Bevacizumab for recurrent alkylator‐refractory anaplastic oligodendroglioma

BACKGROUND:

A retrospective evaluation of single agent bevacizumab was carried out in adults with recurrent alkylator‐refractory 1p19q codeleted anaplastic oligodendrogliomas (AO) with an objective of determining progression‐free survival (PFS). There is no standard therapy for alkylator‐resistant AO, and hence a need exists for new therapies.

METHODS:

Twenty‐two patients aged 24 to 60 years with recurrent AO were treated. All patients had previously been treated with surgery, radiotherapy, adjuvant chemotherapy (temozolomide, 17; carmustine wafers, 4; carmustine, 1), and 1 salvage regimen (procarbazine, lomustine, and vincristine, 15; temozolomide, 6; carmustine wafers, 1). Eleven patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks, and neuroradiographic assessment was made after the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab.

RESULTS:

A total of 391 cycles of bevacizumab (median, 14.5 cycles; range, 2‐39 cycles) were administered. Bevacizumab‐related toxicity included fatigue (14 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (5; 1 grade 3), deep vein thrombosis (4; 1 grade 3), and wound dehiscence (2; 1 grade 3). Fifteen (68%) patients demonstrated a partial radiographic response, 1 (5.0%) demonstrated stable disease, and 6 (27%) demonstrated progressive disease after 2 cycles of bevacizumab. Time to tumor progression ranged from 1 to 18 months (median, 6.75 months). Survival ranged from 3 to 19 months (median, 8.5 months). Six‐month and 12‐month PFS were 68% and 23%, respectively.

CONCLUSIONS:

Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent 1p19q codeleted alkylator‐refractory AO. Cancer 2009. © 2009 American Cancer Society.     

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach

BACKGROUND.

Despite advances in first‐line therapy, there are few data on treatment of glioblastoma multiforme (GBM) at recurrence. Temozolomide (TMZ) is well tolerated and may have activity despite prior TMZ exposure if novel dose schedules are used.

METHODS.

The authors reviewed their experience with a continuous TMZ schedule (50 mg/m² daily), given at progression after conventional 5‐day TMZ. Patients were reported in 3 groups: 1) GBM after progression on conventional TMZ; 2) GBM at first recurrence after completion of standard concomitant and adjuvant TMZ; and 3) patients with other anaplastic gliomas at second relapse on conventional TMZ.

RESULTS.

In Group 1, 21 patients with a median age of 54 years (range, 33 years‐68 years) received a median of 3 cycles (range, 2‐12 cycles) of continuous TMZ at 50 mg/m². Overall clinical benefit (complete response, partial response, and stable disease) was 47%, with 6‐month progression‐free survival (PFS) of 17%. In Group 2, 14 patients with GBM, median age 52 years (range, 38 years‐62 years) received continuous TMZ at progression after initial TMZ/radiotherapy (RT) and adjuvant TMZ. The median interval after adjuvant TMZ was 3 months (range, 2 months‐10 months). A median of 5 cycles of TMZ was given, and 6‐month PFS was 57%. In Group 3, 14 patients with a median age of 49 years (range, 34 years‐56 years) received continuous TMZ; 2 partial responses and 6 with stable disease were seen, with a 6‐month PFS of 42%. Toxicities were mild and well tolerated; lymphopenia was common but no serious opportunistic infections were identified.

CONCLUSIONS.

Although retrospective, our results demonstrate that continuous daily administration of TMZ is an active regimen despite prior TMZ therapy. The excellent tolerability of this regimen may allow future combination with other alkylating agents or with novel therapies. Cancer 2008. © 2008 American Cancer Society.     

A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer

BACKGROUND:

The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum‐sensitive epithelial ovarian cancer (EOC).

METHODS:

Participants were randomized to either weekly docetaxel 30 mg/m² on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m² on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression‐free survival (PFS).

RESULTS:

Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9‐16.8) for cDC and 8.4 months (95% CI, 7.1‐11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08‐2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy–Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013).

