The Impact of High-Dose-Rate Brachytherapy: Measuring Clinical Outcomes in the Primary Treatment of Cervical Cancer.

PURPOSE: Radical concurrent chemoradiotherapy with combined external beam radiotherapy (EBRT) and brachytherapy is used to treat locally advanced cervical cancer. Our institution has transitioned to high-dose-rate (HDR) intracavitary brachytherapy (ICBT) from low-dose-rate (LDR) brachytherapy in 2008, and a review was conducted on the effect of this change on patient outcomes. METHODS AND MATERIALS: A single-arm retrospective chart review was performed on locally advanced (Fédération Internationale de Gynécologie et d'Obstétrique stage IB-IVA) patients with cervical cancer treated with combined external beam radiation therapy and HDR-ICBT with curative intent between 2008 and 2014. Clinical outcomes were evaluated, and multivariate analysis was performed to identify prognostic factors. RESULTS: Of the 76 patients selected, median age was 47.9 years and median follow-up was 5.2 years. Thirteen patients (17.1%) developed locoregional recurrence and 23 patients (30.3%) patients developed distant recurrence. Five-year progression-free survival and overall survival were 63.7% and 69.3%, respectively. A significant survival difference was found between stages (P < .001). Multivariate analysis found nodal involvement was strongly associated with poorer survival (P = .007). CONCLUSIONS: Our experience with the transition to HDR-ICBT as part of concurrent chemoradiotherapy in treatment of locally advanced cervical cancer resulted in acceptable long-term outcomes and toxicity to that of LDR brachytherapy. Potential further improvement of treatment outcomes for patients may be possible with image guided brachytherapy and the addition of effective systemic therapy.

Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial.

PURPOSE: Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS: Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS: Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS (P = .10) or OS (P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION: In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

A comparison of disease recurrence between robotic versus laparotomy approach in patients with intermediate-risk endometrial cancer.

OBJECTIVE: Advances in minimally invasive surgery, particularly with robotic surgery, have resulted in improved peri-operative outcomes in patients with endometrial cancer. In addition, randomized trials have shown that addition of adjuvant radiotherapy following surgery improves loco-regional disease control among stage I intermediate-risk endometrial cancer patients. We aimed to investigate the efficacy and safety of combined treatment of robotic surgery and adjuvant radiotherapy in this patient population. METHODS: A single-center retrospective study was conducted on stage I endometrioid-type endometrial cancer patients with intermediate-risk features (<50% myometrial involvement and grade 2-3 histopathology, or >50% myometrial involvement and grade 1-2 histopathology) treated with hysterectomy and adjuvant radiotherapy between January 2010 and December 2015. Data on surgery and radiotherapy were collected and correlated with clinical and surgical outcomes using log-rank. Oncologic outcomes were then compared between robotic surgery and laparotomy. RESULTS: A total of 179 intermediate-risk endometrial cancer patients were identified, of whom 135 (75.4%) received adjuvant radiotherapy and were included in the final analysis. Median age at diagnosis was 63 years (range 40-89) and median follow-up was 4.7 years (range 1.1-8.8). Seventy-seven patients (57%) underwent robotic surgery and 58 patients (43%) underwent laparotomy. Surgical staging with lymph node dissection was performed on 79.3% of the patients. The majority of patients (79.3%) received vaginal brachytherapy as part of adjuvant radiotherapy, while 20.7% received external-beam radiotherapy. Among the entire cohort, eight (5.9%) patients recurred and all eight recurrences occurred in the robotic surgery group; no recurrence was found in the laparotomy group. This translated into 5 year disease-free survival of 100% in the laparotomy group, compared with 91.8% in the robotic surgery group (p=0.005). No difference in overall survival was found between the two groups (p=0.51). CONCLUSION: Oncologic outcomes for stage I intermediate-risk endometrial cancer treated with hysterectomy and adjuvant radiotherapy at our institution are comparable to the previously published literature. The higher recurrence rate observed with robotic surgery at our institution has not been observed previously and requires further investigation.

Prognostic Significance of Lymphovascular Space Invasion in the Absence of Lymph Node Metastases in Early-Stage Endometrial Cancer.

