K. Greven

Is there a role for a brachytherapy vaginal cuff boost in the adjuvant management of patients with uterine-confined endometrial cancer?

PURPOSE/OBJECTIVE Many patients who have uterine-confined endometrial cancer with prognostic factors predictive of recurrence are treated with adjuvant pelvic radiation. The addition of a brachytherapy vaginal cuff boost is controversial. MATERIALS AND METHODS Between 1983 and 1993, 270 patients received adjuvant postoperative pelvic irradiation following hysterectomy for Stage I or II endometrial cancer. Group A includes 173 patients who received external beam irradiation alone (EBRT), while group B includes 97 patients who received EBRT with a vaginal brachytherapy application. The median dose of EBRT was 45 Gy. Vaginal brachytherapy consisted of a low dose rate ovoid or cylinder in 41 patients, a high dose rate cylinder in 54 patients, and a radioactive gold seed implant in two patients. The median follow-up time was 64 months. The two groups were compared in terms of age, histologic grade, favorable versus unfavorable histology, capillary space invasion, depth of myometrial invasion, and pathologic stage. RESULTS Chi-square analysis revealed that the only difference between the two groups was the presence of more Stage II patients in group B (38% versus 14%). No difference was detected for 5 year pelvic control and disease-free survival rates between groups A and B. CONCLUSION There is no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation is beneficial for pelvic control or disease-free survival for patients with Stage I or II endometrial cancer. Prospective randomized trials designed to study external irradiation alone versus external beam treatment plus vaginal brachytherapy are unlikely to show a positive result. Because EBRT provides excellent pelvic control, protocol development for uterine-confined corpus cancer should focus on identifying patients at risk for recurrence as well as other means of augmenting EBRT (e.g. addition of chemotherapy) in order to improve disease free survival in those subgroups.

Extended-field irradiation and intracavitary brachytherapy combined with cisplatin and amifostine for cervical cancer with positive para-aortic or high common iliac lymph nodes: Results of arm II of Radiation Therapy Oncology Group (RTOG) 0116

Objectives: Radiation Therapy Oncology Group (RTOG) 0116 was designed to test the ability of amifostine (Ethyol; MedImmune LLC, Gaithersburg, MD), a cytoprotective agent, to reduce the acute toxicity of combined therapy with extended-field irradiation, brachytherapy, and cisplatin chemotherapy in patients with cervical cancer with para-aortic or high common iliac disease. This report presents the results of part 2. Materials and Methods: Radiation Therapy Oncology Group 0116 was a 2-part trial. Part 1 delivered extended-field irradiation, brachytherapy, and cisplatin; part 2 added amifostine and required 16 evaluable patients to assess an improved toxicity profile. Eligibility included evidence for high common iliac or para-aortic metastasis. Patients were treated for a total dose of 45 Gy in 25 fractions with intracavitary irradiation. Intensity-modulated radiation therapy was not allowed. The final point A dose was 85 Gy low-dose rate equivalent. High-dose rate techniques were allowed. The positive para-aortic and iliac nodes were to be boosted to 54 to 59.4 Gy. Amifostine at 500 mg was to be delivered with every fraction of radiotherapy. Results: The study opened on August 1, 2001, and closed March 3, 2007, after accruing 45 patients, 18 for the second part with amifostine. This analysis reports the primary end point for the patients entered on part 2 of the study. Three patients were excluded, one was ineligible, and 2 withdrew. The median follow-up was 22.9 months (range, 6.5-45.4 months). The median dose of amifostine delivered was 5000 mg (range, 500-13,500 mg). Thirteen patients (87%) experienced an acute grade 3/4 toxicity (excluding grade 3 leukopenia). This compared to an 81% rate in part 1 of the trial. The estimated median survival was 34.8 months with a 20% late grade 3/4 toxicity rate. Conclusions: Amifostine, as delivered in this study, did not reduce acute toxicity in this patient population.

Changes in gene expression induced by chemoradiation in advanced cervical carcinoma : A microarray study of RTOG C-0128

PURPOSE To evaluate gene expression patterns in patients with advanced cervix cancer before and during chemoradiation in a multi-institutional cooperative group setting. METHODS RTOG C0128 was designed as a Phase II trial of radiation therapy with concomitant chemotherapy and Celecoxib at 400 mg twice daily for one year. Tumor samples were obtained for microarray gene expression analysis before treatment and at the time of the first implant (paired sample). RNA was extracted, linearly amplified, and purity was assessed by gel electrophoresis. Each sample was hybridized against a universal RNA mixture on a customized spotted array consisting of >10,000 genes. Gene expression pre-treatment was compared with clinical characteristics. Changes in gene expression following radiation were assessed within the paired samples (same patient) and then compared across all paired samples. Data were normalized using the AROMA software, and clustering analysis was performed using Wards method in Spotfire. Differences in paired samples were calculated with Significance Analysis of Microarrays (SAM). RESULTS From August 2001 to March 2004, 84 patients were accrued to the trial. Tissue was obtained prior to initiation of therapy from 34 patients (40%). FIGO stages of the patients providing tissue were IB (23%), II (57%), and IIIA-IVA (20%). RNA quality was sufficient in 22 pre-treatment and 14 post-treatment samples. Among pre-treatment samples, no significant differences in gene expression were observed by FIGO stage, age, or race. However, between comparison of histologic subtypes (adenocarcinoma, n=5; squamous cell carcinoma, n=17) demonstrated 45 genes differentially expressed with a false discovery rate of 0.018. Cluster analysis segregated unpaired samples into 2 groups: 18/22 comprising pre-treatment samples and 10/14 in group 2 representing post-treatment samples. In all 13 paired samples, gene expression after chemoradiation was significantly upregulated in 91 genes and downregulated in 251 genes (false discovery rate of 0.0018). Genes significantly upregulated included bax, cdk inhibitor 1, MMP2, and adhesion molecules PECAM1, VCAM1, and ICAM2. Genes significantly downregulated included topoisomerase II alpha, myc, H2AX, MSH2, RAD51, RAD53, PCNA, and cell cycle-regulating molecules chk1, CDK2, cyclinB1, cyclin D3, cdc2, and cdc25. CONCLUSIONS Microarray analysis was successfully performed in a multi-institutional cooperative group trial. Gene expression significantly correlated with histology, but not stage, age or race. Cluster analysis identified two groups of gene expression profiles correlating with pre or post-treatment acquisition of tissue. Notably, paired samples showed significant changes in gene expression following chemoradiation, including several downregulated radiation response genes. Further analysis comparing gene expression to clinical outcomes, acute and late toxicities awaits maturation of clinical data. Hopefully, this data will lead to the development of molecularly based therapies.