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PURPOSE: Tilting of the posterior plaque margin during eye plaque brachytherapy can lead to tumor underdosing and increased risk of local recurrence. We performed a quantitative analysis of the dosimetric effects of plaque tilt as a function of tumor position, basal dimension, height and plaque type using 3D treatment planning software. MATERIALS AND METHODS: Posterior and anterior tumors with largest basal dimensions of 6, 12 and 18 mm and heights of 4, 7 and 10 mm were modeled. Both Eye Physics and COMS plaques were simulated and uniformly loaded. Plans were normalized to 85 Gy at the tumor apex. Posterior plaque tilts of 1, 2, 3 and 4 mm were simulated. RESULTS: Volumetric coverage is more sensitive to tilt than the area coverage. Wide, flat tumors are more susceptible to tilt. Apical dose changed significantly as a function of tumor height and diameter. No other parameter exhibited significant differences. Posterior tumors are slightly more susceptible to tilt due to the use of notched plaques. Plaque type does not significantly alter the effect of plaque tilt. CONCLUSIONS: Wide, flat tumors are the most susceptible to plaque tilt. Tumor location or plaque type does not have a significant effect on dosimetry changes from plaque tilt. Robust clinical procedures such as the use of mattress sutures, pre- and post-implant ultrasound and post-implant dosimetry can all mitigate the risk associated with plaque tilt.

Purpose/Objective(s) I125 Eye Plaque brachytherapy is the standard treatment for medium size uveal melanomas. As a result, most patients have late radiation toxicities (RTT) such as radiation-induced maculopathy (RM), radiation-induced neovascular glaucoma/iris neovascularization (RNGI) and radiation-induced optic neuropathy (RON) that result in vision loss. While tumor size, location and radiation dose have been identified as predictors of radiation toxicity, we hypothesize demographics, pre-treatment tumor characteristics and post-operative complications may also impact radiation toxicities. Materials/Methods An IRB-approved retrospective chart review was performed from 2011-2019 to evaluate patients with posterior uveal melanomas who were treated with brachytherapy at a single institution in the Southeast with a large Hispanic population, with a minimum of 3 months follow-up. We collected patient demographics, pre-treatment tumor characteristics, tumor margin to fovea/optic disk and post-operative complications as potential predictors of RTT. RTT was defined as an event of RM, RNGI, or RON following plaque removal. Univariable analysis (UVA) and multivariable analysis (MVA) were performed using logistic regression model to examine the associations between study variables and the development of RTT. Odds ratios (ORs) and corresponding P-values were reported. All tests were two-sided and statistical significance was considered when P Results A total of 262 patients were evaluated over 8 years. Median follow up was 33.5 months (range 3.02 – 97.31). 178 pts (67.9%) had RTT. 131 pts (50.0%) developed RM. 19 pts (7.3%) developed RNGI. 56 pts (21.4%) developed RO. 41 pts (15.8%) identified as Hispanic. UVA found shorter distance to fovea (OR = 0.97, P = 0.025), post-operative subretinal fluid/exudative retinal detachment (RD) (OR = 2.89, P = 0.002) and vitreous hemorrhage (OR = 3.73, P = 0.002) are associated with RTT and Hispanic ethnicity is not significantly associated with RTT when compared to non-Hispanics (OR = 1.54, P = 0.219). MVA found shorter distance to fovea (OR = 0.95, P = 0.004), post-operative subretinal fluid/exudative RD (OR = 3.14, P = 0.006) and vitreous hemorrhage (OR = 4.50, P = 0.003) are associated with increased RTT. Conclusion These data suggest that shorter distance to fovea and post-operative complications such as subretinal fluid/exudative RD and vitreous hemorrhage are associated with increased risk of RTT. This study can serve as prognostic tools to better counsel patients on the risks and benefits of brachytherapy and allow for early intervention in the management of RTT. These data need to be validated in a prospective trial investigating post-operative complications and subsequent RTT after the treatment of posterior uveal melanomas. Author Disclosure V.A. Peters: None. A. Gurayah: None. D. Kwon: None. W. Zhao: None. W. Jin: Stock; Vit Inc. Partnership; Vit Inc. N.V. Patel: None. A.M. Markoe: None. Z. Correa: None. M.T. Studenski: None. J. Harbour: None. S. Samuels: None.

PURPOSE: From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m(2) of 1,3 bis (2 chloroethyl)-1 nitrosourea on days 1–3 q8 weeks for 1 year. METHODS: Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. RESULTS: Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 mo vs. 13.1 mo (p=0.20) or PFS, with a median PFS time of 5.7 mo vs. 6.9 mo (p=0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio=1.16; p=0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 mo vs. 11.2 mo; p=0.34), anaplastic astrocytoma (MST: 69.8 mo vs 50.0 mo; p=0.91) or anaplastic oligodendroglioma (MST: 92.1 mo vs. 66.5 mo; p=0.33). CONCLUSION: Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

PURPOSE/OBJECTIVE(S) Plaque brachytherapy is an effective vision- and eye-sparing procedure for uveal melanoma. Few have investigated longitudinal tumor outcomes while using advanced dosimetry and plaque planning software. We hypothesize that patients with large tumors, pre-operative eye complications, and molecular class 2 tumors will have worse outcomes. MATERIALS/METHODS We constructed an IRB-approved retrospective database from a single academic institution with uveal melanoma patients receiving Iodine-125 brachytherapy, 85 Gy over 72 hours prescribed to the tumor apex, between 2011-2019 with a minimum of 3-month follow-up. Data on patient demographics, tumor characteristics, pre-treatment (pre-Tx) retinal complications, post-plaque treatments (PPTx), local recurrences (LR), distant metastases (DM) and overall survival (OS) were collected. Univariate (UVA) and multivariate (MVA) Cox models for OS and cumulative incidence of LR/DM and death without LR/DM as competing risk were conducted using SAS version 9.4. Hazard ratios (HRs) and corresponding P-values were estimated. RESULTS 262 patients were identified, with a median follow-up time of 33.5 months (3.02 - 97.3 months). 19 patients (7.3%) had local recurrence, 17 patients (6.5%) had distant metastasis, and 20 patients (7.6%) died. For LR, on UVA pre-Tx ocular melanocytosis (HR = 5.48, P = 0.01), Eye Physics plaque (HR = 3.70, P = 0.013), and PPTx with transpupillary thermotherapy (HR = 4.65, P = 0.002) were associated with increased LR. No association was found between class 2 tumors and LR (HR = 0.51, P = 0.297). For DM, on UVA pre-Tx retinal detachment (HR = 7.26, P = 0.002), class 2 tumors (HR = 4.35, P = 0.005), PPTx with intravitreal triamcinolone (HR = 4.01, P = 0.006), and large tumor height (HR = 1.23, P < 0.001), tumor area (HR = 1.02, P < 0.001), distance to fovea (HR = 1.13, P = 0.002), and prescription depth (HR = 1.23, P = 0.001) were all associated with increased DM. No MVA was conducted for LR and DM because there were too few events. For any tumor progression (LR or DM), on UVA pre-Tx ocular melanocytosis (HR = 4.26, P = 0.005), Eye Physics plaque (HR = 3.41, P = 0.002), any PPTx (HR = 4.50, P = 0.012), PPTx with intravitreal triamcinolone (HR = 3.30; P < 0.01), and large tumor area (HR = 1.01, P < 0.001) were associated with progression. On MVA pre-Tx ocular melanocytosis (HR = 5.55, P < 0.001), Eye Physics plaque (HR = 2.45, P = 0.049), and any PPTx (HR = 4.47, P = 0.017) were associated with progression. PPTx with aflibercept was associated with less progression (HR = 0.13, P = 0.019). CONCLUSION Ocular melanocytosis and receiving any post-plaque treatment had the greatest impact on tumor progression. Class 2 tumors predicted for distant metastases but not local recurrences. These findings inform physicians of predictors of brachytherapy outcomes and allows for better shared-decision making with pre-operative patients. Future studies must validate these findings using a prospective cohort study.

