Marcus Niewald

18F-Deoxyglucose positron emission tomography (FDG-PET) for the planning of radiotherapy in lung cancer: high impact in patients with atelectasis

PURPOSE 18F-deoxyglucose positron emission tomography (FDG-PET) is increasingly applied in the staging of lung cancer (LC). This study analyzes the potential contribution of PET in radiotherapy planning for LC with special respect to tumor-associated atelectasis. METHODS AND MATERIALS Thirty-four patients with histologically confirmed LC, who had been examined by PET during pretreatment staging, were included. All were irradiated after CT-based therapy planning with anterior/posterior (AP) portals encompassing the primary tumor and the mediastinum (CT portals, CP). The result of the PET examination was unknown in treatment planning. In retrospect, a PET portal (PP) was delineated and compared with the CP. RESULTS In 12/34 cases, the shape and/or size of the portals were changed, primarily (n = 10) the size of the fields was reduced. The median area of CP was 182 cm2 versus 167 cm2 of PP. Seventeen of 34 patients had dys- or atelectasis caused by a central primary tumor. In these cases, differences between CP and PP were significantly more frequent than in the other patients (8/17 vs. 3/17, p = 0.03). CONCLUSION In this retrospective analysis, the information provided by FDG-PET would have contributed to a substantial reduction of the size of radiotherapy portals. This applies particularly for patients with tumor-associated dys- or atelectasis.

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

PURPOSE To determine whether or not Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) derived prognostic classes for patients with brain metastases are generally applicable and can be recommended as rational strategy for patient selection for future clinical trials. Inclusion of time to non-CNS death as additional endpoint besides death from any cause might result in further valuable information, as survival limitation due to uncontrolled extracranial disease can be explored. METHODS We performed a retrospective analysis of prognostic factors for survival and time to non-CNS death in 528 patients treated at a single institution with radiotherapy or surgery plus radiotherapy for brain metastases. For this purpose, patients were divided into groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as proposed by the RTOG. RESULTS Median overall survival was 2.9 months (2.0 months for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p < 0.001). We did not find other variables splitting patients with KPS <70% in different prognostic groups. However, advanced age, multiple brain metastases, presence of extracranial metastases, and uncontrolled primary tumor each predicted shorter survival in patients with KPS > or =70%. When grouped into the original RTOG RPA classes, our data set split into three subgroups with different prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p < 0.05). Only 3% of patients fell into the most favorable group. Median time to non-CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II, and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus III). However, it was 8.5 months in RPA class II patients with controlled primary tumor, which was found to be the only prognostic factor for time to non-CNS death in patients with KPS > or =70%. In patients with KPS <70%, no statistically significant prognostic factors were identified for this endpoint. CONCLUSIONS Despite some differences, this analysis essentially confirmed the value of RPA-derived prognostic classes, as published by the RTOG, when survival was chosen as endpoint. RPA class I patients seem to be most likely to profit from aggressive treatment strategies and should be included in appropriate clinical trials. However, their number appears to be very limited. Considering time to non-CNS death, our results suggest that certain patients in RPA class II also might benefit from increased local control of brain metastases.

Rapid course radiation therapy vs. more standard treatment: A randomized trial for bone metastases

PURPOSE In a prospective randomized trial we examined whether radiotherapy of painful bone metastases can be shortened using larger single doses without impairing effectivity. METHODS AND MATERIALS One hundred patients with painful bone metastases having no prior surgical intervention or treatment with x-ray therapy and had a median follow-up of 12 months were analyzed. The primary tumor was located in the breast in 43%, in the lung in 24%, and in the prostate in 14%. The most frequent sites of metastases were the pelvis (31%), the vertebral column (30%), and the ribs (20%). Further percentages of sites were: lower extremity 11%, upper extremity 6%, and skull 2%. Fifty-one patients received a short course radiotherapy with a total dose of 20 Gy in 1 week (daily dose 4 Gy), and 49 patients received 30 Gy in 3 weeks (daily dose 2 Gy). RESULTS There were no significant differences in frequency, duration of pain relief, improvement of mobility, recalcification, frequency of pathologic fractures nor survival. There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. Survival was mostly influenced by primary tumor site, Karnofsky performance status, and possibly by the response to radiotherapy (pain relief). CONCLUSIONS Because of the very short life expectancy of patients with metastatic bone disease, we now use 20 Gy in 1 week as our standard to reduce hospital stay.

Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs.

This retrospective study had the following aims: (a) calculation of actuarial rate of late radiation toxicity after whole-brain radiotherapy (WBRT), (b) correlation of clinical symptoms with changes of computed tomography (CT) scans, and (c) analysis of potentially predictive factors with special regard to concomitant treatment with antiepileptic drugs. We analyzed 49 adult patients, selected from a preexisting data base. Inclusion criteria were as follows: no previous brain irradiation; WBRT without boost; CT, clinical, and neurologic examination before and more than 3 months after completion of WBRT. Uni- and multivariate tests of various patient- and treatment-related parameters as possible predictive factors for clinical symptoms of late radiation toxicity (scored according to the RTOG/EORTC system) as well as cerebral atrophy and white matter abnormalities were performed. Median age was 54 years. Patients were treated for brain metastases (n = 37), primary cerebral lymphoma (n = 2), primary brain tumors (n = 7), or with prophylactic intention (n = 3). Carbamazepine was given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42 patients also received corticosteroids. The median dose of WBRT was 30 Gy (range 27-66 Gy). Median fraction size was 3 Gy (1-3 Gy). Nine patients received two fractions per day. The biologically effective dose (BED) according to the linear-quadratic model ranged between 90 and 141 Gy (median, 120 Gy; alpha/beta value, 1 Gy). Median follow-up was 10 months (range, 4-130 months). In 16 cases, symptoms of late radiation toxicity grade I-III appeared. Actuarial rates were 32% after 1 year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cerebral atrophy were 50% after 1 year and 84% after 2 years (white matter abnormalities: 25% and 85%, respectively). There was a significant correlation between atrophy and white matter abnormalities, but not between CT changes and clinical symptoms. CT changes were dependent on BED, absence of barbiturate use, and preexisting cerebral atrophy. Clinical symptoms usually were dependent on BED too, but treatment with carbamazepine was more important in the multivariate model. Neither other drugs nor other factors influenced late radiation toxicity. A detailed analysis showed that most carbamazepine-treated symptomatic patients took the drug during WBRT as well as during follow-up. Actuarial rates of grade I-III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even after exclusion of carbamazepine-treated patients, CT changes and clinical symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a lower rate of late radiation toxicity after WBRT. The anticonvulsant drug carbamazepine showed a surprisingly clear influence on clinical symptoms of late radiation toxicity; that might be explained by the fact that the side effects of long-term drug treatment are indistinguishable from mild or moderate true radiation sequelae, rather than that it has a role in the pathogenesis of radiation-induced changes.

Relation between local result and total dose of radiotherapy for brain metastases

PURPOSE Some studies published recently focused on the improvement of the treatment results of patients with brain metastases who underwent radiation therapy. They evaluated survival as a measure for the expected improvement, but failed to demonstrate a significant benefit from an increased total dose of radiotherapy. This study was targeted to investigate the effect of dose escalation with a different endpoint, the local response. METHODS AND MATERIALS As a first step, a retrospective analysis of 164 patients treated with a standard regimen of 10 x 3 Gy was performed to find factors correlating with the local result. All patients were systematically followed and underwent regular computed tomography (CT) examinations of the brain after irradiation. The second step was to compare, with respect to local control and survival, 39 patients treated with a total dose of 40-60 Gy with 39 patients treated with the standard regimen selected by means of a matched cohort pairs method. RESULTS The retrospective analysis showed a dependence of the local result after irradiation on three parameters: diameter of brain metastases, primary tumor, and tumor histology. Small-cell and adenocarcinoma were found to be more radiosensitive than squamous-cell carcinoma. The highest radiosensitivity was found in breast cancer metastases. The matching procedure was performed with respect to those parameters and also the number of brain metastases and total cerebral tumor volume. The resulting groups were absolutely equivalent and differed only with regard to the total dose applied. The local response (complete or partial remission) was 48-52% after 30 Gy vs. 77% after 40-60 Gy (p < or = 0.05). Survival was not significantly different. A further analysis of the dose-response relationships showed the tendency of control probability to increase with total dose. CONCLUSION This study suggests that there is a rationale for dose escalation in the treatment of brain metastases with radiotherapy, when local control is the aim. However, it seems questionable whether an improvement in survival results.

