified no survival difference between IDH-wildtype anaplastic astrocytomas and glioblastomas; additionally, these tumors showed similar gene expression profiles. After exclusion of those without 1p/19q co-deletion, patients with oligodendroglial tumors showed excellent survival regardless of tumor grade. Our evaluation of chromosomal aberrations suggests that the MAPK/PI3K pathway plays a role in acquired malignancy of astrocytic tumors, whereas TP53 participates in tumorigenesis. We suspect the RB pathway also plays a role in tumorigenesis of IDH-mutated gliomas. The new WHO classification more clearly reflects the tumorigenesis of gliomas and improves the prognostic power of classification.     

Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines

Summary Because the percentage of dividing cells in malignant glioma is small, cell cycle specific drugs such as VP16 are most effective if given continuously over prolonged periods. In this study, we chose a dose of 50 mg/day to minimize therapy interruptions for myelosuppresion. VP16 was given until the neutrophil count dropped to < 1.0 × 10⁹/L or the platelets fell to < 75 × 10⁹/L and resumed when the counts rose to normal levels. We treated 46 patients with supratentorial malignant glioma (15 anaplastic astrocytoma, 21 glioblastoma multiforme, 9 anaplastic oligodendroglioma, l undifferentiated primary malignant brain tumor) at the time of tumor progression. All had KPS 70 at study entry. All patients had prior RT,13 with adjuvant nitrosourea. Twenty-four had prior nitrosourea chemotherapy for tumor progression, 7 had no prior chemotherapy. We treated 20 patients with VP16 at first progression and 26 at second or later progression. All patients had CT or MR scans and clinical evaluation every 8 weeks. Median time to tumor progression (TTP) was 8.8 weeks for all evaluable patients, 8.6 weeks for those treated at first progression and 8.4 weeks for those treated at second progression, 9.1 weeks for anaplastic astrocytoma, 7.5 weeks for glioblastoma multiforme and 17.1 weeks for anaplastic oligodendroglioma. There were 8 responses and 11 patients with stable disease for at least 8 weeks (R + SD = 42%). Prolonged low-dose oral VP15 is well tolerated, with minimal myelosuppression. Prolonged low-dose oral VP16 is modestly effective treatment for patients with recurrent malignant glioma and is more effective for anaplastic astrocytoma and anaplastic oligodendroglioma than glioblastoma multiforme.     

A phase II study of extended low-dose temozolomide in recurrent malignant gliomas.

Temozolomide is an effective agent in the treatment of recurrent malignant gliomas. The standard dosage is 150-200 mg/m2 per day for 5 days in a 28-day cycle. A prior phase I study established a chronic daily temozolomide dose that significantly increased the total dose administered and suggested a superior response rate. In a prospective phase II trial, we treated 35 patients with recurrent malignant gliomas with temozolomide 75 mg/m2 per day for 42 consecutive days in a 70-day cycle. Median age was 55 years (range, 27-73 years) and median Karnofsky performance score was 70 (range, 60-90). Twenty-eight (79%) patients had glioblastoma multiforme, 3 (9%) anaplastic astrocytoma, 2 (6%) anaplastic oligodendroglioma, and 2 (6%) anaplastic oligoastrocytoma. All but one had prior radiotherapy, and 27 had prior chemotherapy. There were 2 partial (anaplastic astrocytoma) and 3 minor (glioblastoma multiforme) radiographic responses; 17 patients had progressive disease at the end of the first cycle. In 55 cycles of temozolomide, there were 8 episodes of asymptomatic drug-related grade 3 toxicity: 6 lymphopenia, 1 neutropenia, and 1 thrombocytopenia. Median progression-free survival and overall survival were 2.5 and 8.7 months (2.3 and 7.7 months in glioblastoma multiforme patients). At 6 months, progression-free survival and overall survival rates were 27% and 67% (19% and 60% in glioblastoma multiforme). Quality of life scores did not change significantly during treatment. We conclude that the extended low-dose schedule of temozolomide is well tolerated in heavily pre-treated patients; however, our results do not support an improved rate of response or survival.     

