A comparison of three stereotactic radiotherapy techniques; ARCS vs. noncoplanar fixed fields vs. intensity modulation.

PURPOSE: Linac arc based stereotactic radiotherapy is being used with increasing frequency to treat brain tumors. This approach can be used for single or fractionated treatments, and is typically carried out with circular collimators which are optimal for small, spherical targets. Treatment planning using fixed noncoplanar beams or intensity-modulated beams may enhance the ability to conform to irregularly shaped and/or large tumors, especially when combined with stereotactic localization. We compare the dose conformity and normal brain dose characteristics of three stereotactic techniques for various nonspherical target shapes. METHODS AND MATERIALS: Three intracranial test targets were constructed using a 3D treatment planning system after a patient underwent CT simulation. The targets included an ellipsoid with major axis dimensions of 4.0, 2.0, and 2.0 cm, a hemisphere with a diameter of 4.0 cm, and an irregularly shaped patient tumor with a maximum dimension of 5.3 cm. The following stereotactic techniques were compared for each target: a) 5 arcs as used in traditional linac radiosurgery/radiotherapy (noncoplanar arcs [ARCS]), b) 6 fixed noncoplanar custom blocked fields (3D), c) intensity modulation using 6 noncoplanar beams and a mini-multileaf collimator (intensity-modulated radiation therapy [IMRTI). Dose volume histograms were performed for each target/technique combination. RESULTS: For the ellipsoid, dose conformity is similar for all three techniques and normal brain isodose distributions are more favorable with the ARCS plan. For the hemisphere and irregular tumor targets, dose conformity and high/low isodose normal brain volumes are more favorable with the IMRT technique. CONCLUSIONS: For the targets described above, the intensity-modulated technique results in improved dose conformity and decreased dose to nontarget brain in high and low isodose regions as compared to the standard noncoplanar arc technique or noncoplanar fixed fields for the hemisphere and tumor targets. Intensity-modulated treatment delivery may allow for an increase in the therapeutic ratio for treating stereotactically defined large and/or irregularly shaped intracranial targets.

Intensity-modulated stereotactic radiosurgery using dynamic micro-multileaf collimation.

PURPOSE: The implementation of dynamic leaf motion on a micro-multileaf collimator system provides the capability for intensity-modulated stereotactic radiosurgery (IMSRS), and the consequent potential for improved dose distributions for irregularly shaped tumor volumes adjacent to critical organs. This study explores the use of IMSRS to provide improved tumor coverage and normal tissue sparing for small cranial tumors relative to plans based on multiple fixed uniform-intensity beams or traditional circular collimator arc-based stereotactic techniques. METHODS AND MATERIALS: Four patient cases involving small brain lesions are presented and analyzed. The cases were chosen to include a representative selection of target shapes, number of targets, and adjacent critical areas. Patient plans generated for these comparisons include standard arcs with multiple circular collimators, and fixed noncoplanar static fields with uniform-intensity beams and IMSRS. Parameters used for evaluation of the plans include the percentage of irradiated volume to tumor volume (PITV), normal tissue dose-volume histograms, and dose-homogeneity ratios. All IMSRS plans were computed using previously established IMRT techniques adapted for use with the BrainLAB M3 micro-multileaf collimator. The algorithms comprising the IMRT system for optimization of intensity distributions and conversion into leaf trajectories of the BrainLab M3 were developed at our institution. The ADAC Pinnacle(3) radiation treatment-planning system was used for dose calculations and for input of contours for target volumes and normal critical structures. RESULTS: For all cases, the IMSRS plans showed a high degree of conformity of the dose distribution with the target shape. The IMSRS plans provided either (1) a smaller volume of normal tissue irradiated to significant dose levels, generally taken as doses greater than 50% of the prescription, or (2) a lower dose to an important adjacent critical organ. The reduction in volume of normal tissue irradiated in the IMSRS plans ranged from 10% to 50% relative to the other arc and uniform fixed-field plans. CONCLUSION: The case studies presented for IMSRS demonstrate significant dosimetric improvements for small, irregularly shaped lesions of the brain when compared to treatments using multiple static fields or standard SRS arc techniques with circular collimators. For all cases, the IMSRS plan yielded a smaller volume of normal tissue irradiated, and/or a reduction in the volume of an adjacent critical organ (i.e., brainstem) irradiated to significant dose levels.

Determining the optimal block margin on the planning target volume for extracranial stereotactic radiotherapy.

PURPOSE: To determine the block margin that minimizes normal tissue irradiation outside of the planning target volume (PTV) for body stereotactic radiotherapy (Body-SRT) of lung and liver tumors. METHODS AND MATERIALS: Representative patient cases of lung and liver tumors were chosen for analysis. A PTV was constructed for each case and plans were generated which employed an array of block margins ranging from -2.5 mm to 10 mm at isocenter. Plans were generated for cerrobend blocks and for a multileaf collimator. The prescription isodose coverage was renormalized for each case and dose-volume histograms (DVH) and normal tissue complication probabilities (NTCP) were determined for each plan. RESULTS AND CONCLUSION: For the cases studied, the optimal block margin was in the 0.0 mm range. The ranking of plans was identical for both dose-volume based and biological based criteria. The method of blocking had no significant effect on treatment plans. The use of narrow margins for Body-SRT results in normal tissue sparing and creates significant target dose inhomogeneity which may be beneficial for tumor control.