Purpose To build a framework for investigation of the associations between imaging, clinical target volumes (CTVs), and metabolic tumor volumes (MTVs) features for better understanding of the underlying information in the CTVs and dependencies between these volumes. High-throughput extraction of imaging and metabolomic quantitative features from magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging of glioblastoma multiforme (GBM) results in tens of variables per patient. In radiation therapy of GBM the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N -acetyl aspartate (NAA) and choline (Cho). The corresponding clinical target volumes (CTVs) for radiation therapy are based on contrast-enhanced T1-weighted (CE-T1w) and T2-weighted (T2w)/fluid-attenuated inversion recovery MRI. Methods and Materials Necrotic portions, enhancing lesion, and edema were manually contoured on CE-T1w/T2w images for 17 GBM patients. Clinical target volumes and MTVs for NAA (MTV NAA ) and Cho (MTV Cho ) were constructed. Imaging and metabolic features related to size, shape, and signal intensities of the volumes were extracted. Tumors were also scored categorically for 10 semantic imaging traits by a neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and CTVs/MTVs features were visualized as heatmaps. Associations between MTV NAA and MTV Cho and imaging features were studied using Spearman correlation. Results Forty-eight imaging features were extracted per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. Twenty features were extracted from CTVs and MTVs. A series of semantic imaging traits were replaced with automatically extracted continuous variables. There were multiple (22) significant correlations of imaging measures with CTVs/MTV NAA , whereas there were only 6 with CTVs/MTV Cho . Conclusions A framework for investigation of codependencies between MRI and magnetic resonance spectroscopic imaging radiomic features and CTVs/MTVs has been established. The MTV for NAA was found to be closely associated with MRI volumes, whereas very few imaging features were related to MTV Cho , indicating that Cho provides additional information to imaging.

A common treatment planning technique for eye plaque brachytherapy is to model the tumor as an ellipse. For posterior tumors near the optic disc and fovea, this approach may lead to overlap between tumor and the organ at risk (OAR). We hypothesized that a superior plan can be generated by modeling the actual tumor shape.Forty eye plaque patients with tumors1 cm from the optic disc and fovea were selected. Two treatment plans were generated for each patient: an elliptical tumor model plan and a true tumor model plan. Dosimetric data were collected for each plan, and Wilcoxon signed-rank tests were used to asses any statistically significant differences.Equivalent tumor coverage was confirmed between the elliptical and true tumor plans for all patients. Qualitative analysis showed greater dosimetric differences between plans as the distance from the OARs increased from 0 to 2 mm but the largest differences were observed between 2 and 4 mm. Minimal differences between models were seen beyond 4 mm. Statistically significant dosimetric improvements were found for tumors4 mm from the fovea and2 mm from the optic disc.Intuitively, accurate modeling of the tumor accounting for irregularities in the shape should result in a more conformal plan and an overall reduction in OAR dose. However, this technique is only beneficial for tumors that are within 4 mm of the fovea or optic disc. An elliptical tumor model allows for an acceptable plan unless the tumor is located posteriorly and has an irregular shape.

Mycosis Fungoides (MF), the most common cutaneous T cell lymphoma, is usually indolent and characterized by slow progression from patches to plaques and tumor formation with systemic dissemination....

Purpose Gene expression profiling has been shown to yield two distinct molecular genetic signatures for uveal melanoma. These class designations tend to predict tumor aggressiveness and the likelihood of metastasis. Tumors with a class 1 genetic signature are generally much less aggressive than tumors with a class 2 genetic signature. Gene expression analysis for previously treated uveal melanoma has not yet been reported. The authors report three cases where genetic analysis was successfully obtained from uveal melanoma that was previously treated years earlier with radiotherapy. Case report The patients in all three cases received globe-conserving radiotherapy for treatment of choroidal melanoma before gene expression profiling was readily available. The patients in cases 1 and 2 received 125I plaque brachytherapy while the patient in case 3 received proton irradiation therapy. When secondary surgery was necessary to stabilize these eyes from the effects of radiation retinopathy, fine-needle aspiration biopsy was also performed for gene expression profiling. Genomic analysis revealed a class 1 molecular signature for the patient in case 1 and a class 2 molecular signature for the patients in cases 2 and 3. Conclusions Gene expression profiling for uveal melanoma may be obtained from patients who were previously treated with radiotherapy; however, the implication of these results will benefit from ongoing clinical evaluation.

Dural lymphoma (DL) is a rare type of primary CNS lymphoma arising from the dura mater. The optimal treatment is uncertain. A retrospective review was performed on 26 DL patients. Seventeen patients underwent resection and nine had a biopsy. Twenty three patients could be assessed for a response to treatment after surgery. Thirteen received focal radiotherapy (RT), six whole brain RT (WBRT), three chemotherapy alone and one chemotherapy followed by WBRT. Twenty two achieved complete response (CR) and one a partial response (PR). Four patients relapsed (two local and two systemic). Median follow up was 64 months, with median progression free survival (PFS) and OS not reached. Three year PFS was 89% (95% CI 0.64–0.97). All patients are alive at last follow-up, demonstrating that DL is an indolent tumor with long survival. CR is achievable with focal therapy in the majority of cases, but there is a risk for relapses and long-term follow-up is recommended.

