The Taguchi method is a statistical approach to process parameter optimization that determines the combination of parameters that result in the best output. This study utilizes the Taguchi method to evaluate the volumetric modulated arc therapy planning parameters of single isocenter treatment plans for multiple brain metastases. An optimization model based on Taguchi and utility concept is employed to optimize the planning parameters, including arc arrangement, calculation grid size, calculation model, and beam energy (on multiple performance characteristics, namely, conformity index and dose to normal brain). Results were analyzed using ANOVA and F Test and were found to be within the confidence interval. Eight treatment plans, each with 4 metastatic brain lesions, were retrospectively planned using a single-isocenter technique. The collimator angles were optimized to avoid open areas. In this analysis, 4 planning parameters (a-d) were considered: (a) Arc arrangements: set 1: Gantry 181cw179, couch 0; gantry 179ccw0, couch 315; and gantry 0ccw181, couch 45. Set 2: set 1 plus additional arc: Gantry 0cw179, couch 270. (b) Energy: 6 MV; 6 MV FFF. (c) Calculation grid size: 1 mm; 1.5 mm. (d) Calculation models: AAA; dose calculation. A treatment planning system was used. A suitable orthogonal array was selected (L8) to perform the experiments. After conducting the experiments with the combinations of planning parameters, the conformity index (CI) and the normal brain dose S/N ratio for each parameter was calculated. Optimum levels for the multiple response optimizations were determined. Based on the ANOVA and F tests, we determined that the factors most affecting the conformity index are arc arrangement and beam energy. These tests were also used to evaluate dose to normal brain. In these evaluations, the significant parameters were grid size and calculation model. Using the utility concept we determined the combination of options of each of the 4 factors tested in this study that most significantly influence quality of the resulting treatment plans: (a) arc arrangement set 2, (b) 6 MV, (c) calc. grid of 1 mm, (d) dose calculation algorithm. Overall, the dominant significant influences on plan quality are (a) arc arrangement and (b) beam energy. From their corresponding ANOVA results, the beam arrangement (72%) is the most significant parameter followed by beam energy (20%). The results from our experimentation have built confidence that the Taguchi method can be used to identify parameters for optimization of treatment planning solutions. Further investigation should now be performed incorporating treatment planning parameters in a larger orthogonal array (L27) that are not quite so intuitive to experienced treatment planners. Such parameters might include clinical target volume contour geometry, virtual organs at risk and planning target structures, optimization criterion such as normal tissue objective, and importance weighting.

Traditional statistical models, such as Cox’s model, Kaplan-Meier analysis, recursive partitioning analysis (RPA), etc., are well suited for explaining associative data with a limited number of variables. Machine learning approaches provide additional predictive analysis. The purpose of this study is to evaluate the survival predictability of demographic/clinical data for glioblastoma (GBM) patients treated with chemoradiation therapy (CRT) using various machine learning analytic tools. Four hundred fifty-two patients from RTOG 0525 were studied. The predictors that were examined as input to the predictive model included age, gender, race, extent of resection, neurologic function, Karnofsky performance score (KPS), and MGMT status. One-year overall survival (OS 1y) and 6-month progression-free survival (PFS 6m) were first calculated for the predictors. Machine learning models (logistic regression (LR), support vector machine (SVM), decision tree (DT), and neural network (NN)) were applied to evaluate predictability of the calculated endpoints; AUC (area under the receiver operating characteristic (ROC) curve), sensitivity and specificity (and corresponding 95% confidence interval) were determined after repetitions of 10-fold cross-validation. Observed OS 1y and PFS 6m were 63.5% and 65.5%. Higher prediction accuracy of OS 1y was achieved by using LR (AUC = 0.73 ± 0.02, sensitivity 83% ± 2%, specificity 47% ± 2%) and NN (AUC = 0.70 ± 0.02, sensitivity 80% ± 2%, specificity 46% ± 2%) compared to SVM (0.66 ± 0.01, sensitivity 89% ± 1%, specificity 29% ± 2%) and DT (0.65 ± 0.02, sensitivity 79% ± 2%, specificity 41% ± 2%). Although SVM achieved the highest sensitivity (89%), the specificity was the lowest (29%). When predicting PFS6m, similar accuracy was obtained by using DT (AUC = 0.59 ± 0.02, sensitivity 81% ± 1%, specificity 28% ± 2%) and NN (AUC = 0.59 ± 0.02, sensitivity 85% ± 2%, specificity 22% ± 2%). Logistic regression and SVM were not able to achieve meaningful prediction. The prediction accuracy of PFS6m was low reflecting the relative “softness” of this endpoint in this disease. Neural network is the most accurate and consistent model for predicting survival of GBM patients treated with CRT using demographic/clinical data. To achieve more accurate predictions on short-term OS and PFS, advanced analytics tools should be considered; the AUC for OS1y is far superior to that of PFS6m.

