Semi-automatic delineation using weighted CT-MRI registered images for radiotherapy of nasopharyngeal cancer.

PURPOSE: To develop a delineation tool that refines physician-drawn contours of the gross tumor volume (GTV) in nasopharynx cancer, using combined pixel value information from x-ray computed tomography (CT) and magnetic resonance imaging (MRI) during delineation. METHODS: Operator-guided delineation assisted by a so-called "snake" algorithm was applied on weighted CT-MRI registered images. The physician delineates a rough tumor contour that is continuously adjusted by the snake algorithm using the underlying image characteristics. The algorithm was evaluated on five nasopharyngeal cancer patients. Different linear weightings CT and MRI were tested as input for the snake algorithm and compared according to contrast and tumor to noise ratio (TNR). The semi-automatic delineation was compared with manual contouring by seven experienced radiation oncologists. RESULTS: A good compromise for TNR and contrast was obtained by weighing CT twice as strong as MRI. The new algorithm did not notably reduce interobserver variability, it did however, reduce the average delineation time by 6 min per case. CONCLUSIONS: The authors developed a user-driven tool for delineation and correction based a snake algorithm and registered weighted CT image and MRI. The algorithm adds morphological information from CT during the delineation on MRI and accelerates the delineation task.

Stereotactic arc therapy for small elongated tumors using cones and collimator jaws; dosimetric and planning aspects.

Stereotactic arc treatment of small intracranial tumors is usually performed with arcs collimated by circular cones, resulting in treatment volumes which are basically spherical. For nonspherical lesions this results in a suboptimal dose distribution. Multiple isocenters may improve the dose conformity for these lesions, at the cost of large overdosages in the target volume. To achieve improved dose conformity as well as dose homogeneity, the linac jaws (with a minimum distance of 1.0 cm to the central beam axis) can routinely be used to block part of the circular beams. The purpose of this study was to investigate the feasibility of blocking cones with diameters as small as 1.0 cm and a minimum distance between the jaw and the central beam axis of 0.3 cm. First, the reproducibility in jaw positioning and resulting dose delivery on the treatment unit were assessed. Second, the accuracy of the TPS dose calculation for these small fields was established. Finally, clinically applied treatment plans using nonblocked cones were compared with plans using the partially blocked cones for several treatment sites. The reproducibility in dose delivery on our Varian Clinac 2300 C/D machines on the central beam axis is 0.8% (1 SD). The accuracy of the treatment planning system dose calculation algorithm is critically dependent on the used fits for the penumbra and the phantom scatter. The average deviation of calculated from measured dose on the central beam axis is -1.0%+/-1.4% (1 SD), which is clinically acceptable. Partial cone blocking results in improved dose distributions for elongated tumors, such as vestibular schwannoma and uveal melanoma. Multiple isocenters may be avoided. The technique is easy to implement and requires no additional workload.

['Benign' meningioma]. / Een 'goedaardig' meningioom.

Meningioma was diagnosed in four women, aged 40, 24, 41 and almost 75 years, respectively. The first of these patients was treated with surgery, the second and third patients underwent surgery followed by conventional radiotherapy because of a tumour residue or dural tail, and the last patient was treated with stereotactic radiosurgery. They recovered well and were followed by means of regular outpatient check-ups. Twenty percent of all primary brain tumours are meningiomas, over 90% of which are benign. Nevertheless, a large hospital-based population study showed a 5-year survival rate of only 70%. Microsurgery is usually the treatment of first choice. However, in about 25% of cases, excision is incomplete and tumour growth almost always continues. Further surgery influences prognosis unfavourably. New sophisticated radiation techniques help to control tumour progression in about 80-90% of cases. This success, however, may be associated with new cranial nerve deficits or panhypopituitarism. Prospective, comparative studies are not available.

Comparison of different methods to define a target volume for external beam radiation therapy of restenotic coronary arteries.

