Role of radiation therapy in primary central nervous system lymphoma

Journal of Neuro-Oncology - We analyzed patterns of care and outcomes for patients with primary central nervous system lymphoma (PCNSL) in this multi-institutional retrospective study. Between...     

Primary central nervous system lymphoma in AIDS. Results of radiation therapy

Primary central nervous system (CNS) lymphoma is one of the clinical presentations of the acquired immune deficiency syndrome (AIDS). Ten patients had biopsy-proven high-grade lymphomas that were confirmed by further staging as limited to the CNS. All ten patients received cranial irradiation (total dose, 2200 to 5000 cGy). Six patients demonstrated complete response (CR) of the intracranial masses at the time of repeat computed tomography (CT) scan, whereas one attained a partial response (PR). Two of the CR patients died of multiple opportunistic infections, two experienced relapse of lymphoma, and died at 7 and 16 months from diagnosis, and two were alive without evidence of disease at 8 and 14 months from diagnosis. The median survival of the whole group was 5.5 months (range, 2 to 16 months). Patients with AIDS-related primary CNS lymphoma may respond to radiation treatment; however, response duration is usually short, and survival is influenced by refractory disease or systemic opportunistic infections.     

The relative effectiveness of radiation therapy, corticosteroids, and surgery in the management of melanoma metastatic to the central nervous system

The records of all patients who received radiotherapy for melanoma metastatic to brain (63 patients) and epidural space (9 patients) at the American Oncologic Hospital from January, 1971, through March, 1980, were reviewed. Patients were evaluated according to the type of therapy received (corticosteroids, radiotherapy, surgery) and whether their brain metastases were radiographically solitary (60%) or multiple (40%). Forty-nine patients with brain metastases received corticosteroid therapy for 2 to 7 days or more before radiotherapy. Seventy-three percent of these patients had documented responses to corticosteroids. This was substantially higher than the 42% overall response rate that could be attributed to radiotherapy. Fifty-two percent of the patients with solitary and 30% of those with multiple brain metastases responded to radiotherapy. The use of large doses (≥500 rad) per fraction produced a significantly higher response rate than did the use of low doses (≤400 rad) per fraction (P < .02), but only for those patients with solitary brain metastases. Fraction size had no effect on the duration of response or survival. Patients with irradiated solitary brain metastases had a longer duration of response and survival than did those with irradiated multiple brain metastases, but not significantly so. Patients undergoing surgical excision of a solitary brain metastasis and radiotherapy had significantly longer median durations of response (405 days versus 57 days; P = .0047) and survival (448 days versus 96 days; P = .0013) than did patients with solitary brain metastases who did not receive surgery. Re-irradiation was of benefit in relieving recurrent neurologic symptoms, but responses were short and survival was not prolonged. Patients with cord compression undergoing decompressive laminectomy had relief of neurologic symptoms, whereas those not paralyzed who received radiotherapy alone did not respond. Surgical excision with postoperative irradiation is recommended for the management of solitary brain metastases from melanoma. Surgical decompression is recommended for the management of epidural cord compression.     

Neurosurgical management of metastases in the central nervous system

Metastases in the central nervous system (CNS) are identified in up to 30% of patients at autopsy. Rates of CNS involvement in metastatic cancer are believed to be increasing, possibly owing to better control of systemic disease with novel chemotherapies or improved metastasis detection. The neurosurgical treatment of patients with metastatic cancer is an integral component of multimodality therapy for brain and spinal metastases. Survival benefit has been demonstrated for the addition of open surgery as well as the use of stereotactic radiosurgery (SRS) to whole-brain radiation therapy for treatment of patients with isolated cranial and spinal metastases compared with whole-brain radiation therapy alone. New clinical trials that directly compare open surgical procedures with SRS are underway, as are trials examining the role of neurosurgical procedures, such as vertebroplasty and kyphoplasty, in association with radiotherapy as methods for pain control in cancer patients with metastatic lesions in the spinal column. In this article, I review data from current randomized clinical trials that examine the role of neurosurgical intervention in the treatment of patients with CNS metastases.     

原发性中枢神经系统淋巴瘤治疗进展

原发性中枢神经系统淋巴瘤(PCNSL)的发病率近年来上升明显,如何提高其治疗效果备受关注.随着放疗策略和化疗策略的改变以及新化疗药物的应用,PCNSL的治疗取得了新的进展.     

