Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

Radiotherapy-related lung fibrosis enhanced by tamoxifen.

BACKGROUND: Tamoxifen is an anti-estrogen with proven efficacy and low toxicity in the treatment of breast cancer. However, tamoxifen has been shown to exert a number of nonhormonal as well as hormonal effects. One nonhormonal effect of tamoxifen is the induction of transforming growth factor-beta (TGF-beta) secretion. TGF-beta has been implicated in the pathogenesis of radiation-induced fibrosis. PURPOSE: We investigated the development of lung fibrosis in breast cancer patients who were treated after mastectomy with radiotherapy, with or without simultaneous adjuvant treatment with tamoxifen. METHODS: Data from 196 women were included in the analysis. Eighty-four women were postmenopausal patients who participated in a randomized trial testing tamoxifen as an adjuvant to postmastectomy radiotherapy. The radiotherapy technique employed an 8-MV photon field covering the axillary and the infraclavicular and supraclavicular regions of the affected side of the chest; the chest wall was treated with an abutted electron field. Optical density changes in pretreatment and post-treatment chest x-ray films were used to monitor the development of lung fibrosis; lung reactions were assessed in the photon-irradiated field only. Logistic regression analysis was used to explore relationships between radiation dose and the development of lung fibrosis in patients either receiving or not receiving tamoxifen. All P values are from two-sided tests. RESULTS: Among the 84 women who participated in the randomized trial of radiotherapy plus tamoxifen (n = 38) versus radiotherapy alone (n = 46), there was a significant association between tamoxifen treatment and the incidence of marked lung fibrosis (relative risk = 2.0; 95% confidence interval [CI] = 1.2-3.5; P = .01). When logistic regression analysis was used to evaluate data from all 196 patients, a highly significant relationship was found between the incidence of lung fibrosis and total radiation dose (P = .0005). In the full analysis, an increased risk of marked lung fibrosis was found again for patients who received tamoxifen simultaneously with radiotherapy (with patients receiving radiotherapy alone as the referent, odds ratio = 2.9; 95% CI = 1.3-6.3; P = .007). Patient age and menopausal status did not significantly influence the results. CONCLUSION: Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of radiation-induced lung fibrosis. IMPLICATIONS: In view of pre-existing data, we hypothesize that tamoxifen mediates the enhancement of radiation-induced lung fibrosis through the induction of TGF-beta secretion. If this hypothesis is correct, new strategies might be devised for preventing or reducing radiation-induced fibrosis. Because we studied a relatively small portion of the irradiated lung, we cannot recommend changes in current therapeutic measures; however, we strongly encourage additional studies of lung fibrosis in patients receiving tamoxifen and radiotherapy.

Quantitative assessment of radiation-induced lung changes by computerized optical densitometry of routine chest x-rays.

PURPOSE: To develop a quantitative assay of radiological lung changes after postmastectomy radiotherapy applicable for analysis of routine chest x-rays. METHODS AND MATERIALS: The assay relies on measurement of the optical density of chest x-rays by means of a standard personal computer-controlled film densitometer used for scanning dosimetry films. Density profiles were recorded at 1 mm steps along two reference lines in each lung. The crossing between the clavicula and the first rib in the x-ray projection was used as an easily identifiable anatomical landmark and was used to establish two parallel cranio-caudal reference lines separated by 20 mm. The starting point for recording optical densities was 5 mm below a line perpendicular to the reference lines and tangent to the top of the lung. Data were stored in a computer file for subsequent processing. The optical film densities in the apex of the lungs were converted into equivalent absorber thickness (EAT). To minimize the dependency on technical factors, the unirradiated lung was used as a control. Lung density changes were quantified by the relative change in EAT (REAT), which was evaluated as the difference between the summed EATs along the reference lines in the two lungs, corrected for any pretreatment difference in lung density, and taken as a percentage of the pretreatment EAT value of the lung. RESULTS: Four different test were carried out to investigate the reproducibility and validity of the proposed assay. (a) An anthropomorphic phantom was used to test the relationship between REAT and the layer of plastic absorber placed in front of one lung. A linear relationship was found with a correlation coefficient of 0.9993. (b) A series of 10 repeat measurements of the same arbitrarily chosen x-ray showed a mean REAT value of 9.8%, with a standard deviation of 0.21%. (c) Forty-three chest x-rays exposed on the same day were available from the clinical series. These were treated as double determinations of REAT values, and the standard deviation was estimated at 1.35%. (d) REAT values estimated with this assay were significantly correlated with the scores of two experienced specialists, an oncologist and a radiologist (Spearman's rank correlation coefficient being 0.605, p < 10(-8)). CONCLUSION: This assay quantifies radiation-induced lung injury from routine chest x-rays. Thus, it is possible to take advantage of the very large retrospective materials available in most oncological institutions. The assay has been validated in a phantom experiment and shown to be reproducible. Furthermore, it is technically easy to perform.

