Radiation Effects

From: "Robert A. Fink, M.D."
Subject: Re: Radiation effects
PubMed medline query

Med Pediatr Oncol 1998 Dec;31(6):506-11
Subsequent quality of life for children irradiated for a brain tumor before age four years.
Jenkin D, Danjoux C, Greenberg M
Toronto-Sunnybrook Regional Cancer Centre, Ontario, Canada.
BACKGROUND: We wanted to evaluate survival and functional morbidity following radiation treatment of brain tumors in children less than 4 years old. PROCEDURE: Outcome was evaluated for 222 children who were less than 4 years old when they were irradiated at University of Toronto Centres, 1958-1995. The status of the survivors with regard to focal neurological defects, vision, hearing, and education at last follow-up was recorded. In 23 adult survivors older than 21 years at last follow-up, information was obtained with regard to higher education, occupation, and living arrangements. RESULTS: The overall 10-year survival rate was 40%, not significantly different than the 45% for 776 4-16-year-olds with irradiated brain tumors treated at the same institutions. Forty-five percent of the survivors had no major focal neurological, visual, or hearing defects. There were no major differences in the frequencies of these criteria or of schooling between 0-2- and 2-4-year-olds. Among adult survivors, older than 21 at last follow-up, 26% successfully completed higher education, 31% were in full-time employment, and 37% had never been employed. For medulloblastoma, the 5-year survival rate was 61% for 30 children less than 3 years old and treated from 1975-1995. This compared favorably with recent reports of survival following primary chemotherapy with delayed or omitted radiation treatment. SUMMARY: Radiation treatment of a young child with a brain tumor was associated with cure in 1 of every 3 patients. Unfortunately, quality of life for many survivors was not good. Only one of every 3 adult survivors was able to have a normal life-style. This shortfall was the result of focal neurological defects which were present from the time of first treatment, and of the long-term effects of radiation treatment. CONCLUSIONS: The search for less toxic treatment remains appropriate, but is experimental and researchers must recognize that there may be a trade-off between morbidity and mortality.
Ann Neurol 1998 Sep;44(3):313-6
Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study.
Duffner PK, Krischer JP, Horowitz ME, Cohen ME, Burger PC, Friedman HS, Kun LE
SUNY at Buffalo School of Medicine, NY, USA.
Between 1986 and 1990, the Pediatric Oncology Group conducted a study in which 198 children younger than 3 years of age with malignant brain tumors were treated with prolonged postoperative chemotherapy in an effort to delay irradiation and reduce long-term neurotoxicity. Children younger than 2 years of age received 24 months of chemotherapy followed by irradiation, and those between 2 and 3 years of age received 12 months of chemotherapy plus irradiation. Chemotherapy was given in 28-day cycles (AAB, AAB), with cycle A = vincristine (0.065 mg/kg) intravenously on days 1 and 8 and cyclophosphamide (65 mg/kg) intravenously on day 1, and cycle B = cisplatinum (4 mg/kg) intravenously on day 1 and etoposide (6.5 mg/kg) intravenously on days 3 and 4. Five of the 198 children developed second malignancies, with a cumulative risk at 8 years of 11.3% (95% confidence interval [CI], 0-39%). Four of the five second malignancies occurred in children younger than 2 years of age at diagnosis, with a cumulative risk at 8 years of 18.9% (CI, 0-70%). Initial diagnoses were choroid plexus carcinoma (2 children), ependymoma (1 child), desmoplastic infantile ganglioglioma (2 children), and medulloblastoma (1 child). Duration from diagnosis of initial tumor to second malignancy was 33, 35, 57, 66, and 92 months. Three children younger than 2 years of age developed lymphoproliferative disease, that is, myelodysplastic syndrome (2 children), both with monosomy 7 deletions, and acute myelogenous leukemia (1 child), after 24 to 26 cycles of chemotherapy, including 8 cycles of etoposide. Two of 3 received craniospinal irradiation (2,560/3,840 cGy) and (3,520/5,320 cGy). Time to second malignancy was 7 years 8 months, 4 years 9 months, and 2 years 9 months. Two children developed solid tumors, at 5 years 6 months and 2 years 11 months, respectively, after initiation of treatment. A sarcoma developed after 26 cycles of chemotherapy and no irradiation, and a meningioma developed after 12 cycles of chemotherapy and local craniospinal irradiation. Potential causative factors for this high rate of secondary malignancies include prolonged use of alkylating agents and etoposide with or without irradiation. Publication Types: ___ ___Multicenter study Comments:
J Clin Oncol 1998 Jun;16(6):2195-201
Effects of radiation and chemotherapy on cognitive function in patients with high-grade glioma.
Taylor BV, Buckner JC, Cascino TL, O'Fallon JR, Schaefer PL, Dinapoli RP, Schomberg P
Royal Hobart Hospital, Australia.

