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神经肿瘤学会第5届年会热点 （2000-11）

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摘要：神经肿瘤学会第5届年会热点2000年11月9-12日美国伊利诺州芝加哥ConferenceReportKeyReportsfromtheSocietyforNeuro-Oncology......

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神经肿瘤学会第5届年会热点

2000年11月9-12日

美国伊利诺州芝加哥

Conference Report
Key Reports from the Society for Neuro-Oncology Fifth Annual Meeting
November 9-12, 2000
Chicago, Illinois

Michael J. Glantz, MD

Introduction

Although cures for most central nervous system (CNS) malignancies remain elusive, remarkable technologic advances in molecular biology and drug development, coupled with modest successes in therapy, charged this year's Society for Neuro-Oncology annual meeting with excitement.

Driving much of this excitement were initial results of 2 new basic science techniques: cDNA microchip arrays and combinatorial chemistry. Clinically, the first reports on 2 phase 3 trials, one using gene therapy and the other using local chemotherapy, captured the most attention. Equally important studies describing novel strategies for the use of temozolomide, the long-term consequences of brain tumor therapy, the predictors of outcome in patients with brain tumors, and the therapeutic choices made by patients with brain tumors were also presented.

New Technologies for Neuro-oncology

cDNA Microchip Arrays

The cDNA microchip array is a powerful technique that permits rapid screening of a tumor for thousands of potentially important molecular markers using only microgram quantities of tumor RNA. As reviewed by Dr. Fuller,[1] from MD Anderson Cancer Center in Houston, Texas, briefly, genetic probes (oligonucleotides replicating unique sequences identifying specific genes) are affixed in precise, known, sequence-specific arrays onto "chips" smaller than a standard glass microscope slide. Messenger RNA from a specimen of interest is then isolated, converted to complementary DNA (cDNA), fluorescently tagged, and applied to the chip, where cDNA from the specimen binds to corresponding oligonucleotides on the chip.[1-3] Patterns of gene expression ("gene expression profiles") are deciphered using an automated scanner and sophisticated statistical techniques.

Commercially available chips permit screening for the 6800 human genes whose product and function are currently known. Specialized chips contain more specific arrays, for example, genes known to be expressed in gliomas or lymphomas, or genes known to be implicated in tumor invasion and metastasis.

By facilitating rapid screening of specimens for vast numbers of genes, this technique promises to allow researchers to identify novel cancer genes; explain on a molecular basis the variability in clinical behavior between histologically identical tumors[4,5]; distinguish the genotypes of metastasizing vs nonmetastasizing tumors[6]; distinguish normal vs premalignant vs malignant cells[7,8]; compare the genetic profiles of tumors before and after radiation or before and after chemotherapy[6,9]; and compare the profiles of tumors that are sensitive vs resistant to a given chemotherapy drug. This knowledge should ultimately allow clinicians to predict the behavior of a given tumor and the type of treatment to which it might best respond. For example, by compiling gene expression profiles of patients with newly diagnosed gliomas, Fuller's group at MD Anderson has shown that molecular classification segregates tumors into categories that are more prognostically reliable than conventional histologic classification.[1,10] The full potential of this new technique remains to be exploited.

 

Molecular Fingerprinting

In an exciting illustration of a situation where the molecular dissection of a primary brain tumor already has important clinical implications, Dr. Cairncross, of London Regional Cancer Center, London, Ontario, and Dr. Louis, of Massachusetts General Hospital, Boston,[11] presented new data that specifically identify clinically relevant genotypes of anaplastic oligodendrogliomas. In a cohort of 75 patients with this diagnosis, the authors evaluated each tumor for allelic loss of chromosome arms 1p, 10q, and 19q and, in the same tumors, screened for alterations in the p53, PTEN, CDKN2A, and EGFR genes.

They found that patients whose tumors had combined, isolated losses of 1p and 19q uniformly experienced excellent, durable responses to chemotherapy and long survival times. When only 1p loss was present, the tumors continued to be responsive, but those responses were less durable and survival time was shorter. Among tumors without 1p loss, those with p53 mutations frequently responded to chemotherapy but their disease recurred quickly. The absence of 1p loss or a p53 mutation predicted poor chemoresponsiveness and the shortest survival time.

Combinatorial Chemistry

Although the molecular fingerprinting of tumors is essential for better understanding of tumorigenesis, malignant progression, differential response to therapy, and prognosis, equally powerful tools for drug development are required to realize the full benefit of this technique in clinical medicine. Dr. Berens,[12] from the Barrow Neurological Institute in Phoenix, Arizona, discussed such a tool, which now exists in the form of combinatorial chemistry.