CONCLUSIONS:

Both cDC and sDC regimens have activity in recurrent platinum‐sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC. Cancer 2011. © 2011 American Cancer Society.     

Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study

Background

Few data are available on temozolomide (TMZ) in ependymomas.We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy.

Patients and Methods

We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria.

Results

Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1–24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22–30.98) and 30.55 months (95% CI, 12.85–52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome.

Conclusion

TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.     

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer

BACKGROUND:

Sequential treatment with azacitidine can induce re‐expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b‐2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum‐resistant or platinum‐refractory epithelial ovarian cancer.

METHODS:

Patients with pathologically confirmed intermediate‐grade or high‐grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum‐based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease.

RESULTS:

Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression‐free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum‐resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%).

CONCLUSIONS:

To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted. Cancer 2011. © 2010 American Cancer Society.     

Temozolomide for recurrent low-grade spinal cord gliomas in adults

BACKGROUND: There is no standard therapy for surgery- and radiotherapy-resistant, recurrent, low-grade spinal cord gliomas. Therefore, a retrospective study of temozolomide (TMZ) in adults with recurrent low-grade spinal cord gliomas with a primary objective of determining progression-free survival (PFS) was performed. METHODS: Twenty-two patients (11 men and 11 women) aged 20 years to 55 years (median, 35 years) with recurrent spinal cord gliomas (World Health Organization grade 2 astrocytoma in 19 patients and oligoastrocytoma in 3 patients) were treated. All had previously been treated with surgery and involved-field radiotherapy. Thirteen patients underwent repeat surgery. All patients were chemotherapy-naive. TMZ was administered at a dose of 150-200 mg/m(2)/day for 5 consecutive days every 4 weeks (operationally defined as a single cycle). Neurologic and neuroradiographic evaluations were performed every 8 weeks. RESULTS: All patients were evaluable for toxicity and response. A total of 266 cycles of TMZ (median, 14 cycles; range, 2 cycles-24 cycles) was administered. TMZ-related toxicity included constipation (9 patients, 1 with grade 3), lymphopenia (9 patients, 1 with grade 3), fatigue (7 patients, 1 with grade 3), neutropenia (6 patients, 2 with grade 3), and thrombocytopenia (6 patients, 2 with grade 3). Four (18%) patients demonstrated a partial radiographic response, 12 (55%) demonstrated stable disease, and 6 (27%) had progressive disease after 2 cycles of TMZ. Time to tumor progression ranged from 2 months to 28 months (median, 14.5 months). Survival ranged from 4 months to 39 months (median, 23 months). PFS at 6 months, 12 months, 18 months, and 24 months was 64%, 64%, 41%, and 27%, respectively. CONCLUSIONS: TMZ demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent low-grade spinal cord gliomas.     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.     

Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases

BACKGROUND.

Temozolomide (TMZ), an oral methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanomas, and brain metastasis and is presently administered as a 5‐day oral schedule every 4 weeks.

METHODS.

A single‐institution phase 2 clinical trial was conducted to determine the efficacy and the safety profile of a new regimen based on a dose‐intensified, protracted course of TMZ after whole‐brain radiotherapy (WBRT). Patients were eligible if they had at least 1 bidimensionally measurable brain metastasis from breast cancer and nonsmall cell lung cancer (NSCLC). Twenty‐seven patients were treated with 30 grays (Gy) of WBRT with concomitant TMZ (75 mg/m²/day) for 10 days, and subsequent TMZ at a dose of 75 mg/m² per day for 21 days every 4 weeks, for up to 12 cycles.

RESULTS.

Two complete responses (7.4%) and 11 partial responses (40.7%) were achieved. The schedule appeared to be well tolerated, with grade 3 toxicity (graded according to National Cancer Institute Common Toxicity Criteria) observed in only 2 patients. The overall median survival was 8.8 months and the median progression‐free survival was 6 months.

CONCLUSIONS.