PURPOSE: Different methods have been described to define a target volume for the treatment of restenotic (stented) coronary arteries by external beam radiation therapy (EBRT). The purpose of this study was to explore two methods to define a target for such therapy, and to compare these with previously investigated methods. MATERIALS AND METHODS: The 3-D position of a stent throughout the cardiac cycle in the three major epicardial coronary arteries was measured in three patients by single-breathhold multislice spiral CT and breathhold biplane conventional X-ray angiography, both indexed in time with the ECG. The volume through which the stent traversed (STV) during the cardiac cycle was determined by use of displacement measurements. RESULTS: For multislice CT and biplane angiography, respectively, the mean STV was 1.23 cm(3) (range 0.65-2.22 cm(3)) and 2.81 cm(3) (range 1.60-4.99 cm(3)). The STV represented only a fraction of the whole heart volume in all patients, that is, equal to or less than 0.4%. CONCLUSIONS: Multislice CT and biplane angiography allowed the measurement of a relatively small potential target, that is the STV, for EBRT of restenotic stented coronary arteries. Both studied imaging modalities are instrumental for targeting the STV by highly conformal radiation therapy in case of restenotic stented coronary arteries.

Beam intensity modulation using tissue compensators or dynamic multileaf collimation in three-dimensional conformal radiotherapy of primary cancers of the oropharynx and larynx, including the elective neck.

INTRODUCTION: The treatment of midline tumors in the head and neck by conventional radiotherapy almost invariably results in xerostomia. This study analyzes whether a simple three-dimensional conformal radiotherapy (3D-CRT) technique with beam intensity modulation (BIM) (using a 10-MV beam of the MM50 Racetrack Microtron) can spare parotid and submandibular glands without compromising the dose distribution in the planning target volume (PTV). METHODS: For 15 T2 tumors of the tonsillar fossa with extension into the soft palate (To) and 15 T3 tumors of the supraglottic larynx (SgL), conventional treatment plans, consisting of lateral parallel opposed beams, were used for irradiation of both the primary tumor (70 Gy) and the elective neck regions (46 Gy). Separately, for each tumor a 3-D conformal treatment plan was developed using the 3-D computer planning system, CadPlan, and Optimize, a noncommercial program to compute optimal beam profiles. Beam angles were selected with the intention of optimal sparing of the salivary glands. The intensity of the beams was then modulated to achieve a homogeneous dose distribution in the target for the given 3D-CRT techniques. The dose distributions, dose-volume histograms (DVHs) of target and salivary glands, tumor control probabilities (TCPs), salivary gland volumes absorbing a biologically equivalent dose of greater than 40 or 50 Gy, and normal tissue complication probabilities (NTCPs) of each treatment plan were computed. The parameters of the 3D-CRT plans were compared with those of the conventional plans. RESULTS: In comparison with the conventional technique, the dose homogeneity in the target volume was improved by the conformal technique for both tumor sites. In addition, for the SgL conformal technique, the average volumes of the parotid glands absorbing a BED of greater than 40 Gy (V40) decreased by 23%, and of the submandibular glands by 7% (V40) and 6% (V50). Consequently, the average NTCPs for the parotid and submandibular glands were reduced by 7% and 6%, respectively. For the To conformal techniques, the V40 of the parotid glands was decreased on average by 31%, resulting in an average reduction of the NTCP by 49%. Both the average V50 and the NTCP of the submandibular glands were decreased by 7%. CONCLUSION: For primary tumors of the oropharynx, the parotid glands could be spared to a considerable degree with the 3D-CRT technique. However, particularly the ipsilateral submandibular gland could not be spared. For primary tumors of the larynx, the 3D-CRT technique allows sparing of all salivary glands to a considerable and probably clinically relevant degree. Moreover, the conformal techniques resulted in an increased dose homogeneity in the PTV of both tumor sites.

A simplified CT-based definition of the lymph node levels in the node negative neck.