Quantitative clinical radiobiology of early and late lung reactions.

PURPOSE: To quantify the response of human lung to a course of fractionated radiotherapy based on a literature review of published clinical data. MATERIALS AND METHODS: Quantitative clinical radiobiology is concerned with the estimation of parameters that describe the clinical outcome of radiotherapy as a function of patient and treatment characteristics. Here, parameters describing the steepness of the dose-response curve, the response to a change in dose per fraction and to a change in overall treatment time for early and late lung injury are compiled based on published clinical studies. RESULTS: Two phases of lung injury are seen, radiation pneumonitis and lung fibrosis. The first signs of early lung changes are seen almost immediately after irradiation. This reaction peaks after 5 to 6 months, and settles partially before 9-10 months. Around that time, the late changes become manifest and these are stable in most cases. There is an important distinction between lung injury and radiotherapy-related morbidity, as even severe changes in a small volume may not give rise to any clinical symptoms. Many assays have been developed for lung damage, and these highlight various clinical and biological aspects of lung damage. Here, the literature on steepness of dose-response curves and fractionation sensitivity is reviewed and quantified by the alpha/beta ratio of the linear-quadratic model for both radiation pneumonitis and lung fibrosis. For the early phase a significant time factor exists. Current best estimates for these radiobiological parameters are derived. Other external factors affecting these estimates are briefly discussed. CONCLUSIONS: Quantitative estimates of radiobiological characteristics of human lung are available for the pneumonitis phase where the fractionation sensitivity is in the same range as for most late-responding normal tissues. Short intensive schedules may also bear an added risk for pneumonitis as the dose recovered per day is around 0.5 Gy. For the later phase of lung fibrosis, the estimates are fewer and generally less precise. It is clear though, that the alpha/beta ratio is low, possibly 2-3 Gy. No time factor has been demonstrated for the late reaction. Due to the considerable physiological reserve capacity in the normal human lung, the relationship between damage and morbidity depends strongly on the lung volume affected. It therefore seems likely that for small volumes irradiated to high doses, the dose-limiting complications may not be due to restriction of lung function, but rather to haemorrhage and formation of fistulae.

Concomitant boost radiotherapy of supraglottic cancer--preliminary results, morbidity.

Forty-two patients with supraglottic squamous cell carcinoma were irradiated with Co60 using concomitant boost technique, a variant of accelerated fractionation. This technique is characterized by administering the boost as a second daily fraction during the basic wide-field irradiations. Daily dose in the first 4 weeks was 1.8 Gy and during the last 2 weeks it was 1.6 Gy twice daily with 4-6 hours separation. Total dose ranged from 60 to 76 Gy, median 66 Gy. The treatment time ranged from 36 to 56, median 42 days. Acute mucosal reactions were more severe than those of conventional irradiation but acceptable. The follow-up time ranged from 9 to 31 months, median 16 months. The actuarial 18 months survival for all patients was 75%. The actuarial 18 months control for primary site and lymph node was 75% for T1-2 stage, and 47% for T3-4 stage. Severe late complications were not observed so far.

Time course of radiological lung density changes after postmastectomy radiotherapy.

