Winfried Alberti

Prognostic Factors for Local Control and Survival After Radiotherapy of Metastatic Spinal Cord Compression

PURPOSE To evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC). PATIENTS AND METHODS The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC (< or = 15 v > 15 months), number of involved vertebrae (one to two v > or = three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy). RESULTS On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance. CONCLUSION Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.

Quantification of late complications after radiation therapy.

Abstract Background : An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern. Methods : Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days; postoperative irradiation consisted mostly of 15×2 Gy (range, 20–40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature. Results : Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter p a was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate p a remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same ( p a =10–14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively). Discussion : Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae. Conclusions : There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations.

PURPOSE To investigate the relationship between late tissue response after radiotherapy, cellular sensitivity and DNA repair capacity measured in dermal fibroblasts and chromosomal aberrations measured in lymphocytes. The study was in particular designed to compare cellular parameters of patients with maximum differences in late tissue reactions. MATERIALS AND METHODS The study was performed with 16 pair-wise matched head and neck cancer patients 2-7 years after curative therapy exhibiting maximum differences (grade 1 vs. grade 3) in late normal tissue reactions. Clinical endpoints were fibrosis, telangiectasia, mucositis and xerostomia using the radiation therapy oncology group score. Patients with grade 3 reactions were tested for mutations in ataxia telangiectasia (AT), Nijmegen Breakage Syndrome (NBS), MRE11, RAD50 and DNA ligase IV genes by means of polymerase chain reaction-single-strand conformation polymorphism and sequencing analysis. Skin fibroblasts obtained from biopsies were used to determine the cellular sensitivity by colony formation and the induction and repair of DNA double-strand breaks (dsb) using constant-field gel electrophoresis. Lymphocytes were taken to measure chromosomal damage either in metaphase using conventional chromosome analysis or in G(0) using premature chromosome condensation (PCC)-technique. RESULTS Patients with extreme late reactions (grade 3) showed no evidence for an AT, NBS, MRE11 or RAD50 mutation. Studies with fibroblasts revealed that extreme late reactions were associated neither with a pronounced cellular radiosensitivity nor with a difference in dsb repair capacity. In contrast, there was a significant difference in chromosomal damage measured in lymphocytes. After in vitro irradiation with 6Gy, lymphocytes taken from overreacting patients showed on average a significantly higher number of lethal aberrations than lymphocytes isolated from patients with mild reactions (7.2+/-0.8 vs. 5.0+/-0.3). Similar differences were found for PCC fragments. CONCLUSION This study suggests that lymphocytes are more promising than fibroblasts to predict patients normal tissue response after radiotherapy.

Long-term radiation sequelae after breast-conserving therapy in women with early-stage breast cancer: an observational study using the LENT-SOMA scoring system

PURPOSE To evaluate the long-term toxicity after breast-conserving therapy in women with early-stage breast cancer. METHODS AND MATERIALS Late toxicity according to the late effects of normal tissue-subjective, objective, management, and analytic (LENT-SOMA) criteria and cosmetic outcome (graded by physicians) were evaluated in 590 of 2943 women with early-stage breast cancer who were irradiated between 1983 and 1995 using the following fractionation schedules: group A, 1983-1987, 2.5 Gy 4x/wk to 60 Gy; group B, 1988-1993, 2.5 Gy 4x/wk to 55 Gy, group C, 1994-1995, 2.0 Gy 5x/wk to 55 Gy. RESULTS LENT-SOMA Grade 3-4 toxicity was observed as follows: group A (median follow-up 171 months; range 154-222 months), fibrosis 16% (7 of 45), telangiectasia 18% (8 of 45), and atrophy 4% (2 of 45); group B (median follow-up 113 months; range 78-164 months), pain 2% (8 of 345), fibrosis 10% (34 of 345), telangiectasia 10% (33 of 345), arm edema 1% (2 of 345), and atrophy 8% (27 of 345); and group C (median follow-up 75 months, range 51-96 months, n = 200), occurrence of Grade 3-4 late morbidity <or=2%. The cosmetic outcome was very good to acceptable in 78% (35 of 45) of patients in group A, 83% (286 of 345) in group B, and 94% (187 of 200) in group C. CONCLUSION In our population, the long-term side effects after breast-conserving therapy were not rare, but were mainly asymptomatic. The LENT-SOMA breast module is a practical tool to assess radiation-induced long-term toxicity.

Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells

Purpose: Free OH radicals are considered to be the common mediator of DNA damage after ionizing radiation and oxidative stress. In particular, double-strand breaks (dsb) have a major impact on cell killing after irradiation, while the mechanism of cell killing is less clear for oxidative injury. The latter not only affects DNA, but also equally other cell compartments, such as membranes and mitochondria, which may trigger cell death. This study intended to clarify the relationship between DNA damage induction, repair and cell inactivation for hydrogen peroxide and ionizing radiation. Materials and methods: Chinese hamster ovary (CHO) cells were treated with H 2 O 2 in serum-free medium in combination with/without X-irradiation. DNA damage was measured using the alkaline unwinding method or neutral constant-field gel electrophoresis. Cell survival was recorded using the colony-formation assay. Results: Hydrogen peroxide induced a large number of single-strand breaks (ssb>36000/cell) without impairing cell survival. This number reached a maximum (36Gy-equiv. at 3x10 -4 mol/dm3) without further increase after higher concentrations. Repair kinetics of ssb were similar to those after irradiation. Dsb were found only after very high concentrations of H 2 O 2 (>3x10 -2 mol/dm 3) , which is different from irradiation which generated ssb and dsb in the same dose range. A linear-quadratic increase of dsb was found with increasing concentrations of H 2 O 2 suggesting a single or a pairwise action of OH radicals to form a dsb. After either irradiation or peroxide treatment cell killing was observed only after doses which also allowed dsb detection. The number of dsb calculated per lethal event was in the same range but slightly higher after irradiation (1.7-fold) than after H 2 O 2 treatment. Conclusions: Cell killing after irradiation or hydrogen peroxide appears to be due to dsb, whereas cells withstand large numbers of single-strand lesions and other types of non-DNA damage occurring at lower concentrations of hydrogen peroxide. The number of ssb saturates at intermediate concentrations of H 2 O 2 suggesting that a limited amount of chromatin-bound metal ions is available for OH radical generation.PURPOSE Free OH radicals are considered to be the common mediator of DNA damage after ionizing radiation and oxidative stress. In particular, double-strand breaks (dsb) have a major impact on cell killing after irradiation, while the mechanism of cell killing is less clear for oxidative injury. The latter not only affects DNA, but also equally other cell compartments, such as membranes and mitochondria, which may trigger cell death. This study intended to clarify the relationship between DNA damage induction, repair and cell inactivation for hydrogen peroxide and ionizing radiation. MATERIALS AND METHODS Chinese hamster ovary (CHO) cells were treated with H2O2 in serum-free medium in combination with/ without X-irradiation. DNA damage was measured using the alkaline unwinding method or neutral constant-field gel electrophoresis. Cell survival was recorded using the colony-formation assay. RESULTS Hydrogen peroxide induced a large number of single-strand breaks (ssb>36000/cell) without impairing cell survival. This number reached a maximum (36 Gy-equiv. at 3 x 10(-4) mol/dm3) without further increase after higher concentrations. Repair kinetics of ssb were similar to those after irradiation. Dsb were found only after very high concentrations of H2O2 (>3 x 10(-2) mol/dm3), which is different from irradiation which generated ssb and dsb in the same dose range. A linear-quadratic increase of dsb was found with increasing concentrations of H2O2 suggesting a single or a pairwise action of OH radicals to form a dsb. After either irradiation or peroxide treatment cell killing was observed only after doses which also allowed dsb detection. The number of dsb calculated per lethal event was in the same range but slightly higher after irradiation (1.7-fold) than after H2O2 treatment. CONCLUSIONS Cell killing after irradiation or hydrogen peroxide appears to be due to dsb, whereas cells withstand large numbers of single-strand lesions and other types of non-DNA damage occurring at lower concentrations of hydrogen peroxide. The number of ssb saturates at intermediate concentrations of H2O2 suggesting that a limited amount of chromatin-bound metal ions is available for OH radical generation.

