Hadley J. Sharp

Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial

BACKGROUND Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the techniques effectiveness in controlling the symptom burden of spinal metastases has not been well described. We investigated the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms. METHODS 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1-2 study. Patients received a total dose of 27-30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered with ClinicalTrials.gov, number NCT00508443. FINDINGS Median follow-up was 15·9 months (IQR 9·5-30·3). The number of patients reporting no pain from bone metastases, as measured by the BPI, increased from 39 of 149 (26%) before SBRT to 55 of 102 (54%) 6 months after SBRT (p<0·0001). BPI-reported pain reduction from baseline to 4 weeks after SBRT was clinically meaningful (mean 3·4 [SD 2·9] on the BPI pain-at-its-worst item at baseline, 2·1 [2·4] at 4 weeks; effect size 0·47, p=0·00076). These improvements were accompanied by significant reduction in opioid use during the first 6 months after SBRT (43 [28·9%] of 149 patients with strong opioid use at baseline vs 20 [20·0%] of 100 at 6 months; p=0·011). Ordinal regression modelling showed that patients reported significant pain reduction according to the MDASI during the first 6 months after SBRT (p=0·00003), and significant reductions in a composite score of the six MDASI symptom interference with daily life items (p=0·0066). Only a few instances of non-neurological grade 3 toxicities occurred: nausea (one event), vomiting (one), diarrhoea (one), fatigue (one), dysphagia (one), neck pain (one), and diaphoresis (one); pain associated with severe tongue oedema and trismus occurred twice; and non-cardiac chest pain was reported three times. No grade 4 toxicities occurred. Progression-free survival after SBRT was 80·5% (95% CI 72·9-86·1) at 1 year and 72·4% (63·1-79·7) at 2 years. INTERPRETATION SBRT is an effective primary or salvage treatment for mechanically stable spinal metastasis. Significant reductions in patient-reported pain and other symptoms were evident 6 months after SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities. FUNDING National Cancer Institute of the US National Institutes of Health.

STEREOTACTIC BODY RADIATION THERAPY FOR PATIENTS WITH LUNG CANCER PREVIOUSLY TREATED WITH THORACIC RADIATION

PURPOSE Stereotactic body radiation therapy (SBRT) provides excellent local control with acceptable toxicity for patients with early-stage non-small cell lung cancer. However, the efficacy and safety of SBRT for patients previously given thoracic radiation therapy is not known. In this study, we retrospectively reviewed outcomes after SBRT for recurrent disease among patients previously given radiation therapy to the chest. MATERIALS AND METHODS A search of medical records for patients treated with SBRT to the thorax after prior fractionated radiation therapy to the chest at The University of Texas M. D. Anderson Cancer Center revealed 36 such cases. The median follow-up time after SBRT was 15 months. The endpoints analyzed were overall survival, local control, and the incidence and severity of treatment-related toxicity. RESULTS SBRT provided in-field local control for 92% of patients; at 2 years, the actuarial overall survival rate was 59%, and the actuarial progression-free survival rate was 26%, with the primary site of failure being intrathoracic relapse. Fifty percent of patients experienced worsening of dyspnea after SBRT, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% Grade 3 esophagitis. No Grade 4 or 5 toxic effects were noted. CONCLUSIONS SBRT can provide excellent in-field tumor control in patients who have received prior radiation therapy. Toxicity was significant but manageable. The high rate of intrathoracic failure indicates the need for further study to identify patients who would derive the most benefit from SBRT for this purpose.

Human Omental-Derived Adipose Stem Cells Increase Ovarian Cancer Proliferation, Migration, and Chemoresistance

Objectives Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination. Materials and Methods We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. Results O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. Conclusions ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

Current clinical coverage of Radiation Therapy Oncology Group-defined target volumes for postmastectomy radiation therapy