Conventional fractionated radiation therapy vs. radiosurgery for selected benign intracranial lesions (arteriovenous malformations,pituitary adenomas,and acoustic neuromas)

Despite growing interest in radiosurgery, the precise role of radiosurgery relative to that of conventional fractionated external-beam radiation therapy is not fully clear. A critical review of the available data suggests that radiosurgery is both a safe and effective treatment for small arteriovenous malformations, pituitary adenomas and acoustic neuromas. For arteriovenous malformations, the effectiveness of radiosurgery is clearly reduced as the size of the malformation increases. Conventional external-beam radiation therapy is also an effective treatment for pituitary adenomas and acoustic neuromas, while the results for arteriovenous malformations are less encouraging. However, most arteriovenous malformations that have been treated with fractionated radiation therapy were large and received relatively low doses of radiation. Onc can speculate that high doses (50 Gy) of fractionated radiation therapy may be effective in the treatment of small arteriovenous malformations. Differences in the apparent effectiveness of radiosurgery and conventional fractionated radiation therapy are partly due to patient selection. A single fraction of approximately 20 Gy (a dose frequently used during radiosurgery) is probably biologically equivalent to approximately 50 to 110 Gy of fractionated radiation therapy (at 2 Gy/fraction based on the linear quadratic model). In this regard, radiosurgery may be just a means of dose escalation. It remains to be shown that the possible benefit of radiosurgery could not be achieved by simply escalating the doses of fractionated radiation. Further clinical experience is needed to better define the role of radiosurgery. Randomized trials comparing conventional fractionated radiation vs. radiosurgery at approximately equal complication levels may be possible.     

Unyielding progress: recent advances in the treatment of central nervous system neoplasms with radiosurgery and radiation therapy

In the past decade, our understanding of the roles of external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) in the management of brain tumors has dramatically improved. To highlight the changes and contemporary treatment approaches, we review the indications and outcomes of ionizing radiation for benign intracranial tumors and brain metastases. For nonfunctioning pituitary adenomas, SRS is able to achieve radiographic tumor control in at least 90 % of cases. The rate of SRS-induced endocrine remission for functioning pituitary adenomas depends on the tumor subtype, but it is generally lower than the rate of radiographic tumor control. The most common complications from pituitary adenoma SRS treatment are hypopituitarism and cranial neuropathies. SRS has become the preferred treatment modality for vestibular schwannomas and skull base meningiomas less than 3 cm in size. Large vestibular schwannomas and meningiomas remain best managed with initial surgical resection or EBRT for surgically ineligible patients. For small to moderately sized brain metastases, there has been a shift toward treatment of newly diagnosed patients with SRS alone due to similar local control rates compared with surgical resection. RCTs have shown combined SRS and whole brain radiation therapy (WBRT) for brain metastases to decrease rates of local and distant intracranial recurrence compared to SRS alone. However, the improved intracranial control comes at the expense of poorer neurocognitive outcomes and without prolonging overall survival. Therefore, WBRT is generally reserved for salvage therapy. While EBRT has been frequently supplanted by SRS for the treatment pituitary adenomas and brain metastases, it still proves useful in selected cases of large lesions which are not amenable to surgical debulking or for those with widespread disease, poor performance status, and short life expectancy. In recent years, the scope of SRS has extended beyond the intracranial space to include extradural and intradural spinal tumors.     

Role of radiosurgery in the management of central nervous system metastases

Radiosurgery is being used more routinely to treat patients with inoperable, recurrent, or multiple brain metastases from systemic cancer. Results in >2000 treated patients have been published during the past 8 years. These results indicate that permanent local control can be obtained in >80% of treated lesions with complications in <10% of patients. Success is independent of the histology, ie, melanoma vs adenocarcinoma, of the treated lesion or number of lesions treated. The long-term results of radiosurgery compare favorably with those seen following surgical resection. The cost-effectiveness of radiosurgery compared to surgical resection favors an expanded role for this technology in the treatment of selected patients with brain metastases.     

Radiation therapy for benign central nervous system disease

The most common indication for the use of radiation therapy in the treatment of benign central nervous system disease is for the treatment of benign brain tumors, such as meningioma, pituitary adenoma, acoustic neuroma, arteriovenous malformation, and craniopharyngioma. Other less common benign intracranial tumors treated with radiation include chordoma, pilocytic astrocytoma, pineocytoma, choroid-plexus papilloma, hemangioblastoma, and temporal bone chemodectomas. Benign conditions, such as histiocytosis X, trigeminal neuralgia, and epilepsy, are also amenable to radiation treatment. There have also been reports of radiosurgery being used for the treatment of movement disorders and psychiatric disturbances, such as obsessive-compulsive and anxiety disorders. For benign brain tumors, radiation therapy as either primary or adjuvant therapy plays an integral role in improving local control. In the treatment of trigeminal neuralgia, epilepsy, tremor, and some psychiatric disturbances, radiosurgery may help ameliorate or eliminate some symptoms. Patients with benign central nervous system disease are expected to live a long time. As such, treatment should be highly conformal and based on three-dimensional planning using magnetic resonance imaging, computed tomography, or both. It is critical that damage to normal brain be minimized.     