INTRODUCTION AND PURPOSE: Using three dimensional (3D) conformal radiotherapy (CRT) techniques for elective neck irradiation (ENI) may allow for local disease control to be maintained while diminishing xerostomia by eliminating major salivary glands (or parts thereof) from the treatment portals. The standardization of CT based target volumes for the clinically negative (elective) neck is a prerequisite for 3DCRT. The aim of the present study was to substantially modify an existing ('original') CT-based protocol for the delineation of the neck target volume, into a more practical ('simplified') protocol. This will allow for rapid contouring and the implementation of conformal ENI in routine clinical procedures. MATERIAL AND METHODS: An earlier ('original') version of the CT-based definition for elective neck node regions 2-5 was re-evaluated, using 15 planning CT scans of previously treated patients. The contouring guidelines were simplified by (1) using a smaller number of easily identifiable soft tissue- and bony anatomical landmarks, which in turn had to be identified in only a limited number of CT slices, and (2) by subsequently interpolating the contoured lymph node regions. The adequacy of target coverage and the sparing using both 'original' and 'simplified' delineation protocols was evaluated by DVH analysis after contouring the primary tumor, the neck and the major salivary glands in a patient with supraglottic laryngeal (SGL) carcinoma who was treated using a 3DCRT technique. RESULTS: The BEV projections of the 'original' and the 'simplified' versions of the 3D elective neck target showed good agreement and were found to be reproducible. The DVH's of the target and parotid glands were not significantly different using both contouring protocols. CONCLUSIONS: The 'simplified' protocol for the delineation of the 3D elective neck target produced both comparable target coverage and sparing of the major salivary glands. When used together with an interpolation program, this 'simplified' protocol substantial reduced the contouring time and makes ENI with sparing of the major salivary glands a practical and achievable goal.

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.

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.

Evaluation of a target contouring protocol for 3D conformal radiotherapy in non-small cell lung cancer.

BACKGROUND: A protocol for the contouring of target volumes in lung cancer was implemented. Subsequently, a study was performed in order to determine the intra and inter-clinician variations in contoured volumes. MATERIALS AND METHODS: Six radiation oncologists (RO) contoured the gross tumour volume (GTV) and/or clinical target volume (CTV), and planning target volume (PTV) for three patients with non-small cell lung cancer (NSCLC), on two separate occasions. These were, respectively, a well-circumscribed T1N0M0 lesion, an irregularly shaped T2N0M0 lesion, and a T2N2M0 tumour. Detailed diagnostic radiology reports were provided and contours were entered into a 3D planning system. The target volumes were calculated and beams-eye view (BEV) plots were generated to visualise differences in contouring. A software tool was used to expand the GTV and CTV in three dimensions for an automatically derived PTV. RESULTS: Significant inter-RO variations in contoured target volumes were observed for all patients, and these were greater than intra-RO differences. The ratio of the largest to smallest contoured volume ranged from 1.6 for the GTV in the T1N0 lesion, to 2.0 for the PTV in the T2N2 lesion. The BEV plots revealed significant inter-RO variations in contouring the mediastinal CTV. The PTV's derived using a 3D margin programme were larger than manually contoured PTV's. These variations did not correlate with the experience of ROs. CONCLUSIONS: Despite the use of an institutional contouring protocol, significant interclinician variations persist in contouring target volumes in NSCLC. Additional measures to decrease such variations should be incorporated into clinical trials.

1H chemical shift imaging reveals loss of brain tumor choline signal after administration of Gd-contrast.

1H MR spectra obtained by chemical shift imaging (CSI) of contrast-enhancing brain tumors before and after the administration of Gd-contrast agent were quantitated and compared with the results in normal brain tissue included in the volume of interest. Twenty-seven combined magnetic resonance imaging and spectroscopy (MRI, MRS) examinations of brain tumor lesions included T1-weighted MRI and CSI (TR/TE 1500/135 ms double-spin echo) repeated 5-10 min after the administration of Gd-contrast agent (0.1-0.2 mM). In 1H MR spectra of contrast-enhancing tumor Gd-contrast induced a mean loss of 15% of the peak area of choline-containing compounds (Cho, P < 0.001) that was correlated with precontrast Cho linewidth (r = -0.72, P < 0.00001). This phenomenon limits the diagnostic use of brain tumor MRS examinations performed immediately after contrast-enhanced MRI.

Local tumor control in radiation therapy of cancers in the head and neck.