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: experience with Cisplatinum-based chemoradiotherapy in 76 patients.

PURPOSE: Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. METHODS AND MATERIALS: From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum, 50 mg/m2. One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). RESULTS: The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha-fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). CONCLUSION: The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This treatment appears to represent an important therapeutic option for many, but not all, patients with unresectable hepatoma.

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases.

PURPOSE: Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS: Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS: Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was $4119 less costly than SRS. CONCLUSION: HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS: The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS: The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS: The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Cost analysis of erythropoietin versus blood transfusions for cervical cancer patients receiving chemoradiotherapy.

PURPOSE: Red blood cell (RBC) transfusions or erythropoietin (EPO) can be used to evade the detrimental effects of anemia during radiotherapy, but the economic consequences of selecting either intervention are not well defined. The RBC transfusion needs during chemoradiotherapy for cervix cancer were quantified to allow comparison of RBC transfusion costs with the projected cost of EPO in this setting. METHODS AND MATERIALS: For patients receiving pelvic radiotherapy, weekly cisplatin, and brachytherapy, the RBC units transfused during treatment were tallied. RBC transfusion costs per unit included the blood itself, laboratory fees, and expected value (risk multiplied by cost) of transfusion-related viral illness. EPO costs included the drug itself and supplemental RBC transfusions when hemoglobin was not adequately maintained. An EPO dosage based on reported usage in cervix cancer patients was applied. RESULTS: Transfusions were given for hemoglobin <10 g/dL. Among 12 consecutive patients, 10 needed at least 1 U of RBC before or during treatment, most commonly after the fifth week. A total of 37 U was given during treatment, for an average of 3.1 U/patient. The sum total of the projected average transfusion-related costs was $990, compared with the total projected EPO-related costs of $3869. CONCLUSIONS: Because no proven clinical advantage has been documented for EPO compared with RBC transfusions to maintain hemoglobin during cervix cancer treatment, for most patients, transfusions are an appropriate and appealingly less expensive option.

How should we describe the radioblologic effect of extracranial stereotactic radlosurgery: equivalent uniform dose or tumor control probability?

Extracranial stereotactic radiosurgery (ESR) is now undergoing clinical investigation at numerous institutions as a treatment for solitary malignant lesions. Because there is no standard ESR technique, the same minimum dose might be applied through widely variable target dose-volume histograms. For multicenter trials of ESR or interinstitutional comparisons, a reliable index of radiobiological dose equivalency might facilitate the evaluation of dose-response relationships. Equivalent uniform dose (EUD) and tumor control probability (TCP) were considered for this application. While EUD appears more robust for the prospective description of ESR, TCP is expected to remain more valuable for a post hoc estimation of radiosensitivity parameters.

Extracorporeal irradiation of tumorous calvaria. Case report.

This patient with recurrent meningioma grossly involving the frontal bone underwent craniotomy and tumor resection. During the procedure a bone flap was irradiated extracorporeally at a very high dose (120 Gy) sufficient to sterilize residual tumor cells, and the bone was then successfully replaced orthotopically for reconstruction. The use of autologous irradiated bone in this setting offers advantages over cadaveric transplantation and prosthetic implants. Radiation might cause less disruption of the bone's architecture than other techniques of tumor cell eradication.

Conformal radiotherapy: what is it and why does it matter?

Three-dimensional conformal radiotherapy is quickly becoming a standard radiation oncology practice at many academic and community-based departments. Three-dimensional conformal radiotherapy allows clinicians to deliver safer and more accurate treatments to patients. It is also being used to increase tumor doses for situations in which traditional radiation techniques have been unsuccessful. Current and future clinical trials of dose-escalated three-dimensional conformal radiotherapy will examine its ultimate clinical effectiveness.

Long-term local control and survival after concomitant boost accelerated radiotherapy for locally advanced cervix cancer.

Between 1989 and 1994, a prospective clinical trial tested the safety and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for patients with locally advanced cervix cancer. CBASF radiotherapy included 45 Gy/25 fractions to the pelvis and a 14.4 Gy/9 fraction concomitant boost to the primary tumor, followed by brachytherapy for a total point A dose of 85 Gy to 90 Gy. The 22 patients of International Federation of Gynecology and Obstetrics stages IIIA-IVA who received CBASF radiotherapy now have a median follow-up time of more than 8 years. The 7-year actuarial rates of local control and overall survival are 81% and 36%, respectively. Serious late toxicity included bowel injury requiring colostomy in eight patients within 2.5 years after treatment, but no other severe toxicity was observed after longer follow-up intervals. The local control and survival rates achieved with CBASF radiotherapy were higher than those observed within a matched contemporaneous cohort of patients treated with standard radiotherapy alone at the same institution (p = 0.1 for local control, 0.09 for survival). The encouraging trend toward improved tumor control, tempered by the complication rate, suggests an opportunity to apply more sophisticated radiotherapy techniques that might sustain the favorable effects of dose intensification while mitigating the normal tissue toxicity.

