Gastrointestinal Toxicity Rates Research Articles

Cost-Effectiveness Threshold of Magnetic Resonance Image-Guided Radiotherapy for Localized Prostate Cancer

Magnetic resonance image guided radiotherapy (MR-IGRT) is anticipated to reduce toxicity through intrafraction motion detection and smaller treatment margins, but no studies have assessed if the technology can be cost-effective. Our purpose is to determine if MR-IGRT for treatment of localized prostate cancer can achieve cost-effectiveness through toxicity reduction alone compared to CT-based image guided radiotherapy (CT-IGRT). The comparison groups were MR-IGRT and CT-IGRT delivered in conventional 39 fraction and stereotactic body radiotherapy (SBRT) 5 fraction schedules. To determine the cost of delivering radiotherapy to each group, time driven activity-based costing was used with a healthcare cost perspective. Equipment and therapy-related costs for each group were calculated with data from two institutions and literature values assuming a 15-year lifespan per machine and utilization of treatment machines 8 hours/day, 5 days/week, 50 weeks/year. The gastrointestinal and genitourinary toxicity rates associated with CT-IGRT in this model were averaged from 20 prior studies. The costs and utilities associated with various health states were obtained from literature values and cost databases. Markov modeling was used to determine the costs and quality adjusted life years (QALYs) saved with each 1% relative reduction in acute and chronic toxicities by MR-IGRT over 15 years with a discount rate of 3%. Toxicity reduction thresholds for cost-effectiveness were then calculated based on the added cost of MR-IGRT juxtaposed with the cost reduction and QALYs saved for each 1% relative toxicity reduction from Markov modeling. One-way sensitivity analyses were performed. Standard $50,000 and $100,000 per QALY ratios were used. The added cost of MR-IGRT over CT-IGRT was $1,459 per course of SBRT and $10,129 per course of conventionally fractionated radiotherapy. Relative toxicity reductions of 7% and 14% were required for MRI-guided SBRT to be cost-effective compared to CT-guided SBRT using $100,000 and $50,000 per QALY, respectively. MR-IGRT in conventional fractionation required relative toxicity reductions of 50% and 94% to be cost-effective at $100,000 and $50,000 per QALY. In the sensitivity analyses, the cost-effectiveness of MR-IGRT was most dependent on the number of patients treated on the MR-IGRT and CT-IGRT systems as well as the initial and maintenance costs of the MR-IGRT system. From a healthcare perspective, MR-IGRT can be cost-effective through toxicity reduction alone. Hypofractionated schedules, such a five fraction SBRT, are most likely to achieve cost-effectiveness as they require only slight reductions in toxicity (7-14%).

Outcomes After Salvage Radiation Therapy for Recurrent Endometrial Cancer in Patients With No Prior Adjuvant Therapy: An Institutional Review

PurposeAfter definitive surgery, women with early-stage, low-risk endometrial cancer are observed. However, some will require salvage radiation therapy for recurrence. The purpose of this study was to evaluate our experience using salvage radiation for recurrent endometrial cancer in patients who did not receive upfront adjuvant therapy. Methods and MaterialsTwenty-eight women with endometrial cancer who had undergone initial definitive hysterectomy without adjuvant therapy developed isolated local or regional recurrence and were treated with salvage radiation in our department from 2004 to 2018. Salvage radiation included whole pelvic radiation, vaginal brachytherapy, or both. Patient and tumor characteristics, treatment details, and toxicities were recorded and analyzed. ResultsThe median time to first recurrence was 1.7 years. First recurrences consisted of local recurrence in 23 patients, regional recurrence in 4, and both in 1. The median times from hysterectomy to first recurrence, local and regional, were 1.2 and 4.0 years, respectively. All patients underwent salvage radiation for management of their first recurrence. The median total equivalent dose in 2 Gy fractions for this treatment was 67.6 Gy (37.5–81.8 Gy). Two second recurrences occurred following salvage treatment, both local recurrence, at 6.5 and 13.5 months after radiation. The 2-year rates of local control, disease-free survival, and overall survival were 93%, 80%, and 88%, respectively. Treatment was well-tolerated, with low rates of gastrointestinal and genitourinary toxicity. ConclusionsIn this group of patients, salvage radiation therapy for local or regional recurrence of endometrial cancer resulted in excellent control with low rates of acute and chronic toxicities.