Comparable outcomes of radiation therapy without high-dose methotrexate for patients with primary central nervous system lymphoma

BACKGROUND: The previous trials of radiotherapy conducted for primary central nervous system lymphoma (PCNSL) have not been successful. Therefore, we have investigated the clinical outcomes and the role of radiation therapy in the treatment of PCNSL. METHODS: Thirty-three consecutive patients with PCNSL treated with cranial radiotherapy (30-40 Gy whole brain plus 10-20 Gy boost) without administration of high-dose methotrexate were retrospectively analyzed. Nine patients received whole spinal irradiation (WSI) as an additional therapy. The median age of patients was 58 years (range: 28-78 years), and 70% showed a poor performance status (PS). RESULTS: The median survival time (MST) was 13 months, and the 5-year overall survival rate was 35%. The initial response and the number of tumors were significant prognostic factors, and WSI tended toward significance in a multivariate analysis. Four of five patients, who received prophylactic WSI, were 4-year survivors without a tumor relapse and none of them had tumor involvement in the vertebral canal. One patient developed radiation-induced brain necrosis, however, WSI did not seem to affect the late complications. CONCLUSIONS: We consider it important to reduce severe acute and late complications in patients qualified for receiving an aggressive therapy, and to explore the possible tolerable and curative treatment methods that can be used in order to improve the prognosis for PCNSL. Further modifications, including the application of WSI seem to be necessary in the management of PCNSL.     

Busulfan therapy of central nervous system xenografts in athymic mice

We evaluated the antitumor activity of busulfan against a panel of tumor cell lines and xenografts in athymic nude mice derived from childhood high-grade glioma, adult high-grade glioma, ependymoma, and medulloblastoma. Busulfan displayed similar activity against a panel of four medulloblastoma cell lines (D283 Med, Daoy, D341 Med, and D425 Med) and four corresponding sublines with laboratory-generated or clinically acquired resistance to 4-hydroperoxycyclophosphamide [D283 Med (4-HCR), Daoy (4-HCR), D341 Med (4-HCR), and D458 Med] and cross-resistance to melphalan. This is consistent with a nearly total lack of cross-resistance of busulfan to 4-hydroperoxycyclophosphamide. Busulfan was active in the therapy of all but one of the subcutaneous xenografts tested, with growth delays ranging from 14.3 days in D612 EP to 58.4 days in D528 EP. Busulfan produced statistically significant increases in the median survival of mice bearing intracranial D456 MG (66%–90%), D612 EP (18%–33%), and D528 EP (89%) xenografts. These studies suggest that busulfan may be active against medulloblastomas, highgrade gliomas, and ependymomas as well as against cyclophosphamide-resistant neoplasms.This work was supported by National Institutes of Health grants NS 20023, NS 30245, CA 11898, and CA 56115 and American Cancer Society grant DHP-67E     

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24 . © 2017 American Cancer Society.     

Development of blood vessel-related radiation damage in the fimbria of the central nervous system

The identification problem of the dose-limiting tissue component was investigated in the CNS of rats. Moderate single doses of radiation, ranging from 20 to 25 Gy were applied to the brain of adult female rats. The sequence of events was analyzed by scoring a series of morphological changes in one of the white matter structures that appears to represent a sensitive location, that is the fimbria hippocampi. The previously defined "Tissue Injury Unit", characterized by a dilation of the blood vessel lumen, a thickening of the blood vessel wall, an enlargement of endothelial cell nuclei, and a hypertrophy of the adjacent astrocytes which represents a combined score of four different, but related histological changes, proved to be slightly more sensitive and responsive than the earliest recognizable changes in the neurological structures, that is demyelination. In addition, the incidence of demyelination could be expressed as a function of the intensity of the "Tissue Injury Unit". These findings can be interpreted as an additional indication that blood vessel changes and the hypertrophy of the perivascular astrocytes precede degenerative changes in the white matter of the CNS after moderate doses of X rays.     

Conventional radiation therapy of cervical cancer

This review of the present literature about the conventional management of patients with definitive radiotherapy for invasive carcinoma of the cervix will focus on advances in the use of external-beam radiation therapy (EBRT) as well as in the administration of low-dose-rate brachytherapy for the delivery of radiotherapy. Important concepts discussed include: techniques and dose fractionation for EBRT; newer imaging modalities for administration of EBRT; construction of the midline shield for external irradiation of the pelvic nodes following brachytherapy; the role of elective para-aortic nodal external radiotherapy; and the adequate number of brachytherapy applications needed to impact on patient outcome. Considerable attention will be given to multi-institutional clinical data (e.g., the Patterns of Care Study and the Radiation Therapy Oncology Group) to illustrate advances in radiotherapy of patients with cervical carcinoma.     

