Appendix 2 - Commissioning Best Value Programme Cash releasing schemes Comments There are two elements to the Falls Programme; a new community falls pathway and NWAS deflections. The primary care falls pathway to pilot in two practices. This has been delayed as one of the practices originally identified has withdrawn from the process. A replacement practice has been identified but is likely
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Neurooncology.ucla.eduP h a s e I I E v a l u a t i o n o f T e m o z o l o m i d e a n d 1 3 - c i s - R e t i n o i c A c i d
f o r t h e T r e a t m e n t o f R e c u r r e n t a n d P r o g r e s s i v e M a l i g n a n t
G l i o m a : A N o r t h A m e r i c a n B r a i n T u m o r C o n s o r t i u m S t u d y
By Kurt A. Jaeckle, Kenneth R. Hess, W.K. Alfred Yung, Harry Greenberg, Howard Fine, David Schiff, Ian F. Pollack, John Kuhn, Karen Fink, Minesh Mehta, Timothy Cloughesy, M. Kelly Nicholas, Susan Chang, and Michael Prados Purpose: Temozolomide (TMZ) and 13-cis-retinoic acid
Median overall PFS was 19 weeks (95% CI, 16 to 27 weeks),
(cRA) have shown activity in prior single-agent trials of
and median overall survival (OS) was 47 weeks (95% CI, 36
recurrent malignant gliomas (MG). This phase II trial evalu-
to 58 weeks). OS was 46% (95% CI, 36% to 57%) at 52
ated efficacy and toxicity of combination temozolomide and
weeks and 21% (95% CI, 13% to 31%) at 104 weeks. Of 84
cRA treatment in recurrent MG.
assessable patients, there were two (3%) complete re-
Patients and Methods: Adults with recurrent supratento-
sponses and eight (12%) partial responses (complete plus
rial MG for whom surgery, radiation, and/or chemotherapy
partial response, 15%). Among 499 treatment cycles, the
failed were eligible. Treatment included oral TMZ 150 or
most common grade 3/4 events included granulocytopenia
200 mg/m2/d, days 1 through 5, and cRA 100 mg/m2/d,
(1.8%), thrombocytopenia (1.4%), and hypertriglyceride-
days 1 to 21, every 28 days. Primary end point was pro-
gression-free survival at 6 months (PFS 6); secondary end
Conclusion: TMZ and cRA were active, exceeding our
points included response, survival, and PFS12.
20% thresholds for PFS 6 success, assuming 20% improve-
Results: Eighty-eight eligible patients (glioblastoma mul-
ment over our previously reported database (glioblastoma
tiforme [n ؍ 40]; anaplastic gliomas [n ؍ 48; astrocytoma,
multiforme: expected, 30%; observed, 32%; anaplastic gli-
28; oligodendroglioma, 14; mixed glioma, six]) received
oma: expected, 40%; observed, 50%).
treatment. PFS 6 was 43% (95% confidence interval [CI],
J Clin Oncol 21:2305-2311. 2003 by American
33% to 54%) and PFS12 was 16% (95% CI, 10% to 26%).
Society of Clinical Oncology.
DESPITE OPTIMAL treatment for malignant gliomas, re- currence is common within the first 2 years. This poor The study was performed by the NABTC, a National Cancer Institute outcome was underscored by a recent analysis of eight consec- (NCI) consortium of 11 participating institutions (Dana-Farber Cancer utive phase II trials of 375 patients with recurrent glioma treated Institute, University of California at San Francisco, University of Michigan with various chemotherapeutic regimens.1 This analysis revealed Hospital, University of Pittsburgh, Children’s Hospital of Pittsburgh, Uni-versity of Texas Health Sciences Center at San Antonio, University of Texas a 6-month progression-free survival rate (PFS 6) of only 15% for M.D. Anderson Cancer Center, University of Texas Southwestern, Univer- patients with glioblastoma multiforme (GM) and 31% for pa- sity of Wisconsin, University of California at Los Angeles, and University of tients with anaplastic glioma (AG). After recurrence, response to Chicago). The study was activated December 17, 1998 at the University of treatment was observed in only 9% of patients, and overall Texas M.D. Anderson Cancer Center, was expanded to the NABTC on April median survival was only 30 weeks. In meta-analysis studies, 9, 1999, and was closed to accrual on January 30, 2000. All data werecollected and analyzed at the NABTC Data Management Center at the there seems to be modest evidence of a survival benefit whenchemotherapy is added to standard surgical and radiation ther-apy, particularly in selected subsets of newly diagnosed gliomapatients.2,3 However, there is little evidence of benefit of From the University of Texas M.D. Anderson Cancer Center, Houston; chemotherapy after tumor recurrence or progression, and newer University of Texas Health Science Center, San Antonio; and University of agents and regimens need evaluation.