Objective: Adjuvant radiation therapy (RT) is an essential part of combined limb-sparing treatment of soft-tissue sarcoma (STS). Elderly or medically unfit patients often have difficulty in completing 6-7 weeks of standard fractionated daily treatment. Our aim was to evaluate the efficacy of a hypofractionated adjuvant approach with RT for STS in elderly and debilitated patients.Methods: 21 elderly patients were treated with a short course of adjuvant RT (39-48Gy, 3Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for local or distant recurrence and side effects of RT.Results: At a mean 26 months of follow-up, three local recurrences (14%) were detected. Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long-term side effects.Conclusion: Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients.Advances in knowledge: The results of this study might provide an alternative to commonly used standard fractionation of radiotherapy in sarcoma patients.

The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries.

To evaluate the localization accuracy of an investigational gantry-mounted tracking system (RealEye, Navotek Medical Ltd., Israel). The system tracks in real time the location of an implanted fiducial marker containing a low activity iridium-192 source (Tracer, Navotek Medical Ltd) for the purpose of real time patient positioning guidance as well as target position monitoring during treatment. This EC-approved study includes a total of 20 patients implanted with the Tracer. Standard gold seeds were placed as well. Eligibility criteria include non-metastasized adenocarcinoma of the prostate; age ≥ 45 years; estimated prostate volume ≥ 30 ml; scheduled external radiotherapy with curative intent; positioning verification according to the local protocol; no limitations for pelvic imaging (such as hip prosthesis); informed consent. During delivery of radiotherapy, positioning verification is done with the standard on-line verification procedure using MV images based on the implanted gold seeds. At 5 treatment sessions, cone beam CT (CBCT) is made before and after delivery of radiotherapy, and measurements made by the RealEye system are recorded before and after each CBCT. The absolute location of the Tracer as measured from the CBCT images and by the RealEye system are compared (total of 4 comparisons per session). Results from the first 10 patients, a total of 200 comparisons, have been analyzed. Of the CBCT images, 3 could not be used because of smearing of the fiducials due to prostate and/or patient movement. The mean 3D vector length difference between CBCT and RealEye localization for the remaining 194 comparisons was less than 1.5 mm. The results indicate that the RealEye tracking system can localize an implanted radioactive fiducial marker with sufficient accuracy for use in patient positioning and target position monitoring during external beam radiation therapy of the prostate.