The concomitant use of WBRT and protracted low‐dose TMZ appears to be an active, well‐tolerated regimen. The observed antitumor activity suggests the need for further investigation of this schedule in combination with other anticancer agents for the concomitant treatment of brain metastases and primary cancers. Cancer 2008. © 2008 American Cancer Society.     

Adjuvant therapy for high‐grade,uterus‐limited leiomyosarcoma

BACKGROUND:

Between 30% and 50% of women who have high‐grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression‐free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2‐year and 3‐year progression‐free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin.

METHODS:

Women with uterus‐limited, high‐grade uLMS and adequate organ function were eligible. Within 12 weeks of complete resection and after confirmation that they had no evidence of disease on computed tomography (CT) images, the patients received 4 cycles of fixed‐dose‐rate gemcitabine plus docetaxel. Those who were confirmed disease‐free on CT scans after cycle 4 received 4 cycles of doxorubicin. CT imaging for recurrence was performed every 3 months for 2 years, then every 6 months for 3 years.

RESULTS:

In total, 47 women were enrolled (46 evaluable) in 3 years. Characteristics included a median age of 53 years; 1988 International Federation of Gynecology and Obstetrics stage I disease in 81% of patients, stage II disease in 15%, and serosa‐only stage IIIA disease in 4%; American Joint Committee on Cancer stage II disease in 13% of patients and stage III disease in 87%; a median tumor size of 8 cm (range, 2.5‐30 cm); and a median mitotic rate of 18 mitoses per 10 high‐power fields (range, 5‐83 mitoses per 10 high‐power fields). At a median follow‐up of 39.8 months, 21 of 46 patients developed recurrent disease (45.7%). The median time to recurrence was 27.4 months (range, 3‐40 months). Seventy‐eight percent of patients (95% confidence interval, 67%‐91%) were progression‐free at 2 years, and 57% (95% confidence interval, 44%‐74%) were progression‐free at 3 years. The median PFS was not reached and exceeded 36 months.

CONCLUSIONS:

Among women with high‐grade, uterus‐limited uLMS who received treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin, 78% remained progression‐free at 2 years, and 57% remained progression‐free at 3 years. A randomized trial of adjuvant chemotherapy versus observation to determine whether adjuvant chemotherapy can improve survival in women with uterus‐limited uLMS is underway. Cancer 2013. © 2013 American Cancer Society.     

Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a 2-cohort, phase 2 study

BACKGROUND:

Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR‐3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum‐resistant and platinum‐sensitive recurrent ovarian cancer.

METHODS:

Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum‐resistant patients (who had a progression‐free interval <6 months after their last platinum‐based therapy) and 2) platinum‐sensitive patients (who had a progression‐free interval ≥6 months after their last platinum‐based therapy). Eribulin 1.4 mg/m² was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies.

RESULTS:

In the platinum‐resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression‐free survival was 1.8 months (95% confidence interval, 1.4‐2.8 months). In the platinum‐sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression‐free survival was 4.1 months (95% confidence interval, 2.8‐5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum‐resistant patients; 54% of platinum‐sensitive patients).

CONCLUSIONS:

Eribulin produced an objective response in 5.5% of women with platinum‐resistant, recurrent ovarian cancer and in 19% of women with platinum‐sensitive disease. The median progression‐free survival was 1.8 months in the platinum‐resistant group and 4.1 months in the platinum‐sensitive group. Cancer 2012. © 2011 American Cancer Society.     

Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas

BACKGROUND.

Intracranial meningiomas are common, they frequently recur after surgery or radiotherapy, and there are limited data regarding the treatment of intracranial meningiomas with chemotherapy. A phase 2 study was designed to estimate the 6‐month progression‐free survival of patients with recurrent, treatment‐refractory, World Health Organization grade 1 meningiomas who were treated with interferon‐α.

METHODS.

