Peter C. Levendag

Identification of prognostic factors in patients with brain metastases: a review of 1292 patients.

PURPOSE Prognostic factors in 1292 patients with brain metastases, treated in a single institution were identified in order to determine subgroups of patients suitable for selection in future trials. MATERIALS AND METHODS From January 1981 through December 1990, 1292 patients with CT-diagnosed brain metastases were referred to the Department of Radiation Oncology, Daniel den Hoed Cancer Center, Rotterdam. The majority of patients were treated with whole brain radiotherapy (84%), the remainder were treated with steroids only or surgery and radiotherapy. Information on potential prognostic factors (age, sex, performance status, number and distribution of brain metastases, site of primary tumor, histology, interval between primary tumor and brain metastases, systemic tumor activity, serum lactate dehydrogenase, response to steroid treatment, and treatment modality) was collected. Univariate and multivariate analyses were performed to determine significant prognostic factors. Results were compared with literature findings using a review of prognostic factors in 18 published reports. RESULTS Overall median survival was 3.4 months, with 6-month, 1-year, and 2-year survival percentages of 36%, 12%, and 4% respectively. Survival was statistically significantly different between treatment modalities, with median survival of 1.3 months in patients treated with steroids only, 3.6 months in patients treated with radiotherapy, and 8.9 months in patients treated with neurosurgery followed by radiotherapy (p < 0.0001). Multivariate analysis confirmed literature findings of the major prognostic value of treatment modality on survival of patients with brain metastases. Performance status, response to steroid treatment, systemic tumor activity, and serum lactate dehydrogenase were independent prognostic factors with the strongest impact on survival, second only to treatment modality. Site of primary tumor, age, and number of brain metastases were also identified as prognostic factors in our material, although with lesser importance. In patients with lung primaries, sex was found to have significant impact on survival. In patients with breast primaries, interval between primary tumor and development of brain metastases appeared to be a statistically significant prognostic factor. Histology in patients with lung primaries and distribution of brain metastases were not found to be statistically significant in multivariate analysis. CONCLUSIONS In this large database, the value of established prognostic factors was confirmed and, furthermore, some less well-recognized parameters such as response to steroid treatment, serum lactate dehydrogenase, age, sex in lung primaries, and site of primary tumor were established. From the three strongest prognostic factors--performance status, response to steroids, and evidence of systemic disease--simple identification of favorable and unfavorable subgroups of patients with brain metastases can be constructed.

Late Coronary Occlusion After Intracoronary Brachytherapy

BACKGROUND Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy. METHODS AND RESULTS From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary beta-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events. CONCLUSIONS Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.

Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study

The feasibility, toxicity and tumor response of stereotactic body radiation therapy (SBRT) for treatment of primary and metastastic liver tumors was investigated. From October 2002 until June 2006, 25 patients not suitable for other local treatments were entered in the study. In total 45 lesions were treated, 34 metastases and 11 hepatocellular carcinoma (HCC). Median follow-up was 12.9 months (range 0.5–31). Median lesion size was 3.2 cm (range 0.5–7.2) and median volume 22.2 cm3 (range 1.1–322). Patients with metastases, HCC without cirrhosis, and HCC < 4 cm with cirrhosis were mostly treated with 3×12.5 Gy. Patients with HCC ≥4cm and cirrhosis received 5×5 Gy or 3×10 Gy. The prescription isodose was 65%. Acute toxicity was scored following the Common Toxicity Criteria and late toxicity with the SOMA/LENT classification. Local failures were observed in two HCC and two metastases. Local control rates at 1 and 2 years for the whole group were 94% and 82%. Acute toxicity grade ≥3 was seen in four patients; one HCC patient with Child B developed a liver failure together with an infection and died (grade 5), two metastases patients presented elevation of gamma glutamyl transferase (grade 3) and another asthenia (grade 3). Late toxicity was observed in one metastases patient who developed a portal hypertension syndrome with melena (grade 3). SBRT was feasible, with acceptable toxicity and encouraging local control. Optimal dose-fractionation schemes for HCC with cirrhosis have to be found. Extreme caution should be used for patients with Child B because of a high toxicity risk.

