Recommendations for the management of malignant gliomas in the elderly

According to epidemiological estimations, the elderly are going to constitute an increasing proportion of patients with gliomas in the near future. Predominantly glioblastoma histology with invariably fatal outcome, disabling comorbidities and presumed low tolerability of radiochemotherapeutic treatments are the main reasons why elderly patients have been under-represented in the majority of neuro-oncological clinical trials conducted so far. Some small retrospective studies have reported that patients with good performance status receiving surgery plus radiotherapy, and sometimes chemotherapy, may achieve a survival comparable with that of younger patients, however, in the absence of randomized studies, the balance of benefits and adverse effects of aggressive treatments remains controversial. Multidisciplinary evaluation of prognostic factors, such as performance status, cognitive functions, tumor operability and burden of comorbidities, appears to be mandatory in order to choose which patients must not be deprived of an integrated treatment with surgery, full-dose radiotherapy and chemotherapy, and which patients may reasonably be given a shorter radiotherapy plan, or even no treatment at all due to the rapidly fatal course of their disease. Peculiar features of malignant gliomas in the elderly and some practical recommendations of management will be presented and discussed in this review.     

Intravenous BCNU and AZQ in patients with recurrent malignant gliomas

Twenty-four patients with recurrent malignant glioma were treated with intravenous BCNU (80 mg/m²/day × 3 days) alternating with AZQ (8 mg/m²/day × 5 days) every 6–8 weeks. Twenty patients received two or more courses of chemotherapy, ten anaplastic astrocytomas (AA), eight glioblastomas (GBM), and two malignant oligodendrogliomas (Oligo). All had prior surgery and irradiation; one had prior chemotherapy. Median age was 37.5 years. The median Zubrod performance status (PS) was 1. Three patients (15%) achieved response status, and 7 (35%) had stable disease with median times to tumor progression (MTP) of 56 wks and 35 wks. MTP for patients with progression was 11 weeks. No GBM was responsive to chemotherapy and none of the ten patients with stable or responsive disease were older than fifty years. Dose limiting toxicity was consisted of thrombocytopenia and leukopenia. Young patients with recurrent AA and good PS appear more likely to respond to alternating BCNU/AZQ chemotherapy. The overall response rate (response plus stable) of 50% was comparable to that of BCNU alone and the hematologic toxicity was cumulative.     

The basis for current treatment recommendations for malignant gliomas

Although primary brain tumors represent an important cause of cancer related mortality in the United States, advances in the treatment of these tumors has been slow and has generally lagged behind that of most systemic tumors. One of the major reasons for this is the paucity of well conducted, prospective radiation and chemotherapy trials. For the brain tumor trials that have been conducted, small patient numbers, heterogeneous patient populations, and non-uniformity of response criteria, have made the current clinical data base difficult to interpret. Data from several prospective, multi-institutional randomized trials have defined a role for radiation therapy in the treatment of malignant gliomas and on-going trials will help define refinements in technique. Although there does appear to be a place for the use of chemotherapy in the treatment of a subgroup of patients with malignant gliomas, its role for the majority of patients remains unclear. Only through better understanding of the biology of these tumors, more effective therapies, and the implementation of better clinical trial design can we hope to make significant progress in the treatment of malignant gliomas.     

Chemotherapy in the treatment of malignant gliomas

Malignant gliomas are one of the most difficult tumors to treat, with only modest advances being made in the past few decades. Surgery and radiation have had the greatest impact, increasing survival. Chemotherapy modestly increases survival. The use of chemotherapy in the treatment of malignant gliomas is the focus of this paper and the more commonly used agents at diagnosis and relapse are reviewed. Since most patients fail first-, second- and even third-line agents that are commercially available, some of the more relevant new biological compounds will also be discussed. As treatments for brain tumors evolve, it is likely that optimal therapies will come from combination therapies that incorporate target-specific and chemotherapeutic agents.     

恶性脑胶质瘤术后替莫唑胺化疗联合适形放疗的疗效观察

目的：观察替莫唑胺联合适形放疗治疗恶性脑胶质瘤术后病例的临床疗效。方法：30例恶性脑胶质瘤术后的患者，13例行替莫唑胺联合适形放射治疗（治疗组），另17例单纯适形放射治疗（对照组）。结果：治疗组与对照组的中位生存时期为16．5个月和12．7个月；其1、2年生存率分别为76．9％、46．2％和52．9％、17．6％（P〉0．05）。结论：替莫唑胺联合适形放射治疗恶性脑胶质瘤术后有提高生存率的趋势，并发症少。     

Changing boundaries in the treatment of malignant gliomas

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.     