Thirty‐five patients with recurrent meningiomas ranging in age from 36 years to 88 years (median age, 61 years) were treated according to a prospective phase 2 study. All patients had received prior surgery, radiotherapy, (involved‐field radiotherapy in 35 patients andstereotactic radiotherapy in 22 patients), and chemotherapy (hydroxyurea in 19 patients and other in 17 patients). On radiographic documentation of progressive disease, interferon‐α (at a dose of 10 million U/m² administered subcutaneously every other day) was initiated. A complete blood count and chemistry panel was obtained before every cycle, and cranial magnetic resonance images were obtained every 3 months.

RESULTS.

The most common grade 3 and 4 toxicities were fatigue (6 patients; 17%), anemia (3 patients; 8.6%), and leukopenia (3 patients; 8.6%) (toxicities were graded according to the National Cancer Institute's Common Toxicity Criteria [version 3.0]). Three patients went off study because of toxicity, and 7 patients required a dose reduction. There were no treatment‐related deaths or delays in therapy reported. All patients were assessable for response. No patient demonstrated a neuroradiographic complete or partial response. Twenty‐six patients demonstrated stable disease after the first 3 cycles of interferon‐α, and 9 patients had progressive disease. The progression‐free survival rate was 54% at 6 months and 31% at 12 months. The median time to tumor progression was 7 months (range, 2‐24 months). The median survival was 8 months (range, 3‐28 months).

CONCLUSIONS.

Treatment with interferon‐α for recurrent meningiomas was found to be tolerated moderately well and was modestly effective. Cancer 2008. © 2008 American Cancer Society.     

Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma

BACKGROUND:

We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low‐grade glioma.

METHODS:

A total of 64 patients with recurrent/progressive low‐grade glioma were enrolled in this single‐center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme‐inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression‐free survival at 12 months (PFS‐12) and secondary endpoints were safety, median progression‐free survival, and radiographic response rate.

RESULTS:

Thirty‐two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS‐12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%).

CONCLUSIONS:

Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity. Cancer 2012. © 2012 American Cancer Society.     

Phase 2 trial of a novel capecitabine dosing schedule in combination with bevacizumab for patients with metastatic breast cancer

BACKGROUND:

Capecitabine has antitumor activity in metastatic breast cancer (MBC); however, its optimal dose and schedule remain unclear. Mathematical modeling predicts that a capecitabine schedule 7 days of treatment followed by 7 days of rest (7—7) will improve efficacy and minimize toxicity. Bevacizumab has demonstrated the ability to improve outcomes when it is added to chemotherapy, including capecitabine, in the first‐line and second‐line settings.

METHODS:

Patients with measurable MBC received oral capecitabine (2000 mg twice daily; 7—7), and intravenous bevacizumab (10 mg/kg every 2 weeks). The primary endpoint was the response rate. Secondary endpoints included toxicity, the clinical benefit rate, and progression‐free survival (PFS).

RESULTS:

Forty‐one patients were treated. After a median of 7 cycles (range, 1‐32 cycles), partial responses were observed in 20% of patients, and stable disease for ≥6 months was noted in 35% patients. The median PFS was 8 months. The most common treatment‐related toxicities were hand‐foot syndrome (49% grade 2, 20% grade 3/4) hypertension (12% grade 2, 10% grade 3/4), and fatigue (12% grade 2, 2% grade 3/4). Diarrhea (5% grade 2, 0% grade 3/4), nausea (0% grade 2‐4), and vomiting (0% grade 2‐4) were rare.

CONCLUSIONS:

Capecitabine administered for 7 days followed by a 7‐day rest in combination with bevacizumab had modest efficacy and an acceptable toxicity profile in patients with MBC. Gastrointestinal toxicity with this schedule was minimal. Cancer 2011;. © 2011 American Cancer Society.     

A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial,infratentorial, and spinal cord ependymoma

BackgroundNo standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O⁶-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.MethodsPatients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI–Spine Tumor modules were collected.ResultsThe 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.ConclusionsThis treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.     

Temozolomide in paediatric high-grade glioma: a key for combination therapy?

This report describes a single-centre study with temozolomide (TMZ) (200 mg m(-2) day(-1) x 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery+/-radiotherapy+/-chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3-20.5 years). In total, eight patients had >8 cycles (range 3-30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after >4 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks-34+ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy.     

Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma

A retrospective study of bevacizumab only in adults with recurrent temozolomide (TMZ)-refractory anaplastic astrocytoma (AA) with a primary objective of determining progression free survival (PFS). There is no standard therapy for alkylator-resistant AA and hence a need exists for new therapies. Twenty-five patients (15 men; 10 women) ages 26–63 (median 50), with radiographically recurrent AA were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and alkylator-based chemotherapy. Fourteen patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab (10 mg/kg), once every 2 weeks (defined as a single cycle). Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial two cycles of bevacizumab and subsequently after every four cycles of bevacizumab. All patients were evaluable for toxicity and response. A total of 360 cycles of bevacizumab (median 14 cycles; range 2–40) was administered. Bevacizumab-related toxicity included fatigue (14 patients; 2 grade 3), leukopenia (7; 1 grade 3), deep vein thrombosis (5; 2 grade 3), hypertension (5; 1 grade 3), anemia (4; 0 grade 3) and wound dehiscence (1; 1 grade 3). Sixteen patients (64%) demonstrated a partial radiographic response, 2 (8.0%) stable disease and 7 (28%) progressive disease following two cycles of bevacizumab. Time to tumor progression ranged from 1 to 20 months (median: 7). Survival ranged from 2 to 23 months (median: 9.0). 6-month and 12-month PFS were 60 and 20%, respectively. Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator refractory AA.     

Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy

Purpose

A prospective, two-stage phase II trial with octreotide in patients with recurrent high-grade meningioma was conducted. The radiographic partial response (RPR) was set as the primary study endpoint, whereas progression-free survival at 6 months (PFS6) was defined as the secondary endpoint.

Methods

Nine patients (eight men; median age 65) with histological high-grade meningioma (five with grade II and four with grade III) and progression after prior surgery and radiotherapy were included. All had positive brain octreotide SPECT scanning. Octreotide was administered intramuscularly once every 28 days at a dose of 30 mg for the first two cycles and 40 mg for subsequent cycles until progression. Magnetic resonance imaging was performed every 3 months. Progression and RPR were defined as an increase of ≥25 % and as a decrease of ≥50 % in two-dimensional maximum diameters, respectively.

Results

Patients received a median of three octreotide cycles (range 1–8) without grade ≥2 toxicities. No RPRs were observed. Stable disease was the best response in 33.3 % (n = 3). All patients had progressive disease at 10 months of follow-up. Median time to progression was 4.23 months (range 1–9.4), and the PFS6 was 44.4 % (n = 4).

Conclusion

Our study failed to provide evidence to support the use of monthly long-acting somatostatin analogue schedule in recurrent high-grade meningiomas, as none of our patients demonstrated RPR. The modest median PFS of 4–5 months along with the unknown natural history of recurrent meningiomas render the use of this therapy against these aggressive brain tumors uncertain.     

The cisplatin,epirubicin, 5‐fluorouracil,gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma

BACKGROUND:

Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5‐fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA.

METHODS:

PEFG (cisplatin 40 mg/m² and epirubicin 40 mg/m² on Day 1; gemcitabine 600 mg/m² on Days 1 and 8; and 5‐fluorouracil [FU] 200 mg/m² daily as a continuous infusion) was administered to chemotherapy‐naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged ≤75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment.

RESULTS:

Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1‐year OS rate was 52%. The median progression‐free survival (PFS) was 7.9 months, and the 6‐month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles.

CONCLUSIONS:

The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA. Cancer 2010. © 2010 American Cancer Society.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study

BACKGROUND:

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

METHODS:

Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m² on days 1, 8, and 15 of a 28‐day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression‐free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity.

RESULTS:

Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment‐related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0‐9.4) and 16.6 months (95% CI, 12.8‐22.9), with 22 (55%) patients progression‐free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02).

CONCLUSIONS:

A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum‐resistant OC; further study is warranted. Cancer 2011;. © 2011 American Cancer Society.