Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
To study the outcomes in patients treated for localized prostate cancer with 70 Gy delivered at 2.5-Gy/fraction within 5 weeks.
The study sample included all 770 consecutive patients with localized ...prostate cancer treated with hypofractionated intensity-modulated radiotherapy at the Cleveland Clinic between 1998 and 2005. The median follow-up was 45 months (maximum, 86). Both the American Society for Therapeutic Radiology and Oncology (ASTRO) biochemical failure definition and the alternate nadir + 2 ng/mL definition were used.
The overall 5-year ASTRO biochemical relapse-free survival rate was 82% (95% confidence interval, 79-85%), and the 5-year nadir + 2 ng/mL rate was 83% (95% confidence interval, 79-86%). For patients with low-risk, intermediate-risk, and high-risk disease, the 5-year ASTRO rate was 95%, 85%, and 68%, respectively. The 5-year nadir + 2 ng/mL rate for patients with low-, intermediate-, and high-risk disease was 94%, 83%, and 72%, respectively. The Radiation Therapy Oncology Group acute rectal toxicity scores were 0 in 51%, 1 in 40%, and 2 in 9% of patients. The acute urinary toxicity scores were 0 in 33%, 1 in 48%, 2 in 18%, and 3 in 1% of patients. The late rectal toxicity scores were 0 in 89.6%, 1 in 5.9%, 2 in 3.1%, 3 in 1.3%, and 4 in 0.1% (1 patient). The late urinary toxicity scores were 0 in 90.5%, 1 in 4.3%, 2 in 5.1%, and 3 in 0.1% (1 patient).
The outcomes after high-dose hypofractionation were acceptable in the entire cohort of patients treated with the schedule of 70 at 2.5 Gy/fraction.
To quantify and describe the real-time movement of the prostate gland in a large data set of patients treated with radiotherapy.
The Calypso four-dimensional localization system was used for target ...localization in 17 patients, with electromagnetic markers implanted in the prostate of each patient. We analyzed a total of 550 continuous tracking sessions. The fraction of time that the prostate was displaced by >3, >5, >7, and >10 mm was calculated for each session and patient. The frequencies of displacements after initial patient positioning were analyzed over time.
Averaged over all patients, the prostate was displaced >3 and >5 mm for 13.6% and 3.3% of the total treatment time, respectively. For individual patients, the corresponding maximal values were 36.2% and 10.9%. For individual fractions, the corresponding maximal values were 98.7% and 98.6%. Displacements >3 mm were observed at 5 min after initial alignment in about one-eighth of the observations, and increased to one-quarter by 10 min. For individual patients, the maximal value of the displacements >3 mm at 5 and 10 min after initial positioning was 43% and 75%, respectively.
On average, the prostate was displaced by >3 mm and >5 mm approximately 14% and 3% of the time, respectively. For individual patients, these values were up to three times greater. After the initial positioning, the likelihood of displacement of the prostate gland increased with elapsed time. This highlights the importance of initiating treatment shortly after initially positioning the patient.
To analyze changes in parotid gland dose resulting from anatomic changes throughout a course of radiotherapy in a cohort of head-and-neck cancer patients.
The study population consisted of 10 ...head-and-neck cancer patients treated definitively with intensity-modulated radiotherapy on a helical tomotherapy unit. A total of 330 daily megavoltage computed tomography images were retrospectively processed through a deformable image registration algorithm to be registered to the planning kilovoltage computed tomography images. The process resulted in deformed parotid contours and voxel mappings for both daily and accumulated dose-volume histogram calculations. The daily and cumulative dose deviations from the original treatment plan were analyzed. Correlations between dosimetric variations and anatomic changes were investigated.
The daily parotid mean dose of the 10 patients differed from the plan dose by an average of 15%. At the end of the treatment, 3 of the 10 patients were estimated to have received a greater than 10% higher mean parotid dose than in the original plan (range, 13-42%), whereas the remaining 7 patients received doses that differed by less than 10% (range, -6-8%). The dose difference was correlated with a migration of the parotids toward the high-dose region.
The use of deformable image registration techniques and daily megavoltage computed tomography imaging makes it possible to calculate daily and accumulated dose-volume histograms. Significant dose variations were observed as result of interfractional anatomic changes. These techniques enable the implementation of dose-adaptive radiotherapy.
