Michael Kuettel

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

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 ≥3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external‐beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting.

Adenocarcinoma of the Fallopian Tube: Results of a Multi-Institutional Retrospective Analysis of 72 Patients

PURPOSE/OBJECTIVE To determine the prognostic factors for predicting outcome of patients with adenocarcinoma of the fallopian tube and to evaluate the impact of treatment modalities in managing this uncommon disease. MATERIALS AND METHODS A retrospective analysis of the tumor registries from 6 major medical centers from January 1, 1960 up to March 31, 1995 yielded 72 patients with primary adenocarcinoma of the fallopian tube. The Dodson modification of the FIGO surgical staging as it applies to carcinoma of the fallopian tube was utilized. Endpoints for outcome included overall and disease-free survival. Univariate analysis of host, tumor, and treatment factors was performed to determine prognostic significance, and patterns of failure were reviewed. RESULTS The median age of the study cohort was 61 years (range 30-79 years). Stage distribution was 24 (33%) Stage I; 20 (28%) Stage II; 24 (33%) Stage III; and 4 (6%) Stage IV. Adjuvant chemotherapy was administered to 54 (75%) patients, and postoperative radiotherapy was employed in 22 (31%). In the latter treatment group, 14 (64%) had whole pelvic external beam irradiation, 5 (23%) whole abdominal radiotherapy, 2 (9%) P-32 instillation, and 1 (4%) vaginal brachytherapy alone. Chemotherapy was used in 67% of Stage I and in 79% of Stages II/III/IV disease (not significant); radiotherapy was more commonly employed in Stage I than in Stages II/III/IV (46% vs. 23%, p = 0.05). The 5-, 8-, 15-year overall and disease-free survival for the study patients were 44.7%, 23.8%, 18.8% and 27.3%, 17%, 14%, respectively. Significant prognostic factors of overall survival included Stage I vs. II/III/IV (p = 0.04) and age < or = 60 years vs. > 60 years at diagnosis (p = 0.03). Only Stage I vs. II/III/IV (p = 0.05) was predictive of disease-free survival. Patterns of failure included 18% pelvic, 36% upper abdominal, and 19% distant. For all patients, upper abdominal failures were more frequently found in Stages II/III/IV (29%) than in Stage I (7%) (p = 0.03). Relapses solely outside of what would be included in standard whole abdominal radiotherapy portals occurred for only 15% of patients (6 of 40) with failures. Furthermore, patients having any recurrence, including the upper abdomen, were more likely (p = 0.001) to die (45%) than those without any type of relapse (18%). CONCLUSION This retrospective, multi-institutional study demonstrated the importance of FIGO stage in predicting the overall and disease-free survival of patients with carcinoma of the fallopian tube. Future investigations should consider exploring whole abdominal irradiation as adjunctive therapy, particularly in Stage II and higher.

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.

Protein changes associated with ionizing radiation‐induced apoptosis in human prostate epithelial tumor cells

Ionizing radiation (IR) is an important component in the therapy of localized prostate cancer. Identification of protein alterations during IR‐induced apoptosis prostate cancer cells is an important step toward understanding the new metabolic status of the dying cell. In the present study, we report changes in protein profile that define the execution phase of the apoptotic response in the in vitro model of tumorigenic radiation‐transformed SV40‐immortalized human prostate epithelial cells (267B1‐XR), induced to undergo programmed cell death by IR. We employed an approach that involves use of analytical two‐dimensional polyacrylamide gel electrophoresis (2‐D PAGE) coupled with Western blotting with specific antisera. Our results point out that apoptotic cells experience significant reduction in the levels of the intermediate filament proteins, keratins‐18, 19, vimentin and the associated 14‐3‐3 adapter proteins. At the same time, molecular chaperones such as glucose‐regulated protein 94, calreticulin, calnexin, and protein disulfide isomerase exhibit marked accumulation in these dying cells. The present data indicate that apoptosis‐associated processes in prostate epithelial cells include solubilization of the rigid intermediate filament network by specific proteolysis as well as increased levels of endoplasmic reticulum (ER) proteins with chaperone functions.