BACKGROUND: The objective of this study was to identify predictors of locoregional recurrence (LRR) after neoadjuvant therapy (NAT) and postmastectomy radiation (PMRT) in a cohort of patients with stage II through III breast cancer and to determine whether omission of the supraclavicular field had an impact on the risk of LRR. METHODS: The authors reviewed records from 464 patients who received NAT and PMRT from January 1999 to December 2009. RESULTS: The median patient age was 50 years (range, 25-81 years). Clinical disease stage was stage II in 29% of patients, stage III in 71%, and inflammatory in 14%. Receptor status was estrogen receptor (ER)-positive in 54% of patients, progesterone receptor (PR)-positive in 39%, human epidermal growth factor receptor 2 (HER2)-positive in 24%, and negative for all 3 receptors (triple negative) in 32%. All patients received NAT and underwent mastectomy, and 19.6% had a complete pathologic response in the breast and axilla, 17.5% received radiation to the chest wall only, and 82.5% received radiation to the chest wall and the supraclavicular field; omission of the supraclavicular field was more common in patients with lower clinical and pathologic lymph node status. The median follow-up was 50.5 months, and the 5-year cumulative incidence of LRR was 6% (95% confidence interval, 3.9%-8.6%). Predictors of LRR were clinical stage III (P = .038), higher clinical lymph node status (P = .025), higher pathologic lymph node status (P = .003), the combination of clinically and pathologically positive lymph nodes (P 2 cm (P = .045). On univariate analysis, omission of the supraclavicular field was not associated significantly with LRR (hazard ratio, 0.89; P = .833); however, on multivariate analyses, omission of the supraclavicular field was associated significantly with LRR (hazard ratio, 3.39; P = .024). CONCLUSIONS: Presenting stage, receptor status, pathologic response to neoadjuvant therapy, and omission the supraclavicular field were identified as risk factors for LRR after neoadjuvant therapy and PMRT. Cancer 2013. © 2012 American Cancer Society.

Leptomeningeal (LM) failure of retinoblastoma (Rb) has not previously been reported. Upon review of our institutional experience of external beam radiotherapy (EBRT) for Rb, we found three LM failures. We sought to better define the clinical parameters of this type of recurrence. All children with LM failure had Reese-Ellsworth stage Vb eyes. Otherwise, no variables were significantly associated with LM failure. We theorize that this phenomenon is a function of the late-stage eyes for which EBRT is being reserved in the modern era. Pediatr Blood Cancer 2015;62:533–535. © 2014 Wiley Periodicals, Inc.

e14059Background: Primary vitreoretinal lymphoma (PVRL) is a subset of primary central nervous system lymphoma involving the vitreous and retina of the eye and may occur either as an isolated disea...

CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m2) followed 24 h later by VM-26 (125 mg/m2). VP-16 (125 mg/m2) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m2. Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3-31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.

The number of CAG repeats on the androgen receptor (AR) gene is inversely proportional to transcriptional activity. The purpose of this study was to determine if short-term androgen deprivation therapy (RT + HT) can improve outcome in patients with tumors with short CAG repeats (19).Prostate cancer patients were randomized to receive either radiotherapy (RT) alone or (RT + HT) in the RTOG 86-10 study. CAG repeats were measured in 94 tumor specimens (21%; test cohort) of the 456 (parent cohort) analyzable cases. AR flow cytometry measurements were done on 13 patients. The effect on local failure (LF), distant metastases (DM), prostate cancer survival (PSS), and overall survival (OS) was studied.Pretreatment characteristics and assigned treatment arm were not significantly different between the parent and test groups except for a significantly higher risk of death (P = 0.049) in the test group. The median CAG repeat was 19. There were no significant differences in stage, or Gleason score between high (19 or greater) and low CAG (19) patients within each treatment group. Number of CAG repeats alone did not significantly influence LF, DM, PSS, and OS. However, when the CAG repeat outcome was studied in conjunction with androgen deprivation therapy, patients with CAG19 who received H + RT had improved local control as compared with patients who received RT alone (P = 0.026, 5-year rates 4.6% versus 36.4%) and improved local control over patients with CAGor =19 that received H + RT (P = 0.028).Patients with short CAG repeats show a local control benefit with short-term androgen deprivation therapy, but no improvement in survival.

The objective of this study was to determine the toxicity and efficacy of the current phase II chemoradiation protocol. Stage III or IV locally advanced head and neck squamous cell carcinomas arising from the oral cavity, hypopharynx, oropharynx, nasopharynx, paranasal sinuses, or larynx were treated using hyperfractionated radiation (74.4 Gy at twice-daily fractions of 1.2 Gy) in combination with a 5-fluorouracil, cisplatin, paclitaxel regimen, and an amifostine infusion. Thirty-five of 36 eligible patients were evaluable. The overall survival (OVS) was 88%, 82%, and 66% at 1, 2, and 3 years respectively. Twenty-five patients (71%) had a complete response, which was maintained in 20 (57%) patients until last follow up or death. Disease-free survival (DFS) of the complete responders was 92% at 1 year and 77% at 2 years and 3 years, respectively. Percutaneous endoscopic gastrostomy dependency lasted for a median of 7 months. Grade 3 and 4 mucositis occurred in 23 and 3 patients, respectively. Comparison with a similar study (A-2) that did not include amifostine showed no significant benefit to the addition of amifostine in these patients. A locoregional control benefit should be confirmed in a prospective, randomized trial. Alternative amifostine delivery methods should be investigated.

Purpose: To determine quality of life (QOL) after hyperfractionated radiation and chemotherapy. Materials and Methods: Functional Assessment of Cancer Therapy (FACT) and the Functional Assessment of Cancer Therapy-Head and Neck (FACT H-N) questionnaires were administered to protocol patients at baseline study entry, during and at the completion of therapy, and during subsequent follow-up. Results: Twenty-four patients completed baseline QOL questionnaires. Six subsequent assessments were given to patients who were available for follow-up. Social/family well-being and relationship with doctor subscores were not significantly different from baseline. Emotional well-being was not different from baseline initially, but actually showed a significant increase 6 months after completion of radiation, seen on assessments 5 and 6 (P < 0.01). Physical and functional well-being subscores, total FACT-G score, head and neck subscores, and total FACT H-N score all showed initial decreases during, at the completion of radiation, or, in some subscores, up to 3 months postradiation. However, all these scores recovered to baseline levels. These scores subsequently showed a significant increase after 6 months to 1 year in all but the physical well-being and head and neck subscores, which remained at baseline. Conclusion: QOL scores returned to baseline levels or increased at 6 to 12 months postradiation in long-term survivors who completed QOL questionnaires.

