Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Pretransplant Splenic Irradiation in Patients With Myeloproliferative Neoplasms.

Purpose: Allogeneic hematopoietic cell transplantation (HCT) serves as the only curative treatment option for patients with myelofibrosis and other myeloproliferative neoplasms. Splenomegaly commonly manifests in patients with myeloproliferative neoplasms and can lead to delayed or poor engraftment, increased transfusion burden, and worse survival. Methods to decrease the effect of splenomegaly include splenectomy and splenic irradiation. We sought to report on clinical outcomes for patients treated with splenic irradiation as part of their transplant conditioning. Methods and Materials: Patients with splenomegaly measuring greater than 22 cm were referred for splenic irradiation. They received radiation to the entire spleen to 10 Gy in 5 fractions using 3-dimensional conformal radiation with anteroposterior/posteroanterior or opposed tangent fields. Blood counts were monitored closely on treatment. Changes in splenic size were measured using first and last treatment image guided radiation therapy and pre- and posttransplant diagnostic imaging. Results: Seventeen patients completed pretransplant splenic irradiation between 2012 and 2021. Median platelet, white blood cell, and hemoglobin levels decreased on treatment. One patient required platelet transfusion and 3 required packed red blood cell transfusions. Mean decrease in spleen size during radiation was -8.5% in the craniocaudal dimension. Prolonged decreases, measured 2 to 12 months after transplant, averaged 14.64%. All patients engrafted. Fourteen (82.4%) were alive at time of analysis with median follow-up of 4.2 years from hematopoietic cell transplantation. Conclusions: Splenic irradiation offers a safe method of managing significant splenomegaly as part of transplant conditioning. Transplant outcomes in this series were excellent. Prospective data may be beneficial to determine the absolute benefit of this addition to pretransplant conditioning in this patient population.

Multimodal Therapy Including Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Can Result in Long-term Disease-free Survival in Pediatric Desmoplastic Small Round Cell Tumor With Extraperitoneal Disease.

Desmoplastic small round cell tumor is a rare sarcoma with 5-year overall survival of 15%. An 8-year-old female presented with diffuse abdominal/pelvic desmoplastic small round cell tumor including numerous liver metastasis. She underwent neoadjuvant chemotherapy followed by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Residual disease was found shortly after CRS/HIPEC which was resected, followed by whole abdomen/pelvic radiation and autologous hematopoietic cell transplant. Previous papers have reported dismal survival in patients with liver metastasis and residual disease arguing against CRS/HIPEC. Our patient remains disease-free over 6 years after completing therapy indicating long-term survival is achievable with aggressive multimodal therapy.

Prostate-Specific Antigen After Neoadjuvant Androgen Suppression in Prostate Cancer Patients Receiving Short-Term Androgen Suppression and External Beam Radiation Therapy: Pooled Analysis of Four NRG Oncology Radiation Therapy Oncology Group Randomized Clinical Trials.

PURPOSE: To validate whether prostate-specific antigen (PSA) level after neoadjuvant androgen suppression (neoAS) is associated with long-term outcome after neoAS and external beam radiation therapy (RT) with concurrent short-term androgen suppression (AS) in patients with prostate cancer. METHODS AND MATERIALS: This study included 2404 patients. The patients were treated with neoAS before RT and concurrent AS (without post-RT AS) and were pooled from NRG Oncology/RTOG trials 9202, 9408, 9413, and 9910. Multivariable models were used to test associations between the prespecified dichotomized post-neoAS, pre-RT PSA level (≤0.1 vs >0.1 ng/mL) groupings, and clinical outcomes. RESULTS: The median follow-up for surviving patients was 9.4 years. The median post-neoAS, pre-RT PSA level was 0.3 ng/mL, with 32% of patients having levels ≤0.1 ng/mL. Race, Gleason score, tumor stage, node stage, pretreatment PSA level, and duration of neoAS were associated with the groups of patients with PSA levels ≤0.1 and >0.1 ng/mL. In univariate analyses, post-neoAS, pre-RT PSA level >0.1 ng/mL was associated with increased risks of biochemical failure (hazard ratio [HR], 2.04; P < .0001); local failure (HR, 2.51; P < .0001); distant metastases (HR, 1.73; P = .0006); cause-specific mortality (HR, 2.36; P < .0001); and all-cause mortality (HR, 1.24; P = .005). In multivariable models that also included baseline and treatment variables, post-neoAS, pre-RT PSA level >0.1 ng/mL was independently associated with increased risk of biochemical failure (HR, 2.00; P < .0001); local failure (HR, 2.33; P < .0001); and cause-specific mortality (HR, 1.75; P = .03). CONCLUSIONS: Patients with a PSA level >0.1 ng/mL after neoAS and before the start of RT had less favorable clinical outcomes than patients whose PSA level was ≤0.1 ng/mL. The role of post-neoAS, pre-RT PSA level relative to PSA levels obtained along the continuum of medical care is not presently defined but could be tested in future clinical trials.