The purpose of this study was to quantify the time course of radiological lung changes in patients after postmastectomy radiotherapy assessed from routine follow-up chest x-rays. Radiological density changes in the apex of the irradiated lung were quantified by a recent lung densitometry assay. Lung changes were expressed as the so-called Relative change in Equivalent Absorber Thickness (REAT). The clinical series comprised 329 patients treated with postmastectomy radiotherapy between 1978 and 1982. Of these patients 100 were treated with chemotherapy (CTX or CMF) and 41 were given tamoxifen as an additional adjuvant treatment; 290 patients (88.2%) had pretreatment x-rays and at least one x-ray after completion of radiotherapy and these were included in the study. A total of 2,209 chest x-rays was taken during follow-up, and among these 1921 x-rays (86.9%) were judged to be assessable. Late changes were defined as changes occurring more than a year after radiotherapy. A total of 280 patients had at least one chest x-ray taken more than one year after radiotherapy and these were evaluable with respect to late changes. There were 1,390 follow-up x-rays in these patients and 207 patients (73.9%) had three or more follow-up x-rays. Linear regression of REAT vs. observation time was used to identify three patterns of time changes: progressive, regressive, and stable. The results were as follows. Two phases of lung changes were observed. The early phase peaks around 6 months and the density changes may subsequently resolve, completely or in part. In most cases (173 patients or 84%), the lung density changes reached a stable level 12 months after irradiation. Yet, in 16 patients (7.7%) the lung changes progressed for five or more years. Regression of the density changes was seen in 18 patients (8.7%), and in some cases there were signs that this apparent regression was caused by contraction of the fibrotic tissue. We conclude that two phases of lung response can be distinguished and can be graded according to severity using this assay. Early lung changes reach a maximum around 6 months after RT. Late reactions reach a plateau in most patients after one year, but progress in some cases for five or more years.

Sphincter preservation after short-term preoperative radiotherapy for low rectal cancer--presentation of own data and a literature review.

This report is based on a series of 108 patients with clinically staged T2 (9), T3 (94) and T4 (5) rectal cancer treated with preoperative irradiation with 25 Gy, 5 Gy per fraction given for one week. In 77% of patients. the tumour was located within 7 cm of the anal verge and in 15% the anal canal was involved. Surgery was usually undertaken during the week after irradiation. For low tumours, total mesorectal excision was performed, and for middle and upper cancers, the whole circumference of the mesorectum was excised at least 2 cm below the lower pole of a tumour. Tumour was resected in 103 patients, and sphincter-preserving surgery was performed in 73% of them. In the subgroup where the tumour was located higher than 4 cm from the anal verge, sphincter-preserving surgery was performed in 95%. The follow-up period ranged from 10 to 49 months, with a median of 25 months. Local recurrences were observed in 4% of patients. Anorectal dysfunction caused impairment of social life in 40% of patients and 18% admitted that their quality of life was seriously affected however, none of them stated that they would have preferred a colostomy. These preliminary data suggest that following high dose per fraction short-term preoperative radiotherapy a high rate of sphincter-preserving surgery can be reached, with acceptable anorectal function and an acceptable rate of local failure and late complications. The results of our own data and literature review indicate the need for a randomized clinical trial comparing high dose per fraction preoperative radiotherapy with immediate surgery with conventional preoperative radiochemotherapy with delayed surgery.

A feasibility study of concomitant boost radiotherapy for patients with cancer of the supraglottic larynx.

Between February 1988 and December 1989, 65 patients with supraglottic cancer completed a course of concomitant boost radiotherapy. Cases with N3 disease, a Karnovsky performance score less than 70, age above 70 years, or a second primary cancer were not eligible for the study. Distribution of the patients was: Stage T1-T2 30%, T3-T4 70%, N0 68%, N+ 32%. The total dose ranged from 60 Gy to 76 Gy (median 66 Gy); overall treatment time ranged from 36 to 56 days with a median of 42 days. The daily dose during the first 4 weeks was 1.8 Gy, and during the last 2 weeks it was 1.6 Gy b.i.d. with a 4- or (after September 1988) 6-h interval. The clinical impression was that the early mucosal reactions were acceptable but more severe than after conventional treatment, with confluent membranous mucosal reaction being observed in 54% of the patients. Also, this reaction was significantly more frequent in patients treated with a 4-h interval (68%) than with a 6-h interval (41%) between the daily fractions. To relieve severe dysphagia, narcotics were required in 22% of the patients. The follow-up time ranged from 22 to 50 months, median 34 months. Treatment-requiring late complications were observed in 8 patients, and the 3-year actuarial risk was 17% with 95% confidence limits (6%, 27%). Two of these patients had severe complications: one of them required a temporary tracheostomy due to arytenoid edema and the other developed a laryngo-cutaneous fistula which healed after pharmacological treatment. Actuarial 3-year local-regional control was 59% (46%, 71%) and 3-year actuarial crude survival 55% (42%, 67%). There was no significant difference in the incidence of late complications or tumor control between the two groups of patients treated with a 4- or 6-h interval between the daily fractions. This study shows that the concomitant boost regimen tried here is feasible, but also stresses that the interval between dose fractions should be 6 h or more.