Texas Southwestern Medical Center, Dallas, TX; University of Michigan,Ann Arbor, MI; Dana-Farber Cancer Institute, Boston, MA; University of There is preclinical and clinical evidence of activity of Pittsburgh and Children’s Hospital of Pittsburgh, Pittsburgh, PA; University retinoids and/or alkylators in gliomas, either as single agents or of Wisconsin, Madison, WI; University of California at Los Angeles, Los in combination. Two such orally administered agents with Angeles; University of California at San Francisco, San Francisco, CA; different modes of action, temozolomide (TMZ) and 13-cis- University of Chicago, Chicago, IL. retinoic acid (cRA), have shown activity in recurrent malignant Submitted December 17, 2002; accepted March 26, 2003.
This research protocol was supported grants CA62399, CA62422, gliomas without overlapping toxicity in phase II clinical trials.4-6 CA62412, CA16672, CA62455, CA62426, UO1CA62407-08, UO1CA62405, Multiagent combination regimens containing both retinoids and alkylating agents have been active in malignancies of several RR00056, MO1-RR0865, MO1-RR00042, and MO1-RR03186 from the histologic subtypes.7-10 On the basis of these observations, the National Institutes of Health, Bethesda, MD. North American Brain Tumor Consortium (NABTC) chose to Address reprint requests to Kurt A. Jaeckle, MD, Department of Oncology and Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Blvd, Jackson- perform a prospective, phase II, single-arm trial (NABTC ville, FL 32224; email: email@example.com. 98 – 03) of TMZ and cRA in patients with recurrent and 2003 by American Society of Clinical Oncology. Journal of Clinical Oncology, Vol 21, No 12 (June 15), 2003: pp 2305-2311 Information downloaded from www.jco.org and provided by UCLA on April 25, 2006 from 126.96.36.199. Copyright 2003 by the American Society of Clinical Oncology. All rights reserved. University of Texas M.D. Anderson Cancer Center. Approval of the protocol received prior chemotherapy (150 mg/m2/d for those who had received prior and informed consent by local human investigation committees was obtained chemotherapy) days 1 through 5 every 28 days. cRA (Isotretinoin; Roche from each institution, in accord with assurance filed with and approved by the Laboratories, Nutley, NJ) was administered at 100 mg/m2/d to all patients United States Department of Health and Human Services where appropriate.
regardless of prior treatment, in two divided doses, 12 hours apart on days 1 Informed consent was obtained from each subject or subject’s guardian.
through 21 every 28 days. A course was defined as a 28-day period oftreatment. Treatment courses were repeated every 28 days from day 1, provided that all hematologic toxicity from the previous course had resolved The two primary objectives of this study included determination of to grade 2 or less, and all nonhematologic toxicity had recovered to either efficacy and toxicity of the combination of TMZ and cRA in the treatment of grade 0 or 1. If recovery had not occurred by day 28, the subsequent course patients with recurrent and progressive GM or AG. The primary end point of TMZ and cRA was delayed until these criteria were met.
was progression-free survival at 6 months (PFS 6). Secondary end points No dose escalations were allowed. Dose reduction for toxicity was included overall survival, time to progression, and, for assessable patients, allowed in 25-mg reduction increments, for both TMZ and cRA. Only two response. Toxicity was evaluated in all eligible patients receiving at least one dose reductions were permitted, and patients having grade 3 toxicity of any type after two dose reductions were removed from study. Patients werepretreated with oral antiemetics before each TMZ dose and as needed symptomatically. Patients were required to maintain the lowest corticosteroid Eligibility required a prior histologic diagnosis of supratentorial GM or dose necessary for neurologic stability.