Although chemoradiation was viewed as the standard of care in the adjuvant management of gastric cancer since the publication of INT 0116, a more recent phase III trial (MAGIC) did not include radiotherapy in the randomization schema. The subtext of the latter trial (i.e., that radiation may be expendable in this disease) mandates that future prospective studies utilizing radiotherapy optimize its application. We therefore set out to determine whether IMRT could improve upon our published 3-D conformal approach for treatment to the stomach and draining nodes. A total of 10 patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a non-coplanar four-field arrangement (Soyfer et al., IJROBP 2007;69:364-369). In each case, parallel planning using an IMRT approach was carried out for comparative purposes. Two beam arrangements were evaluated: Beam arrangement 1: gantry angles 0° 53° 107° 158° 204° 255° 306°. Beam arrangement 2: gantry angles 30° 90° 315° 345° and gantry angle 320°/couch 30° gantry angle 35°/couch 312°. The plans generated were subsequently assessed for target volume coverage and dose deposition in adjacent critical organs. Dose-volume histograms (DVHs) were generated for the CTV, kidneys, spine, and liver. The comparative study of the CTVs revealed satisfactory coverage by the 95% isodose envelope with either treatment approach (IMRT or 3D). The liver, spine and right kidney showed marginal benefit from the IMRT approach. In the left kidney, the mean dose dropped from 33 Gy in the conformal plan to 13 Gy in the IMRT plan. IMRT offers marginal benefits in the adjuvant treatment of gastric cancer and should only be offered to the small subset of patients with risk factors for kidney disease or pre-existing nephropathy.

Limited information is available in the medical literature on epidemic Kaposi sarcoma (EKS) of the foot. Patients with EKS of the foot can experience severe discomfort that makes it difficult to ambulate and even wear shoes. Between 1985 and 1996, 36 patients with EKS of the foot were treated with palliative intent. Most patients were referred for radiation therapy because of foot discomfort or marked difficulty with ambulation. From the pool of 36 patients, data were available at completion of treatment for 46 sites, and at 1 month for 44 sites. Morbidity was assessed for 35 sites. The median follow-up time for the 44 sites with at least 1 month follow-up was 8 months. The most frequently used regimen was a novel fractionation schedule of three fractions a week at 3.5 Gy/fx to a total dose of 21.0 Gy. The overall response rate and complete response rate for the 44 sites with at least 1 month follow-up were 91% and 80%, respectively. The 46 treated sites evaluated at the completion of treatment had a complete response rate of only 13% and an overall response rate of 63%. Of the 35 sites assessed for acute toxicity, 63% experienced discomfort related to the radiation therapy. This discomfort usually resolved without intervention within 2 weeks of completion of radiation therapy. For patients with and without a history of opportunistic infections, complete responses were observed in 8 of 12 sites (67%) and 25 of 27 sites (93%), respectively (p = 0.06). Radiation therapy for EKS of the foot yields excellent response rates, comparable with responses seen in other cutaneous sites with EKS. Appropriate patient education and support are needed because initial responses to radiation therapy are often disappointing and pedal discomfort can be exacerbated transiently. However, the discomfort resolves and complete response occurs in most patients. The 3.5-Gy triweekly fractionation schedule is a convenient and effective regimen and minimizes treatment visits for patients with ambulatory discomfort. A history of opportunistic infections appears to be a poor prognosticator of response to radiation treatments.

