Klaus Schnabel

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.

Tumor-related prognostic factors for remission of brain metastases after radiotherapy

PURPOSE To study CT determined response to external beam radiotherapy as well as influence of tumor-related factors, especially of tumor volume, on remission and to evaluate whether particular subgroups of metastases are controlled by low-dose radiotherapy. METHODS AND MATERIALS Contrast-enhanced CT scans before and after radiotherapy were analyzed. INCLUSION CRITERIA brain metastases treated with whole-brain radiotherapy (10 fractions of 3 Gy over 2 weeks) since 1983; no additional treatment, for example, surgery or chemotherapy; at least one follow-up CT. Three hundred thirty-six metastases from 108 patients were evaluated with regard to their volume, extent of necrosis, histology of primary tumor, and interval between radiotherapy and follow-up CT. All parameters were correlated with best local result and progression-free survival by uni- and multivariate tests. Volume-response curves were calculated. RESULTS In univariate analysis local result was significantly influenced by each of the four parameters mentioned above. Complete remission was observed in 37% of metastases from small-cell carcinoma, 35% of those from breast cancer, 25% of those from squamous-cell carcinoma, and 14% of those from nonbreast adenocarcinoma. The rate was 52% for metastases <0.5 cm3 and 0% for those >10 cm3. In multivariate analysis, small volume and no necrosis were the most important prognostic factors for complete remission. Progression-free survival was influenced by best local result. CONCLUSION With radiotherapy to a total dose of 30 Gy even small metastases had a complete remission rate of 52% only. Therefore, patients should be treated with locally more effective dose and fractionation schedules when local control is the aim. However, partial remission rate was remarkable even for large and necrotic metastases. This should be considered when palliation is the aim of treatment.

A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs. conventionally fractionated 60 Gy : Results of a randomized equivalence study

PURPOSE Radiation oncologists are often faced with patients with advanced non-small-cell lung cancer (NSCLC), who are not suitable candidates for state-of-the-art radical treatment, but who also are not judged to have a very short life expectancy. Some physicians treat these patients palliatively, whereas others advocate more intensive treatment. To find out if there is a substantial difference in outcome between these approaches, we performed a randomized prospective study. METHODS AND MATERIALS Between 1994 and 1998, 152 eligible patients with advanced NSCLC Stage III (n = 121) or minimal Stage IV (n = 31) were randomized to receive conventionally fractionated (cf; A: 60 Gy, 6 weeks, n = 79) or short-term treatment (PAIR; B: 32 Gy, 2 Gy b.i.d.; n = 73) of tumor and mediastinum. RESULTS One-year survival rate for all patients was 37% with no significant difference between the two treatment arms (A: 36%; B: 38%; p = 0.76). As far as can be judged from limited data available, palliation was adequate and similar for the two treatment arms. Apart from expected differences in the time course of esophagitis, acute side effects were moderate and equally distributed. No severe late effects were observed. CONCLUSIONS In the present randomized trial, survival and available data on palliation were not different after cf to 60 Gy compared to the palliative PAIR regimen. Therefore, for patients who are not suitable for radical treatment approaches, the prescription of a palliative short-term irradiation appears preferable compared to cf over several weeks.

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.

Patterns of relapse and late toxicity after resection and whole-brain radiotherapy for solitary brain metastases