BACKGROUND: A retrospective study of 1,493 head and neck cancer patients was designed to test current radiobiological thinking, postulating the detrimental effect of protracted overall treatment times (OTT) and/or split course (SC) regimes in radiation therapy on local tumor control. METHODS: Primary squamous cell carcinomas of the oral cavity (OC), oropharynx (OP), hypopharynx (HP), nasopharynx (NP), and larynx radiated with a dose of at least 50 Gy were analyzed. Those patients treated by brachytherapy and/or primary surgery were excluded. A detailed analysis of the 997 cancers of the larynx was recently published. This paper focuses on the relationship between local tumor control and treatment characteristics for the 496 tumors originating from the OC, OP, HP, and NP. Total doses of radiation ranged from 50 to 79 Gy, with a mean of 64 Gy. RESULTS: A local failure (LF) was observed for 278 patients. Using Cox regression analysis, T stage and site were strongly related to LF. Corrected for T stage and with reference to OP, tumors in the NP, HP, and OC had a relative LF rate of 0.5, 1.6, and 1.8, respectively. Patients treated with continuous course (CC) and higher doses of radiation therapy fared best. No association was found with OTT and the use of chemotherapy. CONCLUSIONS: The results observed for the OC, OP, HP, and NP are in line with the findings for the larynx. Analyzing all 1,493 patients, for SC regimes lower local control rates were observed as opposed to the CC treatment series. Moreover, for the normalized total doses, a dose-effect relationship could be established. This study corroborates that disruption of the treatment per se and/or the use of suboptimal total doses of RT are detrimental; it is argued that these observations could be of relevance when designing combined modality protocols.

Radiation therapy for cancer of the piriform sinus. A failure analysis.

This paper analyzes the results of 109 piriform sinus (PS) cancers treated between 1973 and 1984 by surgery and/or external beam radiation therapy (EBRT) in a large comprehensive cancer center, and in particular tries to redefine the role of EBRT in the management of these tumors. At the time the policy was to start with EBRT to a dose of 40 Gy. A good response to a first series was to be continued by EBRT (RT-1); in case of poor responding tumors, the primary and neck were to be operated upon (RT-S). Poor responders unfit for S or those refusing S were also carried to a full course of EBRT (RT-2). The RT-S, RT-1, and RT-2 actuarial 5-year locoregional relapse-free survival (LR-RFS) and overall survival (OS) were 60%, 40%, and 20% and 40%, 30%, and 20%, respectively. In a multivariate Cox regression analysis the most important prognostic factor appeared to be N-stage, with hazard ratios of 1.16 (N1), 2.2 (N2), and 3.3 (N3). The RT-S treatment group fared best (hazard ratio 0.5). The risk of relapse for T3,4 was 1.3 times as high as opposed to T1,2. For stage I/II (19/21 treated by EBRT only), a LR-RFS and OS at 5 years of 60% and 40%, respectively, was observed. This analysis supports data for stage III/IV PS cancers to be treated by surgery combined with EBRT; in stage I/II there might be a role for EBRT alone. It is speculated that with further sophistication in RT-techniques, the locoregional control rates by EBRT alone could improve.

[Conformational radiotherapy in cancer of the head and neck: a future perspective]. / Conformatiebestraling in het hoofdhalsgebied. Een blik in de toekomst.

The discovery of X-rays in 1895 by Wilhelm Conrad Röntgen paved the way to a new scientific epoch in the management of cancer. Today, with the XXI century in sight, radiotherapy has matured and has become one of the mainstays in the management of cancer. Although long-term success with the use of ionizing radiation in cancer treatment can be achieved in about half of our patients, significant improvements in tumor control rates and/or reduction in side effects (i.e. quality of life) are needed. As a future perspective, the authors highlight the gains that can be anticipated from research in the field of 3-D conformal radiotherapy, in particular with regard to sparing critical structures (e.g. parotid glands) in cancers of the head & neck.

Simulation accuracy in radiotherapy for maxillary sinus tumors.

PURPOSE: To evaluate the accuracy and clinical importance of beam positioning during simulation of radiation treatment for tumors in the maxillary sinus. METHODS AND MATERIALS: Five patients were prepared as if they were to be treated for a maxillary sinus tumor. A three-beam computed tomography (CT) scan-based computer plan was made for each patient. The location of the central beam axis of each beam was measured, relative to bony anatomical structures. A simulation was performed using the bony references to position the radiation beams during simulation. After this, the simulation procedure was repeated by the use of a noninvasive external localization frame with a known accuracy and reproducibility within 2 mm margins. RESULTS: When defining the clinical target volume as the known tumor with a 1 cm margin, three out of five patients would suffer a partial geographical miss throughout the entire radiation treatment due to erroneous beam positioning at the simulation stage when using bony structures as a guide for beam positioning. The influence of these errors is analyzed as normal tissue complication and tumor control probabilities. CONCLUSION: When defining a planning target volume, one should consider a margin to correct for possible simulation errors. We advise the use of objective, external (and thus nonanatomical) landmarks as a reference during simulation to reduce this extra margin to a minimum. In case of simulation, using bony structures as a reference, an additional margin should be entered, depending on the simulation accuracy that can be obtained.