The concept is deceptively simple. Attach identical "progenitor" molecules to thousands of latex beads. Split the beads into different tubes in which different chemical reactions are carried out. Then recombine the beads (with the chemically altered molecules) and again randomly redistribute the beads into tubes in which further reactions are carried out.

Five iterations of this type can be performed in less than a day, producing tens of thousands of subtly different compounds, each attached to its own latex bead. Robotic technology can then be used to separate the beads, and the technique of small-volume, high-throughput screening can isolate the different compounds.[12,13] Once isolated, each compound can be screened (using micromolar volumes) for an effect on its putative target, which may, for example, be a receptor, an enzyme, an ion channel, or a gene.

Using this technique in conjunction with microchip array analysis, Berens showed how it is possible to phenotypically screen tumors; dissect the mechanism of action of a particular enzyme, receptor, or gene product; and select a target for therapeutic intervention or a drug for a clinical trial.

New Technologies Key Points

Treatment Innovations

Local ("Wafer Implant") Chemotherapy

Two meticulously conducted trials, a phase 1-2 study and a randomized, controlled, phase 3 study, have demonstrated minimal toxicity and a modest (8-week) survival advantage of perioperative placement of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-impregnated, biodegradable wafers (Gliadel ) in the postsurgical resection cavity of patients with recurrent malignant gliomas.[14-16] A very small phase 3 trial suggested a similar benefit in patients with newly diagnosed malignant gliomas.[17]

Westphal and colleagues,[18] from University Hospital Eppendorf, Hamburg, Germany, presented the results of a just-completed, large, randomized, placebo-controlled phase 3 study of BCNU wafer therapy in 240 patients with newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). All patients in this trial received best possible surgery and conventional external beam cranial irradiation, but the cohort was also randomized to receive either placebo or up to 8 wafers each containing 7.7 mg (3.85%) of carmustine implanted in the operative bed.

In an intent-to-treat analysis including all randomized patients, the median survival time of patients treated with BCNU wafer plus cranial irradiation was 13.9 months compared with 11.6 months for those receiving postoperative radiation alone (P = .03). Survival among patients with GBM only also favored the BCNU wafer cohort, though the difference was nonsignificant. Toxic effects were modest and comparable between treatment arms.

Although the analysis of this just completed study is incomplete, the BCNU wafer appears to confer a survival benefit when given to patients with newly diagnosed malignant gliomas. The benefit is modest and similar in magnitude to that seen in patients with recurrent tumors. As with BCNU given systemically, much of the benefit may occur in patients with AAs rather than GBMs.

Gene Transfer Therapy

Giving a high-tech twist to the concept of local chemotherapy, several groups presented data demonstrating that gene therapy is also feasible. In a phase 1 trial, Lang and colleagues[19] at the MD Anderson Cancer Center, used a replication-incompetent adenovirus vector containing a wild-type p53 gene to inject virus intratumorally via catheter into patients with recurrent gliomas. The catheter was left in place following injection, and 3 days later, the tumor and catheter were resected en bloc.

These investigators found this procedure tolerable and also demonstrated that transfer of the p53 gene to human glioma cells, production of functional p53 protein, and induction of apoptosis all occurred. Disappointingly, however, spread of the injected vector averaged only 5 mm from the site of injection.

In a clinical counterpart to this work, Warnick,[20] of the University of Cincinnati Medical School, Cincinnati, Ohio, described a randomized controlled trial of murine retrovirus-mediated transfer of the herpes simplex virus 1 thymidine kinase gene to patients with newly diagnosed GBM. One hundred twenty-four patients in the investigational arm of the trial received virus injection at the time of surgery, followed 2 weeks later by a 14-day course of intravenous ganciclovir and external beam cranial irradiation. The control arm, also consisting of 124 patients, received postoperative cranial irradiation alone. Unfortunately, time to tumor progression (26 weeks) and overall survival time (51 weeks) were identical in both arms, whereas 2 types of postoperative complication (venous thromboembolism, 6% vs 3%; and postoperative hematoma, 7% vs 1%) were more common in the gene therapy arm.

Chemotherapy

Since its introduction into the neuro-oncologist's armamentarium, temozolomide has been widely embraced as treatment not only for recurrent AA but also for recurrent GBM, oligodendrogliomas, and anaplastic oligodendrogliomas, brain metastases, and a variety of other less common CNS malignancies. During the last year, an explosion of information regarding the spectrum of tumors for which temozolomide may be efficacious and details of its clinical pharmacology and optimum dosing schedule has taken place (Table).