Early Postoperative Paclitaxel Followed by Concurrent Paclitaxel and Cisplatin With Radiation Therapy for Patients With Resected High-Risk Head and Neck Squamous Cell Carcinoma: Report of the Phase II Trial RTOG 0024

PURPOSE We sought to improve outcomes for patients with high-risk head and neck squamous cell cancer (HNSCC) after surgical resection by testing the feasibility and safety of early postoperative chemotherapy followed by concurrent chemoradiotherapy. PATIENTS AND METHODS Eligible patients had resected, stages III to IV HNSCC with positive margins, extracapsular nodal extension, or multiple positive nodes. Paclitaxel (80 mg/m(2)) was given once weekly during postoperative weeks 2, 3, and 4 and was given before radiation therapy (RT). Paclitaxel (30 mg/m(2)) and cisplatin (20 mg/m(2)) were given once weekly during the last 3 weeks of RT (60 Gy over 6 weeks, beginning 4 to 5 weeks after surgery). The primary end points were treatment safety and tolerability compared with concurrent cisplatin (100 mg/m(2) every 3 weeks) and RT, as tested in Radiation Therapy Oncology Group trial RTOG 9501. RESULTS The median follow-up time for the 70 patients enrolled was 3.3 years (range, 0.6 to 4.4 years) for surviving patients. Tolerability of all treatment components was comparable to that of RTOG 9501 treatment, which is the current standard of care (compliance rate, 75%; 95% CI, 63% to 85%). One patient died, and seven patients experienced grade 4 nonhematologic toxicities. Rates of locoregional control, disease-free survival, and overall survival exceeded those of RTOG 9501 after adjustment for important prognostic variables (ie, positive margins, extracapsular extension, primary site, and performance status). CONCLUSION Chemotherapy soon after surgery followed by concurrent chemoradiotherapy therapy was feasible; tolerance was in line with standard postoperative chemoradiotherapy; and this regimen led to excellent rates of locoregional control and disease-free survival.

TREATMENT OF FEMALE URETHRAL CARCINOMA IN MEDICALLY INOPERABLE PATIENTS USING EXTERNAL BEAM IRRADIATION AND HIGH DOSE RATE INTRACAVITARY BRACHYTHERAPY

PURPOSE We developed and present our experience with high dose rate brachytherapy for treatment of carcinoma of the urethra in medically inoperable women. MATERIALS AND METHODS Since 1991, 4 women with localized urethral cancer, medically unable to undergo resection or interstitial implantation, were treated with external beam and high dose rate intracavitary implantation rather than external beam irradiation alone. The fractionated implants were delivered with a high dose rate remote afterloader using a shielded vaginal applicator and modified urethral catheter. The urethral catheter was inserted through the lumen of a 20F Foley tube to improve depth dose. Homogeneous dose distribution was achieved and customized to the individual patient. RESULTS All high dose rate brachytherapy treatments were given at the clinic without use of sedation or anesthesia. Treatment was well tolerated, and all patients maintained voluntary urinary function and local control at 12 to 55 months after therapy. Chronic morbidity due to urethral, bladder, vaginal or rectal injury, including urethral stenosis, necrosis or fistula, was not noted. Isodose distributions were compared among this technique, interstitial implantation and external beam radiotherapy alone. CONCLUSIONS Although we prefer interstitial implantation as the boost technique for women with urethral cancer, high dose rate brachytherapy is a reasonable option for medically inoperable patients. This outpatient treatment is well tolerated, preserves voluntary urinary function and enhances quality of life.

Combination external beam radiation and brachytherapy boost with androgen deprivation for treatment of intermediate-risk prostate cancer: long-term results of CALGB 99809

Combined transperineal prostate brachytherapy and external beam radiation therapy (EBRT) is widely used for treatment of prostate cancer. Long‐term efficacy and toxicity results of a multicenter phase 2 trial assessing combination of EBRT and transperineal prostate brachytherapy boost with androgen deprivation therapy (ADT) for intermediate‐risk prostate cancer are presented.

Effect of concurrent radiation therapy and chemotherapy on pulmonary function in patients with esophageal cancer: dose-volume histogram analysis.

