Pediatric brain stem tumors: what have we learned? Regarding Prados et al., IJROBP 32:85-91; 1995.
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Brain Neoplasms↗
Biomedical subjects
C R Freeman
Publications and source records attributed to C R Freeman.
Stereotactic external beam irradiation in previously untreated brain tumors in children and adolescents.
Stereotactically guided external beam irradiation may be a useful form of treatment for small, well-circumscribed, but surgically inaccessible, primary brain tumors that are either benign or of low malignant potential. Between March 1988 and December 1991, 10 children and adolescents with previously untreated primary brain tumors were treated with stereotactic external beam irradiation (SEBI) using a linac-based dynamic technique. Eleven lesions were treated in the 10 patients. Treatment was given using a collimator diameter of 1.5-4 cm (median 2 cm). Single fractions of 18, 20, and 25 Gy were used for 3 lesions in 2 patients. A fractionated schedule delivering a median dose of 42 Gy in 6 fractions over 2 weeks was used in the remaining 8 patients. Morbidity related to treatment was minimal. Three patients suffered a temporary worsening of preexisting neurological symptoms and/or signs at 2, 5, and 5 months posttreatment, with subsequent recovery in all. With a median follow up post-SEBI of 17.5 months (range 5-47 months), improvement in neurological findings related to the lesion was noted for 5 treated lesions; 6 remained clinically stable. Seven of the 11 treated lesions improved radiologically, and only 2 showed evidence of progressive disease. Stereotactic external beam irradiation represents a potentially valuable therapeutic option for selected primary brain tumors in the pediatric and adolescent age group. Morbidity related to the treatment appears acceptable in frequency and type, and preliminary data with regard to response are encouraging. However, in order to assess the impact of such treatment on long-term tumor control and survival, further experience with a larger cohort of patients followed for a longer period of time will be necessary.
Adolescent↗
Resting parasympathetic status and cardiovascular response to orthostatic and behavioral challenges in type I insulin-dependent diabetes mellitus.
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Journal Article↗
Treatment results of high dose rate brachytherapy in patients with carcinoma of the cervix.
PURPOSE: The combination of external beam irradiation and low-dose-rate brachytherapy is known to be an effective form of treatment in carcinoma of the cervix and any change from this well-established therapeutic combination must be able to equal or improve the treatment results. Since 1984 we have been using high dose rate brachytherapy in conjunction with external beam irradiation for patients with carcinoma of the cervix. This paper reports our long term treatment results in terms of local disease control, survival, and complications. METHODS AND MATERIALS: Between January 1984 and December 1989, 187 previously untreated patients with carcinoma of the cervix underwent combined external beam irradiation and high dose rate brachytherapy. The International Federation of Gynecology and Obstetrics stage distribution of patients was as follows: I B = 15, II A = 35, II B = 68, III A = 9, III B = 54, IV A = 6. External beam irradiation to the whole pelvis was delivered by megavoltage irradiation with once-a-day fractionation, to a median dose of 4600 cGy. High dose rate brachytherapy was delivered by a high-dose-rate remote controlled afterloading unit, containing 20 spherical Cobalt 60 sources with a nominal activity of 19 GBq (0.5 Ci) at the time of installation, giving a typical dose rate to point A of 160 cGy/min, decreasing to about 80 cGy/min at the end of the 5-year study. One to 3 high dose rate brachytherapy treatments delivering 800 to 1000 cGy to point A were given weekly concurrently with the last 2 to 3 weeks of radiation therapy, or following its completion. Maximum rectal and bladder doses were routinely measured for each treatment. RESULTS: Overall 5-year actuarial survivals were as follows: I B = 72%, II A = 65%, II B = 66%, III A = 66%, III B = 45%. Five-year actuarial pelvic control rates were as follows: I B = 66%, II A = 83%, II B = 78%, III A = 88%, III B = 40%. At a median follow-up time of 54 months for patients at risk, 23 patients developed 25 complications attributable to radiotherapy (13 rectal, 3 bladder, 8 small bowel, 1 fistula) at a median time of 18 months following completion of treatment. Thirteen complications (7.6%) were grades 3 or 4. Patients with Stage II disease had a higher incidence of complications than patients with Stages I and III disease (p < 0.05). Rectal complications were significantly higher in patients who received a total rectal dose > 5400 cGy (p = 0.045). CONCLUSION: High-dose-rate brachytherapy treatment results are comparable to those obtained with low dose rate brachytherapy techniques. The use of three high dose rate brachytherapy insertions is a practical, economical, and safe treatment for patients with carcinoma of the cervix.
