Use Of Craniospinal Irradiation Research Articles

The Evolving Landscape of Leptomeningeal Cancer from Solid Tumors: A Systematic Review of Clinical Trials.

Leptomeningeal carcinomatosis (LMC) is a fatal but uncommon complication occurring in 5-15% of patients with stage IV cancer. Current treatment options are ineffective at managing leptomeningeal spread, with a median overall survival (mOS) of 2-6 months. We aimed to conduct a systematic review of the literature to identify past and future therapies for LMC from solid tumors. Forty-three clinical trials (CTs) published between 1982-2022 were identified. Of these, 35 (81.4%) were non-randomized CTs and 8 (18.6%) were randomized CTs. The majority consisted of phase I (16.3%) and phase II CTs (65.1%). Trials enrolled patients with LMC from various primary histology (n = 23, 57.5%), with one CT evaluating LCM from melanoma (2.4%). A total of 21 trials evaluated a single modality treatment. Among CTs, 23.7% closed due to low accrual. Intraventricular (ITV)/intrathecal (IT) drug delivery was the most common route of administration (n = 22, 51.2%) vs. systemic drug delivery (n = 13, 30.3%). Two clinical trials evaluated the use of craniospinal irradiation for LMC with favorable results. LMC continues to carry a dismal prognosis, and over the years, increments in survival have remained stagnant. A paradigm shift towards targeted systemic therapy with continued standardization of efficacy endpoints will help to shed light on promising treatments.

Minimizing Anaesthesia Use in Paediatric Radiation Therapy

Although generally safe, anaesthesia in paediatric radiation therapy (RT) is costly and cumbersome. At our institution, a multi-faceted approach to reduce anaesthesia utilization is in place as standard-of-care treatment. The goal of this study was to evaluate the effectiveness of our approach by measuring general anaesthesia (GA) rates across all age categories and to compare with published GA rates in the literature. Paediatric patients aged ≤18 treated with RT from 2014-2018 were retrospectively reviewed. GA use was defined as need for intravenous propofol or inhaled gaseous anaesthetic for at least one CT simulation or treatment session. The following methods were used to reduce GA utilization: presence of a dedicated paediatric nurse for procedural preparation, comfort objects (stuffed animal and blanket), and audio-visual distraction (television). Comparison of GA rates across age categories was done using the chi-square trend test. Multivariable logistic regression was used to identify clinical or disease factors associated with GA use. There were 377 unique patients who received RT over 6 411 fractions of radiation. 939 sessions of GA were administered. The median age of patients was 9.8 years (range, 0-18). Among all patients, 68 (18%) required some or all RT fractions under GA. GA utilization was 100% in those under age 3, 37.5% in those age 3-6, 1% in those age 7-12, and 1% in those ≥12 years of age (p<0.0001). The GA rate between age 5-13 was 2%. No child between age 6-9 required GA. Age was the sole predictor of GA use, with each year increase in age resulting in 2.9-fold decreased odds of requiring any GA (odds ratio 0.344, 95% confidence interval 0.25-0.47, p<0.0001). Body site, diagnosis, treatment technique (including IMRT, VMAT, 3DCRT or total body irradiation), use of craniospinal irradiation, year of treatment, and method of immobilization were not predictive of GA use. Our institutional rates of GA use are low in the age 3-6 category (37.5% vs. 79-95% in the literature) and age 5-12 category (2% vs. 47% in the literature). Our methods of preparing and treating children with RT successfully minimize GA use and may be considered for adoption by other cancer centres.