PURPOSE: The effect of radiotherapy on the long-term cognitive performance of patients treated for intracranial neoplasm is a major concern to clinicians and patients, particularly as long-term survival or cure is possible for a small minority of patients. To assess the effects of cranial radiotherapy and chemotherapy on the cognitive performance of high-grade glioma patients, we analyzed cognitive performance data collected in a series of prospective clinical trials. METHODS: We studied 701 high-grade brain tumor patients entered onto two consecutive North Central Cancer Treatment Group (NCCTG) randomized treatment trials designed to compare radiotherapy and carmustine (BCNU) versus radiotherapy and 1-(2-chloroethyl)-3(2,6 dioxo-l-piperidyl)- 1-nitrosource a (PCNU) (first trial) and radiotherapy and BCNU and interferon alfa (IFN) versus radiotherapy and BCNU (second trial). Folstein Mini-Mental Status Exam (MMSE) score and Eastern Cooperative Oncology Group (ECOG) performance score (PS) recorded at baseline and 6, 12, 18, and 24 months were analyzed to assess cognitive and physical function over time. Patients who did not demonstrate tumor progression within 60 days of the assessment time were considered nonprogressors at that evaluation. A loss of greater than 3 points on the MMSE was considered significant deterioration. RESULTS: The number of patients who experienced a greater than 3-point decrease in MMSE from baseline was 13 of 119 nonprogressors (10.9%; 95% confidence interval [CI], 6.3% to 18.9%) at 6 months, three of 54 nonprogressors (5.5%; 95% CI, 0.5% to 12.8%) at 12 months, three of 30 nonprogressors (10%; 95% CI, 2.1% to 26.5%) at 18 months, and four of 22 nonprogressors (18.2%; 95% CI, 5.2% to 40.3%) at 24 months. The CIs at all times overlapped, which indicates no statistically significant increase in the percentage of patients who experienced a significant decrease in their MMSE score. Patients who demonstrated a significant decrease in their MMSE score were significantly older than those who did not (P = .0017) at 6 months and remained so throughout follow-up; moreover, they had a significantly shorter time to progression and death. ECOG PS was strongly negatively correlated with MMSE score throughout the study, and MMSE score at all time intervals was correlated with baseline PS. CONCLUSION: In this population of glioma patients who received radiotherapy, there is no clear trend to cognitive worsening. Factors such as older age, poorer PS, and subclinical tumor progression may be more significant factors in those patients who did demonstrate a significant cognitive decline. Publication Types: ___ ___Clinical trial ___Randomized controlled trial
Comment in: J Clin Oncol 1998 Sep;16(9):3210-1
PMID: 9626221, UI: 98289461
Long-term survival in cerebral glioblastoma. Case report and critical review of the literature.
Puzzilli F, Ruggeri A, Mastronardi L, Di Stefano D, Lunardi P
Department of Neurological Sciences, University of Rome La Sapienza, Italy.
Glioblastoma multiforme is the most malignant tumor of the glial series. The average survival of patients with this tumor ranges from 6 to 12 months. The case of a patient who survived for more than 11 years after diagnosis of a temporal-occipital glioblastoma which was treated with surgery, radiotherapy and chemotherapy is described. The authors deduce that among patients with glioblastoma multiforme (GM), those with a long disease-free interval after initial diagnosis who undergo multimodal therapy, including aggressive tumor removal, are the most likely long-term survivors (LS). Other factors which appeared to be related to longer survival were younger age and high Karnofsky scores. Publication Types: ___ ___Review ___Review of reported cases
J Neurooncol 1996 Mar;27(3):259-66
Long-term survivors of glioblastoma multiforme: clinical and molecular characteristics.
Morita M, Rosenblum MK, Bilsky MH, Fraser RA, Rosenfeld MR
Department of Neurological Surgery, University of California, San Francisco, School of Medicine, USA.