恶性脑胶质瘤术后三维适形放疗联合三苯氧胺治疗的临床观察

目的:观察恶性脑胶质瘤术后三维适形放疗联合三苯氧胺治疗的疗效及不良反应。方法:60例恶性脑胶质瘤术后患者随机分为三维适形放疗联合三苯氧胺（治疗组）和三维适形放疗联合替莫唑胺（对照组）各30例。放疗采用6MV X线三维适形放射治疗,2.0Gy/次,1次/d,5次/周,DT 56~60Gy。治疗组与对照组分别于放疗第一天开始口服三苯氧胺60mg/m2每日3次或替莫唑胺75mg/m2每日1次,至放疗结束。结果:治疗组与对照组1、2、3年生存率分别为63.3%、30.0%、23.0%和70.0%、33.3%、26.7%（χ2=0.01、0.23、0.09, P＞0.05）,无统计学差异。三苯氧胺主要不良反应为血栓栓塞,发生率为6.7%。结论:三维适形放疗联合三苯氧胺术后患者生存率较好,且价格便宜,并未增加不良反应,适合临床推广应用。     

Intra arterial chemotherapy with ACNU and radiotherapy in inoperable malignant gliomas

Summary For the non-operable malignant glioma patients, prognosis remains poor, with a survival of 8 months for the glioblastomas (G), and 15 months for anaplastic astrocytomas (AA). 27 histologic proven malignant gliomas (17 AA and 10 G) were treated between April 1991 and June 1992. Median age was 48 years. The therapeutic protocol consisted of three courses of intra arterial chemotherapy (IAC) with ACNU, at intervals of six weeks, and a localised 60 Gy radiotherapy between the first and the second IAC course. 72 courses of IAC were delivered (2,4 per patient). Response rate was 51,8%. Median survival (MS) was 13 months, with a survival rate of 28% at 24 months. For the AA, MS was 21 months, with a survival rate of 37% at 24 months. For the G, median survival was 10 months. Responders were 65 % for AA, 30% for G. Non responders all died before 24 months had relapsed with a MS of 9 months. 54% of responding patients had a 2 years survival. Toxicity were acceptable with 7% of haematological toxicity and a partial loss of visual acuity in 11% of the cases. No chronic neurological sequellae were noted. We compare theses results with two previous trials, concerning inoperable patients, treated by an association of radiotherapy and systemic chemotherapy. Survival seems to be equivalent with HeCNU and with this treatment, but toxicity decreases with ACNU. Early radiotherapy does not increase complications. This treatment can be used for patients with inoperable malignant gliomas.     

高分级脑胶质瘤术后同步放化疗联合辅助化疗的临床研究

目的:探讨高分级脑胶质瘤术后同步放化疗联合辅助化疗的临床效果。方法:选取高分级脑胶质瘤手术患者138例,随机分为两组,使其具有可比性。对照组67例,给予单纯放射治疗。观察组71例,在对照组基础上给予同步化疗和辅助化疗。对两组患者治疗效果进行统计。随访三年,记录三年期间生存率。结果:观察组患者完全缓解、部分缓解、稳定、进展和有效率分别为47.89%、40.85%、8.45%、2.82%和88.73%,对照组分别为28.36%、32.84%、13.43%、25.37%和61.19%,观察组患者完全缓解率和有效率均明显高于对照组,两组比较差异有统计学意义（P<0.05）。观察组患者术后一年、两年、三年生存率分别为91.55%、69.01%和50.70%,对照组分别为50.75%、16.42%和10.45%,观察组明显高于对照组,两组比较差异有统计学意义（P<0.05）。观察组患者发生恶心呕吐、中性粒细胞下降以及血小板减少者分别占63.38%、49.30%和52.11%,对照组分别为62.69%、46.27%和52.24%,两组比较差异无统计学意义。结论:高分级脑胶质瘤患者在术后进行同步放化疗联合辅助化疗可以有效提高患者的治疗效果,改善患者预后,不会增加不良反应,因此是一种安全而有效的治疗方案。     

Postoperative hypofractionated radiotherapy versus conventionally fractionated radiotherapy in malignant gliomas. A preliminary report on a randomized trial

A prospective randomized study of 108 patients with cerebral malignant gliomas was carried out at the Department of Radiation Oncology of Maria Sklodowska-Curie Memorial Center in Kraków. 44 patients with histologically proven glioblastoma multiforme and 64 patients with anaplastic astrocytoma received postoperative radiotherapy. Patients were randomized to two treatment arms: Conventionally Fractionated Radiotherapy (CFR) and Hypofractionated Radiotherapy (HF). In the CFR group, the whole brain was irradiated to the total dose of 50 Gy in 25 fractions over 5 weeks, then a 10 Gy boost in 5 fractions in 5 days was delivered to the site of the primary lesion. In the HF group, there were 3 courses of irradiation separated by a one month interval. In each of the two first series the patients received 20 Gy in 5 fractions in 5 days to the whole brain, and in the third course, 10 Gy boost in 5 days was delivered as in the CFR regimen. The tolerance to treatment has been found to be good in both groups. The 2-year actuarial survival rate for patients with anaplastic astrocytoma was 22% for CFR and 18% for HF. Patients with glioblastoma multiforme treated with HF had a better prognosis in comparison to the CFR group with the two-year actuarial survival rates being 23% and 10%, respectively. This difference is statistically significant at the 0.05 level.     