Impact of Age at Diagnosis and Hypothalamic Involvement on Body Mass Index Z-Score Change in Pediatric Brain Tumor Survivors.

BACKGROUND: Obesity risk is increased for pediatric central nervous system tumor survivors. Hypothalamic involvement (HI) by tumor or treatment increases the risk. In healthy children, body mass index (BMI) normally declines until adiposity rebound (AR). We hypothesized that HI and diagnosis before AR would lead to increased BMI at follow-up. METHODS: A chart review of 114 brain tumor survivors diagnosed between 2001-2011 at the Children's Hospital of Wisconsin extracted tumor location, treatment and BMI z-scores at diagnosis and 2-year follow-up. Children were categorized based on age at diagnosis relative to AR and presence/absence of HI. RESULTS: Children diagnosed pre-AR and post-AR with HI had higher BMI z-scores at 2-year follow-up (pre-AR: 1.6, post-AR: 1.3) than at diagnosis (0.5, 0.6). All groups without HI showed no increase in BMI z-score from diagnosis to 2-year follow-up (pre-AR: 0.7-0.6, during AR: 0.7-0.8, post-AR: 0.7-0.8). The pre-AR and during-AR cohorts with HI had a higher BMI z-score at 2-year follow-up relative to those without HI, while the post-AR group did not. CONCLUSION: Except for the post-AR group, patients with HI have increased BMI at 2 years after diagnosis compared to those without HI. Diagnosis pre-AR is associated with greater follow-up BMI z-score.

Comparing the quality of passively-scattered proton and photon tomotherapy plans for brain and head and neck disease sites.

We compare the quality of photon IMRT (helical tomotherapy) with classic proton plans for brain, head and neck tumors, in terms of target dose uniformity and conformity along with organ-at-risk (OAR) sparing. Plans were created for twelve target volumes among eight cases. All patients were originally planned and treated using helical tomotherapy. Proton plans were generated using a passively-scattered beam model with a maximum range of 32 g cm(-2) (225 MeV), range modulation in 0.5 g cm(-2) increments and range compensators with 4.8 mm milling tool diameters. All proton plans were limited to two to four beams. Plan quality was compared using uniformity index (UI), conformation number (CN) and a EUD-based plan quality index (fEUD). For 11 of the 12 targets, UI was improved for the proton plan; on average, UI was 1.05 for protons versus 1.08 for tomotherapy. For 7 of the 12 targets, the tomotherapy plan exhibited more favorable CN. For proximal OARs, the improved dose conformity to the target volume from tomotherapy led to a lower maximum dose. For distal OARs, the maximum dose was much lower for proton plans. For 6 of the 8 cases, near-total avoidance for distal OARs provided by protons leads to improved fEUD. However, if distal OARs are excluded in the fEUD calculation, the proton plans exhibit better fEUD in only 3 of the 8 cases. The distal OAR sparing and target dose uniformity are generally better with passive-scatter proton planning than with photon tomotherapy; proton therapy may be preferred if the clinician deems those attributes critical. However, tomotherapy may serve equally as well as protons for cases where superior target dose conformity from tomotherapy leads to plan quality nearly identical to or better than protons and for cases where distal OAR sparing is not concerning.

Combined online and offline adaptive radiation therapy: a dosimetric feasibility study.