AG, which was defined as anaplastic astrocytoma (AA), anaplastic oligo-dendroglioma, or anaplastic malignant glioma (AMG). The pathologic tissue diagnosis made at the treating institution was accepted; however, thepathology reports on all patients were centrally reviewed to verify the tumor Patients were evaluated for response using a combination of both clinical histology. Unequivocal evidence of recurrence or progression by neuroim- (neurologic examination) and neuroimaging (enhanced MRI or CT) proce- aging procedure (computed tomography [CT] or magnetic resonance imag- dures before every other course (eg, 3, 5, 7, and so on) as compared with ing [MRI]) was required, with the progression observed after surgery and baseline. Neurologic performance was assessed by the grading of symptoms radiation and Յ two prior chemotherapy regimens, either as adjuvant and signs that were considered to be not related to a postictal state or other treatment or at recurrence. Patients more than 4 weeks from complete non–tumor-related process, as compared with the last examination. Patients resection were required to have evidence of measurably enhancing disease on were graded as either definitely better (ϩ2), possibly better (ϩ1), unchanged MRI or CT within 14 days of registration. Those with recent (Յ 4 weeks) (0), possibly worse (Ϫ1), or definitely worse (Ϫ2).
complete resection were eligible without enhancing disease but were not Response was assessed using a modification of the MacDonald criteria.11 assessable for response. Patients were required to be older than 18 years; All final response determinations required that patients had a stable or have a life expectancy greater than 8 weeks; have a Karnofsky performance improved clinical examination as compared with baseline and were on stable status greater than 60; be recovered from toxic effects of prior radiotherapy or decreased doses of corticosteroids as compared with the prior evaluation.
or other therapies; and be at least 2 weeks from vincristine, 6 weeks from Responses (complete response [CR] or partial response [PR]) were required nitrosoureas, and 3 weeks from other chemotherapy. Other eligibility factors to be sustained on two successive scans taken 8 weeks apart to be considered included absolute neutrophil counts of greater than 1,500/mL, platelets Ն valid. Independent central review was performed on all patients considered 100,000/mL, transaminases and alkaline phosphatase less than two times the to be responding by the local investigators, and if the central reviewer was in institutional upper limits of normal, bilirubin less than 1.5 mg %, blood ureanitrogen and creatinine less than 1.5 times the upper limit of institutional agreement, response was designated as confirmed. If all relevant scans normal, negative beta-human chorionic gonadotropin at registration, use of were not all available at the time of central review, the response was effective birth control, and provision of informed, written consent.
Patients were ineligible if they had active infection, were pregnant or Progression-free survival (PFS) and overall survival (OS) were defined as breast feeding, or had history of a prior cancer (unless off therapy and in the time from the first day of treatment until progression or death. Patients complete remission for Ͼ 3 years), excepting nonmelanotic skin cancer and were removed from study if there was progressive disease, development of unacceptable toxicity, an unacceptable status quo or patient refusal, ornoncompliance with protocol requirements.
Toxicity monitoring was performed on patients, on all cycles. Safety parameters included all laboratory and hematologic abnormalities, neuro-logic historical and examination findings, and adverse events reported by The primary objective was to determine whether TMZ and cRA could patients. The NCI common toxicity criteria version 2.0 was used for adverse significantly delay progression in patients with recurrent GM and AG.
event and toxicity reporting. Data forms were submitted to the central Historical values were obtained from analysis of a database of 375 patients NABTC office according to protocol guidelines and entered in the Protocol with recurrent high-grade glioma (225 GM and 150 AA) treated on eight Data Management System. The study was monitored by the Clinical Data consecutive prospective phase II trials,1 in which PFS 6 was 21% (GM, 15%; Update System Version 1.1, with cumulative Clinical Data Update System AA, 31%). The hypotheses tested are H0: p ϭ p0 versus H1: p more than p1, data submitted quarterly to the Cancer Treatment and Evaluation Program.
