来自澳大利亚的罕见病例，我们的联合会诊服务

患者来自澳大利亚， 是一个非常罕见的脊髓高级别胶质瘤。 面对如此罕见病例， 美国好大夫安排了的联合会诊，把北美最好的肿瘤中心的肿瘤内科， 病理科及北美放射肿瘤学的主编先生也拉来做一个专业的放疗第二诊疗。 不到72小时就给澳大利亚的患者及医生发了会诊报告， 而且连参考文献都加上了。

Summary of Clinical History

Mr. Shaw is a 33 year old male, admitted to the Hospital with history of progressive right lower extremity numbness and weakness, several weeks duration

Pre-operative Imaging studies

July 12, 2016. MRI of thoraco-lumbar spine.

Peripherally enhancing intramedullary cystic neoplasm in conus with extensive surrounding edema or infiltrate and expansion. Differential diagnosis ependymoma, less likely astrocytoma.

Operative Report

July 18, 2016. Lower thoracic lumbar spine laminectomy with resection of intradural intramedullary lesion

Post-operative Imaging Study

July 19, 2016. MRI of thoraco-lumbar spine. To assess residual disease.

Comparison with pre-operative MRI.

Post-surgical changes T11-T12 laminectom. Overall images concerning for residual disease, although it is difficult to quantitate exact volume. Possible leptomeningeal disease.

Pathology Report

Diffuse midline high grade glioma, H3F3A K27M mutant (WHO grade IV)

Assessment of clinical situation

33 year old male with WHO grade IV intradural intramedullary glioma, status post laminectomy and partial tumor resection

Review of Pertinent Published Bibliography

Spinal cord gliomas, consisting mostly of ependymomas and astrocytomas, are rare entities. Of the gliomas, infiltrating astrocytomas are particularly challenging entities to treat due to their invasive nature. Surgical resection is oftentimes not possible without subjecting patients to permanent neurological deficits because of the difficulty in establishing clear tissue planes. As more is learned about the molecular genetics, genomics, and biology of these tumors, it is  apparent that there are important differences between these tumors and their more common intracranial counterparts. There also appears to be important clinical differences between low-grade and high-grade astrocytomas. A multidisciplinary approach is needed to optimize the treatment of these difficult tumors. Astrocytomas are the most frequent intramedullary neoplasms. Major prognostic factors are tumor type, histological grade, location, patient age and neurological deficit. The 5 year survival for grade IV astrocytomas is 15- to 20 %.

Currently there are no randomized trials to guide on the role of radiation therapy or Temozolimide on these patients.

The usual treatment for these rare tumors is surgical resection, as technically feasible, with the least neurological deficit possible and post-operative radiation therapy. In a review of 155 patients reported in the literature until March 2015, 19 (13%) underwent surgery only, 14 (10%) received exclusively radiation therapy and one patient (1%) was treated with no more than chemotherapy; 109 (76%) patients underwent a combination of different treatments (surgery + chemotherapy, n = 4; surgery + radiotherapy, n = 47; chemotherapy + radiotherapy, n = 15; surgery + chemotherapy + radiotherapy, n = 43). Gross tumor resection was performed in 24 % of the patients, to avoid severe neurological deficits induced by the surgical procedure. The median radiation dose was 49.2 Gy. In total 63 patients received chemotherapy, the most frequent chemotherapeutic agent was temozolomide, used in 30/63 cases (48%).

In the 1980s high-grade gliomas of spinal origin were thought to have the same outcome as their intracranial counterparts. However, the prognosis of the latter has significantly improved over the past decades and the question arises whether this statement is still true. In a recent article, the estimated average survival”of patients with spinal glioblastomas was 18 months

In a review of 16 patients diagnosed with spinal cord gliomas (8 primary tumors and 8 with metastasis from cerebral gliomas), median total radiation dose was 4500 cGy and 62.5 % of patients received a simultaneous temozolomide. The median overall survival was 6 months (95% CI: 0-27.5 months). Surgical resection of the tumor was a significant predictor of improved survival, compared with radiotherapy alone (p = 0.001). Patients with the diagnosis of a primary spinal cord glioma survived significantly longer than those presenting with a metastatic deposit from a cerebral glioma (p < 0.001). A statistically significant dose-response relationship at dose levels of ≥ 45 Gy vs. < 45 Gy could be derived (p < 0.001). Simultaneous chemotherapy did not influence survival outcome.

With regard to postoperative treatment, in irradiated patients, the gross tumor volume is determined by MRI and surgical findings, with one vertebral body above and below for clinical target volume and a lateral margin of 1.5 cm. The usual dose recommended is 5040 to 5400 cGy in 28-30 fractions, 180 cGy per fraction.

In patients with leptomeningeal involvement consideration should be given to craniospinal irradiation (doses ranging from 3600 to 4500 cGy), with additional dose to the primary tumor GTV-CTV up to 5400 cGy with reduced volumes. Several techniques have been used, including three-dimensional conformal, intensity modulated, Rapid Arc, with photons or protons alone or combined with photons.