This is the first report of the toxicity outcomes using dose level IV (74 Gy) on Radiation Therapy Oncology Group (RTOG) study 9406 for Stage T1-T2 prostate adenocarcinoma.A total of 262 patients were entered in this cooperative group, Phase I-II, dose-escalation trial of three-dimensional conformal radiotherapy for localized prostate carcinoma treated to a dose of 74 Gy (Level IV); 256 patients were analyzable for toxicity. A minimal dose of 2 Gy/fraction was prescribed to the planning target volume (PTV). Patients were stratified according to the risk of seminal vesicle invasion on the basis of the Gleason score and presenting prostate-specific antigen level. Group 1 patients had clinical Stage T1-T2 tumors with a seminal vesicle invasion risk of15%. Group 2 patients had clinical Stage T1-T2 tumors with a seminal vesicle invasion risk of/=15%. Patients in Group 1 were prescribed 74 Gy to a prostate PTV. Patients in Group 2 were prescribed 54 Gy to the prostate and seminal vesicles (PTV1) followed by a boost to the prostate only (PTV2) to 74 Gy. PTV margins between 5 and 10 mm were required. Elective pelvic radiotherapy was not used. The frequency of late effects of Grade 3 or greater was compared with that for a similar group of patients treated in RTOG studies 7506 and 7706, with length of follow-up adjustments made for the interval from therapy completion. A second comparison was made with 206 patients treated to dose level II (73.8 Gy in 1.8-Gy fractions) to see whether the fraction size affected toxicity.The average months at risk for late Grade 3+ toxicity after therapy completion were 28.9 and 23.9 months for Group 1 and 2, respectively. Acute toxicity at dose level IV (74 Gy) was remarkably low, with Grade 3 acute effects reported in only 1% of Group 1 and 3% of Group 2 patients. No Grade 4 or 5 acute toxicities were reported. Late toxicity continued to be low compared with RTOG historical controls. One patient in Group 1 and 4 patients in Group 2 experienced Grade 3 bladder toxicity. Two patients in Group 2 experienced Grade 3 bowel toxicity. No Grade 4 or 5 late effects were reported. The rate of late Grade 2 toxicity (any type) was 23% and 16% in Group 1 and 2, respectively. The observed rate of Grade 3 or greater late effects for Group 1 (1 case) was significantly lower (p0.0001) than the 18.5 cases that would have been expected from the historical control data. The observed rate for Group 2 (6 cases) was also significantly lower (p = 0.0009) than the 21.3 cases expected. No statistically significant difference was noted in the rate of acute or late toxicity in patients who were treated to 73.8 Gy at 1.8 Gy/fraction or 74 Gy at 2.0 Gy/fraction. Patients treated with the larger 2.0-Gy fractions tended to have more Grade 3 or greater toxicity than patients treated with 1.8-Gy fractions (2% vs. 1%, p = 0.09). The results after the longer follow-up with dose level II suggest these differences may increase with additional follow-up.Tolerance to three-dimensional conformal radiotherapy with 74 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size requires additional follow-up.

Purpose: To determine the toxicity and efficacy of concurrent 5-fluorouracil (5-FU), cisplatin, and paclitaxel (Taxol) and hyperfractionated radiotherapy in locally advanced squamous cell carcinoma of the head and neck. Methods and Materials: Twenty-seven patients were entered into this Phase II trial. Eligible patients had Stage III or IV head-and-neck squamous cell carcinoma arising from the oral cavity, hypopharynx, oropharynx, nasopharynx, or larynx. The plan of treatment consisted of hyperfractionated radiotherapy (74.4 Gy at twice daily fractions of 1.2 Gy). Chemotherapy was given on Weeks 1, 5, and 8 as follows: 5-FU at 750 mg/m 2 as a constant infusion for 24 h for 3 days; cisplatin at 50 mg/m 2 in 250–500 mL D5 0.5 NS or NS infusion during 2–4 h, and paclitaxel at 70 mg/m 2 infused in 500 mL NS during 3 h. Results: The overall survival rate of the entire group was 81.5%, 66.7%, and 63% at 1, 2, and 3 years, respectively. The median follow-up was 40.2 months (range 30–62). Of the 27 patients, 19 (70%) had a complete response and an overall survival rate of 100% at 1 year and 94% at 2 and 3 years. The disease-free survival rate of the latter group was 95% at 1 year and 84% at 2 and 3 years. Of the 27 patients, 18 (67%) maintained the complete response until the last follow-up visit or death. Percutaneous endoscopic gastrostomy dependency occurred for a median of 7.1 months. Grade 3 and 4 mucositis occurred in 20 and 3 patients, respectively. Six patients were hospitalized for leukopenic fever. Late toxicities included L'Hermitte syndrome ( n = 3), osteoradionecrosis ( n =1), hypothyroidism ( n = 4), paresthesias ( n = 1), aspiration pneumonia ( n = 3), and esophageal strictures (8 patients underwent dilation). Conclusion: Combining hyperfractionated radiotherapy concurrently with 5-FU, cisplatin, and paclitaxel results in acceptable efficacy and toxicity. However, although a locoregional control benefit is suggested by the preliminary results of this trial, it needs to be confirmed in a prospective randomized trial.

This retrospective study was done to determine whether the number of brachytherapy implants significantly influenced outcome in 86 patients with carcinoma of the cervix treated with radiation alone at the University of Miami/Jackson Memorial Hospital from August 1981 to May 1995. One brachytherapy application was performed in 36 (42%) of the study cohort, whereas 50 (58%) had two implants. Cumulative doses to points A and B ranged from 60.74 Gy to 97.58 Gy (median: 82.46 Gy) and 46.57 Gy to 73.99 Gy (median: 58.51 Gy), respectively. Five-year overall survival (OS) and disease-free survival (DFS) for study patients were 49.4% and 38.7%, respectively. Patients receiving two implants had a higher total dose to point A (p = 0.02), were less likely to complete the radiation in less than 8 weeks (p = 0.01), and showed a trend of having more advanced disease (p = 0.1) and a greater rate of chronic complications (p = 0.09). Univariate analysis failed to demonstrate a statistically significant difference in either OS or DFS concerning one versus two brachytherapy procedures in this series. However, because of the confounding interactions of cumulative dose to point A and overall treatment time in the present series, a prospectively randomized phase III trial is needed to more adequately evaluate this question.

Purpose/Objective(s) To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. Methods and Materials This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. Results Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses ≥45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P =.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. Conclusions External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy.

Purpose: A prospective Phase I dose escalation study was conducted to determine the maximally-tolerated radiation dose in men treated with three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. This is a preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study. Methods and Materials: Each participating institution was required to implement data exchange with the RTOG 3D quality assurance (QA) center at Washington University in St. Louis. 3D CRT capabilities were strictly defined within the study protocol. Patients were registered according to three stratification groups: Group 1 patients had clinically organ-confined disease (T1,2) with a calculated risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2 disease with risk of SV invasion ≥ 15%. Group 3 (G3) patients had clinical local extension of tumor beyond the prostate capsule (T3). All patients were treated with 3D techniques with minimum doses prescribed to the planning target volume (PTV). The PTV margins were 5–10 mm around the prostate for patients in Group 1 and 5–10 mm around the prostate and SV for Group 2. After 55.8 Gy, the PTV was reduced in Group 2 patients to 5–10 mm around the prostate only. Minimum prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level II) and subsequently to 79.2 Gy (level III). This report describes the acute and late toxicity encountered in Group 1 and 2 patients treated to the first two study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the expected probability of observing a ≥ grade 3 late effect more than 120 days after the start of treatment. RTOG toxicity scores were used. Results: Between August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288 cases were analyzable for toxicity. Acute toxicity was low, with 53–54% of Group 1 patients having either no or grade 1 toxicity at dose levels I and II, respectively. Sixty-two percent of Group 2 patients had either none or grade 1 toxicity at either dose level. Few patients (0–3%) experienced a grade 3 acute bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late toxicity was very low in all patient groups. The majority (81–85%) had either no or mild grade 1 late toxicity at dose level I and II, respectively. A single late grade 3 bladder toxicity in a Group 2 patient treated to dose level II was recorded. There were no grade 4 or 5 late effects in any patient. Compared to historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or greater late effects were observed in Group 1 and Group 2 patients when 9.1 and 4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level II, there were no grade 3 or greater toxicities in Group 1 patients and a single grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p = 0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the relative risk of developing acute bladder toxicity was 2.13 if the percentage of the bladder receiving ≥ 65 Gy was more than 30% (p = 0.013) and 2.01 if patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of developing late bladder complications also increased as the percentage of the bladder receiving ≥ 65 Gy increased (p = 0.026). Unexpectedly, there was a lower risk of late bladder complications as the mean dose to the bladder and prescription dose level increased. This probably reflects improvement in conformal techniques as the study matured. There was a 2.1 relative risk of developing a late bowel complication if the total rectal volume on the planning CT scan exceeded 100 cc (p = 0.019). Conclusion: Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality assurance standards and review, 3D CRT can be safely studied in a cooperative group setting. There appears to be a dose-volume relationship with respect to the development of both acute and late bladder toxicities. Whether improvement in efficacy can be gained with this treatment approach will await a prospective randomized trial. Meanwhile, the innovative image/clinical database resulting from this trial will serve as an important resource in the study of late effects and tumor control.