where p was the probability of remaining alive and progression-free at 6 Serious adverse events (AEs) or adverse drug reactions (ADRs) were months, with an alpha of 10% and beta of 5%. For GM, p0 was set at 10% reported using the NCI/Division of Cancer Treatment ADR reporting form.
and p1 at 30%, looking for improvement of 0.2. For AG, p0 was set at 20% The process followed the NABTC and United States Food and Drug and p1 at 40%, looking for an improvement of 0.2. A prior phase II study of Administration guidelines for reporting of ADRs.
TMZ in 116 recurrent AGs showed a PFS 6 of 22%.5 The current study was Quality assurance measures included ongoing (per protocol timetable) designed to accrue 45 GM and 40 AG patients. For GM, success was defined monitoring of protocol compliance and submitted case report forms, on-site as observing more than seven of 40 patients alive and progression-free at 6 months (yielding alpha ϭ 4% and beta ϭ 6%). For AG, declaring success if13 of 45 reached 6 months progression-free would yield an alpha of 5% and beta of 8%. Kaplan-Meier estimates for PFS and OS and exact binomial TMZ (Schering Plough Pharmaceuticals, Kenilworth, NJ) was adminis- confidence intervals (CIs) were computed using S-plus 2000 (MathSoft, Inc, tered orally at a starting dose of 200 mg/m2/d for patients who had not Information downloaded from www.jco.org and provided by UCLA on April 25, 2006 from 188.8.131.52. Copyright 2003 by the American Society of Clinical Oncology. All rights reserved. TMZ AND CRA FOR RECURRENT MALIGNANT GLIOMA Table 1. Temozolomide and cis-Retinoic Acid in Recurrent Malignant
Table 2. Temozolomide and cis-Retinoic Acid in Recurrent Malignant
Gliomas: Clinical Characteristics
Abbreviations: CR, complete response; PR, partial response.
or more surgeries. Almost 90% of patients had a prior partial resection or gross total resection; 13% had received biopsy only.
The surgical procedures performed most proximate to registra- tion were generally biopsy or partial resection. All 88 patients had experienced treatment failure with prior radiotherapy. Most patients (69 [78%] of 88 patients) had experienced treatment failure with one to two prior chemotherapy regimens, but 19 patients (22%) were chemotherapy-naive. All 88 patients were assessable for toxicity, and 84 were assessable for response (four patients were not assessable for response because of gross total resections without measurably enhancing disease at registration).
Of the 84 patients assessable for response (Table 2), there were two CRs (3%) and nine PRs (12%), for an overall response rate (ORR; CR ϩ PR) of 15%. By histologic diagnosis, re- sponses occurred as follows: CR, AA (n ϭ 1), AO (n ϭ 1); PR, GM (n ϭ 2), AA, (n ϭ 2), AMG (n ϭ 3), AO (n ϭ 2).
Radiographic responses were confirmed by independent central review in all patients except one, an unconfirmed PR patient in whom the appropriate scans were unavailable at the time of central review. On review, all responding patients were on stable (four of 11) or no corticosteroids (seven of 11) at the time of the Abbreviations: GM, glioblastoma multiforme; AA, anaplastic astrocy- toma; AO, anaplastic oligodendroglioma; AMG, anaplastic malignantglioma.