A prospective study of short course radiotherapy in elderly patients with malignant glioma

Elderly patients with malignant glioma have a poorprognosis and the benefit of standard radical radiotherapyis equivocal. Twenty-two percent of the adult referralbase with malignant glioma at our centre isof age 70 years or greater. A phaseII study was undertaken to determine if ashorter course of therapy yields a comparable mediansurvival to radical radiotherapy and thus constitutes anappropriate investigational palliative regimen.25 patients were accrued between 1988–1995, all ofwhom had histologically proven malignant glioma, 23 glioblastomamultiforme and 2 anaplastic astrocytoma. The median agewas 73 (range 70–78) and median Karnofsky PerformanceStatus (KPS) was 70. 40% had a stereotacticbiopsy only for diagnosis. Radiotherapy was delivered tolimited fields to a dose of 37.5 Gyin 15 daily fractions over 3 weeks. Anintention-to-treat analysis was undertaken with survival determined fromdate of initial consultation. The median survival ofthe whole group was 8.0 months (95% CI4.8–9.6). Patients with good performance status (KPS >70) had a median survival of 10.4 months(95% CI 9.6–14.7).37.5 Gy in 15 daily fractions appears toyield comparable median survival to that of otherseries of radical radiotherapy. A phase III studyof this regimen is recommended in investigating optimalpalliation of elderly malignant glioma patients.     

Combination chemotherapy with carmustine and cisplatin before,during, and after radiotherapy for adult malignant gliomas

Summary Twenty-two patients, aged 16 to 67, who had malignant gliomas after surgical resection were treated with carmustine and cisplatin intravenous infusion before, during, and after radiotherapy. All patients had subtotal or total resection, or biopsy as the initial procedure. Twenty-one patients who had at least 2 cycles of chemotherapy and finished the whole course of radiotherapy were considered to be evaluable for responses. Among them, 5 had glioblastoma multiforme, 16 had anaplastic astrocytoma. The median time to tumor progression was 35 weeks (range 12–130 weeks) and median survival time was 66 weeks (range 10–156 weeks). Early progression occurred more frequently in patients with biopsy only and subtotal resection, and in patients with glioblastoma than in those with anaplastic astrocytoma. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients, and with ototoxicity in 1 patient, nephrotoxicity in 2 patients. Combination of carmustine and cisplatin with cranial irradiation for malignant gliomas is moderately toxic and appears to offer no obvious survival advantage compared with radiation therapy plus BCNU alone.     

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

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

Intra-arterial cisplatin for the treatment of malignant gliomas

Summary Cisplatin (DDP) is a chemotherapeutic agent that has shown efficacy against primary CNS malignancies. Intraarterial (IA) administration of DDP to patients with brain tumors should produce higher peak levels of drug than intravenous (IV) administration of an identical dose and reduce systemic toxicity. Twelve patients with malignant glioma were entered into the study. All had failed irradiation, 11 had failed IA BCNU. Each patient received IA DDP, 58–100 mg/m², into the internal carotid artery at four to six week intervals. One of 12 patients had a partial response of 6 months. The remaining 11 patients had progressive disease [10] or severe complications [1]. Toxicity included seizures in four patients, weakness and/or aphasia in four patients, coma in two patients, and visual deterioration in two patients. IA DDP has very limited efficacy in patients with malignant gliomas after failure of nitrosoureas and is associated with an unacceptable level of toxicity. IA DDP may be more effective when used as initial chemotherapy of malignant gliomas.     

Parenchymal damage in the territory of the anterior choroidal artery following supraophthalmic intracarotid administration of CDDP for treatment of malignant gliomas

We treated ten patients with malignant glioma by intracarotidchemotherapy with cis-diamminedichloroplatinum (CDDP) and/or3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-3-nitrosourea(ACNU). Three of the patients who underwent supraophthalmic intracarotidinfusion of CDDP developed a low-density area in the basal ganglia on CTscan or an enhancing lesion in the hypothalamic region on MRI, with orwithout neurologic symptoms. No patient had such complications withsupraophthalmic infusions of ACNU, or with cervical intracarotid infusion ofCDDP or selective infusion of CDDP via the anterior or middle cerebralarteries. Supraophthalmic intracarotid administration of CDDP may augmentdrug delivery to tumors and prevent visual complications, but is accompaniedby considerable risk of parenchymal damage in the territory of the anteriorchoroidal artery. Possible mechanisms for such complications are discussed.     

