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Gliadel Wafer（聚苯丙生20与卡莫司汀植入）——第一个治疗脑癌植入药物芯片剂
Gliadel Wafer已被美国FDA批准作为第一脑癌治疗直接递送化疗的肿瘤部位。将产物由FDA用于清除作为辅助手术延长患者的生存复发成胶质细胞瘤多形（GBM）为谁手术切除它被表明。
Gliadel Wafer，一种新的方法，以复发的GBM的治疗，是在该直接传递化疗肿瘤部位最小化的药物暴露在身体的其他部位的手术时植入可生物降解的晶片。Gliadel Wafer补充脑癌其他标准疗法如外科手术，放射和传统静脉内化疗。
临床结果
1996年9月，Gliadel Wafer的基础上，从涉及222例患者接受手术治疗复发性恶性胶质瘤具有里程碑意义的研究数据来自本三期双盲结果清除，安慰剂对照的临床研究表明，Gliadel Wafer六个月存活率增加通过在GBM患者超过50％（从与安慰剂的36％与Gliadel Wafer56％）。
副作用
Gliadel Wafer与在接受手术的恶性脑胶质瘤患者遇到一致的患者中观察到的不良事件的频谱。癫痫的发生率在安慰剂组和Gliadel Wafer组相同，但接受Gliadel患者的早期发作癫痫发作。在III期研究，副作用与安慰剂包括疼痛和愈合的异常较为常见与Gliadel Wafer。其他的副作用较常见比安慰剂组看到，但无统计学显著，分别为脑水肿及局部感染。
GBM是最快速进展和普遍致命所有的癌症之一。有每年诊断在美国大约20,000的原发性脑肿瘤和GBM是最常见的类型。
剂量及用法
每一片Gliadel Wafer含carmustine 7.7 mg，手术植入八片等於投与剂量61.6 mg。一般建议剂量：於脑癌摘除手术后所造成的腔室内植入Gliadel Wafer八片。若空间不够植入八片，则尽可能以最大能植入的片數植入。目前尚无单次手术植入Gliadel Wafer八片以上的臨床经验，因此不建议植入八片以上。 Gliadel Wafer对儿童的安全性及有效性尚未建立。
储存
零下20°C以下。
Gliadel Wafer (polifeprosan 20 with carmustine implant)
DESCRIPTION
GLIADEL® Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Carmustine is a nitrosourea oncolytic agent. The copolymer, polifeprosan 20, consists of poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine. Carmustine is homogeneously distributed in the copolymer matrix.
The structural formula for polifeprosan 20 is:
The structural formula for carmustine is:
CLINICAL PHARMACOLOGY
GLIADEL® Wafer is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine released from GLIADEL® Wafer diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.
Carmustine has been shown to degrade both spontaneously and metabolically. The production of an alkylating moiety, hypothesized to be chloroethyl carbonium ion, leads to the formation of DNA cross-links.
The tumoricidal activity of GLIADEL® Wafer is dependent on release of carmustine to the tumor cavity in concentrations sufficient for effective cytotoxicity.
More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolized by the liver and expired as CO2 in animals.
The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL® Wafer in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL® Wafer implant were not determined. In rabbits implanted with wafers containing 3.85% carmustine, no detectible levels of carmustine were found in the plasma or cerebrospinal fluid.
Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance, and steady-state volume of distribution were 22 minutes, 56 mL/min/kg, and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200 mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2.
GLIADEL® Wafers are biodegradable in human brain when implanted into the cavity after tumor resection. The rate of biodegradation is variable from patient to patient. During the biodegradation process, a wafer remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred. Data obtained from review of CT scans obtained 49 days after implantation of GLIADEL® Wafer demonstrated that images consistent with wafers were visible to varying degrees in the scans of 11 of 18 patients. Data obtained at re-operation and autopsies have demonstrated wafer remnants up to 232 days after GLIADEL® Wafer implantation.
Wafer remnants removed at re-operation from two patients with recurrent malignant glioma, one at 64 days and the second at 92 days after implantation, were analyzed for content. The following table presents the results of analyses completed on these remnants.