BackgroundThis retrospective analysis was performed in order to evaluate the pattern of relapse and the risk of late toxicity for solitary brain metastases treated with surgery and whole-brain radiotherapy and to correlate the results with those from radiosurgical trials.Patients and MethodsFrom a total of 66 patients, 52 received 10×3 Gy and 10 were treated with 20×2 Gy whole-brain radiotherapy after resection of their brain metastases.ResultsThe actuarial probability of relapse was 27% and 55% after 1 and 2 year(s), respectively. The local relapse rate (at the original site of resected brain metastases) was rather high for melanoma, non-breast adenocarcinoma, and squamous-cell carcinoma. No local relapse occurred in breast cancer and small-cell carcinoma. Failure elsewhere in the brain seemed to be influenced by extracranial disease activity. Size of brain metastases and total dose showed no correlation with relapse rate. Occurrence of brain relapse was not associated with a reduced survival time, because 10/15 patients who developed a relapse received salvage therapy. Of the patients, 11 had symptoms of late radiation toxicity (the actuarial probability was 42% after 2 years).ConclusionsMost results of surgical and radiosurgical studies are comparable to ours. Several randomized trials investigate surgical resection versus radiosurgery, as well as the effects of additional whole-brain radiotherapy in order to define the treatment of choice. Some data support the adjuvant application of 10×3 Gy over 2 weeks as a reasonable compromise when local control, toxicity, and treatment time have to be considered.ZusammenfassungHintergrundDas Rezidivmuster und die chronischen Strahlenspätfolgen nach Therapie solitärer Hirnmetastasen wurden retrospektiv ausgewertet. Die Behandlung bestand in einer Metastasenresektion und einer adjuvanten Ganzhirnbestrahlung. Die Ergebnisse wurden mit denen der Radiochirurgie verglichen.Patientengut und MethodeNach der Resektion der Hirnmetastase erhielten 52 von 66 Patienten eine Ganzhirnbestrahlung mit zehn Fraktionen von 3 Gy in zwei Wochen und zehn eine solche mit 20 Fraktionen von 2 Gy in vier Wochen.ErgebnisseDie Kaplan-Meier-Analyse ergab eine, Rezidivrate von insgesamt 27% nach einem bzw. 55% nach zwei Jahren. Rezidive im Bereich der resezierten Metastase wurden am häufigsten bei Melanomen, Adenokarzinomen (mit Ausnahme der Mammakarzinome) und Plattenepithelkarzinomen beobachtet. Dagegen traten bei Mammakarzinomen und kleinzelligen Karzinomen keine solchen Rezidive auf. Das Auftreten von Hirnmetastasen anderer Lokalisation schien vom Vorhandensein unkontrollierter extrakranieller Tumormanifestationen abhängig zu sein. Die Größe der Hirnfiliae und die Gesamtreferenzdosis der Strahlentherapie korrelierten nicht mit den Rezidivraten. Die Überlebenszeit der Patienten, die ein Rezidiv erlitten, unterschied sich nicht von der der anderen, da in zehn von 15 Rezidivfällen eine Salvagetherapie möglich war. Elf Patienten entwickelten chronische Strahlenspätfolgen. Nach Kaplan-Meier-Analyse betrug das Risiko 42% nach zwei Jahren.SchlußfolgerungenDie meisten Ergebnisse operativer und radiochirurgischer Studien sind den eigenen vergleichbar. Derzeit werden beide Verfahren in randomisierten Studien, miteinander verglichen. Auch die Effekte einer zusätzlichen Ganzhirnbestrahlung werden auf diese Weise untersucht. Unter Berücksichtigung der lokalen Kontrollrate, der Nebenwirkungen und der Behandlungszeit lassen einige Literaturangaben die adjuvante Applikation von zehnmal 3 Gy in zwei Wochen als vernünftigen Kompromiß erscheinen.

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.

Ten years disease-free survival after solitary brain metastasis from breast cancer.

The unique case of a 51-year-old woman who developed a solitary brain metastasis as the first site of systemic disease 11 months after a total mastectomy for an undifferentiated infiltrating ductal carcinoma of her right breast is described. After surgery for the pT2pN0 carcinoma, the patient received radiotherapy of the internal mammary and supraclavicular lymph nodes. The brain metastasis was treated with surgery and adjuvant whole-brain radiotherapy to a total dose of 30 Gy in December 1984 and January 1985. Afterwards a hormonal treatment with tamoxifen was initiated, which still continues. Since then no further distant or lymph node metastases have developed. The patient is under regular after-care and undergoes various apparative examinations every 6 months. She is generally well and suffers only from a postoperatively persistent hemianopsia. This is the first case in which a disease-free survival for more than 10 years after brain metastases from breast cancer has been reported. It illustrates the specific biological behaviour of this tumour type and the chance of achieving long-term survival in very selected cases.

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.