Altered properties of human T-lymphoblast soluble low Km 5'-nucleotidase: comparison with B-lymphoblast enzyme.

Soluble low Km 5'-nucleotidases have been purified from human cultured T- and B-lymphoblasts to compare their properties and to examine the mechanism of different rates of nucleotide dephosphorylation. The enzyme from B-lymphoblasts (MGL-8) was 4385-fold purified with a specific activity of 114 mumol/min/mg, while the enzyme from T-lymphoblasts (CEM, MOLT-4) was 4355-fold purified with a specific activity of 35 mumol/min/mg. The activity of both enzymes have an absolute requirement for Mg++. The B-cell enzyme has maximum activity with Mg2+ > Mn2+ > Co2+, while the T-cell enzyme had maximum activity with Co2+ > Mn2+ > Mg2+. The optimum activity was at pH 7.4-9.0 for the B-cell enzyme and pH 9.0 for the T-cell enzyme. Substrate specificity was the same for both enzymes with the following relative Vmax values: CMP > UMP > dUMP > dCMP > dAMP > IMP > GMP > dIMP > dGMP. The Km values for AMP and IMP were 12 and 25 microM for the B-cell enzyme, and 7.0 and 12 microM for the T-cell enzyme. ATP and ADP are competitive inhibitors of these enzymes with apparent Ki values of 100 and 20 microM for the B-cell enzyme, and 44 microM and 8 microM for the T-cell enzyme, respectively. The apparent molecular mass by gel filtration column chromatography is 145 kD for the B-cell enzyme and 72 kDa for the T-cell enzyme. The subunit molecular masses by Western blots are 69.2 kD for both enzymes. These properties suggest that the B-lymphoblast enzyme is identical or similar to the enzyme from human placenta. However, the T-cell enzyme has some different properties. We conclude that these differences plus a lower content of low Km 5'-nucleotidase in T-cells may account for the decreased ability of T-lymphoblasts to dephosphorylate nucleotides and may contribute to the selective cytotoxicity of deoxyribonucleosides for T-lymphoblasts as compared to B-lymphoblasts.

AMP and IMP dephosphorylation by soluble high- and low-Km 5'-nucleotidases.

Three distinct 5'-phosphomonoesterase activities were isolated from soluble fractions of human placenta, cultured human T and B lymphoblasts, and rat liver using 5'-AMP-sepharose 4B affinity chromatography. We define these activities as "low-Km" 5'-nucleotidase, "high-Km" 5'-nucleotidase, and nonspecific phosphatase. High-Km 5'-nucleotidase was eluted with 0.5 M NaCl, low-Km 5'-nucleotidase was eluted with 10 mM ADP, and nonspecific phosphatase was not retained on the column. We have found significant variability in the relative content of high- to low-Km activities in the tissues studied with the ratios ranging from 5.5 to 264. The properties were studied after further purification. The molecular mass of the low-Km enzymes ranged from 72.5 to 209 kDa, optimum pH ranged from 7.4 to 9.0, Km for AMP ranged from 7 to 15 microM, and Km for IMP ranged from 10 to 26 microM. The molecular mass of the high-Km enzymes ranged from 182 to 210 kDa, pH optimum was at 6.5, Km for AMP ranged from 3.0 to 9.4 mM, and the Km for IMP ranged from 0.3 to 0.5 mM. The data indicate that the soluble low- and high-Km 5'-nucleotidase coexist in the mammalian cells and tissues studied. These observations suggest a complex system for the regulation of nucleoside 5'-monophosphate dephosphorylation.

Familial ciliary dyskinesis: a cause of infertility without respiratory disease.

Two brothers were found to have primary infertility and nonmotile sperm secondary to ultrastructural defects, which included absent central doublets and peripheral microtubular translocation. No personal or family history of sinobronchial disease was obtained. Although sporadic cases of this type of ciliary dyskinesis have been reported, our patients constitute the first known occurrence of familial association.