COMPOSITION OF WAFER REMNANTS REMOVED FROM TWO PATIENTS ON RE-OPERATION
| Component |
Patient A |
Patient B |
| Days After GLIADEL® Wafer Implantation |
64 |
92 |
| Anhydride Bonds |
None detected |
None detected |
| Water Content (% of wafer remnant weight) |
95-97% |
74-86% |
| Carmustine Content (% of initial) |
<0.0004% |
0.034% |
| Carboxyphenoxypropane Content (% of initial) |
9% |
14% |
| Sebacic Acid Content (% of initial) |
4% |
3% | The wafer remnants consisted mostly of water and monomeric components with minimal detectable carmustine present.
CLINICAL STUDIES
Primary Surgery
A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with newly-diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection. This trial determined the safety and efficacy of GLIADEL® Wafer implants plus surgery and radiation therapy compared to placebo implants plus surgery and radiation therapy. Two hundred and forty patients with newly-diagnosed malignant glioma were enrolled. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). GLIADEL® Wafers were implanted at the time of the surgery in 120 patients and placebo wafers were implanted in 120 patients. The majority of patients received 6-8 wafers. The majority of patients (93/120, 77.5% in the GLIADEL® Wafer group and 98/120, 81.7% in the placebo group) with newly-diagnosed malignant glioma received a standard course of radiotherapy (55 to 60 Gy) typically starting 3 weeks after surgery. There were 17 patients (14.2%) in the GLIADEL® Wafer group and 12 patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All six patients with anaplastic oligodendroglioma received chemotherapy within 30 days of GLIADEL® Wafer implantation. Patients were followed for at least three years or until death. Only one patient was lost to follow-up. Median survival increased from 11.6 months with placebo to 13.8 months with GLIADEL® Wafer (p-value <0.05, log-rank test). The hazard ratio for GLIADEL® Wafer treatment was 0.73 (95% CI: 0.56-0.95).
Kaplan-Meier Overall Survival Curves for Patients Undergoing Initial Surgery for a High-Grade Malignant Glioma
When only patients with Glioblastoma multiforme were included in the analysis, the hazard ratio with GLIADEL® Wafer treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test).
Surgery for Recurrent Disease
A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with recurrent malignant glioma. This trial determined the safety and efficacy of GLIADEL® Wafer implants plus surgery compared to placebo implants plus surgery.
Ninety-five percent of the patients treated with GLIADEL® Wafer had 7-8 wafers implanted. Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after repeat surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with GLIADEL® Wafer. Median survival increased by 33%, from 24 weeks (5.5 months) with placebo to 32 weeks (7.4 months) with GLIADEL® Wafer treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL® Wafer treatment. Median survival of GBM patients increased by 41% from 20 weeks (4.6 months) with placebo to 28 weeks (6.4 months) with GLIADEL® Wafer treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, GLIADEL® Wafer produced no survival prolongation.
6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM
KAPLAN-MEIER OVERALL SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM
INDICATIONS AND USAGE
GLIADEL® Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. GLIADEL® Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.
CONTRAINDICATIONS
GLIADEL® Wafer contains carmustine. GLIADEL® Wafer should not be given to individuals who have demonstrated a previous hypersensitivity to carmustine or any of the components of GLIADEL® Wafer.
WARNINGS
Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL® Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL® Wafer, including one case leading to brain herniation.
Pregnancy: There are no studies assessing the reproductive toxicity of GLIADEL® Wafer. Carmustine, the active component of GLIADEL® Wafer, can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m2 basis). Carmustine was embryotoxic in rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.
There are no studies of GLIADEL® Wafer in pregnant women. If GLIADEL® Wafer is used during pregnancy, or if the patient becomes pregnant after GLIADEL® Wafer implantation, the patient must be warned of the potential hazard to the fetus.
PRECAUTIONS
General
Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication larger than the diameter of a wafer exists, it should be closed prior to wafer implantation.
Computed tomography and magnetic resonance imaging of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of GLIADEL® Wafers. This enhancement may represent edema and inflammation caused by GLIADEL® Wafer or tumor progression.