The presence of necrosis and/or microvascular proliferation does not influence survival of patients with anaplastic oligodendroglial tumours: review of 98 patients

Accurate prognosis for patients with anaplastic oligodendroglial gliomas is increasingly difficult to make. Characterisation of these tumours remains challenging, increasing proportions of oligodendroglial diagnoses in gliomas are reported, and no WHO 2000 grade IV exists for them, so that highly anaplastic tumours can only be grouped with glioblastoma (GBM) or with grade III oligodendroglioma, which have differing clinical behaviour. Longer survival times reported for patients with glioblastoma containing an oligodendroglial element (GBMO) suggest that a grade IV for oligodendroglial tumours might exist.In patients with anaplastic gliomas containing an oligodendroglial element, we explored whether microvascular proliferation (MVP) and necrosis were associated with shorter survival, sufficient to create a grade IV. Biopsies for 98 patients with anaplastic oligodendroglioma, anaplastic oligoastrocytoma or tumours with an oligodendroglial and GBM element, discharged 1998–2004, were identified from databases at three allied neurosurgery units. Pathology reports were reviewed for the presence of MVP and necrosis. Anaplastic oligoastrocytoma and GBMO were combined to measure the effect of an astrocytic element on survival.For anaplastic oligodendroglioma patients, median survival time was 24 months, while for anaplastic oligoastrocytoma or GBMO patients, it was 9 months. Age 60 or over (P = 0.006) and astrocytic element (P = 0.01) were the only independent predictors of survival. Patients 60 and over with an astrocytic element had 4.6 times the risk of death of patients under 60 with anaplastic oligodendroglioma.A grade IV cannot be created using necrosis or MVP since neither feature predicted survival after adjustment for age and an astrocytic element. However age and an astrocytic element were strong predictors of poorer survival in patients with anaplastic oligodendroglial tumours.     

Recurrent malignant glioma in adults

Opinion statement Meaningful palliation is possible for selected patients with recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) using aggressive treatment. Although long-term disease-free survival occurs in fewer than 10% of patients, most who achieve such survival have been treated for multiple recurrences. Surgical resection with the placement of lomustine-releasing wafers is the only therapy proven in randomized trials to be beneficial for recurrent malignant gliomas. Reoperation is indicated when local mass effect limits the quality of life. Reoperation may make other treatments more effective by removing treatment-resistant hypoxic cells and thereby prolonging high-quality survival. Combination chemotherapy (including procarbazine and a nitrosourea) provides dramatic benefit for many recurrent anaplastic or aggressively behaving oligodendrogliomas and anaplastic mixed oligoastrocytomas. For other recurrent malignant gliomas, single-agent cytotoxic chemotherapy (eg, intravenous lomustine or platinums, oral carmustine, temozolomide, or procarbazine) appears to provide equivalent results and better quality of life at a lower cost than do the combinations of cytotoxic drugs. A randomized phase II trial demonstrates that temozolomide provides longer progression-free survival and better quality of life than standard-dose procarbazine in patients with recurrent glioblastoma multiforme. Because benefits of available cytotoxic chemotherapy for anaplastic astrocytoma and glioblastoma are small, participation in clinical trials is appropriate for most patients. Reirradiation (using stereotactic or three-dimensional conformal techniques with or without concomitant cytotoxic chemotherapy) as radiation sensitization can prolong high-quality survival in selected patients. Specific examples include radiosurgery with the gamma knife or with linear accelerators, intracavitary radiation with the newly US Food and Drug Administration-approved GliaSite (Proxima Therapeutics, Alpharetta, GA) radiation therapy system, low dose rate permanent-seed brachytherapy, and high dose rate stereotactic brachytherapy. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly.     

Dose-intensive,Time-compressed Procarbazine,CCNU, Vincristine (PCV) with Peripheral Blood Stem Cell Support and Concurrent Radiation in Patients with Newly Diagnosed High-grade Gliomas

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2–22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n=6), glioblastoma (n=4), anaplastic astrocytoma (n=2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m² and vincristine 1.5 mg/m² on day 0, and procarbazine 150 mg/m² on days 1–7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.     

Treatment of recurrent gliomas with eflornithine.