A disease-specific enteral nutrition formula improves nutritional status and functional performance in patients with head and neck and esophageal cancer undergoing chemoradiotherapy: Results of a randomized, controlled, multicenter trial

In patients with head and neck and esophageal tumors, nutritional status may deteriorate during concurrent chemoradiotherapy (CRT). The aim of this study was to investigate the influence of enteral nutrition enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on body composition and nutritional and functional status.

Toxicity after radiochemotherapy for glioblastoma using temozolomide - a retrospective evaluation

PurposeRetrospective evaluation of toxicity and results after radiochemotherapy for glioblastoma.Methods46 patients with histopathologically proven glioblastoma received simultaneous radiochemotherapy (RCT). The mean age at the beginning of therapy was 59 years, the mean Karnofsky performance index 80%. 44 patients had been operated on before radiotherapy, two had not. A total dose of 60 Gy was applied in daily single fractions of 2.0 Gy within six weeks, 75 mg/m2/day Temozolomide were given orally during the whole radiotherapy period.ResultsA local progression could be diagnosed in 34/46 patients (70%). The median survival time amounted to 13.6 months resulting in one-year and two-year survival probabilities of 48% and 8%, respectively.Radiotherapy could be applied completely in 89% of the patients. Chemotherapy could be completed according to schedule only in 56.5%, the main reason being blood toxicity (50% of the interruptions). Most of those patients suffered from leucopenia and/or thrombopenia grade III and IV CTC (Common toxicity criteria). Further reasons were an unfavourable general health status or a rise of liver enzymes.The mean duration of thrombopenia and leucopenia amounted to 64 and 20 days. In two patients, blood cell counts remained abnormal until death. In two patients we noticed a rise of liver enzymes. In one of these in the healing phase of hepatitis a rise of ASAT and ALAT CTC grade IV was diagnosed. These values normalized after termination of temozolomide medication. One patient died of pneumonia during therapy.ConclusionOur survival data were well within the range taken from the literature. However, we noticed a considerable frequency and intensity of side effects to bone marrow and liver. These lead to the recommendations that regular examinations of blood cell count and liver enzymes should be performed during therapy and temozolomide should not be applied or application should be terminated according to the criteria given by the manufacturer.

Dose/effect relationships for brain metastases.

Purpose: Only in selected patients with brain metastases, e.g. those with controlled or absent extracranial tumour, may application of higher total doses of radiotherapy improve survival. However, local control is the prerequisite for long-term survival. This study aimed to answer the question whether or not local control can be improved by dose escalation. Methods: Computed tomography scans of 322 patients were analysed in order to evaluate the best local result after radiotherapy and the time to local progression. Total doses of 25–60 Gy were administered (single doses 1.8–5 Gy). The biologically effective dose (BED10) was calculated for statistical evaluation according to the linear-quadratic model assuming an α/β-value of Gy. It ranged between 37.5 Gy and 72 Gy. Results: The best local result was dependent on the number of brain metastases, BED and the histology of the primary tumour (small-cell and breast carcinoma had higher remission rates than squamous-cell carcinoma, non-breast adenocarcinoma and others). Partial remission rates significantly increased with BED, whereas complete remission rates did not improve. Histology was the only significant factor in multivariate tests. The 1-year-failure rate improved with increased BED from 44% to 31% (P > 0.05). Overall survival (median 3 months) was not dependent on total dose. Conclusions: Previous studies suggested that a prolongation of survival can be achieved through better local management (e.g. surgery plus radiotherapy, radiosurgery). However, it is still uncertain whether conventional external-beam radiotherapy with higher total doses leads to comparable results. The optimum dose level still has to be established. For squamous-cell carcinoma and adenocarcinoma a BED of at least 72 Gy seems to be necessary, for small-cell and breast carcinoma, doses between 48 Gy and 60 Gy might be sufficient. The important influence of tumour histology on local remission and progression-free survival should be considered when planning future clinical trials.