Adult↗
Weekly cisplatin plus external beam radiotherapy and high dose rate brachytherapy in patients with locally advanced carcinoma of the cervix.
PURPOSE: Prospective, single arm, Phase I/II trial performed to assess the efficacy and toxicity of the concomitant use of weekly cisplatin and pelvic radiotherapy in patients with locally advanced carcinoma of the cervix. METHODS AND MATERIALS: Between December 1988 and April 1991, 50 previously untreated patients with bulky, locally advanced, squamous cell carcinoma entered the study. All patients were evaluated by a gynecologist and a radiation oncologist and were submitted to standard pre-treatment staging procedures. The International Federation of Gynecology and Obstetrics stage distribution was as follows: IIA three patients, IIB seventeen, IIIA two, IIIB 25, and IVA three. Radiotherapy consisted of 46 Gy external beam irradiation plus three high dose rate intracavitary treatments given on a weekly basis to a total dose of 30 Gy to point A. Cisplatin 30 mg/m2 was also given weekly starting on day 1 of radiotherapy. RESULTS: With a median follow-up time of 27 months, complete response was seen in 88% (44/50) of the patients. The actuarial survival rate at 44 months was 65%. Total pelvic failure rate was 26% (13/50). Of the 44 patients who achieved a complete remission, only seven have failed in the pelvis. Distant disease was observed in 24% of the cases. Treatments were well tolerated with no patient requiring an interruption in the radiotherapy. However, the incidence of late gastrointestinal toxicity was high, with 10 patients developing a rectal ulcer (four colostomies for severe bleeding), two patients a small bowel obstruction, and two patients a recto-vaginal fistula. Moreover, gastrointestinal complications appeared sooner than expected, at a median follow-up time of 11 months after completion of treatment. CONCLUSION: The combination of weekly cisplatin and radiotherapy appears to be a very effective regimen for patients with locally advanced carcinoma of the cervix, but resulted in a relatively high frequency of late gastrointestinal complications.
Adult↗
Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study.
PURPOSE: In September 1984, the Pediatric Oncology Group began accrual to a Phase I/II study designed to assess the efficacy and toxicity of sequentially escalated doses of hyperfractionated (twice daily) radiotherapy in children with poor-prognosis brain stem tumors. Pediatric Oncology Group Study #8495 closed in June 1990 with a total of 136 patients on study. We report here the outcome of patients treated at the third and final dose level (75.6 Gy), and compare the results to those obtained at the 66 and 70.2 Gy dose levels. METHODS AND MATERIALS: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the midbrain, pons or medulla. Histological confirmation of diagnosis was not mandatory provided that the clinical and radiological findings were typical for brain stem glioma. Treatment consisted of radiotherapy delivered to local fields. At the third dose level, fraction sizes of 1.26 Gy were given twice daily, with a minimum interfraction interval of 6 hr to a dose of 75.6 Gy in 60 fractions over 6 weeks. Between 5/89 and 6/90, 41 patients were accrued to the study. Two were excluded from analysis leaving 39 evaluable patients, 21 male and 19 female, whose ages ranged from 3 to 15 years (median 7.5 years). RESULTS: Following treatment, neurological improvement was reported in 30/39 (77%) of the patients. On central review of imaging studies in 29 patients, one patient was found to have had a complete response to radiotherapy, five a partial (> 50% response), and only three had non-responding or progressive disease. The median time to disease progression was 7 months; median survival time was 10 months; survival at 1 year was 39.9% (SE 8.3%) and at 2 years, 7% (SE 4.8%). The pattern of failure was local in all patients; in addition six had evidence of leptomeningeal seeding. Morbidity of treatment included an enhanced skin reaction (21%), otitis media and/or externa (26%), and steroid use > 3 months (62%). Intralesional necrosis was a frequent finding (45%) on imaging studies performed at a median time of 6 weeks post treatment. CONCLUSION: The results of treatment in terms of progression-free survival and overall survival are not significantly different (at p = .55 and p = .46, respectively) from those obtained at the two previous dose levels. There is no evidence that higher doses of hyperfractionated radiotherapy given as in this study improve the outlook of patients with poor-risk brain stem gliomas.