RARE-60. ATYPICAL RHABDOID TERATOID TUMOR: A CASE IN PREGNANCY AND ANALYSIS OF ADULT CASES TO DATE

Atypical rhabdoid teratoid tumors (ATRT) classically develop in infancy and are rare in adults. We present the 48th case to date, the third such during pregnancy. The disease tends to follow a biphasic course i.e. if growth is not arrested following the first relapse/ progression, death is almost universal. While typically rapidly fatal, as in our case, long-term remission appears possible. Uni-variable Cox proportional-hazards models of adult cases showed significantly worse survival with: glial differentiation (HR 7.3, p<0.01), leptomeningeal dissemination (HR 4.3, p<0.01) - these were highly correlated (chi-squared <0.01) and pregnancy (HR 3.9, p=0.09). The finding that glial differentiation worsens outcomes is novel. Improved survival was seen with extent of resection (ordinal scale; p<0.01 for model) and use of craniospinal irradiation (CSI; HR 0.2, p=0.07). Systemic chemotherapy was of marginal significance (HR=0.5, p=0.13). Use of intrathecal chemotherapy was too rare to draw any conclusions. 22/46 cases originated in midline structures next to CSF, thus leading to a high rate of leptomeningeal dissemination. All 10 cases in the pituitary were in females. 3/6 cases in those aged >50 began in/beside the spinal cord. We hypothesise that the cicumventricular organs, particularly the pituitaty and pineal glands are the most common origin of these tumors. There appears to be a pool of cells dividing in the above organs, rapidly in infancy and slowly throughout much of adulthood. Review of immunohistochemistry shows ectodermal elements, with epidermal-to-mesnchymal transition; thus ATRT may be a misnomer. Loss of INI1 is neither necessary not sufficient to account for ATRT. We suggest that the development of ATRT requires an epigenetic change. Treatment options in adults differ from infants in that CSI is a viable adjunct to chemotherapy. Myelotoxicity is a concern with multimodality treatment. We suggest that facilities for peripheral blood stem-cell transplant be available.

Outcome of Patients With Pilocytic Astrocytoma and Leptomeningeal Dissemination

To determine the patient, tumor, and treatment characteristics of patients with pilocytic astrocytoma (PA) and leptomeningeal dissemination (LMD). A PubMed search of English-language studies pertaining to PA with LMD was performed using a combination of keywords that included juvenile pilocytic astrocytoma, low-grade astrocytoma, low-grade glioma, leptomeningeal dissemination, neuraxis spread, and radiotherapy. We found 26 studies with 58 patients between 1976 and 2005 that met these criteria. The median survival for PA patients with LMD was 65 months. The 1-, 2-, and 5-year overall survival (OS) rate after the diagnosis of LMD was 81.1%, 75.7%, and 55.5%. The 1-, 2-, and 5-year progression-free survival (PFS) rate after the diagnosis of LMD was 69.3%, 66.5%, and 34.6%, respectively. Age, gender, primary site location, timing of LMD presentation (synchronous vs. metachronous), and LMD location did not significantly influence OS or PFS. No statistically significant difference was found in OS or PFS between the chemotherapy and radiotherapy groups. Likewise, no difference was found in OS or PFS according to the use of craniospinal irradiation vs. less extensive RT fields. Approximately one-half of PA patients were alive 5 years after the diagnosis of LMD. Both chemotherapy and radiotherapy have efficacy against LMD. Although the use of craniospinal irradiation did not have an effect on PFS, the patient numbers were small and a larger number treated with craniospinal irradiation is needed to determine its efficacy.

Prognostic role of p53 accumulation in patients with metastatic medulloblastoma (M +)

Introduction: Metastatic disease (M+) at diagnosis is the most important negative prognostic clinical marker in medulloblastoma (MB) patients and despite the use of craniospinal irradiation and chemotherapy is one of the leading causes of treatment failure. Few parameters have been evaluated to obtain a prognostic profile for these high-risk patients.

Whole Neuraxis Irradiation to Address Central Nervous System Relapse in High-Risk Neuroblastoma

As systemic control of high-risk neuroblastoma (NB) has improved, relapse in the central nervous system (CNS) is an increasingly recognized entity that carries a grim prognosis. This study describes the use of craniospinal irradiation (CSI) for CNS relapse and compares outcomes to patients who received focal radiotherapy (RT). A retrospective query identified 29 children with NB treated at Memorial Sloan-Kettering Cancer Center since 1987 who received RT for CNS relapse. At CNS relapse, 16 patients received CSI (median dose, 2160cGy), and 13 received focal RT. Of those who underwent CSI, 14 (88%) received intra-Ommaya (IO) radioimmunotherapy (RIT); one patient in the non-CSI cohort received IO-RIT. Patient characteristics were similar between the groups. Time to CNS relapse was 20 and 17 months for the CSI and non-CSI cohorts, respectively. At a median follow-up of 28 months, 12 patients (75%) in the CSI group are alive without CNS disease, including two patients with isolated skeletal relapse. Another patient is alive without disease after a brain relapse was retreated with RT. Three patients died-one with no NB at autopsy, one of CNS disease, and one of systemic disease. The two patients who died of NB did not receive IO-RIT. All 13 patients in the non-CSI cohort died at a median of 8.8 months. Low-dose CSI together with IO-RIT provides durable CNS remissions and improved survival compared with focal RT and conventional therapies. Further evaluation of long-term NB survivors after CSI is warranted to determine the treatment consequences for this cohort.