To report a single-institutional experience with the use of Superficial X-Ray Therapy (SXRT) for head and neck non-melanoma skin cancer (N-MSC) and to compare outcomes by prescribed fractionation ...schedules.
The medical records of 597 patients with 1021 lesions (720 BCC, 242 SCC, 59 SCC in situ) treated with kilovoltage radiation from 1979-2013 were retrospectively reviewed. The majority of patients were treated according to 1 of 3 institutional protocols based on the discretion of the radiation oncologist: 1) 22 x 2.5 Gy; 2) 20 x 2.5 Gy; 3) 30 x 2.0 Gy. "T" stage at first presentation was as follows: Tis (59); T1 (765); T2 (175); T3 (6), T4 (9); Tx, (7). All patients were clinical N0 and M0 at presentation. Chi-square test was used to evaluate any potential association between variables. The Kaplan-Meier method was used to analyze survival with the Log Rank test used for comparison. A Cox Regression analysis was performed for multivariate analysis.
The median follow up was 44 months. No significant difference was observed among the 3 prescribed fractionation schemes (p = 0.78) in terms of RTOG toxicity. There were no failures among SCC in situ, 37 local failures (23 BCC, 14 SCC), 5 regional failures (all SCC) and 2 distant failures (both SCC). For BCC, the 5-year LC was 96% and the 10-year LC was 94%. For SCC the corresponding rates of local control were 92% and 87%, respectively (p = 0.03). The use of >2.0 Gy daily was significantly associated with improved LC on multivariate analysis (HR: 0.17; CI 95%: 0.05-0.59).
SXRT for N-MSC of the head and neck is well tolerated, achieves excellent local control, and should continue to be recommended in the management of this disease. Fractionation schedules using >2.0 Gy daily appear to be associated with improved LC.
Abstract Background The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated ...years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy ADT and radiotherapy dose-escalation. Gleason score (GS) 9–10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons. Objective To compare outcomes of patients with GS 9–10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT + brachytherapy EBRT + BT), and RP. Design, setting, participants Retrospective analysis of 487 patients with biopsy GS 9–10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT + BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy. Outcome measurements and statistical analysis Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). Results and limitations The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT + BT patients (1.2% and 16.1%, p < 0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT + BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p = 0.0005) or RP (79.1% and 61.5%, p < 0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts. Conclusions Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9–10 CaP. Patient summary While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9–10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival.
Stereotactic body radiotherapy harnesses improvements in technology to allow the completion of a course of external beam radiotherapy treatment for prostate cancer in the span of 4 to 5 treatment ...sessions. Although mounting short-term data support this approach, long-term outcomes have been sparsely reported.
To assess long-term outcomes after stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.
This cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase 2 trials and 2 multi-institutional phase 2 trials of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer between January 1, 2000, and December 31, 2012. Statistical analysis was performed based on follow-up from January 1, 2013, to May 1, 2018.
The cumulative incidence of biochemical recurrence was estimated using a competing risk framework. Physician-scored genitourinary and gastrointestinal toxic event outcomes were defined per each individual study, generally by Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. After central review, cumulative incidences of late grade 3 or higher toxic events were estimated using a Kaplan-Meier method.
A total of 2142 men (mean SD age, 67.9 9.5 years) were eligible for analysis, of whom 1185 (55.3%) had low-risk disease, 692 (32.3%) had favorable intermediate-risk disease, and 265 (12.4%) had unfavorable intermediate-risk disease. The median follow-up period was 6.9 years (interquartile range, 4.9-8.1 years). Seven-year cumulative rates of biochemical recurrence were 4.5% (95% CI, 3.2%-5.8%) for low-risk disease, 8.6% (95% CI, 6.2%-11.0%) for favorable intermediate-risk disease, 14.9% (95% CI, 9.5%-20.2%) for unfavorable intermediate-risk disease, and 10.2% (95% CI, 8.0%-12.5%) for all intermediate-risk disease. The crude incidence of acute grade 3 or higher genitourinary toxic events was 0.60% (n = 13) and of gastrointestinal toxic events was 0.09% (n = 2), and the 7-year cumulative incidence of late grade 3 or higher genitourinary toxic events was 2.4% (95% CI, 1.8%-3.2%) and of late grade 3 or higher gastrointestinal toxic events was 0.4% (95% CI, 0.2%-0.8%).