Adolescent↗
Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors.
BACKGROUND: Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Therefore, in 1986, the Pediatric Oncology Group began a study in which postoperative chemotherapy was given in order to permit a delay in the delivery of radiation to the developing brain. METHODS: Children under 36 months of age with biopsy-proved malignant brain tumors were treated postoperatively with two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. This sequence was repeated until the disease progressed or for two years in 132 children 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis. After this, the patients received radiation therapy. The response to the first two cycles of chemotherapy was measured in 102 patients with residual postoperative disease. RESULTS: The first two cycles of cyclophosphamide and vincristine produced complete or partial responses in 39 percent of the 102 patients who could be evaluated. The response rates were highest among patients with medulloblastomas, malignant gliomas, or ependymomas. Patients with brain-stem gliomas or embryonal tumors (primitive neuroectodermal tumors) had little or no response. The progression-free survival rate was 41 percent at one year for children who were 24 to 36 months old at diagnosis and 39 percent at two years for those under 24 months of age at diagnosis. Multivariate analysis identified embryonal tumors as a significant adverse prognostic feature (relative risk, 2.2; 95 percent confidence interval, 1.4 to 3.4) and complete resection as a favorable feature (relative risk, 0.33; 95 percent confidence interval, 0.20 to 0.54). Complete responses to chemotherapy were associated with a progression-free survival rate approaching that achieved with gross total resection. A comparison of cognitive evaluations obtained at base line and after one year of chemotherapy revealed no evidence of deterioration in cognitive function. CONCLUSIONS: Chemotherapy appears to be an effective primary postoperative treatment for many malignant brain tumors in young children. Disease control for one or two years in a large minority of patients permitted a delay in the delivery of radiation and, on the basis of preliminary results, a reduction in neurotoxicity. For patients who had undergone total surgical resection or who had a complete response to chemotherapy, the results are sufficiently encouraging to suggest that radiation therapy may not be needed in this subgroup of children after at least one year of chemotherapy.
Antineoplastic Combined Chemotherapy Protocols↗
Clinical experience with electron pseudoarc therapy.
Between November 1986 and June 1990, 24 patients were treated with electron pseudoarc therapy at McGill University. There were 21 females and three males aged 27 to 81 years (median 62 years). 17 patients, nine of whom had received previous conventional locoregional irradiation, were treated palliatively for locally extensive breast carcinoma. Eight of these 17 patients achieved a complete, and six a partial, response to treatment; nine subsequently developed evidence of progressive disease within the treatment field after intervals of one to 27 months (median 5 months) following therapy. Eight patients developed moist desquamation of the treated chest wall, which was extensive in four; one of these patients developed chronic ulceration of the skin. The latter and one additional patient developed radiation pneumonitis. Seven patients were treated with radical intent, two following mastectomy for breast carcinoma, and one each for chest wall lymphoma, chest wall sarcoma, scalp angiosarcoma, scalp lymphoma and posterior cervical soft tissue sarcoma. Local control was achieved in six of these seven patients with minimal toxicity. Electron pseudoarc therapy is a treatment option for selected breast carcinoma patients for palliation of extensive chest wall disease, although morbidity may be considerable. The technique may, however, play a more useful role in other situations where the superficial portion of large curved surfaces is to be treated with curative intent.
Adult↗
Long source-skin distance rectal irradiation technique: a review of results.