Magnetic resonance imaging (MRI) is more sensitive than computerized tomography in the detection of many intracerebral lesions; however, the significance of some MRI findings may be unclear. Over four years, nine patients, aged 40-79 years, have been encountered whose initial MRI scans were negative or had minimal abnormalities and soon thereafter had high grade glioma. Initial MRI was performed in eight patients for new-onset seizures and one patient for a focal deficit. MRI was negative in four of the patients and mildly abnormal in five of the patients (small areas of increased T2 and/or minimal enhancement). The initial diagnoses usually included inconclusive differentials of stroke and infection with neoplasm less frequently considered. Radiographic progression leading to the diagnosis of high grade glioma became evident on repeat MRI in 1-8 months with six patients showing progression within three months. All patients underwent surgery and had histologic diagnosis of glioma. Although MRI is quite sensitive, four of the initial scans were negative with reasonable quality studies. Conversely, in five of the initial scans, the tumors were detected when so small that the radiographic findings were not typically diagnostic. Glioma must be considered as a possible cause of initial seizures or new neurologic deficits in adults with normal or minimally abnormal MRI. In this group, seizures were the overwhelming hallmark of presentation. In such a clinical situation, close follow-up with short interval repeat MRI should be performed.

Purpose: Stereotactic radiosurgery is currently used to treat patients who are not good candidates for conventional neurosurgical procedures. For treatments of nonvascular tumor cells, it appears that fractionation offers a radiobiological advantage between tumor and normal tissues. Therefore, fractionated stereotactic radiotherapy (FSR) is preferred because it minimizes normal tissue complications and maximizes local tumor control probability. We have implemented a methodology clinically to perform the noninvasive patient repositioning technique. The 3-D data correlation method for high-precision and multiple fraction stereotactic treatments has been presented. Methods and Materials: Three different optimization algorithms (Hooke and Jeeves optimization, simplex optimization, and simulated annealing optimization) are evaluated to calculate the transformation parameters necessary for FSR. A least-square object function is created to perform the 3-D data matching process. By minimizing the unconstrained object function value the best fit can be approached for the reference 3-D data sets. Simulation shows that these algorithms deliver results that are comparable to the previously published correlation algorithm (1, 2) (singular value decomposition [SVD] method). The advantage for optimization algorithms is easily understood and can be readily implemented by using a personal computer (PC). The mathematical framework provides a tool to calculate the transformation matrix which can be used to adjust patient position for fractionated treatments. Therefore, using these algorithms for a high-precision fractionated treatment is possible without an invasive repeat fixation device and has been implemented clinically. A bite plate system was incorporated to acquire 3-D patient data. With a 3-D digital camera localization device, the patient motion can be followed in real time with the system calibrated to the isocenter. Results: Two types of data sets are utilized to study the correlation results. One is using the digitized patient data which were retrieved clinically. The other is using the randomly generated data sets. Simulation errors for the optimization algorithms are all less than 1 mm in translation and less than 1° in rotation. Currently, FSR is performed using special designed repeat fixation devices which assure reproducible patient position for multiple fractions of radiation treatment. Clinical results indicated that this technique provided excellent treatment results. Conclusion: Three optimization algorithms have been applied and evaluated in calculating the transformation parameters between two 3-D contours or digitized data points. The mathematical functions behind these optimization algorithms are straightforward and can be easily implemented. When incorporated with the proper CT/MR image data with an electronic portal imaging (EPI) system, this process can possibly verify the patient's treatment position whenever there is doubt about the movement during the treatment procedure.

This study analyzes a single-institution experience by evaluating the impact on survival of increasing total dose of adjunctive irradiation in patients who had extremity soft-tissue sarcoma (ESTS). A retrospective review of the tumor registry at a university medical center from January 1984 through December 1992 yielded a total of 59 surgical patients of ESTS. With follow-up ranging from 30 to 135 months (median, 65 months), the 2-, 5-, and 8-year overall and disease-free survival for all patients was 86%, 71%, 58% and 76%, 70%, 56%, respectively. Multivariate analyses using the Cox proportional hazards model revealed that total radiation dose (p = 0.02), American Joint Committee on Cancer stage (p = 0.04), and tumor size (p = 0.006) were all significant prognostic factors of overall survival; however, only tumor size was predictive of disease-free survival (p = 0.02). When the effect of tumor size and disease stage were controlled in the Cox model, a dose-response curve between increasing total radiation dose and improved overall patient survival was indicated. This study demonstrates the significance of tumor size on predicting both overall and disease-free survival in patients who have soft-tissue sarcomas of the extremity. It also suggests, however, that a radiation dose-response relation may exist for overall survival. Future investigations should consider evaluating the minimal total radiation dose needed to optimize patient survival after limb-sparing surgery.

BACKGROUND The authors had previously reported preliminary results of a treatment regimen of concurrent hyperfractionated radiation therapy and chemotherapy in patients with locally advanced head and neck carcinoma that demonstrated both feasibility and high local control. In an attempt to reduce acute mucosal and hematologic toxicity, granulocyte-colony stimulating factor (G-CSF) was added during the second phase of this study. METHODS Seventy patients (53 with Stage IV and 17 with Stage III disease) were entered between May 1988 and June 1995 into a Phase I/II trial of concurrent radiation therapy (74.4 gray (Gy) total dose; 1.20 Gy twice daily), 5-fluorouracil (1000 mg/m2/24 hours for 72 hours), and cisplatin (50 mg/m2) for 3 cycles with the addition of mitomycin C (8 mg/m2) in Cycle 2. G-CSF was added after the initial entry of 34 patients. RESULTS At a median follow-up of 41 months (range, 12-80 months), 44 patients were alive with a projected median overall survival of 54 months. Grade 3/4 mucositis, observed in 65% of patients, was equally prevalent and prolonged in both G-CSF-treated (+) and G-CSF-naive (-) patients. Grade 3/4 leukopenia was present in 45% and 36% of G-CSF- and G-CSF+ patients, respectively. The 3-year locoregional control and cause specific survival rates were 68% and 75%, respectively. CONCLUSIONS This regimen was feasible and effective but caused severe mucositis. No benefit was derived from the addition of G-CSF. This regimen deserves further modification to reduce acute mucositis toxicity yet maintain the high locoregional control rate. Cancer 1997; 80:266-76. © 1997 American Cancer Society.