PURPOSE The Radiation Therapy Oncology Group (RTOG) has published consensus guidelines for contouring relevant anatomy for postmastectomy radiation therapy (RT). How these contours relate to current treatment practices is unknown. We analyzed the dose-volume histograms (DVHs) for these contours using current clinical practice at University of Texas MD Anderson Cancer Center and compared them with the proposed treatment plans to treat RTOG-defined targets to full dose. METHODS AND MATERIALS We retrospectively analyzed treatment plans for 20 consecutive women treated with postmastectomy RT for which the treatment targets were the chest wall (CW), level III axilla (Ax3), supraclavicular (SCV), and internal mammary (IM) nodes. The RTOG consensus definitions were used to contour the following anatomic structures: CW; level I, II, and III axillary nodes (Ax1, Ax2, Ax3); SCV; IM; and heart (H). DVHs for these contours and the ipsilateral lung were generated from clinically designed treatment that had actually been delivered to each patient. For comparison regarding dose to normal tissue, new treatment plans were generated with the goal of covering 95% of the anatomic contours to 45 Gy. RESULTS The prescribed dose was 50 Gy in each case. The mean percent of volumes that received 45 Gy (V45) for the RTOG guideline-based contours were CW 74%, Ax1 84%, Ax2 88%, Ax3 96%, SCV 84%, and IM 80%. Mean heart V10 values were 11% for treatment of left-sided tumors and 6% for right-sided tumors. Mean ipsilateral lung V20 values were 28% for left-sided tumors and 34% for right-sided tumors. For the contour-based plans, mean V45 values were CW 94%, Ax1 95%, Ax2 97%, Ax3 98%, SCV 98%, and IM 85%. Mean heart V10 values were 14% for treatment of left-sided tumors and 12% for right-sided tumors. Mean ipsilateral lung V20 values were 32% for left-sided tumors and 45% for right-sided tumors. CONCLUSIONS Clinically derived treatment plans, which have proven efficacy and are the current standard, cover 74% to 96% of the anatomy-based RTOG consensus volumes to the prescription dose. This discrepancy should be considered if treatment planning protocol guidelines are designed to incorporate these new definitions.

Radiation treatment outcomes for unresectable hepatocellular carcinoma

Abstract Background. Hepatocellular carcinoma is one of the most common cancers worldwide. Data regarding the use of radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with radiotherapy in the modern era at a single institution. Material and methods. A total of 29 patients with localized hepatocellular carcinoma treated from 2000–2010 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30 to 75 Gy) with a median biologically effective dose of 80.6 (range 60 to 138.6). Median tumor size at the time of radiation was 5.2 cm (range 2 to 25 cm). Results. Eighty three percent of all patients had either stable disease or a partial response to radiation, based on RECIST criteria. Median change in tumor size following radiation was −17% (range −73.5 to 177.8%). Estimated one-year overall survival and in-field progression-free survival rates for the study population were 56% and 79%, respectively. One-year overall survival in patients treated to a biologically effective dose <75 was significantly lower than in patients treated to a biologically effective dose ≥75 (18% vs. 69%). One-year in-field progression-free survival rate (60% vs. 88%) and biochemical progression-free survival duration (median 6.5 vs. 1.6 months) were also significantly improved in patients treated to a biologically effective dose ≥75. Grade 3 toxicity was seen in 13.8% of patients. Discussion. In a population without endemic viral hepatitis, unresectable hepatocellular carcinoma demonstrates significant response to radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased biologically effective dose is associated with improved survival and local tumor control.

Screening colonoscopy before prostate cancer treatment can detect colorectal cancers in asymptomatic patients and reduce the rate of complications after brachytherapy

PURPOSE To investigate the incidence of undiagnosed, asymptomatic synchronous colorectal cancer (CRC) by using screening colonoscopy before brachytherapy, and to compare the subsequent rates of CRC and rectal toxicity in this screened population with those rates in unscreened patients after brachytherapy. METHODS AND MATERIALS Patient, disease, and treatment characteristics, including history of colonoscopy and CR malignancy, were extracted from the medical records of all men who had undergone brachytherapy as monotherapy for low- or intermediate-risk prostate cancer at a single tertiary cancer care center between January 2000 and December 2009. The frequency of biopsy or polypectomy at screening colonoscopy, incidence of CR malignancy before and after prostate cancer diagnosis, and rate of brachytherapy toxicity including rectal bleeding were compared between men who had had screening colonoscopy before brachytherapy and men who had not. RESULTS Of the 451 men identified, 268 had undergone screening colonoscopy during the 36 months before brachytherapy and 183 had not. Of the 268 men who had had screening colonoscopy, 117 (44%) underwent biopsy or polypectomy, and 6 (3.2%) were found to have asymptomatic CRC. After brachytherapy, CRC was diagnosed in 3 (1.6%) of the 183 men who had not had screening colonoscopy before treatment versus 0 of the 268 men who had had screening colonoscopy (P = 0.035). Rectal toxicity was more common and more severe among men who had not undergone screening colonoscopy compared with those who had had screening colonoscopy before brachytherapy (14% vs 6%, P = 0.003). More unscreened patients (18% vs 5%) underwent postbrachytherapy colonoscopy (P < 0.001), with the potential of subjecting the irradiated rectum to biopsy. CONCLUSIONS More than 3% of men with newly diagnosed prostate cancer in this study presented with undiagnosed, asymptomatic CRC, and the rate of postbrachytherapy rectal complications was higher among unscreened than among screened patients. We recommend screening colonoscopy for men who have not had CRC screening within the 3 years preceding prostate cancer diagnosis before radiation therapy to avoid unnecessary rectal biopsies and the associated risk of major complications.