OBJECTIVE: Lymphovascular space invasion (LVSI) has been defined as a significant adverse prognostic factor in early-stage endometrial cancer, primarily because of its high association with nodal metastases. This study aimed to determine if LVSI provides any prognostic significance in pathologic node-negative surgically staged (T1N0) endometrial cancer patients. METHODS/MATERIALS: This retrospective cohort study included all patients with pathologic stage T1N0 endometrial carcinoma treated at The Ottawa Hospital Cancer Centre from 1998 to 2007. Patient demographics, pathologic findings, treatment, and outcome data were collected. Univariate and multivariate cox regression modeling was used to assess significance and adjust for demographic and histopathologic covariates. Kaplan-Meier curves were used to estimate the 5-year overall and recurrence-free survival. RESULTS: Our study included 400 pathologic stage T1N0 patients who received an initial total hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy. The median age at diagnosis was 62 years, and the median follow-up was 66 months. Fifty-four patients (13.5%) had a positive LVSI status, and 346 (86.5%) had a negative LVSI status. The 5-year overall survival was 97.3% in patients without LVSI and 90.9% in those with LVSI (P < 0.001). The 5-year recurrence-free survival was 95.2% in patients without LVSI and 85.9% in those with LVSI (P = 0.006). Univariate analysis identified grade, stage, and LVSI as the covariates significantly associated with time to recurrence, and identified age, grade, stage, and LVSI to be significantly associated with overall survival. There were no significant covariates for recurrence-free survival by multivariate analysis, and only age and LVSI were significant for overall survival. CONCLUSIONS: Lymphovascular space invasion is an overall poor prognostic factor in T1N0 endometrial cancer. After adjusting for other factors, LVSI remains an independent risk factor for worse overall survival. Therefore, estimation of overall survival in patients with early-stage, node-negative endometrial cancer should take into account LVSI status.

Real-time measurement of urethral dose and position during permanent seed implantation for prostate brachytherapy.

PURPOSE: The in vivo dosimetry tool, RADPOS, has been modified to include a metal oxide-silicon semiconductor field effect transistor (MOSFET) array with an electromagnetic positioning sensor. This allows dose monitoring at five points rather than just at single dose point as in the other versions of the device. The detector has been used in a clinical trial, which is the first to measure both urethral dose and internal motion concurrently during permanent seed implantation for prostate brachytherapy using a single probe. METHODS AND MATERIALS: The RADPOS detector was secured inside a Foley catheter inside the patient's urethra. Spatial coordinates of the RADPOS detector were read every 0.5s, and the timing of events such as needle insertion was noted. The MOSFET readings were taken over two 10-min periods; once all seeds had been implanted both before and after the transrectal ultrasound (TRUS), the probe was removed. Measurements were completed for 16 patients. RESULTS: Maximum integral dose in the prostatic urethral ranged from 89 to 195Gy, and dose varied from -66% to 36% depending on the rectal probe position. The change in position of the RADPOS sensor owing to the removal of the TRUS probe ranged from 1.4 to 9.7mm. CONCLUSIONS: The modified RADPOS detector with MOSFET array is able to provide real-time dose information, which can be used to monitor dose rates while implantation is performed and to estimate the total integrated dose. Changes in position including those owing to the TRUS probe can be significant and should be quantified to evaluate the influence on dose distributions.

Evaluating contemporary radiotherapy approaches in the primary treatment of cervical cancer.

PURPOSE: Radiotherapy with concurrent cisplatinum-based chemotherapy became a standard recommendation for the management of advanced cervical cancer in 1999. We reviewed our experience with this approach to determine the impact on patient outcomes. METHODS: A retrospective review of all cervical cancer patients treated with curative intent using radical radiotherapy +/- chemotherapy from 1992 to 2005 was performed. Survival and relapse rates were analyzed using the Kaplan-Meier method and were compared using the log-rank test. RESULTS: During this period, 224 treated patients were identified: 153 (68%) were treated between 1992 and 1999 (group 1) and 71 (32%) were treated after 1999 (group 2). The median age was 53 and 55 years with a median follow-up of 49 and 34 months for groups 1 and 2, respectively. Stage classification and histological diagnosis were similar for both groups. Treatment usually consisted of external beam pelvic radiotherapy (40-45 Gy in 20-25 fractions) followed by low-dose rate brachytherapy (35-40 Gy to point A). Chemotherapy consisted of weekly intravenous cisplatinum (40 mg/m2) given concurrently with pelvic radiation. The proportion of patients receiving chemotherapy increased significantly after 1999, 12% in group 1 compared with 79% in group 2 (P < 0.01). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 53% and 54% for group 1 and 64% and 67% for group 2. The improvement in PFS for group 2 approached statistical significance (P = 0.06), but the difference in OS did not. CONCLUSIONS: There has been a significant increase in the use of concurrent chemoradiation for cervical cancer treatment after 1999, and this seems to have led to higher rates of PFS and OS, although these have yet to achieve statistical significance.

Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum.