Long term survival is rare in patients with glioblastoma multiforme (GBM). To determine if the tumors of patients with long survivals constitute a subgroup of patients with identifiable molecular genetic characteristics, we studied the p53 gene and Epidermal Growth Factor Receptor (EGF-R) expression in long-term survivors of GBM. A review of the Tumor Registry of Memorial Hospital for Cancer and Allied Diseases documented that 521 patients were treated for GBM between 1954 and 1987 and that 12 patients had seven-year or longer survivals. Six additional long-term survivors were identified from other institutions. After pathological re-examination, the diagnosis of 8 of these 18 (44%) tumors was changed to other histologic tumor types. Using immunohistochemical analysis, 4 of 10 confirmed malignant gliomas had over-expression of p53. Polymerase chain reaction/single-strand conformational polymorphism (PCR/SSCP) analysis and sequence analysis of these 4 tumors showed no p53 mutations in exons 5-8, the region where most mutations have been reported in human malignancies. Immunohistochemical analysis for EGF-R was performed on the tumors of the 10 long-term survivors. EGF-R over-expression was identified in 4 (40%), which is consistent with previous reported studies for GBM in general. These findings suggest that there is a subset of GBM defined by the accumulation of wild-type p53 and that the over-expression of EGF-R does not preclude long-term survival. The seven-year survival rate for confirmed GBM in patients from the Memorial Hospital Tumor Registry was at least 1%. PMID: 8847560, UI: 96267453
Neurosurgery 1993 May;32(5):716-20; discussion 720
Long-term survival in patients with glioblastoma multiforme.
Chandler KL, Prados MD, Malec M, Wilson CB
Department of Neurological Surgery, School of Medicine, University of California, San Francisco.

Few patients with glioblastoma multiforme survive more than 5 years. To identify the factors associated with long-term survival, patients with primary supratentorial glioblastoma multiforme diagnosed between 1969 and 1985 were identified from our computer data base. Twenty- two (5%) of the 449 patients identified survived at least 5 years after surgical diagnosis. There were 12 female and 10 male patients, with a mean age of 39.2 years (range, 15 to 63 yr). Twenty patients had a subtotal resection, and 2 had a gross total resection. The median duration of survival was 9.4 years. As of August 1, 1992, 10 patients were alive 5.2 to 13.6 years after diagnosis, and 1 patient was lost to follow-up after 9.4 years. Ten patients died from their tumors; 2 patients with stable tumors died, 1 from a ruptured intracranial aneurysm and 1 from erythromycin-induced hepatitis. Unusual sequelae were noted in irradiated areas in several cases. One patient had a scalp sarcoma and a basal cell carcinoma, and three patients had strokes; each of these events occurred more than 5 years after diagnosis. We conclude that among patients with glioblastoma multiforme, long- term survival is most likely for those who have a long disease-free interval after the initial diagnosis and receive multimodal therapy, including aggressive tumor removal. Other factors associated with long-term survival were younger age and high Karnofsky scores.
Tumori 1997 Mar-Apr;83(2):613-7
Clinical determinants of long-term survival in patients with glioblastoma multiforme.
Pollak L, Gur R, Walach N, Reif R, Tamir L, Schiffer J
Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel.