334P Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients: Updated phase II results and dose selection

CDK4/6 inhibitors (CDK4/6i) combined with fulvestrant (F) are the established standard of care for HR+/HER2- advanced breast cancer (ABC). Two of the three approved CDK4/6i cause dose-limiting neutropenia requiring a drug holiday, and the third is limited by gastrointestinal (GI) toxicity. Lerociclib is a potent, selective CDK4/6i that is dosed continuously. Initial data presented at SABCS 2019 indicated that lerociclib + F had low rates of GI toxicity and Grade 4 neutropenia, and antitumor activity was comparable with other CDK4/6i + F combinations. This phase I/II study assessed lerociclib with 500 mg F in patients (pts) with HR+/HER2- ABC that had progressed following endocrine therapy. Up to 2 prior chemotherapies in the advanced setting in phase I (dose escalation), and 1 prior in phase II (dose expansion) were allowed. Prior F and CDK4/6i exposure were excluded in phase II. The objectives were to evaluate DLTs, safety, tolerability, PK, preliminary efficacy, and determine the recommended dose of lerociclib when combined with F for future randomized trials. As of Jan 31, 2020, 110 pts had been enrolled across doses of 200–650 mg once daily and 100–250 mg twice daily (BID). Twenty pts received 150 mg BID for a median 6.9 (range 1.7–27.8) months, with median age of 55 years (range 33–84), ECOG of 0 (85%), and median 1 line (range 0–5) of prior anticancer therapy in the advanced setting. The most common lerociclib-related AEs at 150 mg BID were neutropenia (55%), leukopenia (40%), diarrhea (20%), and anemia (20%). Rates of Grade 3 and 4 neutropenia were 30% and 5%, respectively. There were no reports of Grade ≥ 3 nausea, vomiting, or diarrhea. Nineteen pts at 150 mg BID were evaluable for tumor response based on RECIST version 1.1. Six pts (32%) had a confirmed PR; 9 (47%) had SD; 4 (21%) had PD. The CBR (CR+PR+SD ≥ 24 weeks) was 74% (14/19). Subgroup analyses revealed that pts who received no prior chemotherapy in the advanced setting (9/19 pts) had the highest CBR of 89%. Lerociclib 150 mg BID dosed continuously demonstrated a differentiated profile with low rates of GI toxicity and Grade 3/4 neutropenia. Efficacy compares favorably to approved CDK4/6i + F combinations.

Toxicity reduction required for MRI-guided radiotherapy to be cost-effective in the treatment of localized prostate cancer.

To determine the toxicity reduction required to justify the added costs of MRI-guided radiotherapy (MR-IGRT) over CT-based image guided radiotherapy (CT-IGRT) for the treatment of localized prostate cancer. The costs of delivering prostate cancer radiotherapy with MR-IGRT and CT-IGRT in conventional 39 fractions and stereotactic body radiotherapy (SBRT) 5 fractions schedules were determined using literature values and cost accounting from two institutions. Gastrointestinal and genitourinary toxicity rates associated with CT-IGRT were summarized from 20 studies. Toxicity-related costs and utilities were obtained from literature values and cost databases. Markov modeling was used to determine the savings per patient for every 1% relative reduction in acute and chronic toxicities by MR-IGRT over 15 years. The costs and quality adjusted life years (QALYs) saved with toxicity reduction were juxtaposed with the cost increase of MR-IGRT to determine toxicity reduction thresholds for cost-effectiveness. One way sensitivity analyses were performed. Standard $100,000 and $50,000 per QALY ratios were used. The added cost of MR-IGRT was $1,459 per course of SBRT and $10,129 per course of conventionally fractionated radiotherapy. Relative toxicity reductions of 7 and 14% are required for SBRT to be cost-effective using $100,000 and $50,000 per QALY, respectively. Conventional radiotherapy requires relative toxicity reductions of 50 and 94% to be cost-effective. From a healthcare perspective, MR-IGRT can reasonably be expected to be cost-effective. Hypofractionated schedules, such a five fraction SBRT, are most likely to be cost-effective as they require only slight reductions in toxicity (7-14%). This is the first detailed economic assessment of MR-IGRT, and it suggests that MR-IGRT can be cost-effective for prostate cancer treatment through toxicity reduction alone.

The implementation of an empty bladder filling protocol for localised prostate volumetric modulated arctherapy (VMAT): early results of a single institution service evaluation.

