Assessment of long-term rectal function in patients who received pelvic radiotherapy: a pooled North Central Cancer Treatment Group trial analysis, N09C1.

PURPOSE: Pelvic radiotherapy (PRT) is known to adversely affect bowel function (BF) and patient well-being. This study characterized long-term BF and evaluated quality of life (QOL) in patients receiving PRT. METHODS: Data from 252 patients were compiled from two North Central Cancer Treatment Group prospective studies, which included assessment of BF and QOL by the BF questionnaire (BFQ) and Uniscale QOL at baseline and 12 and 24 months after completion of radiotherapy. BFQ scores (sum of symptoms), Uniscale results, adverse-event incidence, and baseline demographic data were compared via t test, χ (2), Fisher exact, Wilcoxon, and correlation methodologies. RESULTS: The total BFQ score was higher than baseline at 12 and 24 months (P < 0.001). More patients had five or more symptoms at 12 months (13 %) and 24 months (10 %) than at baseline (2 %). Symptoms occurring in greater than 20 % of patients at 12 and 24 months were clustering, stool-gas confusion, and urgency. Factors associated with worse BF were female sex, rectal or gynecologic primary tumors, prior anterior resection of the rectum, and 5-fluorouracil chemotherapy. Patients experiencing grade 2 or higher acute toxicity had worse 24-month BF (P values, <.001-.02). Uniscale QOL was not significantly different from baseline at 12 or 24 months, despite worse BFQ scores. CONCLUSIONS: PRT was associated with worse long-term BF. Worse BFQ score was not associated with poorer QOL. Further research to characterize the subset of patients at risk of significant decline in BF is warranted.

Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer.

PURPOSE: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). METHODS AND MATERIALS: Treatment began with two cycles of topotecan (1 mg/m(2)) Days 1 to 5 and paclitaxel (175 mg/m(2)) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard "cohorts of 3" design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m(2)) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade > or =4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade > or =3 dyspnea, or Grade > or =2 pneumonitis. RESULTS: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade > or =3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. CONCLUSION: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine.

Gamma knife radiosurgery for the treatment of uveal melanoma and uveal metastases.

BACKGROUND: This study retrospectively analyzed outcomes for patients undergoing gamma knife radiosurgery (GKR) for uveal melanoma (UM) and intraocular metastases. METHODS: Patients who underwent GKR for UM or intraocular metastases between 1/1/1990 and 6/1/2015 at Mayo Clinic, Rochester, MN, USA, were retrospectively analyzed. RESULTS: Eleven patients (11 eyes) had UM while seven patients (7 eyes) had intraocular metastases. Patients with UM were followed for a median of 19.74 ± 10.4 months. Visual acuity (VA) logMAR 0.30 ± 0.53 (Snellen 20/40) versus 0.40 ± 0.97 (Snellen 20/50), tumor thickness (5.30 ± 2.17 vs. 3.60 ± 2.32 mm), were not significantly different between preoperative and postoperative measurements, respectively. Nine percent (1/11) patients required enucleation. Subsequently, no patients experienced metastases. Patients with intraocular metastases were followed for a median of 6.03 ± 6.32 months. They did not have significant changes in VA (logMAR 0.30 ± 0.59 vs. 0.30 ± 1.57; Snellen 20/40 vs. 20/40) or tumor thickness (3.50 ± 1.36 vs. 1.30 ± 0.76 mm) postoperatively. Fourteen percent (1/7 patients) required enucleation. Complications experienced by patients with UM include radiation retinopathy (2/11), papillopathy (1/11), cystoid macular edema (1/11), vitreomacular traction (1/11), exudative retinal detachment (1/11). Patients with metastases had treatment complicated by recurrence (2/7). Dose to the margin, maximum dose of radiation, and clinical target volume did not correlate with post-procedural VA, risk of enucleation, or death in patients with either UM or patients with intraocular metastases. CONCLUSIONS: Visual outcomes were satisfactory for patients undergoing GKR without significant morbidity and without significant risk of enucleation or metastases.

Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy.

PURPOSE: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). PATIENTS AND METHODS: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. RESULTS: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P =.99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P =.99). CONCLUSION: There is no evidence of a beneficial effect of glutamine during pelvic RT.

Prophylactic cranial irradiation in elderly patients with small cell lung cancer: findings from a North Central Cancer Treatment Group pooled analysis.