Automating RTOG-defined target volumes for postmastectomy radiation therapy

PURPOSE Consistency in defining and contouring target structures in radiation therapy (RT) is critical for highly conformal RT, for evaluating treatment plans, and for quality assurance in multi-institutional RT trials. The Radiation Therapy Oncology Group (RTOG) has published consensus guidelines for contouring targets for postmastectomy RT. To aid in contouring such structures, we evaluated the potential use of an automated contouring technique, known as deformable image registration-based breast segmentation (DEF-SEG). METHODS AND MATERIALS The RTOG definitions were used to contour the chest wall (CW); levels I, II, and III axillary nodes (Ax1, Ax2, Ax3); supraclavicular (SCV) nodes; internal mammary (IM) nodes; and the heart. Left-sided and right-sided templates were created. The DEF-SEG was then used to generate auto-segmented contours from the appropriate template to computed tomographic scans of 20 test cases (10 left, 10 right). To assess the accuracy of this method, those contours were manually modified as necessary to match the RTOG definitions, and the extent of the overlap was compared. The dosimetric impact of the difference in contours was then evaluated by comparing dose-volume histograms for modified and unmodified contours. RESULTS Mean volume-overlap ratios between the unmodified DEF-SEG-generated contours and modified contours were as follows: CW, 0.91; Ax1, 0.68; Ax2, 0.64; Ax3, 0.68; SCV node, 0.66; IM node, 0.32, and the heart, 0.93. Mean differences in volume receiving 45 Gy (V45) for the modified versus unmodified contours were as follows: CW, 2.1%; SCV node, 4.8%; Ax1, 5.1%; Ax2, 5.6%; Ax3, 3.0%; and IM node, 10.1%. Mean differences in V10 between the modified heart and the unmodified heart were 0.4% for right-sided treatment and 0.5% for left-sided treatment. CONCLUSIONS The DEF-SEG can be helpful for delineating structures according to the RTOG consensus guidelines, particularly for the CW and the heart. No clinically significant dosimetric differences were found between the modified and unmodified contours. The DEF-SEG may be useful for evaluating treatment plans for postmastectomy RT in multi-institutional trials.

Cutaneous graft-versus-host disease after proton-based craniospinal irradiation for recurrent Philadelphia-positive acute lymphoblastic leukaemia

Treatment of recurrent acute lymphoblastic leukaemia (ALL) often involves allogeneic stem-cell transplantation (alloSCT) and disease recurrence in the central nervous system may require craniospinal irradiation. Although graft-versus-host disease (GVHD) is a known risk after alloSCT, cutaneous manifestation within radiation fields is rarely seen. The authors report a case of a 25-year-old man with Philadelphia+ALL recurring in the central nervous system after a homologous SCT. Craniospinal radiation was delivered with proton therapy to a total dose of 24 cobalt-Gray-equivalents in 12 fractions. Eight weeks after the proton therapy, significant cutaneous GVHD had developed within the radiation fields. This was treated successfully with tacrolimus (4 mg/day), a short course of methylprednisolone, and topical treatment with 0.1% triamcinolone cream, 0.05% clobetasol ointment. Cutaneous GVHD after SCT can be seen within proton radiation fields probably due to an inherent higher skin dose.

PET/CT in a patient with adenoma malignum of the uterine cervix

The findings of positron emission tomography combined with computed tomography (PET/CT) in a patient with FIGO stage IIA adenoma malignum of the uterine cervix are described in this article. PET/CT showed that the cervical tumor was intensely hypermetabolic with no evidence of disease spread. However, lymphadenectomy revealed metastatic spread to paraaortic lymph nodes. PET/CT may be useful in identifying primary site of disease in patients with adenoma malignum; however, the utility in detecting metastatic nodal disease remains to be determined.

Subacute penile numbness after brachytherapy for prostate cancer.

PURPOSE Penile numbness is a rare complication of permanent prostate brachytherapy, and optimal clinical management remains unclear. We present such a case and discuss pathophysiology and clinical management strategies. METHODS AND MATERIALS A 68-year-old male presented with a serum prostate-specific antigen level of 6.9 ng/mL, Gleason score of 7 (3+4), and clinical T1c adenocarcinoma of the prostate. After a permanent prostate brachytherapy implant with (125)I monotherapy to a dose of 145Gy, the patient developed complete penile numbness postoperatively on the third day. RESULTS The patient experienced complete restoration of penile sensation and function by postoperative day 9 with conservative management. CONCLUSIONS Subacute penile shaft numbness after brachytherapy is rare and is caused by dorsal penile nerve compression. Over the course of a week, the restoration of penile sensation is likely to occur with conservative management.