PURPOSE: The purpose of this work is to explore a new adaptive radiation therapy (ART) strategy, combined "online and offline" ART, that can fully account for interfraction variations similar to the existing online ART but with substantially reduced online effort. METHODS AND MATERIALS: The concept for the combined ART is to perform online ART only for the fractions with obvious interfraction variations and to deliver the ART plan for that online fraction as well as the subsequent fractions until the next online fraction needs to be adapted. To demonstrate the idea, the daily computed tomographic (CT) data acquired during image guided radiation therapy (IGRT) with an in-room CT (CTVision, Siemens Healthcare, Amarillo, TX) for 6 representative patients (including 2 prostate, 1 head-and-neck, and 1 pancreatic cancer, 1 adrenal carcinoma, and 1 craniopharyngioma patients) were analyzed. Three types of plans were generated based on the following selected daily CTs: (1) IGRT repositioning plan, generated by applying the repositioning shifts to the original plan (representing the current IGRT practice); (2) Re-Opt plan, generated with full-scope optimization; and (3) ART plan, either online ART plan generated with an online ART tool (RealArt, Prowess Inc, Concord, CA) or offline ART plan generated with shifts from the online ART plan. Various dose-volume parameters were compared with measure dosimetric benefits of the ART plans based on daily dose distributions and the cumulative dose maps obtained with deformable image registration. RESULTS: In general, for all the cases studied, the ART (with 3-5 online ART) and Re-Opt plans provide comparable plan quality and offer significantly better target coverage and normal tissue sparing when compared with the repositioning plans. This improvement is statistically significant. CONCLUSIONS: The combined online and offline ART is dosimetrically equivalent to the online ART but with substantially reduced online effort, and enables immediate delivery of the adaptive plan when an obvious anatomic change is observed.

Elective lymph node irradiation with intensity-modulated radiotherapy: is conventional dose fractionation necessary?

PURPOSE: Intensity-modulated radiation therapy (IMRT) is the standard of care for head-and-neck cancer (HNC). We treated patients with HNC by delivering either a moderate hypofractionation (MHF) schedule (66 Gy at 2.2 Gy per fraction to the gross tumor [primary and nodal]) with standard dose fractionation (54-60 Gy at 1.8-2.0 Gy per fraction) to the elective neck lymphatics or a conventional dose and fractionation (CDF) schedule (70 Gy at 2.0 Gy per fraction) to the gross tumor (primary and nodal) with reduced dose to the elective neck lymphatics. We analyzed these two cohorts for treatment outcomes. METHODS AND MATERIALS: Between November 2001 and February 2009, 89 patients with primary carcinomas of the oral cavity, larynx, oropharynx, hypopharynx, and nasopharynx received definitive IMRT with or without concurrent chemotherapy. Twenty patients were treated using the MHF schedule, while 69 patients were treated with the CDF schedule. Patient characteristics and dosimetry plans were reviewed. Patterns of failure including local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), overall survival (OS), and toxicities, including rate of feeding tube placement and percentage of weight loss, were reviewed and analyzed. RESULTS: Median follow-up was 31.2 months. Thirty-five percent of patients in the MHF cohort and 77% of patients in the CDF cohort received chemotherapy. No RR was observed in either cohort. OS, DFS, LR, and DM rates for the entire group at 2 years were 89.3%, 81.4%, 7.1%, and 9.4%, respectively. Subgroup analysis showed no significant differences in OS (p = 0.595), DFS (p = 0.863), LR (p = 0.833), or DM (p = 0.917) between these two cohorts. Similarly, no significant differences were observed in rates of feeding tube placement and percentages of weight loss. CONCLUSIONS: Similar treatment outcomes were observed for MHF and CDF cohorts. A dose of 50 Gy at 1.43 Gy per fraction may be sufficient to electively treat low-risk neck lymphatics.

Long-term results of an RTOG Phase II trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate.