There were 88 eligible patients with recurrent supratentorial malignant gliomas (GM, n ϭ 40; AG, n ϭ 48) analyzed by intent to treat (Table 3; Figs 1 and 2). Thirty-eight patients (43%; 95% Eighty-nine patients with recurrent, progressive malignant CI, 33% to 54%) were alive and progression-free at 6 months gliomas were registered. Eighty-eight were eligible; one patient (PFS 6). The overall PFS 12 was 16% (95% CI, 10% to 26%).
without demonstrable radiographic progression at registration Median overall PFS was 19 weeks (95% CI, 16 to 27), and was found to be ineligible. Of the 88 eligible, assessable patients, median OS was 47 weeks (95% CI, 36 to 58). OS was 46% (95% there were 40 patients with GM (one had gliosarcoma) and 48 CI, 36% to 57%) at 52 weeks and 20% (95% CI, 13% to 31%) patients with AG (28 patients with AA, 13 patients with anaplastic oligodendroglioma [AO], one with oligodendrogli- Analysis by histologic strata was also performed. In the 40 patients with GM, PFS 6 was 32% (95% CI, 21% to 51%) PFS 12 The clinical and demographic features of the 88 patients are was 15% (95% CI, 7% to 31%), and median PFS was 16 weeks listed in Table 1. The median age of the patients was 45 years (95% CI, 9 to 26 weeks). The OS 6 for GM was 65% (95% CI, 52% (range, 23 to 70 years). There was a three to two male-to-female to 82%), and median OS was 35 weeks (95% CI, 28 to 79 weeks).
ratio. Median Karnofsky performance status (KPS) was 80, with In the 48 patients with AG (non-GM), the PFS 6 was 50% (95% CI, a minimum of 60. All patients had been unsuccessfully treated 38% to 66%), PFS 12 was 17% (95% CI, 9% to 31%), and median with prior surgery; 41% had one prior surgery and 59% had two PFS was 25 weeks (95% CI, 16 to 32 weeks). The OS 6 for all Information downloaded from www.jco.org and provided by UCLA on April 25, 2006 from 184.108.40.206. Copyright 2003 by the American Society of Clinical Oncology. All rights reserved. Table 3. Temozolomide and cis-Retinoic Acid in Recurrent Malignant Gliomas: Survival
Abbreviations: PFS 6, progression-free survival at 6 months; OS 6, overall survival at 6 months; PFS 12, progression-free survival at 12 months; TMZ, temozolomide; cRA, cis-Retinoic Acid; GM, glioblastoma multiforme; AA, anaplastic astrocytoma; AG, anaplastic glioma; AMG, anaplastic mixed glioma; AO, anaplastic oligodendroglioma;NS, not stated; NR, not yet reached.
*Included 28 AA and seven AMG patients.
patients with AG was 83% (95% CI, 73% to 95%), and median OS (10%) completed at least 12 cycles (approximately 1 year of was 52 weeks (95% CI, 38 to 60 weeks). For the subsets of AG, end therapy), but only three (3.4%) of patients received Ն 24 cycles point parameters for the AO and non-AO AG subsets are provided (approximately 2 years of therapy). Five patients (6%) who did in more detail in Table 3. Regarding the primary end point of the not experience disease progression refused further therapy after study (PFS 6), the results exceeded our 20% thresholds for success, at least one dose, and two additional patients were noncompliant assuming a 20% improvement as compared with our previously during therapy; these were included in the analysis. Sixty-six reported database1 (GM: expected, 30%; observed, 32%; AG: patients went off study as a result of progressive disease after one or more courses, and five additional patients died beforedocumented radiographic progression.
Treatment Intensity and Reasons for Removal From Study The average number of 28 day cycles received was 5.7.
Seventy-four patients (84%) received at least one cycle, and 70 Toxicity was recorded for all grades for all eligible patients patients (79%) completed at least two cycles. Nine patients by type, using the NCI common toxicity criteria (version 2.0).
Fig 1. Overall survival by histologic
subtype (Kaplan-Meier curve). GBM, glio-
blastoma multiforme; AO, anaplastic oligo-
dendroglioma; Oth, other.
Information downloaded from www.jco.org and provided by UCLA on April 25, 2006 from 220.127.116.11. Copyright 2003 by the American Society of Clinical Oncology. All rights reserved. TMZ AND CRA FOR RECURRENT MALIGNANT GLIOMA Fig 2. Progression-free survival by his-
tologic subtype (Kaplan-Meier curve). GBM,
glioblastoma multiforme; AO, anaplastic ol-
igodendroglioma; Oth, other.