Purpose: An individualized midline shield (MLS) has been advocated for delivering homogeneous radiotherapy for patients with invasive cervical carcinoma. yet, many radiation oncologists continue to employ a standard block. In the latter instance, any deviation of the cranial-caudal central axis of the tandem for the patient's midline could result in dose inhomogeneity to tumor. A retrospective review of a single university medical center's experience with constructing the MLS was initiated to determine the outcome of using a standard block vs. a customized block that conforms to the "Point A" isodose line. In addition, participating radiation oncologists associated with the Gynecologic Oncology group (GOG) were polled to assess if there exists a consensus regarding midline block utilization in the management of cervical cancer patients which could be compared to the institutional study. Methods and Materials: from January 1, 1990 through December 331, 1992, 32 patients with invasive cervical carcinoma who underwent low dose rate brachytherapy at a single institution were identified. Patients were grouped as having a standard block (18 cases), customized block (5 cases), or no block 99 cases). The "Point A" isodose distribution from the implant was superimposed onto the whole pelvic simulation film and quantitatively compared to the actual or a hypothetical standard block outlined on the same radiograph. In September of 1995, 56 member and affiliated institutions in the GOG were surveyed concerning their use of a MLS, and the results were tabulated in December of 1995. Results: Approximately 72% of all cases (23 oput of 32) at the single institution had tandem deviation ranging from 0–230 with a median of 50. This translated into a median percent overdosage to "Point A" Right of 15% and "Point A" Left of 12.5%. Although overall survival and incidence of chronic complications have not been affected by type of shielding, patient follow-up is limited with a median of 17.7 months (range: 4.2–58.9 months). Of the 56 surveyed radiation facilities in the GOG, 34 (61%) respondedd. One center was subsequently excluded as it performs only high dose rate brachytherapy. Of the evaluable respondents, 88% (29 out of 33) utilize a MLS in treating their patients with invasive cervical carcinoma. Of the latter group, 76% (22 out of 29), 21% (6 out of 29), and 3% (1 out of 29) employ a standard block, customized block, and a "step-wedge," respectively. For those using a standard block, 77% (17 out of 22) align the central cranial-caudal axis of the MLS along the corresponding midplane of the patient's pelvis on an anteroposterior radiograph rather than along the superior-inferior central axis of the tandem. Conclusions: This study suggests that the use of a standard midline shield could result in potential tumor dose inhomogeneity and should be avoided. A national survye of major academic centers further suggests that the majority of these facilities also utilize a rectangular central block that is not positioned with respect to possible tandem deivation. Further investigation concerning the techniques of midline shield construction should be considered.

Purpose Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N -acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV 46 and CTV 60 , respectively). MTV Cho and MTV NAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results The MRSI coverage of the brain was between 70% and 76%. The MTV NAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P =.001). In contrast, a considerable fraction of MTV Cho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV 46 and CTV 60 . These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV Cho for these patients were outside of CTV 60 . Conclusions This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.

The benefit of whole-brain radiation therapy (WBRT) following stereotactic radiation surgery (SRS) for brain metastases is controversial. We conducted a systematic analysis of published literature to explore the outcome of brain metastases treated with SRS and WBRT versus SRS alone using PubMed and MEDLINE. Outcomes including survival, control, salvage therapy, and other quality of life measures were reported. Three randomized controlled trials involving 389 patients with 1 to 4 brain metastases were selected. In 2 of these trials (n = 190), the mean 1-year survival was 33.2% for SRS + WBRT and 38.7% for SRS alone (P = .5233); 1-year local control was 89% for SRS + WBRT and 71% for SRS alone (P < .001). Mean crude distant recurrence rate for SRS + WBRT was 36.6% and 54% for SRS alone (P < .001). Patients without WBRT were over 3 times more likely to require salvage therapy (P < .001). The addition of WBRT was associated with a decreased health-related quality of life assessment, mini mental status exam, and Hopkins Verbal Learning Test (P < .05). Five retrospective studies (n = 1122) were also included in a separate analysis and yielded findings that supported results from the randomized trials. Our systematic analysis demonstrates that adjuvant WBRT following SRS for the treatment of oligometastases in the brain is more effective at controlling local and distant recurrence than SRS alone, but there is no apparent benefit for survival or symptomology. The proven cognitive decline and neurotoxicity present with WBRT should be weighed against the benefit of local control. Prognosis of brain metastasis is poor regardless of current treatment and further exploration for alternative adjuvant treatment for SRS is warranted.

In 1989, the University of Miami began a program incorporating high-dose-rate (HDR) brachytherapy into the definitive treatment of patients with invasive carcinoma of the cervix. Patients received an average total dose to point A of 5,511 cGy (range 4,280-6,360 cGy) in an average of 57 days (range 39-84 days). An analysis of the first 24 cases found 11 FIGO Stage I-B, four Stage II-A, and nine Stage II-B tumors. At the end of all radiation therapy, 19/24 patients' tumors (79.2%) had undergone a clinical complete response (CR). With median follow-up of 26 months (range 14-63 months), three have relapsed locally, two regionally, and six in extrapelvic sites. Almost two-thirds of all failures occurred in patients with tumors >4 cm, who also took more than 8 weeks to complete their treatment. Overall 2-year actuarial survival for the entire study group is approximately 74%. A univariate analysis determined that clinical stage (P = 0.02), overall treatment time (P = 0.03), tumor size (P = 0.05), and response at the end of therapy (P = 0.005) were significant prognostic factors. Multivariate analysis showed that tumor response to therapy was the most important prognosticator of outcome (P = 0.001). Besides five cases of apical vaginal stenosis, there have been no reported chronic complications in this cohort of patients. A prospectively randomized trial is recommended to compare the efficacy of HDR vs. low-dose-rate brachytherapy in cervical carcinoma.

Purpose : To analyze treatment results and patterns of failure following external beam radiation for retinoblastoma and propose treatment guidelines according to specific clinical variables. Methods and Materials : We analyzed 27 patients (34 eyes) with retinoblastoma who received external beam radiation as initial treatment at Hahnemann University Hospital from October 1980 to December 1991 and have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I–II (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV–V. Doses ranged from 34.5–49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5–2.0 Gy fractions generally delivered through anterior and lateral wedged pair fields. Results : At a mean follow up of 35.2 months (range 12–93 months), local tumor control was obtained in 44% (15 out of 34) of eyes with external beam radiation alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or photocoagulation) controlled an additional 10 eyes (29.5%), so that overall ocular survival has been 73.5%. Local tumor control with external beam radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I–II, but in only 20% (4 out of 20) of eyes in Groups III–V. A total of 67 existing tumors were identified prior to treatment in the 34 treated eyes and local control with external beam radiation alone was obtained in 87% (46 out of 53) of tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a total of 28 failure sites were identified and consisted of progression of vitreous seeds in seven instances (25% of failure sites) recurrences from previously existing tumors in 10 instances (36% of failure sites) and development of new tumors in previously uninvolved retina in 11 instances (39% of failure sites). Conclusions : 1) We find that external beam radiation to a dose of 45 Gy in fractions of 1.5 to 2.0 Gy provides adequate tumor control in retinoblastoma eyes Groups I–II (Reese-Ellsworth classification) or tumors measuring 15 mm in diameter or less. Eyes in more advanced group staging or containing tumors larger than 15 mm seem to require higher radiation doses. We propose treatment guidelines for external beam radiation of retinoblastoma that specifically take into account the important clinical variables of tumor stage and patient age. 2) External beam radiation does not prevent the appearance of new tumors in clinically uninvolved retina. Therefore, the traditional belief that external beam radiation can treat the retina “prophylactically” should be seriously questioned. Due to this finding and their significant less morbidity, focal treatment modalities (plaque brachytherapy, photocoagulation and/or cryotherapy), when clinically feasible, should be considered the treatment of choice for intraocular retinoblastoma. External beam radiation should be considered only when focal treatment modalities are not clinically indicated.