PURPOSE: To evaluate the feasibility of concurrent weekly Cis-platinum chemoradiation (CRT) in the curative treatment of primary vaginal cancer. METHODS: A retrospective review was performed of all primary vaginal cancer patients treated with curative intent at the Ottawa Hospital Regional Cancer Centre between 1999 and 2004 using concurrent Cis-platinum CRT. RESULTS: Twelve patients were treated with concurrent weekly CRT. The median age at diagnosis was 56 years (range, 34-69 years), and the median follow-up was 50 months (range, 11-75 months). Ten patients (83%) were diagnosed with squamous cell carcinoma and 2 patients (17%) with adenocarcinoma. The distribution according to stage was as follows: 6 (50%) Stage II, 4 (33%) Stage III, and 2 (17%) Stage IVA. All patients received pelvic external beam radiotherapy (EBRT) concurrently with weekly intravenous Cis-platinum chemotherapy (40 mg/m(2)) followed by brachytherapy (BT). The median dose of EBRT was 4500 cGy given in 25 fractions over 5 weeks. Ten patients received interstitial BT, and 2 patients received intracavitary BT, with the median dose being 3000 cGy. The 5-year overall survival, progression-free survival, and locoregional progression-free survival rates were 66%, 75%, and 92%, respectively. Late toxicity requiring surgery occurred in 2 patients (17%). CONCLUSIONS: For the treatment of primary vaginal cancer, it is feasible to deliver concurrent weekly Cis-platinum chemotherapy with high-dose radiation, leading to excellent local control and an acceptable toxicity profile.

Feasibility study of using MOSFET detectors for in vivo dosimetry during permanent low-dose-rate prostate implants.

PURPOSE: To investigate the feasibility of using new micro-MOSFET detectors for QA and in vivo dosimetry of the urethra during transperineal interstitial permanent prostate implants (TIPPB). METHODS AND MATERIALS: This study involves measurements for several patients who have undergone the implant procedure with iodine-125 seeds. A new micro-MOSFET detector is used as a tool for in vivo measurement of the initial dose rate within the urethra. MOSFETs are calibrated using a single special order calibration seed. The angular response is investigated in a 100 kVp X-ray beam. RESULTS: micro-MOSFETs are found to have a calibration factor of 0.03 cGy/mV for low energy X-rays and a high isotropic response (within 2.5%). Prostate volume and shape changes during TIPPB due to edema caused by the trauma of needle insertion, making it difficult to achieve the planned implant geometry and hence the desired dose distribution. MOSFET measurements help us to evaluate the overall quality of the implant, by analyzing the maximum dose received by urethra, the prostate base coverage, the length of the prostatic urethra that is irradiated, and the apex coverage. CONCLUSIONS: We demonstrate that ease of use, quick calibration and the instantaneous reading of accumulated dose make micro-MOSFETs feasible for in vivo dosimetry during TIPPB.

Palliative radiotherapy for recurrent granulosa cell tumor of the ovary: a report of 3 cases with radiological evidence of response.

BACKGROUND: The role of radiotherapy for recurrent or residual granulosa cell tumor of the ovary (GCTO) is controversial. One reason for this controversy may be that most published studies on this topic have not utilized sectional imaging to assess response to radiotherapy. We report on three cases of recurrent or residual GCTO that were treated with radiotherapy for which pre- and post-treatment CT scans were available to assess response. CASE REPORTS: Case #1: A 77-year-old woman with a 7 x 10-cm pelvic mass post-surgery was treated with radiotherapy to a dose of 45 Gy in 25 fractions followed by a boost of 10 Gy in 5 fractions. Post-treatment scans revealed a decrease in tumor size to 4 x 2.5 cm. The reduction in tumor volume was 86%, and the duration of response was 13 months. Case #2: A 73-year-old woman with multiple abdominal recurrences was treated with radiotherapy to a dose of 30 Gy in 20 fractions. The dominant mass shrank from 13 x 17 cm to 5.1 x 6.6 cm. The reduction in volume was 85%, and the duration of response has been 5 months. Her symptom of abdominal bloating and early satiety abated. Case #3: An 83-year-old woman with a 20 x 20 x 15-cm mass in the left abdomen was treated with radiotherapy to a dose of 45 Gy in 25 fractions. The mass decreased in size to 3.7 x 2.5 cm post-treatment. The duration of response has been 21 months. Her symptom of left leg swelling disappeared after therapy. CONCLUSION: Radiotherapy is highly effective in treating recurrent or residual GCTO. In these three cases, the tumor volume decreased by 85 to 90%, and the duration of response has, up to now, been 5 to 21 months.

Effective palliative radiotherapy for symptomatic recurrent or residual ovarian cancer.