Purpose: Despite increased utilization of fractionated stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS), the incidence and nature of immediate side effects (ISE) associated with these treatment techniques are not well defined. We report immediate side effects from a series of 78 patients.Materials and Methods: Intracranial lesions in 78 adult patients were treated with SRT or SRS, using a dedicated linear accelerator. Those lesions included 13 gliomas, 2 ependymomas, 19 metastatic tumors, 15 meningiomas, 12 acoustic neuromas, 4 pituitary adenomas, 1 optic neuroma, 1 chondrosarcoma, and 11 arteriovenous malformations (AVM). SRT was used in 51 and SRS in 27 patients. Mean target volume was 9.0 cc. Eleven patients received prior external-beam radiation therapy within 2 months before SRT/SRS. Any side effects occurring during and up to 2 weeks after the course of radiation were defined as ISE and were graded as mild, moderate, or severe. The incidence of ISE and the significance of their association with several treatment and pretreatment variables were analyzed.Results: Overall, 28 (35%) of 78 patients experienced one or more ISE. Most of the ISE (87%) were mild, and consisted of nausea (in 5), dizziness/vertigo (in 5), seizures (in 6), and new persistent headaches (in 17). Two episodes of worsening neurological deficit and 2 of orbital pain were graded as moderate. Two patients experienced severe ISE, requiring hospitalization (1 seizure and 1 worsening neurological deficit). ISE in 6 cases prompted computerized tomography of the brain, which revealed increased perilesional edema in 3 cases. The incidence of ISE by diagnosis was as follows: 46% (6 of 13) for gliomas, 50% (6 of 12) for acoustic neuromas, 36% (4 of 11) for AVM, 33% (5 of 15) for meningiomas, and 21% (4 of 19) for metastases. A higher incidence of dizziness/vertigo (4 of 12 = 33%) was seen among acoustic neuroma patients than among other patients (n < 0.01). There was no significant association of dizziness/vertigo with either a higher average and maximum brainstem dose (p = 0.74 and 0.09, respectively) or with 2-Gy equivalents of the average and maximum brainstem doses (p = 0.28 and 0.09, respectively). Higher RT dose to the margin and higher maximum RT dose were associated with a higher incidence of ISE (p = 0.05 and 0.01, respectively). However, when RT dose to the margin was converted to a 2-Gy dose-equivalent, it lost its significance as predictor of ISE (p = 0.51). Recent conventional external-beam radiation therapy, target volume, number of isocenters, collimator size, dose inhomogeneity, prescription isodose, pretreatment edema, dose of prior radiation, fraction size (2.0-7.0 Gy with SRT and 13.0-21.0 Gy with SRS), fractionation schedule, and dose to brainstem were not significantly associated with ISE. ISE occurred in 26% (8) of 31 patients taking corticosteroids prior to SRT/SRS and in 20 (42%) of 47 patients not taking them (p = 0.15).Conclusion: ISE occur in one third of patients treated with SRT and SRS and are usually mild or moderate and self-limited. Dizziness/vertigo are common and unique for patients with acoustic neuromas and are not associated with higher brainstem doses. We are unable to detect a relationship between ISE and higher margin or maximum RT doses. No specific conclusion can be drawn with regard to the effect of corticosteroids, used prior to SRS/SRT, on the occurrence of ISE. (C) 1999 Elsevier Science Inc.

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.

Postoperative radiotherapy for low-grade gliomas has been shown in retrospective series to improve survival, compared with surgery alone. To determine the proper radiotherapy treatment volume and dose, an understanding of the patterns of failure with current radiotherapy techniques is necessary. We studied 30 consecutive patients who had a pathologic diagnosis of low-grade nonpilocytic glioma treated in our department between 1975 and 1994. Before radiotherapy, 5 patients underwent biopsy, 22 had subtotal resection, and 3 had gross total excision. All had pre-and posttreatment computed tomographic (CT) or magnetic resonance imaging (MRI) scanning. Megavoltage radiotherapy was delivered to shrinking partial (22 patients) or whole-brain (8 patients) fields. Median dose was 59.4 Gy (range, 46.4-64 Gy) in 1.8- to 2-Gy fractions. Median follow-up was 44 months (3-215 months) for the cohort and 105 months for survivors. For the entire series, 5-year overall survival and relapse-free survival rates were 50% and 41%, respectively. Sixteen patients (53%) progressed at a median of 30 months. At the time of failure, 71% (5 of 7) of pathologically evaluated tumors were of high grade. Recurrence originated within the field in all patients. Higher 5-year overall survival and relapse-free survival rates were associated (p < 0.001) with preradiotherapy functional status 1 versus functional status 2 through 4 (60% vs. 0% and 55% vs. 0%, respectively). Seizure as initial presentation was favorable over other symptoms (5-year overall survival, 64% versus 14%; p = 0.057).We conclude that 1) low-grade nonpilocytic gliomas can transform to high-grade lesions after treatment with conventional radiotherapy, 2) recurrence uniformly occurs within the treatment volume, and 3) pretreatment functional status correlates prognostically with survival. The local pattern of failure suggests that radiotherapy dose escalation within conformal fields could improve results.