BACKGROUND: Oral eflornithine in combination with intravenous mitoguazone (methylbisguanylhydrazone) has shown activity against recurrent anaplastic gliomas. Eflornithine alone, however, has not been evaluated against recurrent gliomas. PURPOSE: This study compared the antitumor activity of oral eflornithine with that of oral eflornithine combined with intravenous mitoguazone in the treatment of patients with recurrent or progressive glioblastoma multiforme as well as nonglioblastoma anaplastic gliomas. METHODS: During the 1st year of therapy with eflornithine alone, the drug was given at a dose of 3.6 g/m2 on days 1-14, 22-35, and 43-56 every 8 hours; cycles were repeated every 63 days until progression. For the 2nd year, the drug was given on days 1-14, 29-42, and 57-70, with 84 days between cycles. For the 1st and 2nd years of eflornithine-mitoguazone therapy, eflornithine was given at 1.8 g/m2 on the same schedule. Mitoguazone was given intravenously at 200 mg/m2 on the final day of each 2-week sequence of eflornithine therapy. Response was determined by evaluating changes in the size of contrast-enhanced neuroimages. RESULTS: Because of two cases of lethal hepatic necrosis, the initial random allocation of patients to the eflornithine-mitoguazone arm was stopped after 23 patients had been accrued. Ninety-eight patients were entered in the eflornithine arm; 80 patients (36 glioblastoma multiforme patients and 44 anaplastic glioma patients) were assessable for response. Antitumor activity (partial response, minor response, and stable disease) was seen in 45% of the patients with anaplastic gliomas, for a median of 49 weeks, but in only 17% of patients with glioblastoma multiforme (median not attained). Twenty-one (20%) of the patients with anaplastic glioma and 33% of the patients with glioblastoma multiforme were removed from the study before completing the first 8-week course of therapy because of neurological deterioration and tumor progression by the 5th week of treatment. CONCLUSION: This study suggests that eflornithine alone is an effective palliative therapy for recurrent anaplastic gliomas. Additional studies are needed to confirm our finding.     

Interstitial radiogold implantation for the treatment of recurrent high-grade gliomas

Thirty-three patients were treated at the Methodist Hospital, Baylor College of Medicine (Houston) between 1983 and 1987, for high-grade gliomas which had recurred after conventional external-beam radiation therapy. The mean dose to the tumor volume from the external-beam therapy was 5800 cGy. Thirteen patients had recurrent astrocytoma Grade 4 (glioblastoma), whereas 20 had recurrent astrocytoma Grade 3 (anaplastic astrocytoma). All patients were treated for their recurrence by the combination of reexcision of as much of the tumor mass as was technically feasible and intraoperative radiogold (198Au) seed implantation of the residual tumor and/or tumor bed. The mean dose to the tumor volume from the implant was 4000 cGy. For the 13 patients treated for recurrent glioblastoma the 1-year, 2-year, and 3-year survival rates were 46%, 15%, and 8%, respectively. For the 20 patients treated for recurrent anaplastic astrocytoma the 1-year, 2-year, and 3-year survival rates were 75%, 50%, and 15%, respectively. Survival was measured from the time of implant. The median survival for patients with glioblastoma was 9 months. The median survival for patients with anaplastic astrocytoma was 17 months. One patient died in the immediate postoperative period from a gastrointestinal bleed. No patient required reoperation for radiation necrosis. The authors believe that this technique is an effective treatment for patients with high-grade gliomas recurring after external-beam radiation therapy, and are now including interstitial irradiation in the initial management of selected patients with high-grade gliomas.     

Outcomes of advanced and recurrent cervical cancer treated with cisplatin and generic topotecan: retrospective analysis in a tertiary care hospital in Thailand

Objective

Retrospective evaluation of the outcome of stage IVB, recurrent or persistent cervical cancer treated with cisplatin and generic topotecan (CT) in a tertiary care hospital in Thailand.

Methods

The medical records of patients treated with CT regimen at Chiang Mai University Hospital between January 2005 and December 2007 were reviewed and analyzed. The treatment protocol consisted of IV topotecan 0.75 mg/m² on days 1, 2, and 3; combined with cisplatin 50 mg/m² IV on day 1 and repeated every 21 days until progression or unacceptable toxicity for a maximum of 6 cycles. The outcomes were evaluated based on the response rate, progression free survival (PFS), and overall survival (OS) by using the World Health Organization criteria. The adverse effects of the treatments were also determined.

Results

Twenty-one cervical cancer patients received the CT regimen. The tumor response rate was 28.6%. The median PFS and OS was 4 and 11 months, respectively. With 87 cycles of chemotherapy, the most common grade 3 & 4 hematologic toxicity was neutropenia (57.9%).

Conclusion

Advanced and recurrent cervical cancer patients treated with cisplatin and generic topotecan had a favorable outcome with manageable toxicity.     