OBJECTIVES: To examine the efficacy of prophylactic cranial irradiation (PCI) in elderly patients with small cell lung cancer (SCLC) (≥70 years of age) from a pooled analysis of four prospective trials. MATERIALS & METHODS: One hundred fifty-five patients with SCLC (limited stage, LSCLC, and extensive stage, ESCLC) participated in four phase II or III trials. Ninety-one patients received PCI (30 Gy/15 or 25 Gy/10) and 64 patients did not receive PCI. Survival was compared in a landmark analysis that included only patients who had stable disease or better in response to primary therapy. RESULTS: Patients who received PCI had better survival than patients who did not receive PCI (median survival 12.0 months vs. 7.6 months, 3-year overall survival 13.2% vs. 3.1%, HR = 0.53 [95% CI 0.36-0.78], p = 0.001). On multivariate analysis of the entire cohort, the only factor that remained significant for survival was stage (ESCLC vs. LSCLC, p = 0.0072). In contrast, the multivariate analysis of patients who had ESCLC revealed that PCI was the sole factor associated with a survival advantage (HR = 0.47 [95% CI 0.24-0.93], p = 0.03). Grade 3 or higher adverse events (AEs) were significantly greater in patients who received PCI (71.4% vs. 47.5%, p = 0.0031), with non-neuro and non-heme being the specific AE categories most strongly correlated with PCI delivery. CONCLUSIONS: PCI was associated with a significant improvement in survival for our entire elderly SCLC patient cohort on univariate analysis. Multivariate analysis suggested that the survival advantage remained significant in patients with ESCLC. PCI was also associated with a modest increase in grade 3 or higher AEs.

Prognostic factors differ by tumor stage for small cell lung cancer: a pooled analysis of North Central Cancer Treatment Group trials.

BACKGROUND: An analysis of 14 small cell lung cancer (SCLC) trials was performed to improve the current understanding of potential prognostic factors for overall survival (OS) and progression-free survival (PFS) in groups of patients with limited-stage disease SCLC (LD-SCLC) and extensive-stage disease SCLC (ED-SCLC) separately. METHODS: Data on 688 patients with LD-SCLC and 910 patients with ED-SCLC were included. Clinical and laboratory factors were tested for their prognostic significance using Cox regression models that were stratified by protocol. Recursive partitioning and amalgamation (RPA) analyses were used to identify prognostic subgroups. RESULTS: Poorer performance status (PS) led to worse OS and PFS in the ED-SCLC group but not in the LD-SCLC group. The prognostic impact of PS was strong for men but weak for women in the ED-SCLC group (interaction P value <.012 for OS and PFS). Other negative prognostic factors included increased age and men for the LD-SCLC group and increased age, men, increased number of metastatic sites at baseline, and increased creatinine levels for the ED-SCLC group. In patients with the ED-SCLC, RPA analyses identified 5 subgroups with different prognosis based on baseline PS, creatinine levels, sex, and the number of metastatic sites. CONCLUSIONS: The current pooled analysis identified baseline creatinine levels and the number of metastatic sites as important prognostic factors in patients with ED-SCLC in addition to the well established factors of sex, age, and PS. There was a significant interaction between sex and PS within the ED-SCLC group, suggesting that PS is highly prognostic in men but has no significant impact in women. Within the LD-SCLC group, only age and sex were identified as important prognostic factors. RPA analyses confirmed many of these findings.

Results of a phase II study of high-dose thoracic radiation therapy with concurrent cisplatin and etoposide in limited-stage small-cell lung cancer (NCCTG 95-20-53).

PURPOSE: To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). PATIENTS AND METHODS: A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). RESULTS: Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. CONCLUSION: This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.

Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system.

PURPOSE: This study was performed to evaluate the results and prognostic factors associated with radiotherapy for a detectable serum prostate specific antigen level after radical prostatectomy. MATERIALS AND METHODS: From July 1987 through July 2003, 368 patients received radiotherapy for a detectable prostate specific antigen level (biochemical relapse) as the sole evidence of recurrence after radical prostatectomy for node negative prostate cancer. Estimated survival and relapse-free probabilities were obtained via Kaplan-Meier estimation. Associations of patient factors with survival and biochemical relapse were investigated using Cox proportional hazards models. RESULTS: With a median followup of 5 years the 5 and 8-year freedom from biochemical relapse were an estimated 46% (95% CI 41%-53%) and 35% (95% CI 29%-43%) while survival was 92% (95% CI 89%-95%) and 80% (95% CI 74%-87%), respectively. Patient and treatment variables showing evidence of association with biochemical relapse on multivariate analysis included pathological stage T3a or less vs T3b (seminal vesicle involvement, p = 0.029), pathological Gleason score 7 or less vs 8 or greater (p <0.001) and pre-radiotherapy prostate specific antigen (p <0.001). Four biochemical failure risk groups were created by assigning seminal vesicle involvement, Gleason score and pre-radiotherapy prostate specific antigen each a score of 0 to 2. These individual scores were summed. The freedom from biochemical failure at 5 years for each risk group was 0 to 1-69%, 2-53%, 3-26% and 4 to 5-6%. CONCLUSIONS: The presence of seminal vesicle involvement and high Gleason score in the radical prostatectomy specimen are inherent predictors of adverse outcome. Early referral for salvage radiotherapy can decrease subsequent biochemical relapse.