In this study, stereotactic body radiotherapy for low-risk and intermediate-risk disease was associated with low rates of severe toxic events and high rates of biochemical control. These data suggest that stereotactic body radiotherapy is an appropriate definitive treatment modality for low-risk and intermediate-risk prostate cancer.
To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries.
...Individual patient data were pooled for 344 patients with a minimum follow-up of 24 months. Biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) were estimated using a Kaplan-Meier framework. Fine and Gray competing risk and Cox proportional hazards regression models were developed to assess the association between time to BCR and time to distant metastasis and prespecified variables of interest. Logistic regression models were developed to evaluate associations between acute and late grade ≥2 genitourinary and gastrointestinal and the following a priori-specified variables: age, dose per fraction, ADT use, and nodal radiation therapy.
Median follow-up was 49.5 months. Seventy-two percent of patients received ADT, with a median duration of 9 months, and 19% received elective nodal radiation therapy. Estimated 4-year BCRFS and DMFS rates were 81.7% (95% CI, 77.2%-86.5%) and 89.1% (95% CI, 85.3%-93.1%). The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%.
These data support a favorable toxicity and efficacy profile for SBRT for HRPCa. Further prospective studies are needed to evaluate the optimal dose and target volume in the context of SBRT for HRPCa.
To review the biochemical relapse-free survival (bRFS) rates after treatment with permanent seed implantation (PI), external beam radiotherapy (EBRT) <72 Gy (EBRT <72), EBRT ≥72 Gy (EBRT ≥72), ...combined seeds and EBRT (COMB), or radical prostatectomy (RP) for clinical Stage T1-T2 localized prostate cancer treated between 1990 and 1998.
The study population comprised 2991 consecutive patients treated at the Cleveland Clinic Foundation or Memorial Sloan Kettering at Mercy Medical Center. All cases had pretreatment prostate-specific antigen (iPSA) levels and biopsy Gleason scores (bGSs). Neoadjuvant androgen deprivation for ≤6 months was given in 622 cases (21%). No adjuvant therapy was given after local therapy. RP was used for 1034 patients (35%), EBRT <72 for 484 (16%), EBRT ≥72 for 301 (10%), PI for 950 (32%), and COMB for 222 patients (7%). The RP, EBRT <72, EBRT ≥72, and 154 PI patients were treated at Cleveland Clinic Foundation. The median radiation doses in EBRT <72 and EBRT ≥72 case was 68.4 and 78.0 Gy, respectively. The median follow-up time for all cases was 56 months (range 12–145). The median follow-up time for RP, EBRT <72, EBRT ≥72, PI, and COMB was 66, 75, 49, 47, and 46 months, respectively. Biochemical relapse was defined as PSA levels >0.2 for RP cases and three consecutive rising PSA levels (American Society for Therapeutic Radiology Oncology consensus definition) for all other cases. A multivariate analysis for factors affecting the bRFS rates was performed using the following variables: clinical T stage, iPSA, bGS, androgen deprivation, year of treatment, and treatment modality. The multivariate analysis was repeated excluding the EBRT <72 cases.
The 5-year bRFS rate for RP, EBRT <72, EBRT ≥72, PI, and COMB was 81%, 51%, 81%, 83%, and 77%, respectively (
p <0.001). The 7-year bRFS rate for RP, EBRT <72, EBRT ≥72, PI, and COMB was 76%, 48%, 81%, 75%, and 77%, respectively. Multivariate analysis, including all cases, showed iPSA (
p <0.001), bGS (
p <0.001), year of therapy (
p <0.001), and treatment modality (
p <0.001) to be independent predictors of relapse. Because EBRT <72 cases had distinctly worse outcomes, the analysis was repeated after excluding these cases to discern any differences among the other modalities. The multivariate analysis excluding the EBRT <72 cases revealed iPSA (
p <0.001), bGS (
p <0.001), and year of therapy (
p = 0.001) to be the only independent predictors of relapse. Treatment modality (
p = 0.95), clinical T stage (
p = 0.09), and androgen deprivation (
p = 0.56) were not independent predictors for failure.
The biochemical failure rates were similar among PI, high-dose (≥72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (<72 Gy) EBRT.
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