Special attention should be paid to the tolerance of the spinal cord to radiation therapy. L’Hermitte’s syndrome, characterized by shocklike sensations radiating from the neck to arms and legs usually lasts a few weeks, Late radiation myelopathy depends on region, volume irradiated and total dose and fractionation. Historically, with fractionation schedules of 180-200 cGy per fraction total tolerance dose of 5000 cGy is associated with a 0.2 % incidence of myelopathy. Doses in the range of 5001 to 6000 cGy, particularly to the thoracic spine, are correlated with a myelopathy incidence of 5-6 % (please refer to attached QUANTEC paper)

Post-surgical administration of radiation therapy and Temozolimide (an alkylating agent) has been standard therapy for brain glioblastoma (GBM) and recently it has been recommended in patients with higher grade brain gliomas. Hernandez-Duran et al  performed a medical subject search with the terms “glioblastoma” and “primary spinal cord neoplasms, intramedullary”. The temozolimide (TMZ) subgroup contained nine articles and a total of 19 patients with primary spinal GBM who were treated with adjuvant TMZ. The non-TMZ group consisted of 19 articles including 45 patients who underwent other treatment modalities. The TMZ subgroup had an overall survival of 16 months, compared to the non-TMZ group with a median overall survival of 10 months. The difference between these two groups was not statistically significant (p = 0.57), due to the small patient samples. While this review did not demonstrate a statistically significant difference in long term survival between patients with SC GBM treated with TMZ versus those not treated with TMZ, a slightly longer survival time was seen in the TMZ group.

For patients with anaplastic astrocytoma including anaplastic oligoastrocytoma without LOH 1p/19q, an international Intergroup trial (CATNON [Concomitant and Adjuvant TMZ in Nondeleted Anaplastic Astrocytoma]) led by the EORTC, the British Medical Research Council (MRC), the NCIC, the German Neuro- Onkologische Arbeitsgruppe (NOA), and theUSCooperative Groups RTOG, North Central Cancer Treatment Group (NCCTG), and the Eastern Cooperative Oncology Group has recently been activated.

Patients will be randomly assigned to concomitant TMZ/XRT versus XRT alone, with a second random assignment for the administration of adjuvant TMZ or observation. The trial end point is overall survival; enrollment of more than 800 patients is planned.

Radiation Oncology Recommendations

1. The patient will benefit from a course of radiation therapy to the distal thoracic and upper lumbar spine. Dose that is generally recommended is 5040 to 5400 cGy with a small risk foe late myelopathy, that may result in permanent loss of motor or sensory function in the lower extremities and loss of bladder and/ or anal sphincter control.
2. Because of the suggested leptomeningeal involvement on the post-operative MRI it will be highly advisable to ask the Pathologist to review the laminectomy specimen to try to confirm this finding, with significant unfavorable prognostic implications.
3. If leptomeningeal tumor invasion is documented we recommend strong consideration be given to irradiation of the craniospinal axis, to a dose of 3960- 4500 cGy in 180 cGy fractions, with additional dose administered to the GTV-CTV to complete 5040-5400 cGy.
4. Currently there is no standard of care for spinal high grade glioma that is based on evidence of prospective studies.  Considering the patient’s young age and Grade IV glioma, extrapolating from the current treatment standard of cerebral GBM based on Phase III trials which showed overall survival benefit of concurrent chemoradiation with temozolomide over radiotherapy alone, we can consider radiotherapy concurrently with Temozolomide followed by adjuvant temozolomide especially if the tumor has MGMT gene promoter methylation, depending on recommendations of medical oncology.

Medical Oncology and Pathology

Recommendations:

 Diagnosis: Diffuse midline high grade glioma, H3F3A K27M mutant (WHO grade IV)

1. Pathology: Additional molecular testing, such as O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, ATRX status and IDH by sequencing are recommended. Noticed IDH wild-type by IHC only. If possible, test for EGFR mutation which could be useful for clinical trial.
2. Radiation therapy (XRT) (usually 6 weeks) is the mainstay of the treatment after surgical resection of the tumor.
3. Adding concurrent Temodar with XRT is a reasonable choice especially if there is MGMT promoter methylation. Temodar can be given orally at 75mg/m2 daily along with daily XRT.
4. After patient completes 6 weeks of XRT or XRT/Temodar, if he has MGMT promoter methylation, Temodar should be used as the adjuvant setting.
5. After patient completes 6 weeks of XRT or XRT/Temodar, if he has over-expression on epidermal growth factor receptor (EGFR), erlotinib could be tried as the adjuvant setting.
6. Strongly recommend clinical trials involving HDAC inhibitor (histone deacetylase inhibitor) given this patient has the unique H3F3A K27M mutantion.
7. Bevacizumab could be considered to be part of the treatment along with or after XRT in the setting of possible leptomenigeal spreading. Bevacizumab can be given IV a 10mg/kg every 2-3 weeks.