Therapeutic Interactions
Interactions of GLIADEL® Wafer with other drugs have not been formally evaluated.
The short-term and long-term toxicity profiles of GLIADEL® Wafer when given in conjunction with chemotherapy have not been fully explored. GLIADEL® Wafer, when given in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with GLIADEL® Wafer. Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL® Wafer. Carmustine was given three times a week for six months, followed by 12 months observation, to Swiss mice at i.p. doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m2 basis) and to SD rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on a mg/m2 basis). There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: Carmustine was mutagenic in vitro (Ames assay, human lymphoblast HGPRT assay) and clastogenic both in vitro (V79 hamster cell micronucleus assay) and in vivo (SCE assay in rodent brain tumors, mouse bone marrow micronucleus assay). Impairment of Fertility: Carmustine caused testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m2 basis) in male rats.
Pregnancy
Pregnancy Category D: see WARNINGS.
Nursing Mothers
It is not known if either carmustine, carboxyphenoxypropane, or sebacic acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from carmustine in nursing infants, it is recommended that patients receiving GLIADEL® Wafer discontinue nursing.
Pediatric Use
The safety and effectiveness of GLIADEL® Wafer in pediatric patients have not been established.
ADVERSE REACTIONS
Adverse reactions for the trials are described in the tables below.
Primary Surgery
The following data are the most frequently occurring adverse events observed in 5% or more of the newly-diagnosed malignant glioma patients during the trial.
Body System
Adverse Event |
GLIADEL® Wafer
[N=120]
n (%) |
Placebo
[N=120]
n (%) |
|
| Body as a Whole |
| Aggravation reaction* |
98 (82) |
95 (79) |
| Headache |
33 (28) |
44 (37) |
| Asthenia |
26 (22) |
18 (15) |
| Infection |
22 (18) |
24 (20) |
| Fever |
21 (18) |
21 (18) |
| Pain |
16 (13) |
18 (15) |
| Abdominal pain |
10 (8) |
2 (2) |
| Back pain |
8 (7) |
4 (3) |
| Face edema |
7 (6) |
6 (5) |
| Abscess |
6 (5) |
3 (3) |
| Accidental injury |
6 (5) |
8 (7) |
| Chest pain |
6 (5) |
0 |
| Allergic reaction |
2 (2) |
6 (5) |
| Cardiovascular system |
| Deep thrombophlebitis |
12 (10) |
11 (9) |
| Pulmonary embolus |
10 (8) |
10 (8) |
| Hemorrhage |
8 (7) |
7 (6) |
| Digestive system |
| Nausea |
26 (22) |
20 (17) |
| Vomiting |
25 (21) |
19 (16) |
| Constipation |
23 (19) |
14 (12) |
| Diarrhea |
6 (5) |
5 (4) |
| Liver function tests abnormal |
1 (1) |
6 (5) |
| Endocrine system |
| Diabetes mellitus |
6 (5) |
5 (4) |
| Cushings syndrome |
4 (3) |
6 (5) |
| Metabolic and nutritional disorders |
| Healing abnormal |
19 (16) |
14 (12) |
| Peripheral edema |
11 (9) |
11 (9) |
| Musculoskeletal system |
| Myasthenia |
5 (4) |
6 (5) |
| Nervous system |
| Hemiplegia |
49 (41) |
53 (44) |
| Convulsion |
40 (33) |
45 (38) |
| Confusion |
28 (23) |
25 (21) |
| Brain edema |
27 (23) |
23 (19) |
| Aphasia |
21 (18) |
22 (18) |
| Depression |
19 (16) |
12 (10) |
| Somnolence |
13 (11) |
18 (15) |
| Speech disorder |
13 (11) |
10 (8) |
| Amnesia |
11 (9) |
12 (10) |
| Intracranial hypertension |
11 (9) |
2 (2) |
| Personality disorder |
10 (8) |
9 (8) |
| Anxiety |
8 (7) |
5 (4) |
| Facial paralysis |