Table 4 lists all grade 1 to 5 toxicity observed, with each figure alone, with the exception of elevated triglycerides, which was representing the sum of the highest grade of toxicity attained, per considered to be secondary to the cRA.
toxicity, per course for all patients. In the total of 499 treatment courses, we observed 505 grade 1 to 4 AEs; there were no grade5 AEs. There were 35 (7%) grade 3 AEs, and 17 (3%) grade 4 The prognosis of patients with recurrent malignant astrocytoma AEs. The most common grade 3 to 4 AEs were granulocytopenia remains poor. Wong et al1 published an analysis of clinical (1.8%), thrombocytopenia (1.4%), and hypertriglyceridemia outcomes in 375 patients with recurrent malignant glioma (GM, (1.2%). Grade 3 elevation in ALT was observed in 5.7%. No 225; AG, 150) who received chemotherapy in eight consecutive patient went off study because of toxicity, and no deaths were prospective phase II trials. The overall 6-month PFS rate was only attributed to the drug regimen. No observable additive toxicity 31% and 15% for patients with recurrent AA and GBM, respec- was observed with the combination as compared with TMZ tively. Because of these dismal results, there has been heightenedinterest in the investigation of new agents and combinations.
TMZ is an orally bioavailable imidazotetrazine derivative of Table 4. Temozolomide and cis-Retinoic Acid in Recurrent Malignant
dacarbazine. TMZ undergoes chemical degradation to its active Gliomas: Toxicity
metabolite, monomethyl triazenoimidazole carboxamide, at physiologic pH.12-14 Evidence to date suggests that cytotoxicity of monomethyl triazenoimidazole carboxamide is primarily due to methylation at the O6 position of guanine.12-14 TMZ addition- ally acts as an inhibitor of DNA mismatch repair and can induce apoptosis.15 Additive or synergistic effects on growth inhibition have been reported in preclinical models, including cell lines and human glioma xenograft models.16-20 Concentrations of TMZ in the CNS reach approximately 30% of plasma concentrations after systemic administration.21 TMZ has also shown evidence of activity in clinical trials of human malignant gliomas. Yung et al5 reported a CR ϩ PR rate of 35%, a PFS 6 of 46%, and overall survival of 13.6 months in a phase II trial of TMZ in patients with recurrent AA. Another randomized study of 116 recurrent malignant glioma patients compared single-agent TMZ with procarbazine.4 In that study, PFS 6 of 21% was observed with TMZ, versus 8% with procarbazine (P ϭ .008). Noncumulative myelosuppression, in the form of thrombocytopenia and neutro- penia, was the dose-limiting toxicity in clinical studies.4,9 Information downloaded from www.jco.org and provided by UCLA on April 25, 2006 from 18.104.22.168. Copyright 2003 by the American Society of Clinical Oncology. All rights reserved. Subsequently, TMZ was conditionally approved by the United mg/m2/d for 3 weeks, followed by 1 week of rest every 28 days.
States Food and Drug Administration for the indication of A response rate of 23% (PR, 7%; minor response, 16%) was observed, with median time to progression of 16 weeks and Synthetic retinoids induce apoptosis and differentiation while median survival of 58 weeks for GM and 34 weeks for AA.
inhibiting cell proliferation.22 Inhibition of migration and prolif- Clinical trials of combination chemotherapy with retinoids eration has been observed after retinoic acid treatment in primary and alkylating agents have shown activity in recurrent squamous glioma cultures but to a lesser degree in established glioma cell carcinoma of the head and neck, non–small-cell lung lines.23 Inhibition of proliferation and induction of apoptosis in carcinoma, pancreatic cancer, and childhood and acute promy- human glioma cell lines may be concentration dependent and elocytic leukemia.7-10 It was our hypothesis that the combination involve signal transduction transcription factors.24 Trans- of TMZ and cRA would have therapeutic potential in glioma, retinoic acid has been shown to downregulate leukemia inhibi- based on observations of preclinical and clinical activity with tory factor and telomerase activity, resulting in inhibition of each agent, different mechanisms of action, and predominantly tumor growth and producing differentiation effects in medullo- blastoma cells.25 Retinoic acid also inhibits tenascin-C expres- The current study was a modestly sized (N ϭ 88) single-arm sion in C6 glioma cell lines.26 cRA modulates nuclear retinoic prospective trial, with separate stratification for GM and AG.