PURPOSE: External-beam radiation therapy combined with low-doserate permanent brachytherapy are commonly used to treat men with localized prostate cancer. This Phase II trial was performed to document late gastrointestinal or genitourinary toxicity as well as biochemical control for this treatment in a multi-institutional cooperative group setting. This report defines the long-term results of this trial. METHODS AND MATERIALS: All eligible patients received external-beam radiation (45 Gy in 25 fractions) followed 2-6 weeks later by a permanent iodine 125 implant of 108 Gy. Late toxicity was defined by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. Biochemical control was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus definition and the ASTRO Phoenix definition. RESULTS: One hundred thirty-eight patients were enrolled from 20 institutions, and 131 were eligible. Median follow-up (living patients) was 8.2 years (range, 2.7-9.3 years). The 8-year estimate of late grade >3 genitourinary and/or gastrointestinal toxicity was 15%. The most common grade >3 toxicities were urinary frequency, dysuria, and proctitis. There were two grade 4 toxicities, both bladder necrosis, and no grade 5 toxicities. In addition, 42% of patients complained of grade 3 impotence (no erections) at 8 years. The 8-year estimate of biochemical failure was 18% and 21% by the Phoenix and ASTRO consensus definitions, respectively. CONCLUSION: Biochemical control for this treatment seems durable with 8 years of follow-up and is similar to high-dose external beam radiation alone or brachytherapy alone. Late toxicity in this multi-institutional trial is higher than reports from similar cohorts of patients treated with high-dose external-beam radiation alone or permanent low-doserate brachytherapy alone, perhaps suggesting further attention to strategies that limit doses to normal structures or to unimodal radiotherapy techniques.

Continuous-course reirradiation with concurrent carboplatin and paclitaxel for locally recurrent, nonmetastatic squamous cell carcinoma of the head-and-neck.

PURPOSE: To examine the efficacy and toxicity of continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin for the treatment of locally recurrent, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN) in a previously irradiated field. METHODS AND MATERIALS: Patients treated with continuous course-reirradiation with concurrent carboplatin and paclitaxel at the Medical College of Wisconsin and the Clement J. Zablocki VA from 2001 through 2009 were retrospectively reviewed. Patients included in the analysis had prior radiation at the site of recurrence of at least 45 Gy. The analysis included patients who received either intensity-modulated radiotherapy (RT) or three-dimensional conformal RT techniques. All patients received weekly concurrent carboplatin (AUC2) and paclitaxel (30-50 mg/m(2)). RESULTS: Thirty-eight patients with nonmetastatic SCCHN met the entry criteria for analysis. The primary sites at initial diagnosis were oropharyngeal or laryngeal in most patients (66%). Median reirradiation dose was 60 Gy (range, 54-70 Gy). Acute toxicity included Grade 2 neutropenia (5%), Grade 3 neutropenia (15%), and Grade 1/2 thrombocytopenia (8%). No deaths occurred from hematologic toxicity. Chemotherapy doses held (50%) was more prevalent than radiation treatment break (8%). Sixty-eight percent of patients required a gastrostomy tube in follow-up. Significant late toxicity was experienced in 6 patients (16%): 1 tracheoesophageal fistula, 1 pharyngocutaneous fistula, 3 with osteoradionecrosis, and 1 patient with a lingual artery bleed. Patients treated with three-dimensional conformal RT had more frequent significant late toxicites than patients treated with intensity-modulated RT (44% and 7% respectively, p < 0.05). The median time to progression was 7 months and progression-free rates at 1, 2, and 5 years was 44%, 34%, and 29% respectively. The median overall survival was 16 months. Overall survival at 1, 3, and 5 years was 54%, 31%, and 20% respectively. CONCLUSIONS: Continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin has an acceptable toxicity profile and offers a potentially curative option in a subset of patients with few other options.

Semicontinuous low-dose-rate teletherapy for the treatment of recurrent glial brain tumors: final report of a phase I/II study.

PURPOSE: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. METHODS AND MATERIALS: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. RESULTS: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed ≥ Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. CONCLUSION: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.

The effects of comorbidity and age on RTOG study enrollment in Stage III non-small cell lung cancer patients who are eligible for RTOG studies.

PURPOSE: To determine the influence of measured comorbidity in Radiation Therapy Oncology Group (RTOG) combined modality therapy (CMT) study enrollment in Stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: One hundred and seventy-one patients with a Karnofsky Performance Score ≥70 and clinical Stage III NSCLC were analyzed retrospectively for comorbidity, RTOG study eligibility, and enrollment at initial consultation. Effect of comorbidity scores (Cumulative Illness Rating Scale) were tested on patient selection for CMT, RTOG enrollment, and overall survival. RESULTS: Comorbidity (Grade 4; p < 0.005) and use of radiation only (p ≤ 0.001) were associated with inferior survival independent of other factors. Patient selection for CMT was affected by age (≥70, p < 0.001), comorbidity (severity index [SI] > 2, p = 0.001), and weight loss (>5%, p = 0.001). Thirty-three patients (19%) were enrolled in a CMT RTOG study (Group 1). Forty-nine patients (29%) were eligible but not enrolled (Group 2), and 57 (33%) were ineligible (Group 3). The most common ineligibility reasons were weight loss (67%) and comorbidity in the exclusion criteria of the RTOG studies (63%). Group 1 patients were the youngest (p = 0.02), with the lowest comorbidity scores (p < 0.001) and SI (p < 0.001) compared with Groups 2 and 3. Group 3 patients were the oldest with the most unfavorable comorbidity profile. Comorbidity scores (SI >2; p = 0.006) and age (≥70; p = 0.05) were independent factors influencing RTOG study enrollment in patients meeting study eligibility requirements (Groups 1 and 2). CONCLUSIONS: Comorbidity scales could be useful in stratification of patients in advanced lung cancer trials and interpretation of results particularly regarding the elderly population.

