Lawrence Berk

Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline

PURPOSE To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS A systematic search of the National Library of Medicines PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation.

RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for localized (1-3) spine metastases: Phase 2 results

PURPOSE The phase 2 component of Radiation Therapy Oncology Group (RTOG) 0631 assessed the feasibility and safety of spine radiosurgery (SRS) for localized spine metastases in a cooperative group setting. METHODS AND MATERIALS Patients with 1-3 spine metastasis with a Numerical Rating Pain Scale (NRPS) score ≥5 received 16 Gy single fraction SRS. The primary endpoint was SRS feasibility: image guidance radiation therapy (IGRT) targeting accuracy ≤2 mm, target volume coverage >90% of prescription dose, maintaining spinal cord dose constraints (10 Gy to ≤10% of the cord volume from 5-6 mm above to 5-6 mm below the target or absolute spinal cord volume <0.35 cc) and other normal tissue dose constraints. A feasibility success rate <70% was considered unacceptable for continuation of the phase 3 component. Based on the 1-sample exact binomial test with α = 0.10 (1-sided), 41 patients were required. Acute toxicity was assessed using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. RESULTS Sixty-five institutions were credentialed with spine phantom dosimetry and IGRT compliance. Forty-six patients were accrued, and 44 were eligible. There were 4 cervical, 21 thoracic, and 19 lumbar sites. Median NRPS was 7 at presentation. Final pretreatment rapid review was approved in 100%. Accuracy of image guided SRS targeting was in compliance with the protocol in 95%. The target coverage and spinal cord dose constraint were in accordance with the protocol requirements in 100% and 97%. Overall compliance for other normal tissue constraints was per protocol in 74%. There were no cases of grade 4-5 acute treatment-related toxicity. CONCLUSIONS The phase 2 results demonstrate the feasibility and accurate use of SRS to treat spinal metastases, with rigorous quality control, in a cooperative group setting. The planned RTOG 0631 phase 3 component will proceed to compare pain relief and quality of life between SRS and external beam radiation therapy.

Integrating Patient-Reported Outcomes Into Cancer Symptom Management Clinical Trials Supported by the National Cancer Institute–Sponsored Clinical Trials Networks

Patient-reported outcomes (PROs) are often the primary end point in symptom management trials. The scientific field of PROs is evolving, as evidenced by the US Food and Drug Administrations February 2007 release of a draft guidance for using PROs in effectiveness claims for drug labeling. This article presents issues encountered during use of PROs in National Cancer Institute-sponsored symptom management trials. Selected trials are presented that exemplify the challenges often seen in symptom management trials, and solutions are described. The examples presented include defining the appropriate end point, selecting and validating assessments, and answering the research questions through statistical analysis and interpretation. Progress has been made in addressing some of the unique challenges of PRO-based symptom management research. Many challenges still remain, but a foundational body of work now exists for more consistent and rigorous application of PROs into symptom management trials. There remains a need for more research in several methodologic aspects of design, analysis, and interpretation of symptom management trials.

Phase III Trial of an Emulsion Containing Trolamine for the Prevention of Radiation Dermatitis in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Trial 99-13

PURPOSE This multicentered phase III trial was designed to compare an emulsion containing trolamine against the usual supportive care within each participating institution for patients with head and neck cancer undergoing radiation therapy. PATIENTS AND METHODS Patients with biopsy-proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to one of the following treatments: prophylactic trolamine emulsion, interventional trolamine emulsion, or declared institutional preference. The primary outcome was the reduction in grade 2 or higher skin toxicity, as per National Cancer Institute Common Toxicity Criteria version 2.0. Secondary outcomes included patient-reported quality of life (QOL). RESULTS From October 2000 to April 2002, 547 patients from 51 institutions were entered onto the trial. The average age was 59 years. Patients were predominately male (79%) and most continued to use tobacco products (52%). The rates of grade 2 or higher radiation dermatitis were 79%, 77%, and 79% in the prophylactic, interventional, and institutional preference arms of the study, respectively. No significant differences in QOL were found. CONCLUSION The results of this trial demonstrate no advantage for the use of trolamine in reducing the incidence of grade 2 or higher radiation dermatitis or improving patient-reported QOL. The use of 15 different local standards of care highlights the need to continue research that will result in evidence-based recommendations to reduce the burden of radiation dermatitis.

Single-fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases-equivalent efficacy, less toxicity, more convenient: a subset analysis of Radiation Therapy Oncology Group trial 97-14.