Intraoperative radiotherapy (IORT) combined with external beam radiotherapy (EBRT) for soft-tissue sarcomas – a retrospective evaluation of the Homburg experience in the years 1995–2007

PurposeTo retrospectively evaluate the results after a regimen of surgery, IORT (intraoperative radiotherapy), and EBRT (external beam radiotherapy) for soft-tissue sarcomasMethods38 consecutive patients underwent IORT for soft-tissue sarcoma; 29 were treated for primary tumours, 9 for recurrences. There were 14 cases with liposarcomas, 8 with leiomyosarcomas, 7 with malignant fibrous histiocytomas. 27/38 tumours were located in the extremities, the remaining ones in the retroperitoneum or the chest. Radical resection was attempted in all patients; a R0-resection was achieved in 15/38 patients, R1 in 12/38 pats and R2 in 4/38 pats. IORT was performed using a J-125 source and a HDR (high dose rate) afterloading machine after suturing silicone flaps to the tumour bed. The total dose applied ranged from 8–15 Gy/0.5 cm tissue depth measured from the flap surface. After wound healing external beam radiotherapy (EBRT) was applied in 31/38 patients with total doses of 23–56 Gy dependent on resection status and wound situation. The mean duration of follow-up was 2.3 years.ResultsA local recurrence was found in 10/36 patients, lymph node metastases in 2/35, and distant metastases in 6/35 patients. The actuarial local control rate was 63%/5 years. The overall survival rate was 57%/5 years. There was no statistically significant difference between the results after treatment for primaries or for recurrences. Late toxicity to the skin was found in 13/31 patients, wound healing problems in 5/31 patients. A neuropathy was never seen.ConclusionThe combination of surgery, IORT, and EBRT yields favourable local control and survival data which are well within the range of the results reported in the literature. The complication rates, however, are considerable although the complications are not severe, they should be taken into account when therapy decisions are made.

ACCELERATED RADIOTHERAPY FOR BRAIN METASTASES

BACKGROUND AND PURPOSE Two novel fractionation schedules for whole-brain irradiation were applied to patients with brain metastases. Both schedules were aimed at reduction of treatment time, whereby tumour control should be increasing with the application of a higher total dose (schedule 2). MATERIALS AND METHODS We applied 2 x 2.5 Gy/day to a total dose of 30 Gy (schedule 1) or 2 x 1.8 Gy/day to a total dose of 50.4 Gy (schedule 2). The interval between daily fractions was 6 h. Treatment was interrupted on weekends. The 30 Gy schedule was also used in adjuvant treatment for resected brain metastases. We compared the results of 15 patients who underwent the 50.4 Gy schedule and 47 patients who were treated up to 30 Gy with those of a historical patient group, treated with one daily fraction of 3 Gy up to 30 Gy (n = 283). RESULTS Local result, clinical course and survival were similar for the 30 Gy groups, whereby prognostic factors were equally distributed. Despite a favourable patient selection no therapeutic gain was seen for the 50.4 Gy group. Patients treated with the accelerated 30 Gy schedule had a significantly worse progression-free survival and a higher rate of late radiation toxicity than the historical group. In contrast, no severe acute toxicity was observed. CONCLUSIONS Considering progression-free survival and late toxicity, the accelerated 30 Gy schedule can not be recommended without hesitation. Radiotherapy with a higher total dose (50.4 Gy) showed no advantage.