Endocavitary rectal irradiation is a well established curative treatment for patients with selected early cases of adenocarcinoma of the rectum. At McGill we use a long source-skin distance (SSD) rectal irradiation technique as an alternative to the standard short SSD rectal irradiation technique originally described by Papillon. Eight patients, seven women and one man, were treated between April 1986 and November 1988. Median age was 72.5 years (range 46-86 years). Seven patients were treated with curative intent, and one for palliation. The mean follow-up period for all patients was 43 months, with a median of 54 months (range 3-65 months). Actuarial survival and disease-free survival were 86% and 72% at 65 months for the seven patients treated with curative intent. Treatments were well tolerated by all patients and only one patient developed localized proctitis that required steroid enemas, which resulted in complete resolution of symptoms. Our results are comparable with those in other reports in the literature. The complications were similar in type and frequency to other published series.
Adenocarcinoma↗
Clinical experience with a single field rotational total skin electron irradiation technique for cutaneous T-cell lymphoma.
Between October 1981 and December 1989, 44 patients with cutaneous T-cell lymphoma (CTCL) were treated with a single field rotational total skin electron irradiation (RTSEI) technique developed in the McGill University, Department of Radiation Oncology. Only 11 (25%) of the 44 patients had received no prior treatment. Three-quarters (33/44) had advanced (T3 or T4) disease. Complete responses were seen in 32/44 (73%) of patients (91% T2, 71% T3 and 58% T4), but only 3/11 (27%) of patients with T2 disease and 3/21 (14%) of patients with T3 disease remain in continuous complete remission in the skin, after median intervals of 58 and 35 months, respectively. Median cause-specific survival for the whole group is 43 months and survival at 5 years is 38%. Survival was significantly better for patients with T2 disease than for patients with T3 disease (relative risk 4.3; 95% CI 1.4-13.2) and patients with T4 disease (relative risk 3.1; 95% CI 0.8-12.1). The RTSEI technique used at McGill has depth-dose characteristics and photon contamination similar to other commonly used TSEI techniques. It is relatively simple and provides a homogenous dose distribution over the entire skin surface in a short treatment time. Results of treatment are similar to those obtained with other techniques. For T2 disease, TSEI is an effective treatment modality with a possibility of long-term tumor control. For more advanced disease, more aggressive treatment, which may include TSEI, is necessary.
Adult↗
Hyperfractionated radiation therapy in brain stem tumors. Results of treatment at the 7020 cGy dose level of Pediatric Oncology Group study #8495.
Between May 1986 and February 1988, 57 patients were accrued to the second dose level of a Phase I/II Pediatric Oncology Group (POG) study exploring the use of hyperfractionated radiation therapy (HRT) in children with high-risk brain stem tumors. Local fields were treated with fraction sizes of 117 cGy given twice daily, with a minimum interfraction interval of 6 hours, to a total dose of 7020 cGy in 60 fractions over 6 weeks. Information regarding clinical status during HRT was available for 55 patients (44 [80%] improved, 6 remained stable, and 5 deteriorated). Results of initial and follow-up computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were available for review for 52 patients. One patient had a complete response (CR) to treatment, 3 had a partial response (PR) (more than 50% response), and 40 remained stable, for a total response rate (CR + PR + stable) of 77%. Median time to disease progression was 6 months. Median survival time was 10 months. Survival rate was 39.6% (standard error [SE] = 6.6%) at 1 year and 23% (SE = 5.8%) at 2 years. Complications of treatment included an enhanced skin reaction in six patients and otitis media and/or externa in nine. One patient bled into tumor shortly after completion of HRT, and three had intralesional necrosis. Five patients continued taking steroids for protracted periods in the face of improved clinical and/or radiologic findings. Complications related to the use of steroids included opportunistic infections, impaired glucose tolerance, hypertension, osteoporosis, and significant mood changes. In no patient was there evidence of any late injury attributable to HRT. When compared with results of treatment with HRT at a lower dose level (6600 cGy), there appears to be a trend toward improved survival at 7020 cGy despite a less favorable patient population at the higher dose level. A second dose escalation to 7560 cGy in 60 fractions over 6 weeks has been implemented as planned.