Epstein-Barr virus-associated intracranial leiomyosarcoma in an HIV-positive adolescent.

SUMMARY: A 17-year-old African American female with human immunodeficiency virus infection presented with an unresectable intracranial neoplasm with mass effect upon the brainstem. Stereotactic biopsy revealed an Epstein-Barr virus (EBV)-associated leiomyosarcoma. Radiation therapy and gemcitabine were used to shrink the mass with the aim to make it surgically resectable. Prolonged neutropenia and recurrent skin infections led to the discontinuation of gemcitabine. The mass stabilized after radiation therapy and has decreased in size in 15 months of follow-up. EBV has been demonstrated in most smooth muscle tumors associated with acquired immunodeficiency syndrome and other immunocompromised states. This is the first documented case of an EBV-positive intracranial leiomyosarcoma in a pediatric human immunodeficiency virus patient.

Interfractional variations in patient setup and anatomic change assessed by daily computed tomography.

PURPOSE: To analyze the interfractional variations in patient setup and anatomic changes at seven anatomic sites observed in image-guided radiotherapy. METHODS AND MATERIALS: A total of 152 patients treated at seven anatomic sites using a Hi-Art helical tomotherapy system were analyzed. Daily tomotherapy megavoltage computed tomography images acquired before each treatment were fused to the planning kilovoltage computed tomography images to determine the daily setup errors and organ motions and deformations. The setup errors were corrected before treatment and were used, along with the organ motions, to determine the clinical target volume/planning target volume margins. The organ motions and deformations for 3 representative patient cases (pancreas, uterus, and soft-tissue sarcoma) and for 14 kidneys of 7 patients are presented. RESULTS: Interfractional setup errors in the skull, brain, and head and neck are significantly smaller than those in the chest, abdomen, pelvis, and extremities. These site-specific relationships are statistically significant. The margins required to account for these setup errors range from 3 to 8 mm for the seven sites. The margin to account for both setup errors and organ motions for kidney is 16 mm. Substantial interfractional anatomic changes were observed. For example, the pancreas moved up to +/-20 mm and volumes of the uterus and sarcoma varied

Late toxicity and biochemical recurrence after external-beam radiotherapy combined with permanent-source prostate brachytherapy: analysis of Radiation Therapy Oncology Group study 0019.

BACKGROUND: The combination of external-beam radiotherapy and brachytherapy is used commonly to treat men with prostate cancer. In this analysis, the authors examined the rate of biochemical recurrence (BR) and late grade > or =3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external-beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting. METHODS: All eligible patients received external-beam radiotherapy (45 Gray [Gy] in 25 fractions) followed 2 to 6 weeks later by an interstitial implant using iodine-125 to deliver an additional 108 Gy. BR was defined in 2 ways: according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Definition (ACD) and according to the Phoenix definition (PD) (prostate-specific antigen nadir +2 ng/mL). The Radiation Therapy Oncology Group(RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used to grade all toxicity. RESULTS: One hundred thirty-eight patients were enrolled, and 130 were eligible for the current analysis. The median follow-up for surviving patients was 49 months (range, 20-60 months). The 48-month estimate of late grade > or =3 GU/GI toxicity was 15% (95% confidence interval [95% CI], 8-21%), and the 48-month estimate of BR was 19% (95% CI, 12-26%) and 14% (95% CI, 8-20%) according to the ACD and PD, respectively. CONCLUSIONS: The morbidity observed in this multiinstitutional, cooperative group study was slightly higher than that reported in recent RTOG studies using brachytherapy alone or high-dose external-beam radiotherapy. The BR rate observed in this report was similar to that observed with high-dose external-beam radiotherapy alone in similar patients.