To examine the impact of an empty bladder filling protocol on patients receiving radical RT for localised prostate cancer on post RT toxicity and biochemical progression free survival (bPFS). Records of patients receiving radical external beam RT (EBRT) for localised prostate cancer with a full or empty bladder were reviewed. These included the bladder size on planning CT, daily online image guided RT (IGRT) setup data, treatment time and post treatment follow up data.These included bPFS, gastrointestinal(GI) and genitourinary(GU) toxicity scoring post RT using the CTCAE v4.0 scoring system. All patients included in the study were planned and treated under the same departmental clinical protocol with VMAT and daily online IGRT corrections. 90 patients were treated with 60 Gy in 20 fractions with a median follow up of 48 months. At 4 years bPFS in the empty bladder group was 100 and 98% in the full bladder group (p = 0.27). There were no statistically significant differences in cumulative ≥Grade 2GU (p = 0.10) and GI (p = 0.27) toxicity rates between the two bladder filling protocols. No statistically significant differences in the IGRT setup between the two groups of patients. Although the median treatment times per fraction were not statistically different between the two groups (p = 0.47), patients in the full bladder filling group were required to spend a longer time in the RT department per treatment session for bladder filling. An empty bladder filling protocol has non-inferior bPFS, GI and GU toxicities at 4 years in patients with localised prostate cancer using advanced RT techniques in comparison to a full bladder filling protocol. A longer follow up with a larger sample size is required to validate this approach. This study suggests that an empty bladder filling protocol can be used in external beam EBRT for localised prostate cancer with non-inferior treatment outcomes.

Long-term outcomes of intensity-modulated radiation therapy (IMRT) and high dose rate brachytherapy as adjuvant therapy after radical hysterectomy for cervical cancer

ObjectiveCompared with 3D-planned pelvic radiation, intensity-modulated radiation therapy (IMRT) has been shown to reduce acute toxicity in cervical cancer patients after radical hysterectomy. This study evaluated late toxicity and patterns...

Transitioning from conformal radiotherapy to intensity-modulated radiotherapy after radical prostatectomy: Clinical benefit, oncologic outcomes and incidence of gastrointestinal and urinary toxicities.

The purpose of this study was to review genitourinary (GU) and gastrointestinal (GI) toxicity associated with high-dose radiotherapy (RT) delivered with 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) following radical prostatectomy (RP). RP is a therapeutic option for the management of prostate cancer (PrCa). When assessing postoperative RT techniques for PrCa, the published literature focuses on patients treated with 2-dimensional conventional methods without reflecting the implementation of 3D-CRT, IMRT, or VMAT. A total of 83 patients were included in this analysis; 30 patients received 3D-CRT, and 53 patients received IMRT/VMAT. Acute and late symptoms of the GU and lower GI tract were retrospectively graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer radiation toxicity grading systems. The relapse failure-free rate and overall survival were also evaluated. The rate of acute GU toxicity was 9.4% vs. 13.3% for the IMRT/VMAT and 3D-CRT groups (p = 0.583). The 5-year actuarial rates of late GI toxicity for IMRT/VMAT and 3D-CRT treatments were 1.9% and 6.7%, respectively. The rate of late GU toxicity for the IMRT/VMAT and 3D-CRT treatment groups was 7.5% and 16.6%, respectively (p = 0.199). We found no association between acute or late toxicity and the RT technique in univariate and multivariate analyses. Postprostatectomy IMRT/VMAT and 3D-CRT achieved similar morbidity and cancer control outcomes. The clinical benefit of highly conformal techniques in this setting is unclear although formal analysis is needed.

A Comparison of the BEAM and MITO/MEL Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Hodgkin Lymphoma: An Analysis of Efficiency and Treatment-Related Toxicity

BackgroundApproximately half of patients with relapsed chemosensitive disease achieve robust responses with BEAM (BCNU, etoposide, cytarabine, and melphalan) and autologous stem cell rescue. The scarcity of comparative studies further limits alternative treatment protocols, such as the MITO/MEL (mitoxantrone, melphalan) protocol. Patients and MethodsIn this retrospective multicenter study, we compared the BEAM and MITO/MEL regimens used before autologous hematopoietic stem cell transplantation (ASCT) in terms of efficacy and side effects in patients with Hodgkin lymphoma. Data met international accreditation rules. Before ASCT, 108 patients received the MITO/MEL, and 34 patients received the BEAM. ResultsThe median follow-up time was 36 months in the MITO/MEL group (range, 3-178) and 23 months in the BEAM group (range, 4-99). After ASCT, the 3-year expected overall survival and disease-free survival rates were 86.1% and 86.1% for the MITO/MEL group and 91.3% and 76.5% for the BEAM group, respectively. Although 50% of patients developed febrile neutropenia attacks in the MITO/MEL group, this rate was 91.1% in the BEAM group. The grade II and higher rates of hepatic, renal, gastrointestinal, and cardiac toxicities were similar in both groups. However, the rate of pulmonary toxicity was determined to be 1.9% in the MITO/MEL group and 29.4% in the BEAM group (P < .001). ConclusionThe MITO/MEL conditioning regimen seems to be as effective as the BEAM regimen but has better tolerability in terms of pulmonary toxicity and may be used as an alternative option if necessary, depending on the comorbidity status of the patient.