Management of malignant gliomas during pregnancy: a case series

BACKGROUND.

Limited data are available on the management of glioma in pregnant women. Therefore, the aim of the current article was to describe the outcome of women with malignant gliomas who were exposed to chemotherapy early in the gestation period of their pregnancies.

METHODS.

The authors presented a case series of 6 women with malignant gliomas who during glioma‐directed treatment were discovered to have an unplanned pregnancy. All patients elected to discontinue chemotherapy and carry their pregnancy to term.

RESULTS.

All women had uneventful pregnancies with no glioma‐related complications. All women delivered healthy newborns without evidence of congenital malformations despite exposure to cytotoxic chemotherapy and anticonvulsant medications.

CONCLUSIONS.

Management of malignant glioma during pregnancy is challenging; however, normal delivery and healthy live birth is possible. Cancer 2008. © 2008 American Cancer Society.     

Radiotherapy and combination chemotherapy with carmustine,vincristine, and procarbazine (BVP) in primary brain tumors

Summary 26 patients with astrocytoma grade 11–111, and 36 with malignant glioma (astrocytoma grade IV or glioblastoma) were submitted three days after surgery to a cycle of combination chemotherapy, including BCNU, VCR, PCZ (BVP). Eighteen days after surgery, patients received 40 Gy (astrocytoma grade 11–111) or 45 Gy (malignant glioma) of megavoltage whole-brain irradiation, with an additional boost to the tumor bed of 20 Gy, delivered in 6 weeks. Vincristine was injected weekly during radiotherapy. At the end of radiotherapy, patients received BVP every 6 weeks for at least 8 cycles or until a recurrence or progressive disease. Performance status of grade 1 or 2 was achieved in 15 (60%) and in 5 (20%), respectively, of patients with astrocytoma grade 11–111 after 6 months, and in 6 ps. (29%) and in 9 ps. (42%) after 12 months of follow-up. Only 2 (5.5%) and 18 (64%) patients with malignant glioma achieved a performance status of grade 1 or 2 after 6 months, and these proportions are 6% and 35%, respectively, after 12 months. After a 5-year follow-up, 59% of patients with astrocytoma are still alive, with a median survival time of 60+ months, whereas only 4% of patients with malignant glioma are alive, with a median of 11.2 months.     

Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA)

Summary Twenty patients with malignant supratentorial gliomas progressing after radiation therapy and chemotherapy with nitrosoureas received intravenous carboplatin, 450 mg/m². Courses of therapy were repeated every four weeks. Therapeutic evaluation was performed monthly using neurologic examination and CT scan of the brain. Of 19 patients evaluable for response, 2 (10%) responded to therapy and 6 (30%) had stable disease. The estimated median time to tumor progression for responding and stable patients was 6 months. Median duration of survival was 6 months for all patients. Of 20 patients evaluable for toxicity, none had renal or auditory toxicity. Side effects consisted of hematologic toxicity in 4 patients (20%): one patient had grade 4 toxicity requiring discontinuation of carboplatin and 3 patients had grade 2–3 toxicity.Abbreviation HECNU 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea     

Phase II evaluation of high-dose intravenous cisplatin for treatment of adult malignant gliomas recurrent after chloroethylnitrosourea failure

Summary Twenty-one patients with recurrent malignant glioma who had failed prior chemotherapy with nitrosoureas were treated with high-dose intravenous cisplatin on days 1 and 8 of successive 4 week cycles. Fourteen patients were evaluable for response. Four patients showed partial responses; mean time to tumor progression (MTP) was 8 weeks. Six patients stabilized; MTP was 11 weeks. Four patients showed no response. There were no infectious or hemorrhagic complications, but partial hearing loss occurred in 7 patients and severe vomiting in 8 patients. High-dose intravenous cisplatin demonstrates substantial activity against malignant gliomas recurrent after chloroethylnitrosourea (CENU) failure.     

Treatment of malignant gliomas with surgery,intraarterial chemotherapy with ACNU and radiation therapy

Summary Forty-five patients with malignant gliomas were treated after aggressive surgical resection with alternating intravenous carmustine and cisplatin both during and after radiation therapy. Thirty-three patients were considered evaluable for responses, 17 had glioblastoma multiforme (GBM),14 had anaplastic astrocytoma (AA) and 2 had anaplastic oligodendroglioma (AO). The median age of the evaluable patients was 47 years. The median time to tumor progression was 34.5 weeks, and the median survival for the entire group was 76 weeks. Early progression occurred more frequently in patients with glioblastoma than in those with AA or AO. Seventeen patients (55%) were alive at 18 months (6 GBM, 9 AA, 2 AO). Toxicity was mainly hematologic, otic and tolerable. The results suggest that further trial is warranted to assess the efficacy of alternating carmustine and cisplatin in conjunction with radiation therapy postoperatively in patients with malignant gliomas.