Repeated reports of more than ten years postoperative survival in patients with glioblastoma multiforme (GM) have appeared in the literature over the last decades. Authors have tried to identify the clinical, therapeutic and histological features determining long-term survival. We present two patients in whom, after radical removal of the tumor followed by conventional radiation, there has been no recurrence for at least ten years. The young age of the patients and the radical surgical approach were in accordance with previous reports of long- term survival. Nevertheless, one tumor originated from the thalamus, a location considered to be of unfavorable prognosis. We therefore further discuss the value of clinical signs as determinants in the prognosis of GM.
Tumori 1997 Mar-Apr;83(2):613-7
Clinical determinants of long-term survival in patients with glioblastoma multiforme.
Pollak L, Gur R, Walach N, Reif R, Tamir L, Schiffer J
Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel.

Repeated reports of more than ten years postoperative survival in patients with glioblastoma multiforme (GM) have appeared in the literature over the last decades. Authors have tried to identify the clinical, therapeutic and histological features determining long-term survival. We present two patients in whom, after radical removal of the tumor followed by conventional radiation, there has been no recurrence for at least ten years. The young age of the patients and the radical surgical approach were in accordance with previous reports of long- term survival. Nevertheless, one tumor originated from the thalamus, a location considered to be of unfavorable prognosis. We therefore further discuss the value of clinical signs as determinants in the prognosis of GM.
J Fla Med Assoc 1993 Mar;80(3):181-4
Long-term survival in malignant glioma. Prognostic factors.

Phuphanich S, Ferrall S, Greenberg H
Department of Neurology, University of South Florida College of Medicine, Tampa.

Mean survival of patients with malignant glioma is six months. Only 7.5% of these patients survive two years. We identified 14 patients, nine with glioblastoma multiforme and five with anaplastic astrocytoma, who survived more than two years. All were treated initially with surgery, radiation and adjuvant chemotherapy. One patient who received three years of nitrosourea has lived longer than 7.3 years. Seven of the 14 patients have no sign of tumor recurrence four years after diagnosis. Nine surviving patients were younger than 45 years of age at the time of diagnosis. Five died of tumor recurrence with the median survival time of 3.5 years. This data suggests that onset at a younger age (less than 45 years), multimodality therapy, high Karnofsky Performance Scale and frontal lobe tumors were the major prognostic factors that contributed to long-term survival.
Ann Neurol 1990 Dec;28(6):818-22
Effects of treatment on long-term survivors with malignant astrocytomas.
Imperato JP, Paleologos NA, Vick NA
Department of Radiology, Northwestern Medical School, Evanston Hospital, IL 60201.

We reviewed the records of 160 consecutive patients with glioblastoma and anaplastic astrocytoma to evaluate the long-term consequences of radiation therapy and chemotherapy. We defined long-term survivors as those patients with glioblastoma or anaplastic astrocytoma who lived at least 100% longer than median survival of historical controls, for example, 2 years for patients with glioblastoma and 4 years for patients with anaplastic astrocytoma. There were 9 (5.6%) long-term survivors. Three (30%) became demented and died without evidence of tumor recurrence. One, after survival of 10 years, died of tumor recurrence. Of the remaining survivors, 2 (22%) have significantly impaired short-term memory function and other neurological deficits such as gait apraxia. Three (30%) can function independently. It is likely but cannot be proved that it is radiotherapy and not chemotherapy that is the causal factor of this dismal therapeutic outcome. Our study suggests restraint in the use of radiotherapy for patients with brain tumors that have more favorable prognoses than glioblastomas and anaplastic astrocytomas, such as low-grade astrocytomas and oligodendrogliomas.
Surg Neurol 1992 Nov;38(5):359-63
Long-term survival after the diagnosis of malignant glioma: a series of 22 patients surviving more than 4 years after diagnosis.
Vertosick FT Jr, Selker RG
Center for Neuro-Oncology, West Penn Hospital, Pittsburgh, Pennsylvania.