8 (7) |
5 (4) |
| Neuropathy |
8 (7) |
12 (10) |
| Ataxia |
7 (6) |
5 (4) |
| Hypesthesia |
7 (6) |
6 (5) |
| Paresthesia |
7 (6) |
10 (8) |
| Thinking abnormal |
7 (6) |
10 (8) |
| Abnormal gait |
6 (5) |
6 (5) |
| Dizziness |
6 (5) |
11 (9) |
| Grand mal convulsion |
6 (5) |
5 (4) |
| Hallucinations |
6 (5) |
4 (3) |
| Insomnia |
6 (5) |
7 (6) |
| Tremor |
6 (5) |
8 (7) |
| Coma |
5 (4) |
6 (5) |
| Incoordination |
3 (3) |
8 (7) |
| Hypokinesia |
2 (2) |
8 (7) |
| Respiratory system |
| Pneumonia |
10 (8) |
9 (8) |
| Dyspnea |
4 (3) |
8 (7) |
| Skin and appendages |
| Rash |
14 (12) |
13 (11) |
| Alopecia |
12 (10) |
14 (12) |
| Special senses |
| Conjunctival edema |
8 (7) |
8 (7) |
| Abnormal vision |
7 (6) |
7 (6) |
| Visual field defect |
6 (5) |
8 (7) |
| Eye disorder |
3 (3) |
6 (5) |
| Diplopia |
1 (1) |
6 (5) |
| Urogenital system |
| Urinary tract infection |
10 (8) |
13 (11) |
| Urinary incontinence |
9 (8) |
9 (8) | Adverse events coded to the COSTART term "aggravation reaction" were usually events involving tumor/disease progression or general deterioration of condition (e.g. condition/health/Karnofsky/neurological/physical deterioration).
Surgery for Recurrent Disease
The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL® Wafer at recurrent surgery. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the GLIADEL® Wafer group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.
COMMON ADVERSE EVENTS OBSERVED IN ≥ 4% OF PATIENTS RECEIVING GLIADEL® WAFER AT SURGERY FOR RECURRENT DISEASE
Body System
Adverse Event |
GLIADEL® Wafer with Carmustine
[N=110]
n (%) |
PLACEBO Wafer without Carmustine
[N=112]
n (%) |
|
| Body as a Whole |
| Fever |
13 (12) |
9 (8) |
| Pain* |
8 (7) |
1 (1) |
| Digestive System |
| Nausea and Vomiting |
9 (8) |
7 (6) |
| Metabolic and Nutritional Disorders |
| Healing Abnormal* |
15 (14) |
6 (5) |
| Nervous System |
| Convulsion |
21 (19) |
21 (19) |
| Hemiplegia |
21 (19) |
22 (20) |
| Headache |
16 (15) |
14 (13) |
| Somnolence |
15 (14) |
12 (11) |
| Confusion |
11 (10) |
9 (8) |
| Aphasia |
10 (9) |
12 (11) |
| Stupor |
7 (6) |
7 (6) |
| Brain Edema |
4 (4) |
1 (1) |
| Intracranial Hypertension |
4 (4) |
7 (6) |
| Meningitis or Abscess |
4 (4) |
1 (1) |
| Skin and Appendages |
| Rash |
6 (5) |
4 (4) |
| Urogenital System |
| Urinary Tract Infection |
23 (21) |
19 (17) | p < 0.05 for comparison of GLIADEL® Wafer versus placebo groups
Post-marketing experience includes spontaneous reports of cyst formation after GLIADEL® wafer implantation. These occurred at varying time intervals post-implantation. Cyst formation has also been reported in patients following resection of malignant glioma who have not had Gliadel® implanted.
The following four categories of adverse events are possibly related to treatment with GLIADEL® Wafer. The frequency with which they occurred in the randomized trials along with descriptive detail is provided below.
1. Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving GLIADEL® Wafer and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of GLIADEL® Wafer-treated patients and 4.2% of placebo treated patients. The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL® Wafer group and 4.2% in the placebo group. The time from surgery to the onset of the first post-operative seizure did not differ between the GLIADEL® Wafer and placebo treated patients.