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores

PURPOSE The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA) scores were compared in a group of breast cancer patients. The impact of the classification system on grading late effects was evaluated. MATERIALS AND METHODS Telangiectasia, skin pigmentation, and fibrosis were scored according to both LENT/SOMA and RTOG criteria. The results were compared with respect to up- or downgrading and correlated (Spearmans rho). Other side effects were recorded using LENT/SOMA criteria. Interobserver variability was calculated with Cohens kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent breast-conserving therapy between 1981 and 1995 were examined. The median dose of radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31 patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were used. Two doctors examined 45 patients jointly. RESULTS Of all patients, 20% had telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77% retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearmans rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy were observed in 226 patients using LENT/SOMA criteria. Interobserver variability was similar for both classification systems and ranged from Cohens kappa 0.3 (retraction) to 0.91 (telangiectasia). CONCLUSIONS LENT/SOMA criteria seem to be the better tool in grading and recording late radiation toxicity compared with the RTOG scale. There was some upgrading with the RTOG score when skin toxicity is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of the LENT/SOMA scoring system should be considered to standardize reporting of late radiation morbidity.

Individual Radiosensitivity Measured With Lymphocytes May Predict the Risk of Acute Reaction After Radiotherapy

PURPOSE We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy. METHODS AND MATERIALS Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions. RESULTS Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy. CONCLUSION Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.

Well-differentiated neurocytoma: What is the best available treatment?

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Role of radiotherapy in the treatment of motor dysfunction due to metastatic spinal cord compression: comparison of three different fractionation schedules.

PURPOSE The optimum fractionation schedule for radiotherapy (RT) of metastatic spinal cord compression (MSCC) is still debated in the literature. Several reports have compared different fractionation schedules for pain relief. To our knowledge, this retrospective analysis is the first to compare three different schedules for functional outcome. METHODS AND MATERIALS For posttreatment functional and ambulatory outcome, three schedules, 30 Gy in 10 fractions (n = 93), 37.5 Gy in 15 fractions (n = 80), and 40 Gy in 20 fractions (n = 74), were compared. Motor function was evaluated by a 6-point scale before and at the end of RT and 3, 6, and 12 months later. A multivariate analysis was performed for functional outcome, including fractionation schedule and the three relevant prognostic factors (primary tumor type, time of developing motor deficits before RT, and ambulatory status). RESULTS No significant difference was observed for posttreatment motor function or ambulatory rates among the three schedules. According to the multivariate analysis, the radiation schedule had no significant impact on functional outcome (p = 0.223) in contrast to the three prognostic factors (p <0.001, p <0.001, and p = 0.012). CONCLUSION The three fractionation schedules were comparable for functional outcome. The least time-consuming schedule (30 Gy in 10 fractions) should be considered for patients with a markedly reduced life expectancy.

Is there a dose-effect relationship for the treatment of symptomatic vertebral hemangioma?

PURPOSE Symptomatic vertebral hemangiomas are rare vascular lesions. Radiotherapy is the most common treatment. Because of a lack of information in the literature, uncertainty exists about the total radiation dose to be applied. METHODS AND MATERIALS Individual data from our own and published patients with symptomatic vertebral hemangioma treated with radiotherapy alone were obtained. The data were pooled, and the impact of the total dose on complete pain relief was evaluated using the chi-square test. Because different single-fraction doses were used, the equivalent dose in 2-Gy fractions (EQD(2)) was used for the analysis. RESULTS Complete data could be obtained from 117 patients. Patients were categorized according to total dose (EQD(2)) into two groups of similar size (Group A: 20-34 Gy, n = 62; and Group B: 36-44 Gy, n = 55). Radiation-induced complete pain relief was achieved in 39% (24/62) of the patients in Group A and in 82% (45/55) of the patients in Group B. The difference was statistically significant (p = 0.003). CONCLUSIONS The data suggest a dose-effect relationship in the radiotherapy of symptomatic vertebral hemangiomas. We recommend a total radiation dose 36-40 Gy with a dose per fraction of 2.0 Gy.