BACKGROUND Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

This study involved a comprehensive review of the histologic slides of 62 patients who were diagnosed with uterine sarcoma from 1978 through 1988 at a single institution. In addition, DNA content (ploidy level) could be determined from the HE slides of these tumors using image analysis. Also, 42 of these cases had retrievable cell blocks on which DNA analysis was performed by means of flow cytometry. A linear regression analysis found a high degree of correlation (r = 0.8) between the measurement of the DNA index of these tumors by these two techniques. All cases were retrospectively restaged using the newly adopted FIGO surgical staging criteria which found the following distribution: 22 (35.5%) Stage I, 10 (16.1%) Stage II, 12 (19.4%) Stage III, and 18 (29%) Stage IV. A multivariate analysis of 60 evaluable patients using the Cox proportional hazard model found that surgical staging was the most significant prognostic factor with respect to the endpoint of overall survival (P = 0.00004). Both patient age at diagnosis and mitotic index were independent from surgical staging in predicting outcome. Furthermore, there was a trend suggesting that DNA index also had prognostic value. Of particular interest was that patients with diploid tumors (DNA index, 0.9-1.1) had a 5-year overall survival of 72% and did not approach median survival; however, hyperdiploid tumors (DNA index1.1) and hypodiploid tumors (DNA index0.9) were associated with median survivals of 18 and 12 months, respectively. In conclusion, this study supports the use of surgical staging of patients with uterine sarcomas in order to optimally determine their chance for survival. Further biologic investigations which may result in identifying those patients who could benefit from adjunctive treatment are recommended.

Purpose Report of clinical cancer control outcomes on Radiation Therapy Oncology Group (RTOG) 9406, a three-dimensional conformal radiation therapy (3D-CRT) dose escalation trial for localized adenocarcinoma of the prostate. Methods and Materials RTOG 9406 is a Phase I/II multi-institutional dose escalation study of 3D-CRT for men with localized prostate cancer. Patients were registered on five sequential dose levels: 68.4 Gy, 73.8 Gy, 79.2 Gy, 74 Gy, and 78 Gy with 1.8 Gy/day (levels I–III) or 2.0 Gy/day (levels IV and V). Neoadjuvant hormone therapy (NHT) from 2 to 6 months was allowed. Protocol-specific, American Society for Therapeutic Radiation Oncology (ASTRO), and Phoenix biochemical failure definitions are reported. Results Thirty-four institutions enrolled 1,084 patients and 1,051 patients are analyzable. Median follow-up for levels I, II, III, IV, and V was 11.7, 10.4, 11.8, 10.4, and 9.2 years, respectively. Thirty-six percent of patients received NHT. The 5-year overall survival was 90%, 87%, 88%, 89%, and 88% for dose levels I–V, respectively. The 5-year clinical disease-free survival (excluding protocol prostate-specific antigen definition) for levels I–V is 84%, 78%, 81%, 82%, and 82%, respectively. By ASTRO definition, the 5-year disease-free survivals were 57%, 59%, 52%, 64% and 75% (low risk); 46%, 52%, 54%, 56%, and 63% (intermediate risk); and 50%, 34%, 46%, 34%, and 61% (high risk) for levels I–V, respectively. By the Phoenix definition, the 5-year disease-free survivals were 68%, 73%, 67%, 84%, and 80% (low risk); 70%, 62%, 70%, 74%, and 69% (intermediate risk); and 42%, 62%, 68%, 54%, and 67% (high risk) for levels I–V, respectively. Conclusion Dose-escalated 3D-CRT yields favorable outcomes for localized prostate cancer. This multi-institutional experience allows comparison to other experiences with modern radiation therapy.

Seventeen patients were entered into a Phase I/II trial of concurrent hyperfractionated radiation therapy (7,440 cGy total dose; 120 cGy b.i.d.) combined with constant infusion of 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours for 72 hours) and cisplatin (DDP) (50 mg/m2) for a total of three cycles. Thirteen patients had Stage IV disease; three, Stage III disease; and one, Stage II hypopharyngeal disease. Thirteen of 17 patients had positive cervical lymph nodes, and the mean size of the largest lymph node was 5.5 x 5.1 cm. The patients were not treated with planned adjunctive surgery except for one patient who had a radical neck dissection for massive, rapidly growing cervical adenopathy, which recurred promptly within 1 month before the initiation of protocol therapy. After the initial six patients were entered, mitomycin-C (Mito 8 mg/m2) was added during the second cycle. All the patients completed the planned course of radiotherapy with a median dose of 7,440 cGy and a mean dose of 7,248 cGy except for two patients who died--one from toxicity and the other, suicide. The predominant toxicity was mucositis, which was grade 3/4 in 11 of 15 patients, resulting in an average interruption of radiation therapy of 12 days. Weight loss was significant and was on the average 12% of baseline weight. Hematological toxicity was mild in the 5-FU/DDP group (only one grade 3 toxicity of six) and severe in the 5-FU/DDP/Mito-treated patients (five of eight patients having grade 3/4 toxicity including one leukopenic pneumonitis death). Additional toxicity included one parapharyngeal cellulitis, which responded to antibiotics. Noncompliance with the complex regimen was only seen in three patients. One patient refused b.i.d. radiation therapy, and one patient refused further chemotherapy after the first cycle. Additionally, one patient who had a severe ethanol withdrawal reaction during the first cycle of 5-FU/DDP did not receive further chemotherapy. The complete response rate of both primary site and neck by the protocol regimen alone was 71%. However, two patients, one from each group, did undergo salvage neck dissection, and the locoregional control is currently 73%, with a mean follow-up time of 18.4 months. The feasibility of combining hyperfractionated radiation therapy with aggressive concurrent chemotherapy was demonstrated. The response and local control rate justifies the added toxicity of concurrent chemotherapy and radiation therapy.