An abundance of information on temozolomide was presented at this meeting.[21-29] To summarize:

Treatment Innovations Key Points

Quality of Life and Patient Preferences

Late Effects of Therapy

In the face of exciting clinical and laboratory advances and definitive cures of some malignant primary brain tumors, particularly in children, Dr. Packer, of the Children's National Medical Center, Washington, DC,[30] presented sobering preliminary results from the Childhood Cancer Survival Study as it applies to children with primary brain tumors.

In this study, investigators identified 20,345 children with the diagnosis of cancer before the age of 21 years who had survived at least 5 years from the time of diagnosis, along with 3465 sibling controls. Of these 20,345 children and their families (69%), including 1202 children with gliomas and 280 with medulloblastomas, agreed to participate by completing a detailed survey regarding diagnosis, treatment, and long-term quality of life.

In a disappointing perspective on the success of therapy, 177 children (10% of the total sample) had epilepsy; 522 had either seizures, blackouts, or confusional episodes; 666 had headaches (37.6% of whom had gliomas, 40.8% medulloblastomas); and 878 had impaired balance (48% with gliomas, 59% with medulloblastomas). Vertigo, visual loss, tinnitus (11.7%); hearing loss (9.3% [but 15% of patients with medulloblastoma]); and weakness or paralysis (20% to 30%) were also common. Most concerning of all, the educational achievement of these children was severely curtailed: 22.5% of children completed the 8th grade or less, 16% left school between the 9th and 12th grades, and only 22% graduated from high school. Only 23.8% attended technical school following high school, and a mere 15.6% graduated from college.

Although many smaller studies have suggested that long-term quality of life in childhood brain tumor survivors is frequently compromised, this is the largest and most systematic study of its kind. The results demonstrate the urgent need for equally effective but less toxic therapies and also emphasize the critical importance of careful, ongoing, multidisciplinary follow-up of patients with brain tumors from neurologic, endocrinologic, social, and neuropsychological perspectives

Outcome Predictors

As with survivors of congenital heart disease in an earlier decade, the significant problems seen in brain tumor survivors must temper our enthusiasm for current treatment options. In fact, in a small study presented at the same session, Farace and colleagues,[31] of the University of Virginia Health Sciences Center, Charlottesville, found that patient cognitive impairment (particularly verbal and executive function) was more predictive of patient and caregiver quality of life than more traditional measures such as motor deficits or level of physical functioning.

Interestingly, in an unrelated study, Groves and associates,[32] from MD Anderson Cancer Center, reported that treatment-related cognitive decline may be predictable from the pretreatment magnetic resonance image and patient's age. The authors hypothesized that the corpus callosum area is a marker for "cognitive reserve," that minimum corpus callosum thickness is a surrogate for corpus callosum area, and that the smaller the cognitive reserve, the more likely patients with brain tumors are to experience cognitive decline.

In this small series of patients with anaplastic gliomas enrolled in 1 of 2 chemoradiotherapy protocols, corpus callosum minimum height (in 0.1-cm increments) did predict posttherapy cognitive decline (relative risk, 2.7; 95% confidence interval, 1.22-8.55; P = .04). Age at diagnosis (in 10-year intervals) was also predictive (relative risk, 2.3) but with very wide confidence intervals. If these predictors are confirmed in larger trials, it may be possible to modify treatment or intervene before the onset of cognitive deficits.

Alternative Therapies

Two reports on the results of another large, multi-institutional, prospective study shed important light on the consequences of our failure to adequately address quality-of-life issues in adult patients with malignant gliomas. Hariharan and colleagues[33] from the Glioma Outcomes Project examined the frequency of alternative therapy use in patients with malignant gliomas. Overall, the authors found that 29.8% of patients used some form of alternative therapy within 3 weeks of surgery (first or second) for their brain tumor (19.5% used 1 type, 6.3% used 2 types, 4% used 3 or more types). Previous studies have shown that alternative therapy use among patients with cancer is most common in those with CNS cancer.[34]

The most common form of alternative therapy used by patients in the Glioma Outcomes Study was high-dose vitamins (8.5% of all patients, 22.4% of those using some form of alternative therapy), followed by meditation (9.9% and 17.2%) and herbs (7.8% and 18.3%). Younger age and higher Karnofsky Performance Score (KPS) were significantly correlated with alternative therapy use. Trends toward increased use as the disease progressed and in better-educated, higher-income patients were also seen. These results are strikingly similar to those of a smaller Canadian study,[35] which also identified young age, frequent clinic visits, and receiving conventional therapy, but not KPS, income, or education, as predictors of alternative therapy use. Neither major side effects nor tumor responses were seen in patients using alternative therapies.