OBJECTIVE: To evaluate the efficacy of radiotherapy (RT) for symptomatic recurrent or residual ovarian cancer. METHODS: A review was conducted on patients (pts) treated with palliative RT for symptomatic ovarian cancer at The Ottawa Hospital Regional Cancer Centre between 1990 and 2003. Patient demographics, tumor factors, treatment variables, and clinical outcome were entered into a database. Symptom response was defined as complete (CR), partial (PR), or none. RESULTS: 62 courses of RT were delivered to 53 pts. The symptoms treated were: bleeding (40%), pain (37%), and "others" (23%). The most common dose fractionation scheme was 30 Gy in 10 fractions (f) (range: 5 Gy/1 f to 52.5 Gy/20 f). The overall response rate was 100%, with 68% achieving a CR. The CR rates were 88, 65, and 36% for the symptoms of bleeding, pain, and "others", respectively (P = 0.003). The median duration of response was 4.8 months (range: 1-71 months). In multivariate analysis, the only factors that were found to be significant positive predictors of symptom control were: the symptom bleeding (P = 0.015) and stage III/IV disease at presentation (P = 0.01). The most commonly reported toxicities were grades 1 and 2 nausea/vomiting and diarrhea. There were no grade 3/4 toxicities reported. CONCLUSIONS: Radiotherapy is highly effective in palliating symptomatic ovarian cancer. Excellent results are achieved for patients presenting with bleeding or pain. Symptomatic patients should be strongly considered for palliative radiotherapy. Higher doses of radiotherapy should be considered for those with symptoms other than bleeding or pain and those with longer life expectancies.

Radiotherapy for the treatment of primary vaginal cancer.

Disease control rates and toxicity were evaluated among 28 primary vaginal cancer patients treated with curative intent using radiotherapy. At 5 years, the majority (60%) of patients were disease-free and local control was 73% when a combination of external beam radiotherapy and brachytherapy were used. Serious late toxicity was seen in 11% of patients.

Radical radiotherapy for cervix cancer: the effect of waiting time on outcome.

PURPOSE: To assess the effect of treatment waiting time on clinical outcome for patients with cervix cancers treated with radical radiotherapy. METHODS AND MATERIALS: A retrospective analysis was conducted on all cervix cancer patients treated with radical radiotherapy between 1990 and 2001 at the Ottawa Regional Cancer Centre. Analyses were performed according to the three following separate definitions of waiting times: interval from start of radiotherapy to (1) date of initial biopsy, (2) date of examination under anesthesia, and (3) date of radiation oncology consultation. Associations between waiting times and patient characteristics and disease control were investigated using t-tests, analyses of variance, and Cox regression analyses. RESULTS: A total of 195 patients were studied. The vast majority of patients were treated within 5, 6, and 8 weeks of their consultation (91%), examination under anesthesia (88%), and biopsy (81%), respectively. On average, delays between initial biopsy and treatment start were greater for older patients (p = 0.025) (5.8 weeks for <40 years old vs. 6.6 weeks for >70 years old) and those with smaller tumors (p < 0.001) (5.0 weeks for >4 cm vs. 6.3 weeks for < or =4 cm). Univariate analysis revealed no adverse effect of treatment delay on tumor control. Multivariate analysis, with the inclusion of multiple prognostic tumor and treatment parameters, revealed an adverse effect of treatment delay on survival outcomes. CONCLUSIONS: Longer radiotherapy waiting times were found to be associated with diminished survival outcomes for patients treated radically for cervix cancer. The significance of this observed association requires further investigation.

Correlating the degree of needle trauma during prostate brachytherapy and the development of acute urinary toxicity.

PURPOSE: To determine if there is an association between the degree of prostate trauma during prostate brachytherapy and development of acute urinary toxicity. METHODS AND MATERIALS: In a consecutive prospective cohort of permanent (125)I prostate brachytherapy patients, the number of times each needle was repositioned was tracked, and the dosimetry plans were used to determine the number of times needles within 1 cm of the urethra were manipulated. Additionally, prostate volume, total number of needles, number of needles/prostate volume, and the number of periurethral needle manipulations/prostate volume were determined. The need for catheterization beyond 24 hours and the Radiation Therapy Oncology Group (RTOG) urinary toxicity score at 4 weeks were recorded. The independent samples t test was used to search for a correlation between these parameters and the recorded toxicity scores. RESULTS: Twenty-eight consecutive implant patients were evaluated in the study. Median (range) values were as follows: prostate volume 35 cc ( range, 15-51 cc), number of needles per patient 32 (range, 21-41), number of needle manipulations per patient 94.5 ( range, 55-147), and number of periurethral needle manipulations 42 (range, 17-65). The only significant association between urinary toxicity and these variables was for the number of periurethral needle manipulations (p = 0.025). CONCLUSIONS: These data provide evidence that needle prostate trauma during brachytherapy contributes to acute urinary toxicity.