Long-term survival after the diagnosis of malignant glioma is uncommon but not rare. To define better the population of patients who have extended survival with this disease, we reviewed the records of 22 of our patients who survived more than 4 years after the biopsy-proven diagnosis of anaplastic astrocytoma, malignant mixed glioma, or glioblastoma multiforme. Surprisingly, 21 of the 22 patients are still alive and being actively followed by the authors. The long-term survivors were typically young and with minimal or no functional impairment at the time of diagnosis. Survivals ranged from 4.2 to 15.8 years. The quality of survival was generally good, with the surviving patients having a mean Karnofsky Performance Score of 76. Three-quarters of the patients had no enhancement or mass effect on their most recent computed tomography scans. A review of the available literature, together with our own series, suggests that death from recurrent disease is unusual in glioma patients who survive more than 4 or 5 years.
Neurosurgery 1994 Feb;34(2):213-9; discussion 219-20
Long-term survival in patients with malignant astrocytoma.
Salcman M, Scholtz H, Kaplan RS, Kulik S
Department of Neurosurgery, George Washington University, Washington, District of Columbia.

From 1978 to 1988, 314 patients with malignant astrocytoma were treated by our neuro-oncology team. Twenty-five patients were excluded from further analysis because of a lack of adequate follow-up, the brain- stem location of the tumor, or an age of less than 18 years. Of the 289 remaining patients in the valid study group, 213 had Grade IV tumors (73.7%) and 76 had Grade III tumors; 167 patients were male (57.8%) and 112 were female, and 89 were less than 40 years of age (30.8%). There were 58 long-term survivors (> 36 mo) in the series (20%). Long-term survivors were much more likely to be less than 40 years of age (x = 41.8; P < 0.005), to have undergone repeated surgery (x = 17.3; P < 0.005), to have received more than 60 Gy of radiation (x = 11.6; P < 0.005), to have Grade III tumors (x = 10.6; P < 0.005), and to have received nitrosoureas (x = 6.09; P < 0.02). Neither sex nor blood type were significantly associated with long-term survival. Patients undergoing repeated surgery were more likely to be less than 40 years of age (x = 5.72; P < 0.02), but neither sex nor histological findings was associated with repeated surgery. For the series as a whole, the observed 5-year survival rate was 6%. We conclude that an aggressive multidisciplinary approach can produce sizable numbers of long-term survivors in malignant astrocytoma patients with favorable prognostic factors.
Cancer 1985 Mar 1;55(5):919-27
The value of radiation therapy in addition to surgery for astrocytomas of the adult cerebrum.
Garcia DM, Fulling KH, Marks JE

A retrospective review of 86 adults (age 15 years or older) treated from 1950 to 1979 for well-differentiated astrocytoma or anaplastic astrocytoma of the cerebrum at Washington University Medical Center- Barnes Hospital was undertaken to determine the influence of postoperative radiation therapy on survival and neurologic function. Analysis was facilitated by a temporal change in treatment approach, with reliance on surgery alone before 1960 and routine use of postoperative irradiation after 1970. Six patients had astrocytomas with a juvenile pilocytic histologic pattern. Outcome was uniformly favorable in these cases regardless of therapy (100% survival; median follow-up, 14 years). Actuarial survival for the 80 patients with diffusely infiltrating astrocytoma was significantly better with the addition of postoperative irradiation than with surgery alone (median survival, 5 versus 2.2 years, respectively; 5-year survival, 50% versus 21%, respectively). Posttreatment neurologic function was also superior in the group managed with surgery and postoperative irradiation. The relationship to survival of age, degree of histologic anaplasia, extent of surgical resection, tumor size, and radiation dose was also investigated.
Neurosurgery 1979 Sep;5(3):301-8
Radiotherapy of intracranial astrocytomas: analysis of 417 cases treated from 1960 through 1969.
Scanlon PW, Taylor WF