Late gastrointestinal toxicity after radiotherapy for rectal cancer: a systematic review.

Although the multimodal cancer treatment techniques have greatly improved over the years, irradiation-induced late gastrointestinal toxicity remains a great concern as it may highly affect the quality of life of a patient. The aim of this study was to define the prevalence of late gastrointestinal toxicities. Electronic databases of Cochrane Library, Embase, Web of Science, CENTRAL and PubMed were searched until September 2019. We used the following keywords: radiotherapy, radiation therapy, irradiation, rectal cancer, gastrointestinal toxicity, adverse effects, late effects, pelvic radiation and pelvic radiation disease. Nine studies were included into this review out of 4785 that were preidentified as potentially relevant. Overall prevalence of severe (Grade 3 or higher) late irradiation-induced gastrointestinal toxicities was up to 19%. Most frequent toxicities of any grade were reported to be diarrhoea (up to 35%), faecal incontinence (22%), incontinence to gas (71%), rectal bleeding (9%), rectal pain (13%) and obstruction (7.4%). Preoperative treatment approaches and more advance radiotherapy techniques such as intensity-modulated and image-guided radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) turn out to result in lower late gastrointestinal toxicity rates. After great improvements in rectal cancer treatment, late gastrointestinal toxicity after radiotherapy is experienced less frequent and less severe; however, it remains a great concern associated with worse quality of life.

Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer

Background and purposeLocal recurrences after radiotherapy for prostate cancer (PCa) often originate at the location of the macroscopic tumour(s). Since PCa cells are known to be sensitive to high fraction doses, hypofractionated whole gland stereotactic body radiotherapy (SBRT) in conjunction with a simultaneous ablative microboost to the macroscopic tumour(s) within the prostate could be a way to reduce the risk of local failure. We investigated the safety of this treatment strategy. Materials and methodsPatients with intermediate or high risk PCa were enrolled in a prospective phase II trial, called hypo-FLAME. All patients were treated with extreme hypofractionated doses of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the multiparametric (mp) MRI-defined tumour(s). Treatment-related toxicity was measured using the CTCAE v4.0. The primary endpoint of the trial was treatment-related acute toxicity. ResultsBetween April 2016 and December 2018, 100 men were treated in 4 academic centres. All patients were followed up for a minimum of 6 months. The median mean dose delivered to the visible tumour nodule(s) on mpMRI was 44.7 Gy in this trial. No grade ≥3 acute genitourinary (GU) or gastrointestinal (GI) toxicity was observed. Furthermore, 90 days after start of treatment, the cumulative acute grade 2 GU and GI toxicity rates were 34.0% and 5.0%, respectively. ConclusionSimultaneous focal boosting to the macroscopic tumour(s) in addition to whole gland prostate SBRT is associated with acceptable acute GU and GI toxicity.

Comparison of Treatment-Related Toxicity With Hypofractionated or Conventionally Fractionated Radiation Therapy for Prostate Cancer: A National Population-Based Study

AimsRandomised controlled trials have shown comparable early oncological outcomes after hypofractionated and conventionally fractionated radiotherapy in the radical treatment of prostate cancer (PCa). The effect of hypofractionation on treatment-related gastrointestinal and genitourinary toxicity remains uncertain, especially in older men and those with locally advanced PCa. Materials and methodsA population-based study of all patients treated with radical conventionally fractionated radiotherapy (n = 9106) and hypofractionated radiotherapy (n = 3027) in all radiotherapy centres in the English National Health Service between 2014 and 2016 was carried out. We identified severe gastrointestinal and genitourinary toxicity using a validated coding framework and compared conventionally fractionated and hypofractionated radiotherapy using a competing-risks proportional hazards regression analysis. ResultsThe median age in our cohort was 72 years old and most patients had locally advanced disease (65%). There was no difference in gastrointestinal toxicity (conventionally fractionated radiotherapy: 5.0 events/100 person-years; hypofractionated radiotherapy: 5.2 events/100 person-years; adjusted subdistribution hazard ratio: 1.00, 95% confidence interval: 0.89–1.13; P = 0.95) or genitourinary toxicity (conventionally fractionated radiotherapy: 2.3 events/100 person-years; hypofractionated radiotherapy: 2.3 events/100 person-years; adjusted subdistribution hazard ratio: 0.92, 95% confidence interval: 0.77–1.10; P = 0.35) between patients who received conventionally fractionated radiotherapy and those who received hypofractionated radiotherapy. ConclusionsThis national cohort study has shown that the use of hypofractionated radiotherapy in the radical treatment of PCa does not increase rates of severe gastrointestinal or genitourinary toxicity. Our findings also support the use of hypofractionated radiotherapy in older men and those with locally advanced PCa.