Clinical accuracy of the respiratory tumor tracking system of the cyberknife: assessment by analysis of log files.

PURPOSE To quantify the clinical accuracy of the respiratory motion tracking system of the CyberKnife treatment device. METHODS AND MATERIALS Data in log files of 44 lung cancer patients treated with tumor tracking were analyzed. Errors in the correlation model, which relates the internal target motion with the external breathing motion, were quantified. The correlation model error was compared with the geometric error obtained when no respiratory tracking was used. Errors in the prediction method were calculated by subtracting the predicted position from the actual measured position after 192.5 ms (the time lag to prediction in our current system). The prediction error was also measured for a time lag of 115 ms and a new prediction method. RESULTS The mean correlation model errors were less than 0.3 mm. Standard deviations describing intrafraction variations around the whole-fraction mean error were 0.2 to 1.9 mm for cranio-caudal, 0.1 to 1.9 mm for left-right, and 0.2 to 2.5 mm for anterior-posterior directions. Without the use of respiratory tracking, these variations would have been 0.2 to 8.1 mm, 0.2 to 5.5 mm, and 0.2 to 4.4 mm. The overall mean prediction error was small (0.0 +/- 0.0 mm) for all directions. The intrafraction standard deviation ranged from 0.0 to 2.9 mm for a time delay of 192.5 ms but was halved by using the new prediction method. CONCLUSIONS Analyses of the log files of real clinical cases have shown that the geometric error caused by respiratory motion is substantially reduced by the application of respiratory motion tracking.

Acute morbidity reduction using 3DCRT for prostate carcinoma : A randomized study

PURPOSE To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose-volume histograms (DVHs) were used. METHODS AND MATERIALS From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system. RESULTS Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs. CONCLUSIONS The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity.

Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome

PURPOSE To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax. RESULTS The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p=0.197). All local recurrences (n=4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade > or = 4 toxicity occurred. CONCLUSION Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.

A three-dimensional CT-based target definition for elective irradiation of the neck

INTRODUCTION Elective treatment of the clinically node-negative neck by radiation results in excellent control rates. However, radiation therapy with its organ-preserving properties is not without morbidity. Side effects of elective neck irradiation are mainly due to damage of the major and minor salivary glands, resulting in the dry mouth syndrome. Given that RT is the preferred treatment modality in case of elective treatment of the neck in many institutions, it is of utmost importance to try and reduce the associated sequelae of RT. MATERIAL AND METHODS With the introduction of CT-planning systems and the development of 3D conformal radiation therapy (3D CRT) techniques, it has become feasible to deliver adequate doses of radiation to the target (neck) and at the same time saving (parts of) the salivary glands from doses beyond tolerance. A prerequisite for these techniques is that they require a precise knowledge of the target (i.e., of the elective neck) on CT. To be able to correlate borders of the surgical levels in the neck (I-VI) with structures seen on CT, an anatomical study, using two fixed (phenol, formaldehyde) human cadavers, was performed. Subsequently, the 6 potential lymph node regions in the neck on CT were defined. RESULTS AND DISCUSSION The reference for the current 3D CT-based definition of the lymph node regions in the neck is the official report of the American Academy of Otolaryngology, describing, based on surgical anatomy, the lymph node groups in the neck by Levels I-VI. The present investigation depicts reproducible landmarks on transversal CT images, corresponding to anatomical reference structures known from surgical levels (I-VI) and, this way, CT-based lymph node regions (1-6) were constructed.

Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up

BACKGROUND AND PURPOSE In patients with Hodgkins disease treated by radiotherapy with a moderate total dose and a low (mean) fraction dose to the heart, the risk of ischemic heart disease was investigated during long-term follow-up. MATERIALS AND METHODS The medical records of 258 patients treated in the period 1965-1980 with radiotherapy alone as the primary treatment were reviewed. The median follow-up was 14.2 years (range 0.7-26.2). The mean total dose and fraction dose to the heart were 37.2 Gy (SD 2.9) and 1.64 Gy (SD 0.09), respectively. The impact on the development of ischemic heart disease of treatment-related parameters, such as the applied (fraction) dose, irradiation technique (one or two fields per day), and chemotherapy in case of a relapse, was investigated. The incidence of ischemic heart disease in this patient population was compared with the expected incidence based on gender, age and calendar period-specific data for the Dutch population. RESULTS Thirty-one patients (12%) experienced ischemic heart disease (actuarial risk at 20-25 years: 21.2% (95% C.I. 15-30). Twenty-five of them were hospitalized. When compared with the expected incidence, the relative risk (RR) of hospital admission for ischemic heart disease was 2.7 (95% C.I. 1.7-4.0). There were 12 deaths (4.7%) due to ischemic myocardial or sudden death (actuarial risk at 25 years: 10.2% (95% C.I. 5.3-19), compared to 2.3 cases that were expected to have died from these causes, yielding a standardized mortality ratio (SMR) of 5.3 (95% C.I. 2.7-9.3). Gender (male), pretreatment cardiac medical history and increasing age appeared to be the only significant factors for the development of ischemic heart disease. CONCLUSIONS Despite the moderate total dose and the low (mean) fraction dose to the heart, the observed incidence of ischemic heart disease is high, especially after long follow-up periods. Treatment related cardiac disease in patients treated for Hodgkins disease has only been reported for doses above 30 Gy. Although the optimum curative dose is still under debate, some studies recommend a dose as low as 32.5 Gy. The observed high rate of severe heart complications in this study advocates a dose reduction to this level, particularly in the regions where the coronary arteries are located.

Geometric Vascular Remodeling After Balloon Angioplasty and β-Radiation Therapy: A Three-Dimensional Intravascular Ultrasound Study

BACKGROUND Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. METHODS AND RESULTS Twenty-one consecutive patients treated with balloon angioplasty and beta-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451+/-128 to 490.9+/-159 mm(3) and 201.2+/-59 to 241.7+/-74 mm(3); P=0.01 and P=0.001, respectively), whereas luminal volume remained unchanged (250.8+/-91 to 249.2+/-102 mm(3); P=NS). The edges demonstrated an increase in mean plaque volume (26.8+/-12 to 32. 6+/-10 mm(3), P=0.0001) and no net change in mean EEM volume (71. 4+/-24 to 70.9+/-24 mm(3), P=NS), resulting in a decrease in mean luminal volume (44.6+/-16 to 38.3+/-16 mm(3), P=0.01). CONCLUSIONS A different pattern of remodeling is observed in coronary segments treated with beta-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

GEC-ESTRO recommendations for brachytherapy for head and neck squamous cell carcinomas.

Both primary and recurrent squamous cell carcinoma of the head and neck are classic indications for brachytherapy. A high rate of local tumor control at the cost of limited morbidity can be achieved with brachytherapy through good patient selection, meticulous source implantation and careful treatment planning. However, no randomized trials have been performed, and there is scant evidence in the literature especially regarding practical clinical recommendations for brachytherapy for head and neck subsites. The Head and Neck Working Group of the European Brachytherapy Group (Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) therefore decided to formulate the present consensus recommendations for low-dose rate, pulsed-dose rate and high-dose rate brachytherapy. The use of brachytherapy in combination with external beam radiotherapy and/or surgery is also covered as well as the use of brachytherapy in previously irradiated patients. Given the paucity of evidence in the literature, these recommendations are mainly based on clinical experience accumulated by the members of the working group over several decades and the respective publications. The recommendations cover in a general part (1) patient selection, the pre-treatment work up and patient care, (2) treatment strategy, (3) target definition, (4) implant techniques, (5) dose and dose rate prescription, (6) treatment planning and reporting, (7) treatment monitoring (8) catheter removal, and (9) post-treatment patient care and follow-up. The recommendations are then specified for the classical brachytherapy tumor sites following an analogue more focussed structure (patient selection, implant technique, target definition, dose and dose rate prescription, results): lip, oral mucosa, mobile tongue, floor of mouth, oropharynx, nasopharynx, paranasal sinuses.