The Impact of Radiotherapy Fields in the Treatment of Patients With Choroid Plexus Carcinoma

To perform a comprehensive literature review and analysis of cases dealing with choroid plexus carcinoma (CPC) to determine the optimal radiotherapy (RT) treatment field. A PubMed search of English language articles from 1979 to 2008 was performed, yielding 33 articles with 56 patients who had available data regarding RT treatment field. The median age at diagnosis was 2.7 years (range, 1 month-53 years). Of 54 patients with data regarding type of surgery, 21 (38.9%) had complete resection. Chemotherapy was delivered to 27 (48%) as part of initial therapy. The RT treatment volume was the craniospinal axis in 38 (68%), whole brain in 9 (16%), and tumor/tumor bed in 9 (16%). Median follow-up for surviving patients was 40 months. The 5-year overall survival and progression-free survival (PFS) rates were 59.5% and 37.2%, respectively. Complete resection (p = 0.035) and use of craniospinal irradiation (CSI; p = 0.025) were found to positively affect PFS. The 5-year PFS for patients who had CSI vs. whole brain and tumor/tumor bed RT were 44.2% and 15.3%. For the 19 patients who relapsed, 9 (47%) had a recurrence in the RT field, 6 (32%) had a recurrence outside the RT field, and 4 (21%) had a recurrence inside and outside the irradiated field. Patients with CPC who received CSI had better PFS compared with those receiving less than CSI. This study supports the use of CSI in the multimodality management of patients with CPC.

Pediatric Central Nervous System Germ Cell Tumors: A Review

Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.

Whole neuraxis irradiation to address central nervous system (CNS) relapse in high-risk neuroblastoma (NB)

10050 Background: CNS relapse in high-risk NB is on the rise as extracranial disease control improves. Management of CNS relapse with radiotherapy (RT) that does not address the entire neuraxis has been ineffective in preventing further progression and ultimate death. The purpose of the present study is to describe the use of craniospinal irradiation (CSI) for CNS relapse in high-risk NB and compare outcomes to a historical cohort of patients who did not receive CSI. Methods: A retrospective query identified 24 children with high- risk NB treated at MSKCC since 1987 who received RT for CNS relapse. All patients received appropriate initial therapies and were in remission at the time of CNS recurrence. 14 patients received CSI, and 10 received focal RT that did not address the entire neuraxis. CSI was delivered to a median dose of 2160 cGy, and 10 patients received a boost to a median dose of 2520 cGy. Of those who underwent CSI, 13 (93%) received intrathecal (IT) immunotherapy with 131I-8H9 or 131I-3F8. None of the patients in the non-CSI cohort received IT immunotherapy. Results: The demographic and relapse characteristics were similar between the two groups with the exception that patients who underwent CSI represented a more modern cohort. The age at and time to CNS relapse was 5 and 1.5 years, respectively, in both cohorts. At a median follow-up of 18.3 months (range 1.5–53) after CNS relapse, 10 (71%) patients in the CSI group are alive without evidence of disease. In contrast, all 10 patients in the non-CSI cohort died of disease at a median of 8.1 months (range 4.2–12.9). One patient in the CSI cohort died 1.5 years after CNS relapse of progressive leptomeningeal disease; this was also the only patient in that cohort who did not receive IT immunotherapy. One patient in the CSI cohort died 22 months after CNS relapse of unrelated causes. Two patients developed bone recurrence, but remain free of CNS disease. Conclusions: Based on this small cohort of patients, low-dose CSI in conjunction with IT immunotherapy provides durable CNS remissions and improved survival relative to the experience with focal RT and conventional therapies alone. Further evaluation of long-term NB survivors after CSI is warranted to determine the unique long-term treatment consequences for this young patient cohort. No significant financial relationships to disclose.