Moderately hypofractionated carbon ion radiotherapy for prostate cancer; a prospective observational study \u201cGUNMA0702\u201d

BackgroundCarbon ion Radiotherapy for prostate cancer is widely used, however reports are limited from single institute or short follow up. We performed a prospective observational study (GUNMA0702) to evaluate the feasibility and efficacy of carbon ion radiotherapy for localized and locally advanced prostate cancer.MethodsBetween June 2010 and August 2013, 304 patients with localized prostate cancer were treated, with a median follow-up duration of 60 months. All patients received carbon ion radiotherapy with 57.6 Gy (RBE) in 16 fractions over 4 weeks. Hormonal therapy was given according to the risk group. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 by the National Cancer Institute.ResultsThe overall 5-year biochemical relapse-free rate was 92.7%, with rates of 91.7, 93.4, and 92.0% in low-risk, intermediate-risk, and high-risk patients, respectively. The 5-year local control and overall survival rates were 98.4 and 96.6%, respectively. Acute grade 3 or greater toxicity was not observed. Late grade 2 and grade 3 genitourinary and gastrointestinal toxicity rates were 9 and 0.3%, and 0.3, and 0%, respectively.ConclusionsThe present protocol of carbon ion radiotherapy for prostate cancer provided low genitourinary and gastrointestinal toxicity with good biochemical control within 5 years.Trial registrationUniversity Medical Information Network Clinical Trial Registry number: UMIN000003827.

Microbial Diversity and Composition Is Associated with Patient-Reported Toxicity during Chemoradiation Therapy for Cervical Cancer

Patients receiving pelvic radiation for cervical cancer experience high rates of acute gastrointestinal (GI) toxicity. The association of changes in the gut microbiome with bowel toxicity from radiation is not well characterized. Thirty-five patients undergoing definitive chemoradiation therapy (CRT) underwent longitudinal sampling (baseline and weeks 1, 3, and 5) of the gut microbiome and prospective assessment of patient-reported GI toxicity. DNA was isolated from stool obtained at rectal examination and analyzed with 16S rRNA sequencing. GI toxicity was assessed with the Expanded Prostate Cancer Index Composite instrument to evaluate frequency, urgency, and discomfort associated with bowel function. Shannon diversity index was used to characterize alpha (within sample) diversity. Weighted UniFrac principle coordinates analysis was used to compare beta (between sample) diversity between samples using permutational multivariate analysis of variance. Linear discriminant analysis effect size highlighted microbial features that best distinguish categorized patient samples. Gut microbiome diversity continuously decreased over the course of CRT, with the largest decrease at week 5. Expanded Prostate Cancer Index Composite bowel function scores also declined over the course of treatment, reflecting increased symptom burden. At all individual time points, higher diversity of the gut microbiome was linearly correlated with better patient-reported GI function, but baseline diversity was not predictive of eventual outcome. Patients with high toxicity demonstrated different compositional changes during CRT in addition to compositional differences in Clostridia species. Over time, increased radiation toxicity is associated with decreased gut microbiome diversity. Baseline diversity is not predictive of end-of-treatment bowel toxicity, but composition may identify patients at risk for developing high toxicity.

Patient and physician reported toxicity with two-fraction definitive high-dose-rate prostate brachytherapy: the impact of implant interval

PurposeHigh-dose-rate (HDR) brachytherapy is an effective method of treating localized prostate cancer. There are limited data on the relationship between implant interval and outcomes. This study aims to assess if the implant interval between HDR treatments has an impact on patient-reported health-related quality of life (QOL) and physician-graded toxicity in men treated for localized prostate cancer.Material and methodsPatients were treated with HDR brachytherapy as monotherapy with 27 Gy in 2 fractions, given over two implants, performed 1-2 weeks apart. Patients were dichotomized into one-week and two-week cohorts. Patient-reported EPIC-26 genitourinary (GU), gastrointestinal (GI), and sexual QOL were assessed. Linear regression, chi-squared testing, and generalized linear mixed effect models were used to assess the differences in patient characteristics, patient-reported QOL, and physician-graded toxicity.ResultsOutcomes of 122 patients were analyzed. Median follow-up was 18 months. Patient-reported GU and GI QOL worsened after treatment with a return towards baseline over time, while patient-reported sexual QOL worsened after treatment, but did not return towards baseline. There were no differences in patient-reported health related QOL as a function of implant interval. Maximum physician-graded GU, GI, and sexual toxicity rates of grade 2 or 3 were 68%, 3%, and 53%, respectively. There was no difference in rates of grade 2 or 3 toxicity as a function of implants interval.ConclusionsHDR brachytherapy for prostate cancer is a well-tolerated treatment. The interval between treatments is not associated with differences in patient-reported QOL or physician-graded toxicities.

Ultrahypofractionation Should be a Standard of Care Option for Intermediate-Risk Prostate Cancer

Ultrahypofractionation Should be a Standard of Care Option for Intermediate-Risk Prostate Cancer

Stereotactic Body Radiation Therapy Vs Hypofractionated Intensity Modulated Radiation Therapy for Localized Prostate Cancer (SHRAPNEL): An International Meta-Analysis of 24 Prospective Trials

We aimed to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) vs. hypofractionated intensity modulated radiation therapy (HIMRT) for the definitive treatment of localized prostate cancer. The primacy outcome measure was efficacy, defined by 5-year disease free survival (DFS), based on the “prostate specific antigen nadir + 2 ng/mL” definition. The secondary outcome measure was safety, defined as incidence of grade ≥2 late genitourinary (GU) or gastrointestinal (GI) toxicities per the Common Terminology Criteria for Adverse Events or Radiation Therapy Oncology Group. PICOS/PRISMA/MOOSE methods were used to identify eligible studies. Inclusion criteria were: (1) patients diagnosed with localized prostate cancer; (2) HIMRT, >2 (<5) Gy/fraction; or SBRT, ≥ 5 Gy/fraction in ≤ 5 fractions; (3) either no control group, or another definitive RT control arm; (4) at least one of the primary or secondary outcome measures were reported; (5) single or multi arm phase III (HIMRT) and/or phase I-II (SBRT) prospective study. Androgen deprivation therapy (ADT) was prescribed per protocol specifications. Weighted random effects meta-analyses using the DerSimonian and Laird method were conducted to characterize summary effect sizes for each outcome. Meta-regression and Wald-type tests were used to compare each outcome by treatment, where the null hypothesis was rejected for p<0.05. After initial screening of 130 studies, 24 prospective trials containing 6,952 patients (3,027 SBRT [57% low-risk, 37% intermediate, 6% high] and 3,925 HIMRT [25% low, 60% intermediate, 15% high]) from 3 countries were included. ADT use was assessed (12% SBRT and 61% HIMRT). The median follow-up was 5.8 years for SBRT vs. 5.2 years for HIMRT. Prescription doses for SBRT ranged from 19-38 Gy in 2-4 fractions to 50 Gy in 5 fractions, and those of HIMRT ranged from 51.6 Gy in 12 fractions to 70.2 Gy in 26 fractions. The 5-year DFS rates for SBRT ranged from 81%-100% vs. 79%-91% for HIMRT. The random effects estimate for 5-year DFS was 95.3% (95% confidence Interval [CI]: 92.1%-97.8%) for SBRT vs. 85.7% (95% CI: 82.7%-88.5%) for HIMRT (p=0.0004). Rates of late grade 2+ GU toxicity for SBRT ranged from 0%-32.1% vs. 6.1%-49.3% for HIMRT. The random effects estimate for late grade 2+ GU toxicity was 14.4% (95% CI: 10.9%-18.3%) for SBRT vs. 20.9% (95% CI: 9.8%-34.7%) for HIMRT (p=0.27). Rates of late grade 2+ GI toxicity ranged from 0%-29% for SBRT vs. 7.4%-25.6% for HIMRT. The random effects estimate for late grade 2+ GI toxicity was 2.7% (95% CI: 1%-4.9%) for SBRT vs. 14.7% (95% CI: 9.4%-20.9%) for HIMRT (p<0.0001). In this select patient population with prospectively collected outcomes, SBRT had superior biochemical control with fewer long-term GU and GI toxicity rates over HIMRT in the treatment of localized prostate cancer. Prospective clinical trials directly comparing these therapies are pending, but these results support standard use of SBRT in the interim.

Association between Severe Gastrointestinal Toxicity and Molecular Targeted Therapy in Patients Received Radiotherapy for Metastatic Bone Tumor or Myeloma

Purpose of this study is to examine the association between severe gastrointestinal (GI) toxicity and molecular targeted therapy in patients received radiotherapy (RT) for bone lesions. This study included the patients who received RT for metastatic bone tumor or myeloma of abdominopelvic region between 2013 and 2014 at 6 institutions. Patient/tumor characteristics, RT dose, molecular targeted therapy, chemotherapy and GI toxicities were analyzed. GI toxicity was graded according to the CTCAE v4.0. Fisher’s exact test was used to examine the statistical significance. In total, 403 patients were included. Follow-up period was median 168 days (1-1798). Previous abdominopelvic surgery was performed in 145 patients. RT regimens were various, and major regimens were 30 Gy in 10 fractions and 20 Gy in 5 fractions. Total 21 different molecular targeted agents were administered in 185 patients. Vascular epidermal growth factor inhibitor (VEGFI) was administered in 85 patients; bevacizumab, sorafenib, axitinib, sunitinib, pazopanib, ramucirumab and regorafenib in 41, 24, 9, 13, 5, 1 and 2 patients. There were 30 (7.4%) patients who suffered ≥grade (G) 2 GI toxicities. G2, 3, 4 and 5 toxicities were observed in 15 (3.7%), 7 (1.7%), 4 (1.0%) and 4 (1.0%) patients, respectively. Duration between the beginning of RT and occurrence of GI toxicities was median 48.5 days (1-999 days). Perforation, bleeding, obstruction, diarrhea, gastroenteritis, vomiting and esophagitis were observed in 5 (1.2%), 7 (1.7%), 8 (2.0%), 4 (1.0%), 2 (0.5%), 1 (0.25%) and 3 (0.74%) patients, respectively. Among patients received molecular targeted therapy, there were in 3 (1.6%), 3 (1.6%), 4 (2.2%), 2 (1.1%), 3 (1.6%), 0 and 2 (1.1%) patients, respectively. Use of molecular targeted agents and use of VEGFIs showed no significant difference in occurrence of ≥G3 toxicities (3.8% vs 3.7%, p=1.0, and 7.2% vs 2.8%, p=0.095). History of previous abdominopelvic surgery (6.9% vs 1.6%, p=0.009) was only a significant factor. Among patients with molecular targeted agents use, ≥G3 toxicities in patients with VEGFIs use were significantly more than those in patients with other agents use (7.2% vs 1.0%, p=0.046). Moreover, among patients with VEGFIs use, ≥G3 toxicities in patients with VEGFIs use concurrently or during 7 days before and after RT were significantly more than those in patients with VEGFIs use during other period (18.2% vs 3.3%, p=0.04). Previous abdominopelvic surgery showed significantly higher occurrence rate of severe GI toxicities. Combination of RT with VEGFIs was significantly riskier than with the other agents. Use of VEGFIs concurrently or during 7 days before and after RT seems to be avoided.

Outcomes Based on Risk Factors in Intermediate Risk Prostate Cancer: a Secondary Analysis of a Randomized Phase III Trial

Intermediate risk prostate cancer (IRPC) patients (pts) are stratified in favorable and unfavorable subgroups. To identify pts benefiting from therapeutic de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiotherapy (DERT), we measured biochemical failure (BF) and overall survival (OS) rates in IRPC pts according to risk classification subgroups. From 12/2000 to 9/2010, 600 pts with IRPC were randomized to ADT+ RT 70 Gy vs. ADT+DERT76 vs. DERT76 alone. First, we analyzed outcomes based on 3 prognostic risk factors (RF) using T stage (T1-T2a vs.T2b-T2c), PSA level (<10 vs. ³10) and Gleason (6 vs. 7). We then compared BF and OS between arms for the presence of 1, 2, or 3 RF. Using the same 600 pts, we further refined the group of pts with only 1 RF to a favorable intermediate risk (FIR) by excluding pts with a more aggressive biologic profile: Gleason pattern 4+3 or ≥50% of positive biopsy cores. The remaining pts represented an unfavorable intermediate risk (UIR) group. We compared BF and OS outcomes for FIR vs. UIR. BF was analyzed with competing risks methods and OS with Kaplan Meier method and the log rank test. Overall 122 pts (20%) developed BF. The rate of BF increased with number of RF from 14% for 1 to 41% for 3 RF, p<0.001. In the presence of 1 RF only, the incidence of BF increased significantly in DERT76 compared to ADT+RT70 or ADT+DERT76, p=0.02 and p=0.04, respectively, with no difference between ADT+RT70 and ADT+DERT76, p=0.5. There was no difference in OS between groups in the presence of 1 RF only. In the presence of 2 or 3 RF, BF was significantly higher in DERT76 alone compared to ADT+RT70, p=0.047 or ADT+DERT76, p<0.001. There was a trend in favor of ADT+DERT76 for better BF control compared to ADT+RT70 [HR=1.86 (CI, 0.98-3.54), p=0.06]. There was no difference in OS between the 3 arms in the presence of 2 or 3 RF. When comparing outcomes from the FIR group, there was no significant difference in BF or OS between the 3 arms. In the UIR group, BF was significantly higher for DERT76 alone compared to ADT+RT70 or ADT+DERT76, p=0.005 and p<0.001, respectively. No significant difference seen between ADT+RT70 and ADT+RT76 for BF and no difference in OS between arms. Late gastro-intestinal (GI) toxicity was significantly higher in patients receiving 76 Gy. In IRPC, when using prognostic RF and stratifying pts by subgroups, therapeutic de-escalation is possible for the end-point of BF. To avoid ADT side effects, DERT76 alone can be used in pts with only 1 RF and without Gleason 4+3 or ≥50% positive biopsies (FIR). ADT+RT70 can be safely used for the remaining pts with only one RF and including Gleason 4+3 or ≥50% positive biopsies, with dose de-escalation leading to a lower rate of late GI toxicity. For those pts with 2 or 3 RF, ADT seems to be an important component for BF control. Further studies are needed in these heterogeneous IRPC pts.