Adolescent↗
Accelerated fractionation for high-grade cerebral astrocytomas. Preliminary treatment results.
A Phase I/II accelerated fractionation study for high-grade cerebral astrocytomas began in October 1987. Forty-two patients, 25 men and 17 women, were entered in the study. Median age was 58.5 years of age (range, 32 to 78 years). Performance status was 0, 1, 2, and 3 on Eastern Cooperative Oncology Group (ECOG) scale for 13, 19, 9, and 1 patients, respectively. Thirty-six patients had undergone partial resection, and six had stereotactic biopsy only. All patients had histologically proven astrocytomas (6 Grade 3, and 36 Grade 4). Treatment consisted of radiation therapy doses of 4400 cGy in 22 daily fractions to the whole brain plus a boost of 1600 cGy in 8 fractions given concomitantly with the last 8 whole-brain treatments using a twice daily schedule with an interfraction interval of 8 hours. Median survival time was 57 weeks from the date of starting irradiation. Survival was 50% and 28% at 1 and 2 years, respectively. Alopecia and scalp erythema were seen in all patients; nine patients had localized areas of moist desquamation in the retroauricular region. Decreased hearing and serous otitis media were seen in five patients within 1 to 2 months from the end of treatment. Increasing somnolence was marked in eight patients with progressive deterioration of performance status; computerized axial tomography (CAT) scan studies in all eight patients showed evidence of disease recurrence with associated brain edema and mass effect. Three patients had a second resection for a recurrent tumor with no evidence of brain necrosis at craniotomy. To date, the accelerated fractionation schedule appears to be well tolerated with valuable shortening of overall treatment time. The preliminary results are encouraging, and longer follow-up time is required to evaluate tumor control and toxicity.
Adult↗
High dose rate afterloading intracavitary therapy in carcinoma of the cervix.
From January 1984 through December 1986, 87 patients with previously untreated carcinoma of the cervix received external beam pelvic irradiation and high dose rate intracavitary therapy (HDRT). There were 18 Stage IIA patients, 39 Stage IIB, and 30 Stage IIIB. The median age was 60 years and the median follow-up time was 42 months for patients at risk. Radiotherapy consisted of external megavoltage irradiation to the whole pelvis (median dose 4600 cGy) combined with one (6 patients), two (51 patients), or three (30 patients) HDRT insertions. A high dose rate remote afterloading unit with 60Co sources was used to deliver the HDRT. The prescribed dose to point A was between 800 and 1000 cGy per treatment. The dose rate at point A initially was approximately 150 cGy/min and dropped to approximately 100 cGy/min during the duration of the study. Treatments with multiple fractions were given at weekly intervals. The overall actuarial survival at 5 years was 88% for Stage IIA, 64% for Stage IIB and 32% for Stage IIIB patients. Pelvic recurrence remained the major cause of failure. Grade III and IV late complications included proctitis and bowel obstruction in six patients each. We conclude that HDRT results are similar to those obtained with conventional low dose rate intracavitary systems. HDRT is cost effective and minimizes exposure to personnel. Several questions, such as the total number of insertions required, dose per HDRT insertion, and optimal HDRT insertion schedule remain unanswered and further experience is needed to better clarify these issues.
Adult↗
Physical aspects of the angle-beta concept in electron arc therapy.
A technique for the determination of treatment parameters that are required to achieve a desired depth dose distribution in electron arc therapy is discussed and a method for calculating isodose distributions is presented. Both the treatment technique and the dose calculation method rely on the angle beta concept, which uniquely describes the dependence of the radial percentage depth doses in electron arc therapy on the nominal field width, isocenter depth, and virtual source-axis distance. The angle beta concept is discussed in detail and the electron pseudo-arc therapy technique used at McGill is described. Also presented is the method used to achieve dose homogeneity in target volumes treated with the pseudo-arc technique.