In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving GLIADEL® Wafer and placebo. In this study, 12/22 (54%) of patients treated with GLIADEL® Wafer and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL® Wafer and 61 days in placebo patients.
2. Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with GLIADEL® Wafer and in 19.2% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL® Wafer or its remnants.
3. Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of GLIADEL® Wafer: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of GLIADEL® Wafer treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of GLIADEL® Wafer recipients and 0.8% of those given placebo. During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak.
In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in GLIADEL® Wafer treated patients and 5% in patients receiving placebo wafers.
4. Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL® Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL® Wafer and 1% in patients receiving placebo.
The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL® Wafer in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL® Wafer caused these events cannot be determined.
Body as a Whole: peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%)
Cardiovascular System: hypertension (3%); hypotension (1%)
Digestive System: diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)
Hemic and Lymphatic System: thrombocytopenia (1%); leukocytosis (1%)
Metabolic and Nutritional Disorders: hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)
Musculoskeletal System: infection (1%)
Nervous System: hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with GLIADEL® Wafer.
Respiratory System: infection (2%); aspiration pneumonia (1%)
Skin and Appendages: rash (2%)
Special Senses: visual field defect (2%); eye pain (1%)
Urogenital System: urinary incontinence (2%)
OVERDOSAGE
There is no clinical experience with use of more than eight GLIADEL® Wafers per surgical procedure.
DOSAGE AND ADMINISTRATION
Each GLIADEL® Wafer contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight wafers are implanted. It is recommended that eight wafers be placed in the resection cavity if the size and shape of it allows. Should the size and shape not accommodate eight wafers, the maximum number of wafers as allowed should be placed. Since there is no clinical experience, no more than eight wafers should be used per surgical procedure.
Handling and Disposal1-7: Wafers should only be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use of double gloves is recommended and the outer gloves should be discarded into a biohazard waste container after use. A surgical instrument dedicated to the handling of the wafers should be used for wafer implantation. If repeat neurosurgical intervention is indicated, any wafer or wafer remnant should be handled as a potentially cytotoxic agent.
GLIADEL® Wafer should be handled with care. The aluminum foil laminate pouches containing GLIADEL® Wafer should be delivered to the operating room and remain unopened until ready to implant the wafers. The outside surface of the outer foil pouch is not sterile.
Instructions for Opening Pouch Containing GLIADEL® Wafer
Figure 1: To remove the sterile inner pouch from the outer pouch, locate the folded corner and slowly pull in an outward motion.
Figure 2: Do NOT pull in a downward motion rolling knuckles over the pouch. This may exert pressure on the wafer and cause it to break.
Figure 3: Remove the inner pouch by grabbing hold of the crimped edge and pulling upward.
Figure 4: To open the inner pouch, gently hold the crimped edge and cut in an arc-like fashion around the wafer.
Figure 5: To remove the GLIADEL® Wafer, gently grasp the wafer with the aid of forceps and place it onto a designated sterile field.
Once the tumor is resected, tumor pathology is confirmed, and hemostasis is obtained, up to eight GLIADEL® Wafers (polifeprosan 20 with carmustine implant) may be placed to cover as much of the resection cavity as possible. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but wafers broken in more than two pieces should be discarded in a biohazard container. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, the resection cavity should be irrigated and the dura closed in a water tight fashion.
Unopened foil pouches may be kept at ambient room temperature for a maximum of six hours at a time.
HOW SUPPLIED
GLIADEL® Wafer is available in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile.
GLIADEL® Wafer must be stored at or below -20°C (-4°F).