Stereotactic proton beam therapy for intracranial arteriovenous malformations

PURPOSE: To investigate hypofractionated stereotactic proton therapy of predominantly large intracranial arteriovenous malformations (AVMs) by analyzing retrospectively the results from a cohort of patients. METHODS AND MATERIALS: Since 1993, a total of 85 patients with vascular lesions have been treated. Of those, 64 patients fulfilled the criteria of having an arteriovenous malformation and sufficient follow-up. The AVMs were grouped by volume: <14 cc (26 patients) and > or =14 cc (38 patients). Treatment was delivered with a fixed horizontal 200 MeV proton beam under stereotactic conditions, using a stereophotogrammetric positioning system. The majority of patients were hypofractionated (2 or 3 fractions), and the proton doses are presented as single-fraction equivalent cobalt Gray equivalent doses (SFEcGyE). The overall mean minimum target volume dose was 17.37 SFEcGyE, ranging from 10.38-22.05 SFEcGyE. RESULTS: Analysis by volume group showed obliteration in 67% for volumes <14 cc and 43% for volumes > or =14 cc. Grade IV acute complications were observed in 3% of patients. Transient delayed effects were seen in 15 patients (23%), becoming permanent in 3 patients. One patient also developed a cyst 8 years after therapy. CONCLUSIONS: Stereotactic proton beam therapy applied in a hypofractionated schedule allows for the safe treatment of large AVMs, with acceptable results. It is an alternative to other treatment strategies for large AVMs. AVMs are likely not static entities, but probably undergo vascular remodeling. Factors influencing angiogenesis could play a new role in a form of adjuvant therapy to improve on the radiosurgical results.     

Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s

PURPOSE: Results of radiation therapy for primary central nervous system lymphoma (PCNSL) were poor in the 1970-1980s, with most reported 5-year survival rates being less than 10%. To investigate whether the prognosis of PCNSL patients treated by radiation alone remains still poor, we investigated the results of radiation monotherapy in the 1990s. METHODS AND MATERIALS: We collected data on 132 patients with histologically proven PCNSL treated by radiation alone in the 1990s from three nationwide or regional multiinstitutional studies conducted by the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) Lymphoma Study Group or the Chubu Radiation Oncology Group. Follow-up data were updated as far as possible. Eleven patients who did not complete planned radiotherapy were included. The data were analyzed in relation to patient and tumor characteristics. The median patient age was 63 years, and the World Health Organization performance status (PS) was 3 or 4 in 40% of the patients. Multiple tumors were seen in 34%. Whole-brain irradiation with or without focal boost was used in 92%. The median radiation dose to the tumor site was 50 Gy (range, 8-74 Gy). RESULTS: For all 132 patients, the median survival time was 18 months and the 5-year survival rate was 18.0%. For 62 patients with PS 0-3 and aged 16-65 years (i.e., those eligible for the European Organization for Research and Treatment of Cancer 20962 study), the median survival was 26 months and 5-year survival was 24%. The 5-year survival was 25% for patients 63 years old or younger, and 9.8% for those older than 63 years (p = 0.0005). The 5-year survival was 22% for patients with PS 0-2 and 13% for those with PS 3 or 4 (p = 0.0040). Multivariate analysis confirmed the negative influence of higher age on patient prognosis. CONCLUSIONS: The results of radiation monotherapy for PCNSL appear to have improved as compared with those reported previously. The results of new treatment should be evaluated in light of this finding. Since most prospective studies on the combined treatment exclude poor PS and high-age patients, the 5-year survival rate of 30% may not be regarded as a marked improvement over radiation alone.     

An analysis of radiation necrosis of the central nervous system treated with bevacizumab

Radiation necrosis is a devastating complication following radiation to the central nervous system. The purpose of this study was to perform a comprehensive analysis of cases in the literature using bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as treatment for radiation necrosis. A MEDLINE/PubMed search of articles about the use of bevacizumab for radionecrosis treatment yielded 16 studies published between 2007 and 2012. Data was summarized according to patient characteristics, treatment received and outcomes measured. A total of 71 unique cases were identified that met the inclusion criteria. The median age at the time of treatment with bevacizumab was 47 years. The most common tumors treated were glioblastoma (31 %), anaplastic glioma (14 %), and metastatic brain tumors (15 %). The median time from ending radiotherapy to starting treatment with bevacizumab was 11 months and the median follow up time after bevacizumab treatment was 8 months. The median number of cycles of bevacizumab was administered was 4, and the median dosage of bevacizumab was 7.5 mg/kg. The median time elapsed between cycles of bevacizumab was 2 weeks. Overall, pre and post treatment imaging revealed a median decrease in T1 contrast enhancement of 63 %, and a 59 % median decrease in T2/FLAIR signal abnormality. Treatment with bevacizumab resulted in a significant radiographic response for patients with radionecrosis. The median dosage of bevacizumab of 7.5 mg/kg for four cycles every 2 weeks should be considered as a treatment option in this patient population.