In a review of 417 intracranial astrocytomas treated radiotherapeutically at the Mayo Clinic from 1960 through 1969, the well-known correlation of tumor grade with survival was verified. Totally unexpected was the finding that age was fully as important a discriminant as tumor grade. Another unexpected finding was that patients treated with biopsy only followed by radiation therapy did as well as or slightly better than those subjected to resection followed by postoperative radiotherapy. We could not verify the importance to survival of either large dose or large volume radiotherapy, which has been emphasized by some. Patients receiving less than 1400 rets did just as well as or slightly better than those receiving more than 1400 rets. With low grade astrocytomas, survival beyond 4 years was significantly worse (higher death rates) in the group receiving more than 1400 rets. This suggested the possibility of radiation damage with delayed manifestations. We also could not verify an increased effectiveness for the generally accepted use of total brain irradiation for high grade gliomas.
Cancer 1975 Jun;35(6):1551-7
The role of radiation therapy in the treatment of astrocytomas.
Leibel SA, Sheline GE, Wara WM, Boldrey EB, Nielsen SL

One hundred forty-seven patients with astrocytoma were treated between 1942 and 1967.There were 25 postoperative deaths. The 14 patients in whom the tumor was thought tohave been completely removed were not irradiated and all survived 5 years or longer. Seventy-one of the 108 patients with imcompletely excised lesions received radiation therapy. The 5-year survival rate for those with imcomplete resection alone was 19%, compared to 46% when irradiation was given. Based on observations up to 20 years, after incomplete removal postoperative irradiation significally prolonged useful life and may have lead to permanent control in some. There was no evidence of radiation damage. Most of these tumors were fibrillary astrocytomas, and the results apply particularly to this histologic type. Only 1 of 11 patients with gemistocytic astrocytoma survivied 5 years. The survival rate for Grade i tumors was appreciably greater than for Grade iilesions; in both grades, it was improved by irradiation.
Bull Cancer Radiother 1995;82(4):388-95
Radiation therapy with or without surgery in the management of low- grade brain astrocytomas. A retrospective study of 120 patients.
Touboul E, Schlienger M, Buffat L, Balosso J, Minne JF, Schwartz LH, Pene F, Masri-Zada T, Lot G, Devaux B
Services de cancerologie-radiotherapie A et B, hopital Tenon, Paris, France.

From 1977 to 1988, 120 consecutive patients with a diagnosis of low- grade astrocytoma were referred to our department for radiotherapy. Fourty-one patients (group 1) underwent surgery and post operative external radiation therapy (2 gross total resections and 39 subtotal resections). Sixty-nine patients underwent exclusive external radiotherapy (group 2). In ten patients, the irradiation was delivered by stereotactic implantation of iridium-192 wires into the tumor with or without external irradiation (group 3). Ten had pilocytic astrocytomas (mean age, 24 years) and twenty had microcystic astrocytomas (mean age, 35.4 years). The 5- and 10-year survival rates were 55.6% and 44.4%, respectively and 55% and 48%. Ninety astrocytomas were classified as "ordinary" astrocytoma (mean age, 36.8 years). The 5- and 10-year overall survival rates were 51% and 20.5%, respectively. The same probabilities at 5 and 10 years were 65% and 37% respectively, for group 1, 38.8% and 12.7% for group 2 and, 78.8 and 22.5% for group 3. In multivariate analysis, two prognostic factors had a significant impact on overall survival: IK score (IK < 90 vs IK > or = 90, p = 0.0001), surgical resection (surgical resection and post operative radiotherapy vs radiation therapy alone, p = 0.012). However, the patients who underwent surgical resection were those in the best condition, having tumors that were easily accessible and less invasive.