Although alternative therapy use is often thought of as "antiscientific," Chang and associates[36] reported that only 21% of 711 patients enrolled in the Glioma Outcomes Project participated in a clinical trial. Although this number is substantially higher than the 10% cited in an earlier survey,[37] members of the Glioma Outcomes Project were selected because of demonstrated commitment to enrolling patients in clinic trials. White race, level of education, KPS, and type of insurance, but not tumor histology, age, sex, satisfaction with care, use of alternative therapy, or care provided in a teaching hospital, were significantly associated with clinical trials participation.

Taken together, the data presented by Hariharan and colleagues[33] and by Chang and colleagues[36] suggest that patients with brain tumors remain unconvinced of the importance or benefit of participation in clinical trials and that these patients feel substantial unmet needs that are addressed, at least in part, by the use of alternative therapies. Interestingly, many of the same patient characteristics predict both participation in clinical trials and utilization of alternative therapies. Further study in more diverse patient populations is required if the goal of greater participation in clinical trials is ever to be realized.

Quality of Life Key Points

Table. Enlarging the Spectrum of Therapy With Temozolomide

Disease Study Regimen Patients Efficacy Toxic Effects Study Newly diagnosed GBM Phase 2 TMX, 75 mg/m2/d for 6 weeks with RT, then 200 mg/m2/d for 5 days every 28 days for 6 cycles 64 Median survival, 11 months (95% CI, 4-18 months) Mild and predictable except for grade III/IV lymphopenia in nearly all patients Stupp et al[21] Newly diagnosed AA and GBM Phase 2 TMZ, 200 mg/m2/d for 5 days every 28 days for 4 cycles (maximum) GBM 33, AA 18 Median survival (GBM/AA), 13.2/23.5 months; response rate (CR+PR): 48/38% Modest myelosuppression; 47% completed all 4 cycles Gilbert et al[22] Recurrent AA, GBM, AO Phase 2 TMZ, 150-200 mg/m2/d for 5 days every 28 days, plus CRA, 100 mg/m2/d for 1-21 days every 28 days GBM 42, AA 32, AO 15 Median survival, 46 weeks (range, 36-69 weeks); PFS, 19 weeks (range, 16-27 weeks); 1 CR, 10 PR (12% combined response rate) Modest myelosuppression and hypertriglyceridemia Jaeckle et al[23] Recurrent GBM Phase 2 BCNU, 150 mg/m2, plus TMX , 55 mg/m2 every 6 weeks 39 eligible, 36 evaluable Median survival, 34 weeks (range, 28-49 weeks); PFS, 11 weeks (range, 7-15 weeks); 4 PR (11%) Moderate myelosuppression (27 grade 4, 38 grade 3 episodes) Prados et al[24] Recurrent AA, GBM, AO Phase 2 TMX 200 mg/m2, then 90 mg/m2 every 12 hours for 9 doses every 28 days 11 GBM, 1 AA, 4 AO 2 CR (GBM), 2 PR (1 GBM, 1 AA) Mild myelosuppression (<10% of cycles) Balmaceda et al[25] Recurrent AO and MAG Phase 2 TMX 150-200 mg/m2/d for 5 days every 28 days 39 AO, 9 MAG Median survival, 10.9 months; PFS, 7.5 months; CR+PR 49% (AO), 22% (MAG) Modest myelosuppression Chinot et al[26] Recurrent O, mixed oligoastrocytoma Phase 2 TMX 150-200 mg/m2/d for 5 days every 28 days 22 O, 8 mixed 3 CR, 5 PR (27%) Modest toxicity Van den Bent et al[27] Newly diagnosed A or O Phase 2 TMX 200 mg/m2/d for 5 days every 28 days 18 A, 12 O Mean reduction in tumor size at 6 months, 26% (range, 10%-48%) Minimal toxicity Brada et al[28] Brain metastases Randomized phase 2 TMX 75 mg/m2/d for 28 days with RT, then 200 mg/m2/d for 5 days every 28 days for 6 cycles 15 TMX plus RT, 13 RT alone CR/PR, 7/3 vs 2/5 No grade 3 toxicity Antonadou et al[29]

GBM, glioblastoma multiforme; TMX, temozolomide; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; MAG, anaplastic mixed glioma; O, oligodendroglioma; A, astrocytoma; RT, radiation therapy; CRA, 13-cis retinoic acid; BCNU, carmustine; CI, confidence interval; CR, complete remission; PR, partial remission; PFS, progression-free survival.

References

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Hariharan S, Landolfi J, More J, et al. Alternative therapy use by malignant glioma patients: data from the glioma outcomes (GO) project. Program and abstracts of the Society for Neuro-Oncology Fifth Annual Meeting; November 9-12, 2000; Chicago, Illinois. Abstract 92.

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