acid receptor and the alpha and beta retinoid x-receptors in The patient accrual numbers were derived from a hypothesis that glioma cell lines.27 Binding of retinoids to the nuclear retinoic a 20% improvement in PFS 6 would be observed with the acid receptor and retinoid x-receptor produces a downstream combination of TMZ and cRA for both strata, based on data from decrease in hepatocyte growth factor expression, interrupting a the historical database.1 In our study, for all patients, the PFS 6 potential autocrine proliferative loop; hepatocyte growth factor was 43%. PFS 6 was 32% for GM and 50% for all AG combined and the related c-Met receptor is present in high levels in human (46% for the non-AO AG subset and 61% for pure AO subset).
gliomas.28 Antitumor activity of retinoic acid has been observed These results, as compared with the PFS 6 observed in the database in the GL-15 glioblastoma29 and the U343 malignant glioma cell (GM, 15%; AG, 31%), met the criteria for PFS 6 success, exceeding lines.30 Pharmacokinetic studies have shown that adequate concen- the 20% improvement for both the GM and AG strata. At the time trations of cRA can be reached in rodent CNS after systemic of design of the current protocol, the PFS 6 for TMZ alone was not administration, but with a relatively short terminal half-life in rat yet reported; subsequent clinical trials of single-agent TMZ reported brain tissue (0.57 to 1.02 hours).31 These data support a schedule of frequent or continuous oral dosing of cRA in human clinical trials.
An interesting aspect of this study involved the group of A prior phase II trial (Radiation Therapy Oncology Group patients with pure AO. In this group, the PFS 6 was 62%, and OS 91–13) of all-trans-retinoic acid in 30 patients with recurrent was 55 weeks. A prior study of TMZ in treatment of 30 patients malignant glioma disclosed minor activity, with tolerable side with recurrent AO showed a response rate of 30%.35 Although effects; a response rate of 12% was observed, with a median time specific survival end points were not reported, 13 (44%) of the to progression of 3.8 months and a median OS of 5.7 months.32 AO patients were progression-free at 6 months. Although direct A similar single-institution phase II trial of all-trans-retinoic acid comparisons are not possible, the greater survival noted with the in 36 patients with recurrent glioma did not show much evidence TMZ/cRA combination in this trial deserves further study. In of activity, with a 3% minor response rate, and median time to addition, survival of the recurrent AO cohort was much longer progression of only 8 weeks.33 A recent phase II trial of the than the GM and non-AO AG cohorts, raising the question of combination of radiotherapy and cRA plus interferon alfa-2a in whether the AO patients should be stratified separately.
patients with newly diagnosed high-grade glioma did not show Caution is advised with regard to statistical comparisons of an improvement in survival as compared with historical con- these uncontrolled results with the historical database1 or prior trols.34 Yung et al6 conducted a phase II prospective study of 43 TMZ trials.4,5 Nevertheless, the results from the current phase II patients with recurrent malignant glioma treated with cRA as a trial suggest that the combination of TMZ and cRA may be a single agent, administered at a daily oral dose of 60 to 100 more active regimen in recurrent malignant gliomas.
1. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic 5. Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial of factors in recurrent glioma patients enrolled onto phase II clinical trials.
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HAMLINE JOURNAL OF PUBLIC LAW & POLICY [Vol. MEDIATION: ITS ORIGIN & GROWTH IN INDIA I. BACKGROUND Mediation is not something new to India. Centuries before the British arrived, India had utilized a system called the Panchayat system, whereby respected village elders assisted in resolving community disputes. Such traditional mediation continues to be utilized even today in vil