Electrons↗
Is post-operative intracavitary therapy a necessary component of treatment for carcinoma of the endometrium?
The role of intracavitary therapy in combination with external pelvic radiotherapy for endometrial carcinoma remains controversial. To determine the pelvic failure rat in patients receiving only external pelvic radiotherapy following total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) for carcinoma of the endometrium, we undertook a retrospective review of all patients referred to the Radiation Oncology Department from January 1977 through December 1984. Patients with grade I, superficially invading tumors were excluded from this analysis. 52 patients were eligible for the study. Three patients who were lost to follow-up immediately after completion of external beam irradiation were excluded, leaving a total of 49 evaluable patients. The median follow-up time is 61 months. Pelvic failure was seen in only 2 patients (4%), both of them occurring concurrent with distant disease. No vaginal vault failures were observed. Overall actuarial survival at 5 years was 82%. We conclude that external beam pelvic radiotherapy alone without intracavitary boost appears to be an adequate treatment for patients undergoing TAHBSO for carcinoma of the endometrium.
Adenocarcinoma↗
Subjective and objective measures of sleepiness: effect of benzodiazepine and caffeine on their relationship.
As part of a larger project on the effects of benzodiazepine and caffeine on daytime sleepiness, performance and mood, this study examined the relationship among the Multiple Sleep Latency Test, lapses during a tapping task, a Visual Analog Scale, and the Stanford Sleepiness scale. Subjects were 80 male, adult nonsmokers aged 20.3 +/- 2.7 years. The Multiple Sleep Latency Test, Stanford Sleepiness Scale, and the Visual Analog Scale were obtained at two-hour intervals beginning at 0700 h and ending at 1700 h. The tapping task (lapses) was administered each day at 0600 h, 1000 h, and 1400 h. A lapse was a 3-s or greater pause between taps. Correlations between the Multiple Sleep Latency Test and subjective (Visual Analog Scale and the Stanford Sleepiness Scale) measures were significant at 0600 h, but became nonsignificant as the day progressed. Correlations between lapses and the two subjective measures were generally nonsignificant. The two objective measures were significantly correlated in the total group but not in all treatment groups. The subjective measures were significantly correlated in the total sample and in each treatment group. This study reaffirms the importance of time of day when measuring sleepiness, and suggests that subjective and objective measures may measure different aspects of sleepiness.
Adult↗
Radiotherapy dose-fractionation schedules. Hyperfractionation and accelerated treatment regimens.
It has become increasingly evident that conventional, once-daily, radiotherapy dose-fractionation schedules, developed over the years on the basis of observed normal tissue reactions, may not be ideal for all clinical situations. Differences in kinetics between normal and malignant tissues, especially repair of radiation injury in normal tissues and repopulation in tumors, suggest modifications to conventional dose-fractionation schedules that might be expected to result in an improved therapeutic ratio. Of these, hyperfractionation and accelerated treatment regimens appear to hold the most promise. The theoretical basis for these altered schedules is reviewed as is the clinical experience accumulated to date. The implications for treatment of children with brain tumors are presented.
Brain Neoplasms↗
The use of CT densitometry to predict lung toxicity in bone marrow transplant patients.
Total body irradiation (TBI) is considered an integral part of the preparation of patients with hematological malignancies for marrow transplantation. One of the major causes of death following bone marrow transplantation is interstitial pneumonia. Its pathogenesis is complex but radiation may play a major role in its development. Computed tomography (CT) has been used in animal and human studies as a sensitive non-invasive method for detecting changes in the lung following radiotherapy. In the present study CT scans are studied before and up to 1 year after TBI. Average lung densities measured before TBI showed large variations among the individual patients. On follow-up scans, lung density decreases were measured for patients who did not develop lung complications. Significant lung density increases were measured in patients who subsequently had lung complications. These lung density increases were observed prior to the onset of respiratory complications and could be correlated with the clinical course of the patients, suggesting the possibility for the usage of CT lung densitometry to predict lung complications before the onset of clinical symptoms.
Adolescent↗