PURPOSEThe pulmonary effects of concurrent radiation therapy and chemotherapy were studied in patients enrolled in a phase I trial for esophageal cancer. MATERIALS AND METHODSPulmonary function tests were performed prospectively before and after combined-modality therapy (oxaliplatin, 5-fluorouracil, and radiation therapy) in 20 patients with esophageal cancer. Cumulative and differential lung DVH analysis from 0 to 5400 cGy in 25-cGy intervals was performed for the last 15 patients. Correlation between radiation exposure in various dose ranges and percent reduction in pulmonary function tests was calculated as an exploratory analysis. RESULTSSignificant reductions in carbon monoxide diffusion capacity corrected for hemoglobin (12. 3%) and total lung capacity (2. 5%) were evident at a median of 15. 5 days after radiation therapy. DVH analysis revealed that the single dose of maximum correlation between lung volume radiation exposure and lung function reduction was less than 1000 cGy for all pulmonary functions. The percent lung volume that received a total dose between 700 and 1000 cGy maximally correlated with the percent reductions in total lung capacity and vital capacity, and the absolute lung volume that received a total dose between 700 and 1000 cGy maximally correlated with the percent reductions in total lung capacity, vital capacity, and carbon monoxide diffusion capacity. DISCUSSIONSignificant declines in carbon monoxide diffusion capacity and total lung capacity are evident immediately after the administration of conformal radiation therapy, oxaliplatin, and 5-fluorouracil for esophageal cancer. Other lung functions remain statistically unchanged. The percent or absolute lung volume that received a total dose between 700 and 1000 cGy may be significantly correlated with the percent decline of carbon monoxide diffusion capacity, total lung capacity, and vital capacity. These associations will be evaluated further in a follow-up study

Combination External Beam Radiation and Brachytherapy Boost With Androgen Suppression for Treatment of Intermediate-Risk Prostate Cancer: An Initial Report of CALGB 99809

PURPOSE Transperineal prostate brachytherapy (TPPB) can be used with external beam radiation therapy (EBRT) to provide a high-dose conformal boost to the prostate. The results of a multicenter Phase II trial assessing safety of combination of EBRT and TPPB boost with androgen suppression (AST) in treatment of intermediate-risk prostate cancer are present here. MATERIALS AND METHODS Patients had intermediate-risk prostate cancer. Six months of AST was administered. EBRT to the prostate and seminal vesicles was administered to 45Gy followed by TPPB using either (125)I or (103)Pd to deliver an additional 100Gy or 90Gy. Toxicity was graded using the National Cancer Institute CTC version 2 and the Radiation Therapy Oncology Group late radiation morbidity scoring systems. RESULTS Sixty-three patients were enrolled. Median follow-up was 38 months. Side effects of AST including sexual dysfunction and vasomotor symptoms were commonly observed. Apart from erectile dysfunction, short-term Grade 2 and 3 toxicity was noted in 21% and 7%, primarily genitourinary related. Long-term Grade 2 and 3 toxicities were noted in 13% and 3%. Two patients had Grade 3 dysuria that resolved with longer follow-up. The most common Grade 2 long-term toxicity was urinary frequency (5%). No biochemical or clinical evidence of progression was noted for the entire cohort. CONCLUSIONS In a cooperative group setting, combination EBRT and TPPB boost with 6 months of AST was generally well tolerated with expected genitourinary and gastrointestinal toxicities. Further follow-up will be required to fully assess long-term toxicity and cancer control.

Expression of cytokeratin-19 as a marker of neoplastic progression of human prostate epithelial cells

Our earlier studies demonstrated neoplastic transformation of SV40‐immortalized neonatal human prostate epithelial cells (267B1) by fractionated doses of ionizing radiation or by introduction of v‐ki‐ras oncogene. X‐ray‐treated 267B1 cells represent three different stages of neoplastic progression: nontumorigenic F3‐SAC cells that acquired morphological changes and anchorage independence when treated with 2 × 2 Gy of X‐rays; malignantly transformed 267B1‐XR and 267B1‐SXR cells that received 2‐Gy doses to a total of 30 Gy. We also reported alterations in cell size, morphology, actin stress fibers, and levels of actin‐binding proteins in these transformed human prostate cells.