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.

Purpose/Objective: Many patients who have uterine-confined endometrial cancer with prognostic factors predictive of recurrence are treated with adjuvant pelvic radiation. The addition of a brachytherapy vaginal cuff boost is controversial.Materials and Methods: Between 1983 and 1993, 270 patients received adjuvant postoperative pelvic irradiation following hysterectomy for Stage I or II endometrial cancer. Group A includes 173 patients who received external beam irradiation alone (EBRT), while group B includes 97 patients who received EBRT with a vaginal brachytherapy application. The median dose of EBRT was 45 Gy. Vaginal brachytherapy consisted of a low dose rate ovoid or cylinder in 41 patients, a high dose rate cylinder in 54 patients, and a radioactive gold seed implant in two patients. The median follow-up time was 61 months. The two groups were compared in terms of age, histologic grade, favorable versus unfavorable histology, capillary space invasion, depth of myometrial invasion, and pathologic stage.Results: Chi-square analysis revealed that the only difference between the two groups was the presence of more Stage II patients in group B (38% versus 14%). No difference was detected for 5 year pelvic control and disease-free survival rates between groups A and B.Conclusion: There is no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation is beneficial for pelvic control or disease-free survival for patients with Stage I or II endometrial cancer. Prospective randomized trials designed to study external irradiation alone versus external beam treatment plus vaginal brachytherapy are unlikely to show a positive result. Because EBRT provides excellent pelvic control, protocol development for uterine-confined corpus cancer should focus on identifying patients at risk for recurrence as well as other means of augmenting EBRT (e.g. addition of chemotherapy) in order to improve disease free survival in those subgroups. (C) 1998 Elsevier Science Inc.

Purpose: Renal cell carcinoma has traditionally been regarded as a radioresistant cancer, yet controversy continues as to whether escalation of the palliative radiation dose can overcome the inherent resistance of such tumors when they metastasize. Recently, the linear quadratic model has emerged as a paradigm to assess biologically effective dose of radiotherapy. This study was undertaken to determine the ability of radiotherapy to palliate focally symptomatic metastatic renal cell carcinoma and to assess whether the delivery of higher biologically effective dose was more likely to bring about a palliative response.Materials and Methods: Between 1966 and 1995, 107 patients with renal cell metastases at 150 sites were irradiated with palliative intent; Sites irradiated included bone (89), soft tissue (16), brain (20), spinal cord (9) and pulmonary (16). To determine dose effectiveness the biologically effective dose was calculated according to the formula, Gy(10) = total dose(1 + fractional dose/alpha-beta), using an alpha-beta of 10.Results: For the entire group 86% of patients derived a palliative response after treatment with irradiation, while 49% derived a complete palliative response. The median duration of palliation was 6 months (range 1 to 150). With respect to overall (that is, complete and partial) response rates, those presenting with high Karnofsky performance status were most likely to respond (status 70 or greater versus less than 70, 88% versus 78%, p < 0.043. With respect to the rate of complete palliative response, performance status (status 70 or greater versus less than 70, 55% versus 31%, p < 0.03) and the use of higher biologically effective doses of irradiation (Gy(10) 50 or greater versus less than 50, 59% versus 39%, p = 0.001) were associated with a statistically significant increased rate of response. The independent prognostic value of performance status and higher biologically effective doses of irradiation were maintained in multivariate analysis.Conclusions: Despite the prevailing concept that renal cell carcinoma is generally resistant to radiotherapy, the overwhelming majority of patients seen at our institution in whom metastatic renal cell carcinoma developed were palliated with radiotherapy. A complete palliative response is more likely when higher biologically effective doses of irradiation are delivered, especially to patients with a relatively high performance status.