A descriptive analysis of postimplant dosimetric parameters from Radiation Therapy Oncology Group P0019.

BACKGROUND: To date, there are few descriptive analyses of postimplant dosimetry from multi-institutional clinical trials. The purpose of this report is to describe the postimplant dosimetry achieved in Radiation Therapy Oncology Group (RTOG) 0019. METHODS AND MATERIALS: Patients were treated with external beam radiation therapy (45 Gy/25 fractions) followed by a prostate implant (I-125, prescription dose 108 Gy). Postimplant dosimetric assessment was accomplished by obtaining a CT scan of the prostate 1 month after the date of the implant procedure. Prostate volume was outlined by the first author. Dose-volume histograms were calculated by the Radiologic Physics Center. Four dosimetric quantifiers (DQs) were examined: D90 is the dose (reported as percentage of the prescription dose) received by 90% of the prostate; V100, V150, V200 is the percentage of the prostate volume receiving 100%, 150%, and 200% of the prescription dose, respectively. For the purposes of analysis, institutions were divided into three groups according to accrual (<5, 6-9, 10-12). RESULTS: One hundred thirty-eight patients from 27 institutions were registered in the study. Nineteen patients were excluded from this analysis; 14 who had no data and 5 who were ineligible, leaving 119 for analysis. The mean, median, and range of the four DQs are as follows: D90 105.6%, 106.0%, 57.6-174.8%; V100 89.8%, 92.6%, 11.2-100%; V150 58.4%, 59.6%, 0.9-93.7%; and V200 27.9%, 25.1%, 0.3-85.2%. Statistically significant differences according to institutional accrual were observed for D90 (p = 0.0283) and V200 (p = 0.0075), but not for V100 (p = 0.1534) and V150 (p = 0.0509). CONCLUSIONS: The DQ observed in this multi-institutional prospective study are roughly comparable to series from single institutions with considerable brachytherapy experience. Differences in DQs were observed according to institutional accrual. These data could be used to determine a community standard with respect to postimplant dosimetry.

Age is independent of comorbidity influencing patient selection for combined modality therapy for treatment of stage III nonsmall cell lung cancer (NSCLC).

OBJECTIVES: To determine the influence of age and comorbidity in patient selection for treatment of stage III NSCLC with combined modality therapy (CMT). METHODS: There were 102 patients with a Karnofsky Performance Score greater than or equal to 70, and clinical stage III NSCLC analyzed retrospectively for comorbidity. All patients received radiotherapy, and 57 (56%) received CMT with sequential and/or concurrent chemotherapy. Comorbidity was rated retrospectively using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). The effect of an extremely severe comorbidity score on patient selection and overall survival (OS) was evaluated. RESULTS: Presence of a grade 4 comorbidity (P = 0.02) and use of radiation only (P < 0.01) were associated with a statistically significant inferior OS on multivariate analysis, whereas age greater than or equal to 70, clinical stage IIIB, >5% weight loss, and radiation dose >63 Gy were not. Patients receiving CMT were significantly younger (P < 0.001), with less comorbidity (P < 0.001), and weight loss (P = 0.003) compared with patients receiving radiotherapy alone. A multivariate analysis revealed that age (P < 0.001), comorbidity (P = 0.007), and weight loss (P = 0.002) were independent factors influencing patient selection for CMT. CONCLUSIONS: Age effects patient selection for CMT independent of comorbidity and weight loss in patients with stage III NSCLC and good performance status. This might be related to physician's biases regarding tolerability of CMT in the elderly, and might explain under-representation of elderly in clinical trials of lung cancer. Comorbidity assessment should be included in protocols studying locally advanced stage NSCLC and may be useful for stratification.

A phase II study of external beam radiotherapy combined with permanent source brachytherapy for intermediate-risk, clinically localized adenocarcinoma of the prostate: preliminary results of RTOG P-0019.