The Radiation Therapy Oncology Group (RTOG) trial 97‐14 revealed no difference between radiation delivered for painful bone metastases at a dose of 8 gray (Gy) in 1 fraction (single‐fraction radiotherapy [SFRT]) and 30 Gy in 10 fractions (multifraction radiotherapy [MFRT]) in pain relief or narcotic use 3 months after randomization. SFRT for painful vertebral bone metastases (PVBM) has not been well accepted, possibly because of concerns about efficacy and toxicity. In the current study, the authors evaluated the subset of patients that was treated specifically for patients with PVBM.

A Phase II Study of Intensity Modulated Radiation Therapy to the Pelvis for Postoperative Patients With Endometrial Carcinoma: Radiation Therapy Oncology Group Trial 0418

PURPOSE To determine the feasibility of pelvic intensity modulated radiation therapy (IMRT) for patients with endometrial cancer in a multi-institutional setting and to determine whether this treatment is associated with fewer short-term bowel adverse events than standard radiation therapy. METHODS Patients with adenocarcinoma of the endometrium treated with pelvic radiation therapy alone were eligible. Guidelines for target definition and delineation, dose prescription, and dose-volume constraints for the targets and critical normal structures were detailed in the study protocol and a web-based atlas. RESULTS Fifty-eight patients were accrued by 25 institutions; 43 were eligible for analysis. Forty-two patients (98%) had an acceptable IMRT plan; 1 had an unacceptable variation from the prescribed dose to the nodal planning target volume. The proportions of cases in which doses to critical normal structures exceeded protocol criteria were as follows: bladder, 67%; rectum, 76%; bowel, 17%; and femoral heads, 33%. Twelve patients (28%) developed grade ≥2 short-term bowel adverse events. CONCLUSIONS Pelvic IMRT for endometrial cancer is feasible across multiple institutions with use of a detailed protocol and centralized quality assurance (QA). For future trials, contouring of vaginal and nodal tissue will need continued monitoring with good QA and better definitions will be needed for organs at risk.

Epidemiologic Aspects of Toilet Training

Toilet training is becoming an increasingly important child care issue as child raising becomes an institutional enterprise. This paper reviews the literature of the last 40 years, focusing on the epidemiology of the development of day and night bladder control. The studies indicate that bladder control is usually obtained between 24 months and 48 months of age. Many variations exist between studies, especially the endpoint used to indicate completion of training. Modifying the endpoint used and the related training practices could decrease the age at which children are trained.

Aging and human cone photopigments

We used a noninvasive technique to investigate changes in photoreceptor function with aging in observers 13-69 years of age. This technique, steady-state color matching, provides estimates of the optical density of cone photopigments, the illuminance that bleaches half of the photopigment, and the ratio of the primaries required at moderate light levels. In normal human retinas, we found that the optical density for a 4-deg field is affected minimally by aging from the second through the seventh decades. The average optical density is 0.27 +/- 0.054. The optical densities of older observers varied more than those of younger observers. The change in optical density with age is nonmonotonic, with slightly lower values for the youngest and oldest observers in our study. The retinal illuminance that bleaches half of the cone photopigment varied little across observers, averaging 4.37 log Td +/- 0.119. The change with age, which averages 0.00018 log Td per year over all observers, also is nonmonotonic. Moderate illuminance color matches did change with age, as expected, with a monotonic decrease with age in the ratio of the long-wavelength primary to the short-wavelength primary required for the color match.

Systemic pilocarpine for treatment of xerostomia

Background: Xerostomia is the feeling of dryness in the mouth, usually owing to hypofunctioning of the salivary glands. Causes of xerostomia include medications, the effects of radiation therapy on the salivary glands during the treatment of head and neck cancer or thyroid cancer, and autoimmune diseases such as Sjögrens syndrome. The primary treatment to reduce xerostomia is oral pilocarpine. Objective: This review discusses the randomized trials available on the efficacy and tolerability of oral pilocarpine for the treatment of xerostomia. Methods: The randomized trials of pilocarpine for xerostomia available in the medical literature are reviewed. Results/conclusion: Pilocarpine has some efficacy in the treatment of xerostomia from radiation therapy, graft-versus-host disease and Sjögrens syndrome. It has limited activity for the prevention of xerostomia during radiation therapy. It may have increased efficacy in combination with newer forms of radiation therapy.

Randomized, Double‐Blinded, Placebo‐Controlled Crossover Trial of Treating Erectile Dysfunction with Sildenafil After Radiotherapy and Short‐Term Androgen Deprivation Therapy: Results of RTOG 0215

INTRODUCTION Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT. AIM The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. METHODS   In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data. MAIN OUTCOME MEASURES The primary end point was improved erectile function, as measured by the IIEF. RESULTS The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving ≤ 120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase. CONCLUSIONS This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer.