M.A. Hallman

Comparison of outcomes and toxicities among radiation therapy treatment options for prostate cancer

We review radiation therapy (RT) options available for prostate cancer, including external beam (EBRT; with conventional fractionation, hypofractionation, stereotactic body RT [SBRT]) and brachytherapy (BT), with an emphasis on the outcomes, toxicities, and contraindications for therapies. PICOS/PRISMA methods were used to identify published English-language comparative studies on PubMed (from 1980 to 2015) that included men treated on prospective studies with a primary endpoint of patient outcomes, with ⩾70 patients, and ⩾5year median follow up. Twenty-six studies met inclusion criteria; of these, 16 used EBRT, and 10 used BT. Long-term freedom from biochemical failure (FFBF) rates were roughly equivalent between conventional and hypofractionated RT with intensity modulation (evidence level 1B), with 10-year FFBF rates of 45-90%, 40-60%, and 20-50% (for low-, intermediate-, and high-risk groups, respectively). SBRT had promising rates of BF, with shorter follow-up (5-year FFBF of >90% for low-risk patients). Similarly, BT (5-year FFBF for low-, intermediate-, and high-risk patients have generally been >85%, 69-97%, 63-80%, respectively) and BT+EBRT were appropriate in select patients (evidence level 1B). Differences in overall survival, distant metastasis, and cancer specific mortality (5-year rates: 82-97%, 1-14%, 0-8%, respectively) have not been detected in randomized trials of dose escalation or in studies comparing RT modalities. Studies did not use patient-reported outcomes, through Grade 3-4 toxicities were rare (<5%) among all modalities. There was limited evidence available to compare proton therapy to other modalities. The treatment decision for a man is usually based on his risk group, ability to tolerate the procedure, convenience for the patient, and the anticipated impact on quality of life. To further personalize therapy, future trials should report (1) race; (2) medical comorbidities; (3) psychiatric comorbidities; (4) insurance status; (5) education status; (6) marital status; (7) income; (8) sexual orientation; and (9) facility-related characteristics.

Prostate Cancer Patients With Unmanaged Diabetes or Receiving Insulin Experience Inferior Outcomes and Toxicities After Treatment With Radiation Therapy

Micro‐Abstract We evaluated the effect of type 2 diabetes, and medications used in its management, on prostate cancer patients receiving radiation therapy. Men who were receiving insulin and those not receiving any medication had increased risk of death and toxicity than those without diabetes. Background: The purpose of the study was to determine the effect of type 2 diabetes mellitus (T2DM) on outcomes and toxicities among men with localized prostate cancer receiving definitive radiation therapy. Patients and Methods: We performed a retrospective review of 3217 patients, from 1998 to 2013, subdivided into 5 subgroups: (I) no T2DM; (II) T2DM receiving oral antihyperglycemic agent that contains metformin, no insulin; (III) T2DM receiving nonmetformin oral agent alone, no insulin; (IV) T2DM receiving any insulin; and (V) T2DM not receiving medication. Outcome measures were overall survival, freedom from biochemical failure (BF), freedom from distant metastasis, cancer‐specific survival, and toxicities. Kaplan–Meier analysis, log rank tests, Fine and Gray competing risk regression (to adjust for patient and lifestyle factors), Cox models, and subdistribution hazard ratios (sHRs) were used. Results: Of the 3217 patients, 1295 (40%) were low‐risk, 1192 (37%) were intermediate‐risk, and 652 (20%) were high risk. The group I to V distribution was 81%, 8%, 5%, 3%, and 4%. The median dose was 78 Gy, and the median follow‐up time was 50 (range, 1‐190) months. Group V had increased mortality (sHR, 2.1; 95% confidence interval [CI], 0.66‐1.54), BF (sHR, 2.14; 0.88‐1.83), and cause‐specific mortality (sHR, 3.87; 95% CI, 1.31‐11). Acute toxicities were higher in group IV versus group I (genitourinary: 38% vs. 26%; P = .01; gastrointestinal: 21% vs. 5%; P = 001). Late toxicities were higher in groups IV and V versus group I (12%‐14% vs. 2%‐6%; P < .01). Conclusion: Men with T2DM not receiving medication and men with T2DM receiving insulin had worse outcomes and toxicities compared to other patients. Graphical abstract: Figure. No Caption available.

Patient-reported quality of life after stereotactic body radiation therapy versus moderate hypofractionation for clinically localized prostate cancer

BACKGROUND AND PURPOSE Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer. MATERIALS AND METHODS In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression. RESULTS 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]). CONCLUSIONS Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.

A comparison of robotic arm versus gantry linear accelerator stereotactic body radiation therapy for prostate cancer

Prostate cancer is the most prevalent cancer diagnosed in men in the United States besides skin cancer. Stereotactic body radiation therapy (SBRT; 6–15 Gy per fraction, up to 45 minutes per fraction, delivered in five fractions or less, over the course of approximately 2 weeks) is emerging as a popular treatment option for prostate cancer. The American Society for Radiation Oncology now recognizes SBRT for select low- and intermediate-risk prostate cancer patients. SBRT grew from the notion that high doses of radiation typical of brachytherapy could be delivered noninvasively using modern external-beam radiation therapy planning and delivery methods. SBRT is most commonly delivered using either a traditional gantry-mounted linear accelerator or a robotic arm-mounted linear accelerator. In this systematic review article, we compare and contrast the current clinical evidence supporting a gantry vs robotic arm SBRT for prostate cancer. The data for SBRT show encouraging and comparable results in terms of freedom from biochemical failure (>90% for low and intermediate risk at 5–7 years) and acute and late toxicity (<6% grade 3–4 late toxicities). Other outcomes (eg, overall and cancer-specific mortality) cannot be compared, given the indolent course of low-risk prostate cancer. At this time, neither SBRT device is recommended over the other for all patients; however, gantry-based SBRT machines have the abilities of treating larger volumes with conventional fractionation, shorter treatment time per fraction (~15 minutes for gantry vs ~45 minutes for robotic arm), and the ability to achieve better plans among obese patients (since they are able to use energies >6 MV). Finally, SBRT (particularly on a gantry) may also be more cost-effective than conventionally fractionated external-beam radiation therapy. Randomized controlled trials of SBRT using both technologies are underway.