Author reply

I appreciate the comments provided by Moll et al. regarding my article.1 I agree with their comment that we truly will never know whether screening is beneficial without a prospective trial. However, I disagree with certain points they have made. First, Moll et al. state that screening is beneficial only if the screened disease is treatable, implying that trilateral retinoblastoma is not treatable. I would like to point out that there are at least 6 children reported in the literature who have survived ≥ 2 years after the diagnosis of trilateral retinoblastoma; in fact, 1 patient was alive 8 years after the diagnosis of the pineoblastoma.1, 2 Whereas in the past pineoblastomas and other supratentorial primitive neuroectodermal tumors (PNETs) had a dismal prognosis, current treatment strategies involving surgical resection of the primary tumor, chemotherapy, and craniospinal radiotherapy have yielded 3-year overall and progression free survivals of 73% and 61% respectively, for pineoblastoma and 57% and 45%, respectively, for other supratentorial PNETs.3 Because of these new data and major advances in treatment, the prognosis of patients who develop a PNET after bilateral or hereditary retinoblastoma should improve within the next decade. The pessimism shared by Moll et al. dates back to the time when PNET largely was incurable. Second, Moll et al. stated that for screening to be effective, the rate of incidence of the screened disease should be high. It should be noted that screening for an intracranial tumor should not be performed for all patients with retinoblastoma but only for the subset with hereditary or bilateral retinoblastoma. In this population of children, approximately 6–10% will develop an intracranial PNET.4 Third, Moll et al. state that obtaining magnetic resonance imaging (MRI) scans will detect “irrelevant abnormalities that may lead to inadvertent ‘treatment’.” This statement opens another Pandora's box in the management of trilateral retinoblastoma. Is a biopsy of a pineal or suprasellar mass necessary when a patient with hereditary or bilateral retinoblastoma develops intracranial disease? Moll et al. describe a case with clinically benign disease in a patient they have been following with brain MRI. We know that in isolated pineal tumors biopsy is recommended because of the variety of neoplasms that can occur in this region, including 10–15% that are benign.5 The histology of the tumor dictates the type of treatment and does not necessarily translate into the use of craniospinal irradiation. Fourth, Moll et al. state that craniospinal irradiation results in extensive neuropsychologic sequelae. When examining the neuropsychologic sequela of craniospinal irradiation, three factors appear to be most important: the age of the patient, dose of radiation, and volume of tissue irradiated. The young age of patients with retinoblastoma obviously is an important factor in the development of cognitive problems. Recent advances in treatment have lowered the craniospinal dose in PNET of the posterior fossa and have resulted in an improvement in neuropsychologic outcome.6 The use of conformal radiotherapy techniques also will limit the high dose region in patients treated in the current era.7, 8 Finally, as with the majority of tumors, the size of the lesion usually correlates with outcome. Screening of patients with bilateral or hereditary retinoblastoma will detect smaller tumors. In a meta-analysis by Kivelä, patients with intracranial tumors < 15 mm had the best prognosis.9 In analyzing all the available data, I believe that the gloomy picture for children with trilateral retinoblastoma painted by Moll et al. is not justified in a climate of modern technology and advances in the treatment of intracranial PNET. Arnold C. Paulino M.D.*, * Division of Radiation Oncology, The University of Iowa, Hospitals and Clinics, Iowa City, Iowa

Is craniospinal irradiation required to cure children with malignant (anaplastic) intracranial ependymomas?