Radiation recall dermatitis refers to an inflammatory skin reaction at a previously irradiated field subsequent to chemotherapy administration. A number of antineoplastic agents have been reported to cause this phenomenon. We observed radiation recall dermatitis in a patient with stage IV nodular sclerosing Hodgkin's disease after methotrexate therapy for acute graft-versus-host disease (GVHD) prophylaxis. The patient had previously undergone matched related bone marrow transplantation with busulfan and cyclophosphamide as a preparative regimen. Subsequently, she received cyclosporine and methotrexate for acute GVHD prophylaxis. Two areas of skin previously irradiated to 3,000 cGy developed radiation recall dermatitis after two doses of methotrexate given 2 days apart and exacerbated by the third and fourth doses. This reaction occurred 34 days after the last dose of radiation therapy (RT). We believe this is the first case of radiation recall dermatitis after methotrexate therapy. Given the increased use of methotrexate in several neoadjuvant and adjuvant protocols in association with RT, its potential to produce radiation recall reactions should be considered.

Computer controlled high dose-rate (HDR) brachytherapy afterloading machines are equipped with a single, miniaturized, high activity Ir-192 source that can be rapidly moved in fine increments among several channels. Consequently, by appropriate programming of source dwell positions and times, the dose distribution can be optimized as desired. We have explored the optimization potential of this new technology for two applications: (a) cervix brachytherapy, and (b) transvaginal irradiation. Cervix brachytherapy with a gynecologic ring applicator was simulated by 48 sources of relative activities ranging from 0.17 to 1.00 that were equally distributed between the tandem and the ring. The results confirmed that the optimized distribution of physical doses are superior to those achievable with standard brachytherapy sources and applicators. For example, with five-point optimization, the relative dose-rate in the rectum was only 47% of that in point A; for standard application the dose rate was 47% higher. For transvaginal application 27 sources of relative activities between 0.07-0.79 were placed in the ring and a single source of unit strength in the tandem. Using dose distribution homogeneity as an optimization criterion, the results (+/- 2.5%) were again superior to those obtained for commonly used double ovoid (+/- 15%), linear cylinder (+/- 27%), or a "T" source (31%).

Ameloblastoma of the jaw is an aggressive benign tumor of epithelial origin that has generally been treated surgically even for metastases. This article is a review of the literature and a report of a previously unpublished case. Despite earlier reports, it is suggested that the available data clearly indicate that it is a radiosensitive tumor. In this report, specific recommendations for radiation therapy are outlined, and guidelines for treatment planning, radiation dosage, and fractionation expected outcome and follow-up are given.

Purpose To update the incidence of late toxicity of RTOG 9406, a three-dimensional conformal radiation therapy (3DCRT) dose escalation trial for prostate cancer. Methods and Materials A total of 1,084 men were registered to this Phase I/II trial of 3DCRT (eligible patients, 1,055). The dose for level I was 68.4 Gy; 73.8 Gy for level II; 79.2 Gy for level III; 74 Gy for level IV; and 78 Gy for level V. Patients in levels I to III received 1.8 Gy/fraction, and those in levels IV to V received 2.0 Gy/fraction. Disease group I patients were treated at the prostate only, group 2 patients were treated at the prostate and at the seminal vesicles with a prostate boost, and group 3 patients were treated at the prostate and seminal vesicles. The median follow-up period for surviving patients was 6.1 y (level V) to 12.1 y (level I). Results The incidence rates of RTOG grade 3 or less gastrointestinal or genitourinary toxicity were 3%, 4%, 6%, 7%, and 9% in group 1 and 6%, 2%, 6%, 9%, and 12% in group 2 at dose levels of I, II, III, IV, and V, respectively. In group 1, level V patients had a higher probability of grade2 late or greater gastrointestinal or genitourinary toxicity than those in levels I, II, and III (hazard ratio [HR] = 1.93, p = 0.0101; HR=2.29, p = 0.0007; HR=2.52, p = 0.0002, respectively). In group 2, dose level V patients had a higher probability of grade 2 or greater late gastrointestinal or genitourinary toxicity than those in dose levels II, III, and IV (HR = 2.61, p = 0.0002; HR=2.22, p = 0.0051; HR=1.60, p = 0.0276, respectively). Conclusions Tolerance to high-dose 3DCRT remains excellent. There is significantly more grade 2 or greater toxicity with a dose of 78 Gy at 2 Gy/fraction than with 68.4 Gy to 79.2 Gy at 1.8 Gy/fraction and with 74 Gy at 2 Gy/fraction.

This is a retrospective review of treatment results in 63 children with retinoblastoma (RB) who received therapeutic irradiation from January 1975 to June 1988. Patient ages ranged from birth to 5 years with a mean age of 12.5 months. Three treatment groups were identified. in Group A, episcleral plaque was the only irradiation modality. in this group, 24 patients and 25 eyes with tumors of Reese-Ellsworth Stages I to III, and selected Stage VB tumors were irradiated using eye plaques. Twenty-two of 25 (88%) eyes are without evidence of disease (NED), and all patients are alive. Two eyes were enucleated for recurrent RB. Two of 23 eyes developed minimal cataracts. in Group B, external-beam was the only irradiation modality. Twelve patients with 21 involved eyes comprise this group. Thirteen eyes received EBRT alone. Seventy-seven percent of 13 eyes have NED. Four eyes developed cataracts. Three of 13 eyes required enucleation for progression of disease; one of these was Stage IVA and two of them were Stage VA. for Group C, external-beam plus episcleral plaque was used. Twenty-seven patients and 51 eyes with advanced retinoblastoma were included in this group. Episcleral plaque was used in 29 eyes as a salvage procedure for recurrent RB, or in selected cases was used as a boost after initial external beam irradiation. Fifteen of 29 eyes (52%) remain with NED with useful vision, and nine developed cataracts. Enucleation was performed in 14 eyes for recurrent RB. The authors conclude that radiation therapy has a major role in the management of RB due to its ability to control even advanced disease, allowing preservation of vision in a significant number of patients.

Results of different radiotherapy schedules used for early stage (T1-2, N0-1, M0) cutaneous T-cell lymphoma (CTCL) are compared in a series of 45 patients (22 patients treated with high dose total skin electron beam therapy (TSEB) with curative intent, 18 patients treated with palliative radiotherapy, and 5 patients treated with high dose local electron beam). At 3, 5, and 10 years after diagnosis the high dose TSEB treatment group had a probability of overall survival of 91%, 86%, and 75%, respectively, compared with 94%, 88%, and 88% for the palliative treatment group. The complete response (CR) rate for the high dose TSEB treatment group was 82% (18/22), compared with a 57% (4/7) complete response rate for seven patients in the palliative group who received low dose TSEB (less than 25 Gy in 6-7 weeks) followed by daily application of topical mechlorethamine hydrochloride (HN2). However, the probability of continued remission at 3, 5, and 10 years was 44%, 44%, and 33%, respectively, for the high dose TSEB group and 25%, 25%, and 0%, respectively, for the low dose TSEB + HN2 group. The median disease-free survival was 17.5 months for the high dose TSEB group versus 5.5 months for the low dose TSEB + HN2 group. The five patients who were treated with high doses of local electrons to a single local field had an overall survival rate of 80%, a median survival rate of 64 months, and a median length of continued remission of 31 months. These results indicate that high-dose electron beam can result in long-term disease-free survival in patients with localized and limited extent skin involvement with cutaneous T-cell lymphoma.