GLIADEL(CARMUSTINE)IMPLANT;INTRACRANIAL卡莫司汀植入膜剂-强推为脑癌罕用药
Guilford制药公司日前宣布，其治疗脑癌的专利药：以聚苯丙生20为载体的卡莫司汀植入膜剂（polifeprosan 20 with carmustine implant，Gliadel）为罕用药，在治疗接受一期切除术的恶性胶质瘤患者领域享有的市场独占期。
本品为一种白色至灰白色的一角硬币大小的薄膜，包含生物可降解聚合物聚苯丙生20和7.7mg卡莫司汀（carmustine，BCNU），卡莫司汀是治疗恶性胶质瘤的常用静脉给药的化疗药物。当手术切除脑瘤时，在经手术创建的空腔中可最多植入8片本品。在植入处，本品将缓慢溶解，直接向肿瘤部位释放高浓度卡莫司汀，使扩散到其它部位的药物减至最少。
本品适应证是新诊断为高度恶性胶质瘤的患者的手术和放疗辅助药物，也可作为多形性胶质母细胞瘤（GBM）复发患者的手术辅助用药。
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=783EC80B-95D7-44C7-8B90-FA7394F50F67
GLIADEL® Wafer (polifeprosan 20 with carmustine implant)
Gliadel Wafers
GLIADEL® Wafer (polifeprosan 20 with carmustine implant) is indicated in patients with newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation. It is also indicated in patients with recurrent glioblastoma multiforme as an adjunct to surgery. It should not be given to patients who have demonstrated a previous hypersensitivity to carmustine or any of the components of GLIADEL Wafer. Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL Wafer, including cases leading to brain herniation. Carmustine, the active component of GLIADEL Wafer, can cause fetal harm when administered to a pregnant woman. It is recommended that patients receiving GLIADEL Wafer discontinue nursing.
Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication larger than the diameter of a wafer exists, it should be closed prior to wafer implantation.
CT and MRI of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of GLIADEL Wafer. This enhancement may represent edema and inflammation caused by GLIADEL Wafer or tumor progression.
The short-term and long-term toxicity profiles of GLIADEL Wafer when given in conjunction with chemotherapy have not been fully explored.
The following 4 categories of adverse events are possibly related to treatment with GLIADEL Wafer:
Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving GLIADEL Wafer and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of GLIADEL Wafer–treated patients and 4.2% of placebo-treated patients. The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL Wafer group and 4.2% in the placebo group.
In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving GLIADEL Wafer and placebo. In this study, 12/22 (54%) of patients treated with GLIADEL Wafer and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first 5 post-operative days.
The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL Wafer and 61 days in placebo patients.
Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with GLIADEL Wafer and in 19.2% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrences, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL Wafer or its remnants.
Healing Abnormalities: The following healing abnormalities have been reported in GLIADEL Wafer clinical trials: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of GLIADEL Wafer–treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of GLIADEL Wafer recipients and 0.8% of those given placebo.
During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak. In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in GLIADEL Wafer–treated patients and 5% in patients receiving placebo wafers.
Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in GLIADEL Wafer patients and 1% in patients receiving placebo
GLIADEL® Wafer (polifeprosan 20 with carmustine implant)-全球第一个治疗脑癌植入药物芯片剂的专利药品
美国FDA于1996年批准由Guilford公司开发，以BCNU为活性成分，聚苯丙生20为释放基质，制成植入药物芯片Gliadel，治疗复发性恶性脑瘤的申请，可在手术后，将药物直接放置于复发性恶性胶质细胞瘤之脑组织中，让药物缓慢释放，进行持续性化学治疗。经过多年多中心临床试验，FDA于2003年加大其治疗适应症，批准Gliadel用于原发性恶性脑瘤的治疗，据文献报道，Gliadel可延长原发性及复发性恶性脑瘤患者的中间存活期。
该治疗方法的独特之处在于其给药方式及释放系统。在外科手术过程中，先将肿瘤组织切除，留下一个小空腔，然后植入这种定期释放的芯片。这些芯片会在2~3周之内慢慢地分解、融化，释放出的药物可直接进入肿瘤区，杀死那些在外科手术中没有切除干净的肿瘤细胞，并且能在不损害其它组织的情况下使病变局部能达到有效的血药浓度，延缓了疾病的进展。
美国癌症中心联盟(National Comprehensive Cancer Network, NCCN)针对恶性脑瘤的最新治疗原则中指出，原发及复发恶性脑瘤患者皆可予以手术切除肿瘤时同时置入Gliadel(BCNU)，术后辅以放射线治疗或Temozolomide等化疗药物治疗，据文献报道，采用此治疗模式可有效延长患者的存活中位数。
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