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation

ABSTRACT The release of inflammatory cytokines has been implicated in the toxicity of conventional radiotherapy (CRT). Transforming growth factor β (TGF-β) has been suggested to be a risk marker for pulmonary toxicity following radiotherapy. Pulsed low-dose rate radiotherapy (PLDR) is a technique that involves spreading out a conventional radiotherapy dose into short pulses of dose with breaks in between to reduce toxicities. We hypothesized that the more tolerable toxicity profile of PLDR compared with CRT may be related to differential expression of inflammatory cytokines such as TGF-β in normal tissues. To address this, we analyzed tissues from mice that had been subjected to lethal doses of CRT and PLDR by histology and immunohistochemistry (IHC). Equivalent physical doses of CRT triggered more cellular atrophy in the bone marrow, intestine, and pancreas when compared with PLDR as indicated by hematoxylin and eosin staining. IHC data indicates that TGF-β expression is increased in the bone marrow, intestine, and lungs of mice subjected to CRT as compared with tissues from mice subjected to PLDR. Our in vivo data suggest that differential expression of inflammatory cytokines such as TGF-β may play a role in the more favorable normal tissue late response following treatment with PLDR.

Radiation therapy to the primary tumor in locally advanced prostate cancer is not “closing the barn door after the horse has bolted”

The National Cancer Institute of Canada (NCIC) Clinical Trials Group PR.3/Medical Research Council PR07/ Intergroup T94-0110 (1) was a randomized controlled trial (RCT) of radiation therapy (RT) and androgen deprivation therapy (ADT) vs. ADT alone, for men with locally advanced prostate cancer. The authors defined locally advanced as: (I) T3-4, N0/X, M0; or (II) T1-2 with prostate specific antigen (PSA) > 40 ng/mL; or (III) PSA 20-40 ng/mL and Gleason 8-10. Men were randomized to lifelong ADT vs. ADT + RT, 65-69 Gy in 1.8 Gy fractions, using 3D conformal RT, to the prostate and pelvis or prostate alone. Of the 1,205 patients treated between 1995 and 2005, 602 received ADT alone and 603 received ADT + RT. Overall survival (OS) was significantly improved in the patients allocated to ADT + RT [hazard ratio (HR) =0.70; 95% CI, 0.57-0.85; P<0.001]. Prostate cancer specific mortality (CSM) was improved in the patients allocated to ADT + RT (HR =0.46; 95% CI, 0.34-0.61; P<0.001). Although patients on ADT + RT arm reported a higher rate of gastrointestinal (GI) toxicity, only 2 of 589 patients had grade 3 or greater diarrhea at 24 months after RT.

Effects of interruptions of external beam radiation therapy on outcomes in patients with prostate cancer

To evaluate if interruptions of external beam radiation therapy impact outcomes in men with localized prostate cancer (PCa).

Absence of Pathological Proof of Cancer Associated with Improved Outcomes in Early-Stage Lung Cancer

Objectives: The purpose of this study was to assess the trends in use of clinical diagnosis and its impact on treatment outcomes in patients receiving radiation therapy for early‐stage lung cancer. Methods: The Surveillance, Epidemiology, and End Results registry was queried from 2004 to 2012 for patients at least 18 years old in whom stage I (clinical stage T1a–T2a) lung cancer had been diagnosed and who underwent radiation therapy alone. Trends in diagnostic confirmation patterns were characterized. A Cox proportional hazards model was used to assess overall survival, and competing risk regression analysis was used to assess cancer‐specific survival (CSS). Results: A total of 7050 patients were included; the disease of 6399 of them (90.8%) was pathologically diagnosed and that of 651 (9.2%) was clinically diagnosed. There was no significant change in the utilization of clinical versus pathologic diagnosis (p = 0.172) over time. Patients with T1 disease (p < 0.001), tumors 0 to 1.9 cm in size (p < 0.001), and upper lobe tumors (p = 0.004) were more likely to have been clinically diagnosed. On multivariable analysis, clinical diagnosis was associated with an improved CSS (hazard ratio [HR] = 0.82, 95% confidence interval [CI]: 0.71–0.96) but was not associated with an improved overall survival (HR = 1.01, 95% CI: 0.90–1.13). When stratified by T stage, patients whose disease had been clinically diagnosed as stage T1a had an improved CSS (HR = 0.75, 95% CI: 0.58–0.96, p = 0.022). There was a trend toward improved CSS in patients with clinical stage T1b tumors (HR = 0.74, 95% CI: 0.55–1.00, p = 0.052). Conclusions: The improved CSS in patients with a clinical diagnosis suggests treatment of benign disease, particularly in smaller tumors. Prudent patient selection is needed to reduce the potential for overtreatment.