David M. Peereboom

Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check

PURPOSE This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006. RESULTS Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking. CONCLUSION In this article, we review drug delivery across the BBB, as well as blood-tumor and -cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.

Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience

PURPOSE Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. PATIENTS AND METHODS This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age > or = 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS > or = 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. CONCLUSION This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.

Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer

OBJECTIVES To report the results of a Phase II trial of neoadjuvant estramustine and etoposide before radical prostatectomy in patients with locally advanced disease. METHODS Treatment consisted of three cycles of estramustine (10 mg/kg/day) and etoposide (50 mg/m(2)/day) orally on days 1 through 21, repeated every 28 days, followed by radical prostatectomy. The eligibility criteria included locally advanced prostate cancer (clinical Stage T2b/c or T3, prostate-specific antigen [PSA] level of 15 ng/mL or greater, or Gleason score of 8 or higher) without evidence of metastatic disease. The median PSA level was 14 ng/mL (range 5.3 to 50), the median Gleason score was 7 (range 6 to 9), and 44% had Stage T2b/c or T3 disease. The primary endpoint was feasibility of neoadjuvant therapy and radical prostatectomy, including drug and surgery-related toxicities. Secondary endpoints included the pre-prostatectomy PSA level, local response, pathologic outcomes, and time to PSA failure. RESULTS Eighteen patients were entered and completed all three cycles of therapy, and 16 (89%) underwent radical prostatectomy. A local response occurred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA reached undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two with deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. The median operative time was 125 minutes, the mean blood loss was 665 mL, and the mean length of stay was 2.5 nights. Five minor surgical complications occurred in 4 patients. The pathologic analysis demonstrated residual carcinoma with squamous metaplasia and androgen deprivation effect in all patients. Five patients (31%) had organ-confined disease and 9 patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively and at a median follow-up of 14 months (range 5 to 20) and without additional therapy, all 14 patients with negative lymph nodes were disease free. CONCLUSIONS This trial confirms the feasibility of radical prostatectomy with acceptable surgical morbidity after neoadjuvant therapy with estramustine and etoposide in patients with locally advanced prostate cancer. However, this regimen is associated with estramustine-induced thromboembolic toxicity. The results of the pathologic analysis suggest a higher than expected rate of organ-confined and specimen-confined disease, but little histologic evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm with other drug regimens is warranted.

Successful re-treatment with taxol after major hypersensitivity reactions.

PURPOSE To describe the successful re-treatment of eight patients who had major hypersensitivity reactions (HSRs) to taxol and to suggest a regimen for re-treating patients who develop major HSRs. PATIENTS AND METHODS The treatment courses of eight patients who developed major HSRs and were rechallenged with taxol were reviewed. Patients in this report represent all patients who are known to have been rechallenged with taxol after major HSRs. RESULTS The most common approach used to rechallenge patients consisted of premedication with multiple high doses of corticosteroids and H1- and H2-histamine antagonists followed by the initiation of the taxol infusion at a reduced rate. All patients who experienced major HSRs were rechallenged successfully. After the rechallenge, these patients received 32 additional courses of taxol without HSRs. CONCLUSION Re-treatment with taxol after major HSRs is feasible using multiple high doses of corticosteroids and antihistamine premedications and a reduced taxol infusion rate under close supervision. This approach may represent a valid alternative to the termination of taxol; however, a prospective evaluation is required to determine the true efficacy of this approach.

A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306).

Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing.

Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases *

Elderly patients have largely been excluded from randomized trials for glioblastoma multiforme (GBM). We reviewed the results of treatment approaches, which included surgery, chemotherapy, and radiation in this group of patients. Patients were treated during the period 1979-2007 and were 70 years of age and older with histologically confirmed GBM. Overall survival (OS) was the primary endpoint of this retrospective study. Two hundred six patients 70 years of age and older were identified. Median age was 75 years (range 70-90). Median OS time was 4.5 months. Univariate analysis showed that OS was significantly impacted by KPS score (1.8 months for KPS ≤ 50 to 17.2 months for KPS ≥ 90, P < .001), age at diagnosis (5.1 months for age 70-79 versus 3.1 months for age ≥ 80, P < .001), and extent of disease (worse for bilateral disease [P = .003], multifocal disease [P = .005], and multicentric disease [P = .02]). On multivariate analysis, higher KPS score (P = .006), surgical resection (any surgery beyond biopsy) (P < .001), radiation therapy (P < .001), and chemotherapy (P < .001) were all found to be independently associated with improved OS. In this study of newly diagnosed glioblastoma patients over the age of 70 years, aggressive treatment with radiation, chemotherapy, and surgery is associated with OS.

Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC)

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily × 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patients tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1–16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.

A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma

The objectives of this study were to determine the safety and efficacy of polyinosinic-polycytidylic acid stabilized with poly-l-lysine and carboxymethylcellulose (poly-ICLC) when added to radiation and temozolomide (TMZ) in adults with newly diagnosed glioblastoma (GB). Patients received external beam radiation with concurrent TMZ (75 mg/m(2)/day) followed by adjuvant TMZ (150-200 mg/m(2)/day for 5 consecutive days once every 9 weeks) and intramuscular poly-ICLC (20 mg/kg/dose given 3× per week for weeks 2-8). An adjuvant cycle was operationally defined as 9 weeks and patients continued adjuvant therapy until toxicity or disease progression. Ninety-seven patients were enrolled (60 men) with a median age of 56 years (range 21-85) and Karnofsky performance status of 90% (range 60%-100%). Fourteen patients did not start adjuvant treatment. Common treatment-related Grade 3-4 toxicities included neutropenia (20.6%), leukopenia (16.5%), thrombocytopenia (9%), and rash (1%). The entire cohort had a median survival of 17.2 months (95% CI: 15.5-19.3 months) with survival at 12, 18, and 24 months of 73.2%, 47.4%, and 29.9%. For subjects 18-70 years old, median overall survival was 18.3 months (95% CI: 15.9-19.8 months), as compared with 14.6 (95% CI: 13.2-16.8) reported by the EORTC 26981/22981 trial. These results demonstrate that poly-ICLC can be added to standard radiation and TMZ in patients with newly diagnosed GB without additional significant toxicities. Survival data at 12 and 18 months suggest that this may improve the efficacy of chemoradiation and adjuvant TMZ in this patient population.

Recursive partitioning analysis of prognostic factors for glioblastoma patients aged 70 years or older.

The most‐used prognostic scheme for malignant gliomas included only patients aged 18 to 70 years. The purpose of this study was to develop a prognostic model for patients ≥70 years of age with newly diagnosed glioblastoma.

Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131

The primary objectives of this phase II study were to evaluate the use of preirradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA). Preirradiation temozolomide (150 mg/m(2)/day) was given on a 7-day-on/7-day-off schedule for up to six cycles. The primary end point was the response rate during the 6-month, pre-RT chemotherapy. Tumor tissue was analyzed for the presence of chromosomal deletions on 1p and 19q and for MGMT-promoter methylation. Forty-two patients were enrolled; 39 were eligible. The objective response rate was 32% (6% [complete response, CR], 26% [partial response PR]), and the rate of progression during pre-RT chemotherapy was 10%. The worst nonhematological toxicity was grade 4 in three patients (8%). Twenty-two patients completed concurrent chemotherapy and RT. There were no grade 4 nonhematological toxicities during the concurrent chemotherapy and RT. Seventeen of 28 (60.7%) evaluable cases had codeletion of 1p/19q; all 17 were free from progression at 6 months. Sixteen of 20 (80%) evaluable cases had MGMT-promoter methylation; all 16 were free from progression at 6 months. In conclusion, the rate of progression of 10% during pre-RT temozolomide chemotherapy for newly diagnosed AO and MAO compared favorably with prior experience with pre-RT PCV chemotherapy (20% in RTOG 9402). The toxicity of the dose-intense pre-RT regimen used in this study may warrant evaluation of other, less intense dosing strategies. Future studies will need to prospectively stratify patients according to the presence of deletions of chromosomes 1p and 19q.