Desmoplastic malignant melanoma of the palatal alveolar mucosa: sustained disease-free survival after surgery and postoperative radiotherapy.

Aggressive surgical and radiotherapeutic management of a patient with desmoplastic malignant melanoma arising from the mucosa of the oral cavity has resulted in disease-free survival of more than 2(1/2) years after diagnosis. This case represents only the tenth reported instance of desmoplastic malignant melanoma arising from the oral cavity and only the third for which survival has exceeded 2 years. Details of the clinical, histopathologic, and therapeutic features of the case are provided to augment the paucity of literature available to clinicians managing this rare disease.

Ear effect and gender difference of spontaneous otoacoustic emissions in children with auditory processing disorder.

Spontaneous otoacoustic emissions (SOAEs) are found in most healthy ears, and can be used to measure the health of the cochlear structures and feedback mechanism. According to existing literature, right ears tend to exhibit greater numbers of SOAEs than left ears (Bilger et al., 1990) and females tend to show higher incidence of SOAEs than males (Moulin et al., 1993). The SOAE prevalence has not been extensively studied in children with Auditory Processing Disorder (APD), a disorder with unknown etiology that reduces one's ability to process auditory information. This study examined the prevalence and ear advantage of SOAEs between genders in children diagnosed with APD. SOAEs were investigated in 19 children (7 girls and 12 boys) with APD and 2 4 typically developing children (14 girls and 10 boys) aged 7-12. Right ear advantage was more prevalent in control (71%) than APD subjects (42 %). However, over 30% more females exhibited a right ear advantage than males in each group. Although the results are not significant, our findings indicate that the lack of right ear advantage for SOAE is more prevalent in children with APD, particularly in males, suggesting that cochlear mechanisms or their control might be somehow affected in APD.

Effect of interstitial and/or systemic delivery of tirapazamine on the radiosensitivity of human glioblastoma multiforme in nude mice.

The purpose of this study was to investigate the feasibility and the efficacy of administering tirapazamine by a slow-releasing polymer disc that was implanted interstitially into a U251 (human glioblastoma multiforme) tumor grown in nude mice. Tumor-bearing animals, with a tumor nodule 0.8 cm3 in size, were distributed to groups receiving combinations of empty or drug-containing polymer implants in the tumor or contralateral leg, intraperitoneal (i.p.) drug, and/or irradiation. The drug (i.p.) alone (14 mg/kg x6) or in combination with tumor drug implant (2 mg) did not significantly increase the tumor volume doubling time compared to that of control animals. Given with 12 Gy of irradiation in twice a day 2-Gy fractions, combined i.p. drug and tumor drug implant significantly delayed tumor growth compared to irradiation alone, which was not achieved with either drug treatment alone added to irradiation. Toxicity, as manifested by transient weight loss, was primarily seen in animals receiving radiation and i.p. tirapazamine. These results indicated that a slow-releasing tirapazamine disc can be produced and the addition of an interstitially implanted tirapazamine disc further increased the effectiveness of i.p. tirapazamine.

Accelerated radiotherapy regimen for malignant gliomas using stereotactic concomitant boosts for dose escalation.

The purpose of this pilot study was to determine the feasibility and toxicities of an accelerated treatment program by using a concomitant stereotactic radiotherapy boost given weekly during a course of standard external-beam irradiation (EBXRT) in patients with malignant gliomas. Twelve patients underwent biopsy or subtotal resection of a malignant glioma and were enrolled on the protocol, which delivered 44 Gy-EBXRT and a 12-Gy stereotactic radiotherapy boost given on 3 consecutive weeks of treatment for a total dose of 80 Gy over 33 days. Three patients with anaplastic astrocytoma and nine patients with glioblastoma multiforme had median survival times of 33 months and 16 months, respectively. All of the tumor recurrences were within or were closely adjacent to the region of high-dose irradiation. None of the patients required a treatment break, and there were no acute complications. Two patients developed seizures in the follow-up period, and four patients were diagnosed with radionecrosis at the time of the second operation. The treatment program was found to be feasible and was well tolerated, and it resulted in a rate of late complications similar to those of radiosurgery or interstitial brachytherapy.

Gynecologic brachytherapy: digital fluoroscopy for placement verification and treatment planning.

The authors evaluated the feasibility of using digital fluoroscopic images for device placement verification and dosimetric planning for gynecologic brachytherapy. Adequate images were obtained rapidly, and the limited pincushion distortion on digital fluoroscopic images produced negligible variations in brachytherapy dose calculations compared with those calculated with standard radiographs. Intraoperative digital fluoroscopy can facilitate both placement verification and dosimetric planning for gynecologic brachytherapy.