Attempted dose intensified cyclophosphamide,etoposide, and granulocyte colony-stimulating factor for treatment of malignant astrocytoma

Summary Patients with malignant astrocytoma continue to respond poorly to chemotherapy and have a dismal prognosis. Cyclophosphamide (CTX) and etoposide demonstrate activity against malignant astrocytoma at standard dosages, with bone marrow suppression as the limiting toxicity. In order to allow dose intensification, minimize leukopenia, and improve efficacy granulocyte colony-stimulating factor (G-CSF) was used in combination with CTX and etoposide. The protocol consisted of CTX (2 mg/m²/d, days 1, 2), etoposide (200–300 mg/m²/d, days 1–3), and G-CSF (5–10 g/d subcutaneously, days 4–18), every 4 weeks. Nine evaluable patients (7 glioblastoma multiforme, 2 anaplastic astrocytoma) were treated, ranging in age from 26–67 (mean 41). One of 9 patients responded (11%) with a partial response (13+ months), 3 had stable disease (33%; 8, 5, 2.5 months), and 5 had progressive disease (3, 2.5, 2, 1.5, 1 months). The median time to progression for responders was 6.5 months, while overall it was 2.5 months. Overall median survival was only 7.0 months. Toxicity was frequent and severe, typically delaying treatment cycles. The most common complications were severe myeolosuppression (9), sepsis (8), rash (6), urinary infection (5), and anorexia (5). Treatment delays caused by infections and other complications occurred often, abrogating the intended dose intensification. The received dose intensity (DI) for CTX was 400–425 mg/m²/week (relative DI 0.41), while for etoposide it was 75 mg/m²/ week (relative DI 0.42). In summary, as used in this protocol, dose intensive chemotherapy with CTX, etoposide, and G-CSF does not improve efficacy over standard regimens and results in excessive toxicity.     

Treosulfan Chemotherapy for Recurrent Malignant Glioma

Treosulfan is a bifunctional alkylating prodrug with activity against various solid tumors. To improve the outcome for patients with recurrent malignant glioma, we assessed the efficacy of intravenous treosulfan (6–10g/m² 4-weekly) as salvage therapy for patients with recurrent or progressive glioblastoma (GB, n = 14) or anaplastic astrocytoma (AA, n = 2). All patients had prior involved-field radiotherapy and adjuvant nitrosourea-based chemotherapy. A total of 56 cycles were administered. Tumor responses were assessed radiologically and clinically prior to each cycle. All patients were assessable for toxicity, response and survival. There were no complete or partial responses (CR, PR). Two patients progressed after the first cycle, 14 patients had initially stable disease (SD). Median progression-free survival was 3.25 months for the GB patients. Five patients were progression-free at 6 months (30%), including the 2 AA patients. The 2 AA patients are stable at 22 months. Myelosuppression was the dose-limiting toxicity in this cohort of nitrosourea-pretreated patients. Treosulfan has modest activity in patients with recurrent malignant glioma. Further evaluation of treosulfan in chemonaive malignant glioma patients is warranted.     

Treatment of recurrent malignant supratentorial gliomas with the association of procarbazine,thiotepa and vincristine: A phase II study

Summary Twenty patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosourea for malignant supratentorial gliomas received a combination of procarbazine, thiotepa and vincristin (P.T.V.) at tumor recurrence. Procarbazine was given at a dose of 100 mg/m² per os from day 1 (D1) to day 15 (D15), thiotepa was administered IV at a dose of 35–45 mg/m² at D1, and vincristine at a dose of 1,4 mg/m² at D1 and D8. Courses of therapy were repeated every four weeks. Tolerance was evaluated in 20 patients. Three patients developed peripheral neuropathy after 2 or 3 courses of vincristin which was then discontinued. Blood toxicity over grade I occurred in 8 patients (40%). One patient developed a grade IV pancytopenia. All 20 patients could be evaluated for therapeutic response. A partial response was noted in 3 patients (15%): 1 glioblastoma multiforme, 1 anaplastic oligodendroglioma and 1 anaplastic astrocytoma. In these three patients time to tumor progression was 10, 11 + and 5 months, respectively. Stabilization lasting 4 months was observed in one patient (anaplastic astrocytoma). Estimated median duration of survival for the entire group was 4,5 months following the onset of PTV (13 months following the date of histology).     

Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke

BACKGROUND: Topotecan activity was evaluated for the treatment of malignant glioma. METHODS: Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan [AU: Please verify all dosages here and throughout text.]at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS: Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS: These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used.