Between 1970 and 1989, 17 children with histologically malignant intracranial ependymomas received treatment at the University of Pennsylvania (Philadelphia, PA). Eleven were treated with prophylactic cranial or craniospinal irradiation plus a local boost (CS-XRT), five with local (L-XRT) irradiation only, and one was treated without (NRT) irradiation. With a median survival of 2 years and a median follow-up time for long-term survivors of 6.0 years, five of 11 patients who received CS-XRT are alive compared with none treated with L-XRT and none treated with NRT. Two-year actuarial survival rates are 40% (L-XRT) and 52% (CS-XRT). When examined for other factors, age and local radiation dose remain the most significant prognostic indicators of survival. The 2-year actuarial survival for children younger than 4 years at diagnosis is 20% compared with 83% for their older counterparts. Likewise, the 2-year survival for patients treated with local radiation doses over 4500 cGy was 55% compared with 0% for patients treated with lesser doses. To date there are a total of 28 recurrences. All have occurred with local components except for six (unknown) who died before the exact site(s) could be determined. There is no significant difference in the failure rates outside the original tumor bed in the three groups. These data suggest that local relapse remains the most significant component of failure. Because intrinsic and extrinsic factors such as age and radiation dose seem to be interrelated and at least as important as the use of craniospinal irradiation, the need for prophylactic treatment for children with anaplastic ependymoma could neither be substantiated nor refuted. The use of local radiation alone, however, should be restricted to carefully designed clinical trials in which meticulous pretreatment evaluation is performed, and vigilant posttreatment evaluation of the spine and brain is mandatory.

Is craniospinal irradiation required to cure children with malignant (anaplastic) intracranial ependymomas?

Between 1970 and 1989, 17 children with histologically malignant intracranial ependymomas received treatment at the University of Pennsylvania (Philadelphia, PA). Eleven were treated with prophylactic cranial or craniospinal irradiation plus a local boost (CS-XRT), five with local (L-XRT) irradiation only, and one was treated without (NRT) irradiation. With a median survival of 2 years and a median follow-up time for long-term survivors of 6.0 years, five of 11 patients who received CS-XRT are alive compared with none treated with L-XRT and none treated with NRT. Two-year actuarial survival rates are 40% (L-XRT) and 52% (CS-XRT). When examined for other factors, age and local radiation dose remain the most significant prognostic indicators of survival. The 2-year actuarial survival for children younger than 4 years at diagnosis is 20% compared with 83% for their older counterparts. Likewise, the 2-year survival for patients treated with local radiation doses over 4500 cGy was 55% compared with 0% for patients treated with lesser doses. To date there are a total of 28 recurrences. All have occurred with local components except for six (unknown) who died before the exact site(s) could be determined. There is no significant difference in the failure rates outside the original tumor bed in the three groups. These data suggest that local relapse remains the most significant component of failure. Because intrinsic and extrinsic factors such as age and radiation dose seem to be interrelated and at least as important as the use of craniospinal irradiation, the need for prophylactic treatment for children with anaplastic ependymoma could neither be substantiated nor refuted. The use of local radiation alone, however, should be restricted to carefully designed clinical trials in which meticulous pretreatment evaluation is performed, and vigilant posttreatment evaluation of the spine and brain is mandatory.

Primary malignant lymphoma of the central nervous system. Results of treatment of 11 cases and review of the literature.

Eleven patients with primary malignant lymphoma of the central nervous system (CNS) were treated at the Medical College of Wisconsin Affiliated Hospitals between 1964 and 1984. Three patients had a prior history of immunosuppressive therapy following renal transplantation. All patients had biopsy-proven disease and 10 of the 11 were treated with external radiation therapy. The doses to the primary tumor ranged from 34 to 59.4 Gray (Gy). Actuarial (life-table) survival rate was 82% at 1 year and 43% at 3 years. No recurrence was seen after 13 months. Eighty-six reports totaling 693 cases of primary malignant lymphoma of the CNS were found in the literature. Of these, 308 cases were treated with a combination of surgery and irradiation. Overall survival at 5 years for those patients who received more than 50 Gy compared with less than 50 Gy to the primary tumor was 42.3% versus 12.8% (p less than 0.05). Twenty-one patients survived longer than 5 years. Late relapse was notable, with 10 (47.6%) of 21 tumors recurring between 5 and 12.5 years after diagnosis. Based on this review, a minimum of 50 Gy radiation to the primary tumor is recommended. While no statement regarding the efficacy of craniospinal irradiation or chemotherapy can be made in view of the small numbers, the use of craniospinal irradiation and/or systemic chemotherapy should be considered for future trials.