Proton beam therapy delivered using pencil beam scanning vs. passive scattering/uniform scanning for localized prostate cancer: Comparative toxicity analysis of PCG 001-09

Background and purposePatient-level benefits of proton beam therapy (PBT) relative to photon therapy for prostate cancer (PC) continue to be the focus of debate. Although trials comparing the two modalities are underway, most are being conducted using “conventional” PBT (passive scattering/uniform scanning [PS/US]) rather than pencil beam scanning (PBS). The dosimetric benefits of PBS are well-known, but comparative data are limited. This analysis compares PBS toxicity rates with those of PS/US in a prospective multicenter registry. MethodsWe evaluated acute/late gastrointestinal (GI) and genitourinary (GU) toxicity rates for men with low-to-intermediate risk PC enrolled in PCG 001-09. Acute toxicities with the two techniques were compared using χ2 tests, and the cumulative incidence methods for late toxicity. Multivariable analyses (MVAs) for acute toxicity were performed using logistic regression, and cox proportional hazards models for late toxicity. ResultsPatients were treated using PS/US (n = 1105) or PBS (n = 238). Acute grade ≥2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47). Acute grade ≥2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). In MVA, PBS was significantly associated with increased acute grade ≥2 GU toxicity (RR = 1.57, p < 0.001). Late grade ≥2 GI and GU toxicities did not differ significantly between groups. ConclusionsThis is the first multi-institutional comparative effectiveness evaluation of PBT techniques in PC. Differences in acute GU toxicity warrant further evaluation, and highlight the urgent need for prospective data using PBT.

Salvage reirradiation for local prostate cancer recurrence after radiation therapy. For who? When? How?

PurposeLiterature review reporting results of salvage brachytherapy and stereotactic body radiotherapy for prostate recurrence only after radiotherapy for prostate cancer. Materials and methodsA total of 38 studies (including at least 15 patients per study) were analysed: 19 using low-dose-rate brachytherapy, nine high-dose-rate brachytherapy and ten stereotactic body radiotherapy. Only five studies were prospective. The median numbers of patients were 30 for low-dose-rate brachytherapy, 34 for high-dose-rate brachytherapy, and 30 for stereotactic body radiotherapy. The median follow-up were 47months for low-dose-rate brachytherapy, 36months for high-dose-rate brachytherapy and 21months for stereotactic body radiotherapy. ResultsLate genitourinary toxicity rates ranged, for grade 2: from 4 to 42% for low-dose-rate brachytherapy, from 7 to 54% for high-dose-rate brachytherapy and from 3 to 20% for stereotactic body radiotherapy, and for grade 3 or above: from 0 to 24% for low-dose-rate brachytherapy, from 0 to 13% for high-dose-rate brachytherapy and from 0 to 3% for grade 3 or above (except 12% in one study) for stereotactic body radiotherapy. Late gastrointestinal toxicity rates ranged, for grade 2: from 0 to 6% for low-dose-rate brachytherapy, from 0 to 14% for high-dose-rate brachytherapy and from 0 to 11% for stereotactic body radiotherapy, and for grade 3 or above: from 0 to 6% for low-dose-rate brachytherapy, and from 0 to 1% for high-dose-rate brachytherapy and stereotactic body radiotherapy. The 5-year biochemical disease-free survival rates ranged from 20 to 77% for low-dose-rate brachytherapy and from 51 to 68% for high-dose-rate brachytherapy. The 2- and 3-year disease-free survival rates ranged from 40 to 82% for stereotactic body radiotherapy. Prognostic factors of biochemical recurrence have been identified. ConclusionDespite a lack of prospective data, salvage reirradiation for prostate cancer recurrence can be proposed to highly selected patients and tumours. Prospective comparative studies are needed.