PURPOSE: To estimate the rate of acute and late Grade 3-5 genitourinary and gastrointestinal toxicity after treatment with external beam radiotherapy and permanent source brachytherapy in a multi-institutional, cooperative group setting. METHODS AND MATERIALS: All patients were treated with external beam radiotherapy (45 Gy in 25 fractions), followed 2-6 weeks later by an interstitial implant using 125I to deliver an additional 108 Gy. Late genitourinary toxicity was graded according to the Common Toxicity Criteria Version 2.0, and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used for all other toxicity. RESULTS: A total of 138 patients from 28 institutions were entered on this study. Acute toxicity information was available in 131 patients, and 127 patients were analyzable for late toxicity. Acute Grade 3 toxicity was documented in 10 of 131 patients (7.6%). No Grade 4 or 5 acute toxicity has been observed. The 18-month month estimate of late Grade 3 genitourinary and gastrointestinal toxicity was 3.3% (95% confidence interval, 0.1-6.5). No late Grade 4 or 5 toxicity has been observed. CONCLUSIONS: The acute and late morbidity observed in this multi-institutional, cooperative group study is consistent with previous reports from single institutions with significant prostate brachytherapy experience.

High-dose whole abdominal and pelvic irradiation for treatment of ovarian carcinoma: long-term toxicity and outcomes.

PURPOSE: To evaluate the role of high-dose whole abdominal and pelvic irradiation (WART) in the treatment of epithelial ovarian carcinoma. METHODS AND MATERIALS: A retrospective review was performed on 71 patients with Stage I-III ovarian carcinoma who were treated with WART using an open field technique after total abdominal hysterectomy and bilateral oophorectomy with or without omentectomy. Whole abdominal doses greater than typically recommended were used in a series of patients to enhance local control and to decrease abdominal recurrence. None of the patients had received chemotherapy before RT. Thirty-one patients received Alkeran or cyclophosphamide and two received cisplatin-based chemotherapy after WART. The median whole abdominal dose was 36 Gy (range 9-45.5), delivered in a median of 30 fractions (range 8-46). A pelvic boost was delivered using AP-PA fields during whole abdominal RT to a total midline pelvic dose of 200 cGy/d. The median pelvic dose was 51 Gy (range 16-59). The right lobe and a portion of the left lobe of the liver were shielded with custom blocks at a median dose of 25 Gy (range 9-41). The kidneys were shielded either AP-PA or PA from the first day of RT. The median dose to the kidneys was 19 Gy (range 4-30). RESULTS: The 5-year overall survival rate was 93%, 48%, and 29% for Stage I, II, and III patients, respectively. On multivariate analysis, stage and the extent of residual disease were independent prognostic factors. The 5- and 10-year overall survival rate for the 46 patients in the intermediate-risk group was 61% and 54%, respectively. For this group, a total abdominal dose of > or /=36 Gy was associated with a longer overall survival independent of stage, grade, and the amount of residual disease. This was most likely due to a significant reduction in the incidence of abdominal recurrence in patients receiving >36 Gy to the whole abdomen (18% vs. 49%, p = 0.006). Multivariate analysis revealed that grade (p = 0.023) and abdominal dose (p = 0.018) were independent factors influencing the rate of abdominal recurrence. Pelvic recurrence was rare as a first site of failure (6%). Twenty-one percent (n = 15) of the patients developed Grade 3 or 4 (Radiation Therapy Oncology Group [RTOG] criteria) chronic small or large bowel toxicity. Eleven percent of all patients had a small bowel obstruction requiring surgery. A whole abdominal dose >30 Gy and a pelvic dose >50 Gy were associated with a significant increase in small bowel obstruction (p = 0.01) independent of other factors. Chronic Grade 3 or 4 (Common Toxicity Criteria) anemia, thrombocytopenia, and leukopenia were seen in 7%, 1%, and 4% of the patients, respectively. Transient liver enzyme elevation was common (62%). Two patients had Grade 3 (RTOG) hepatic toxicity. Grade 3 or 4 renal toxicity (RTOG) was observed in 4%, and 2 patients (3%) were diagnosed with pelvic insufficiency fractures that were managed conservatively. CONCLUSION: Survival after RT for ovarian carcinoma rivals that achieved with systemic chemotherapy. The results of this study suggest a possible dose-control relationship between the whole abdominal dose and the risk of abdominal recurrence; however, a higher rate of small bowel obstruction was observed when greater abdominal doses and greater pelvic doses were combined. Careful attention to balancing toxicity and efficacy is imperative if RT is to have a future role in the treatment of this disease.