Alan Herschtal

Online Adaptive Radiotherapy for Muscle-Invasive Bladder Cancer: Results of a Pilot Study

PURPOSE To determine the advantages and disadvantages of daily online adaptive image-guided radiotherapy (RT) compared with conventional RT for muscle-invasive bladder cancer. METHODS AND MATERIALS Twenty-seven patients with T2-T4 transitional cell carcinoma of the bladder were treated with daily online adaptive image-guided RT using cone-beam computed tomography (CBCT). From day 1 daily soft tissue-based isocenter positioning was performed using CBCT images acquired before treatment. Using a composite of the initial planning CT and the first five daily CBCT scans, small, medium, and large adaptive plans were created. Each of these adaptive plans used a 0.5-cm clinical target volume (CTV) to planning target volume expansion. For Fractions 8-32, treatment involved daily soft tissue-based isocenter positioning and selection of suitable adaptive plan of the day. Treating radiation therapists completed a credentialing program, and one radiation oncologist performed all the contouring. Comparisons were made between adaptive and conventional treatment on the basis of CTV coverage and normal tissue sparing. RESULTS All 27 patients completed treatment per protocol. Bladder volume decreased with time or fraction number (p < 0.0001). For the adaptive component (Fractions 8-32) the small, medium, large, and conventional plans were used in 9.8%, 49.2%, 39.5%, and 1.5% of fractions, respectively. For the adaptive strategy, 2.7% of occasions resulted in a CTV V95 <99%, compared with 4.8% of occasions for the conventional approach (p = 0.42). Mean volume of normal tissue receiving a dose >45 Gy was 29% (95% confidence interval, 24-35%) less with adaptive RT compared with conventional RT. The mean volume of normal tissue receiving >5 Gy was 15% (95% confidence interval, 11-18%) less with adaptive RT compared with conventional RT. CONCLUSIONS Online adaptive radiotherapy is feasible in an academic radiotherapy center. The volume of normal tissue irradiated can be significantly smaller without reducing CTV coverage.

Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis.

PURPOSE The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. PATIENTS AND METHODS Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. RESULTS After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). CONCLUSION These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.

Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging.

PURPOSE Given that proliferating hematopoietic stem cells are especially radiosensitive, the bone marrow is a potential organ at risk, particularly with the use of concurrent chemotherapy and radiotherapy. Existing data on bone marrow distribution have been determined from the weight and visual appearance of the marrow in cadavers. 18F-fluoro-L-deoxythymidine concentrates in bone marrow, and we used its intensity on positron emission tomography imaging to quantify the location of the proliferating bone marrow. METHODS AND MATERIALS The 18F-fluoro-L-deoxythymidine positron emission/computed tomography scans performed at the Peter MacCallum Cancer Centre between 2006 and 2009 on adult cancer patients were analyzed. At a minimum, the scans included the mid-skull through the proximal femurs. A software program developed at our institution was used to calculate the percentage of administered activity in 11 separately defined bony regions. RESULTS The study population consisted of 13 patients, 6 of whom were men. Their median age was 61 years. Of the 13 patients, 9 had lung cancer, 2 had colon cancer, and 1 each had melanoma and leiomyosarcoma; 6 had received previous, but not recent, chemotherapy. The mean percentage of proliferating bone marrow by anatomic site was 2.9%±2.1% at the skull, 1.9%±1.2% at the proximal humeri, 2.9%±1.3% at the sternum, 8.8%±4.7% at the ribs and clavicles, 3.8%±0.9% at the scapulas, 4.3%±1.6% at the cervical spine, 19.9%±2.6% at the thoracic spine, 16.6%±2.2% at the lumbar spine, 9.2%±2.3% at the sacrum, 25.3%±4.9% at the pelvis, and 4.5%±2.5% at the proximal femurs. CONCLUSION Our modern estimates of bone marrow distribution in actual cancer patients using molecular imaging of the proliferating marrow provide updated data for optimizing normal tissue sparing during external beam radiotherapy planning.

High rates of tumor growth and disease progression detected on serial pretreatment fluorodeoxyglucose-positron emission tomography/computed tomography scans in radical radiotherapy candidates with nonsmall cell lung cancer.

The authors studied growth and progression of untreated nonsmall cell lung cancer (NSCLC) by comparing diagnostic and radiotherapy (RT) planning fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/computed tomography (CT) scans before proposed radical chemo‐RT.

TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.

Intra-fraction prostate displacement in radiotherapy estimated from pre- and post-treatment imaging of patients with implanted fiducial markers

PURPOSE To determine intra-fraction displacement of the prostate gland from imaging pre- and post-radiotherapy delivery of prostate cancer patients with three implanted fiducial markers. METHODS AND MATERIALS Data were collected from 184 patients who had two orthogonal X-rays pre- and post-delivery on at least 20 occasions using a Varian On Board kV Imaging system. A total of 5778 image pairs covering time intervals between 3 and 30 min between pre- and post-imaging were evaluated for intra-fraction prostate displacement. RESULTS The mean three dimensional vector shift between images was 1.7 mm ranging from 0 to 25 mm. No preferential direction of displacement was found; however, there was an increase of prostate displacement with time between images. There was a large variation in typical shifts between patients (range 1 +/- 1 to 6 +/- 2 mm) with no apparent trends throughout the treatment course. Images acquired in the first five fractions of treatment could be used to predict displacement patterns for individual patients. CONCLUSION Intra-fraction motion of the prostate gland appears to be a limiting factor when considering margins for radiotherapy. Given the variation between patients, a uniform set of margins for all patients may not be satisfactory when high target doses are to be delivered.

Impact of post-therapy positron emission tomography on prognostic stratification and surveillance after chemoradiotherapy for cervical cancer

A study was undertaken to investigate the detection of relapse and survival outcomes in patients with cervical cancer treated with curative intent chemoradiotherapy, and evaluated with a post‐therapy 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) scan.

Association Between Pulmonary Uptake of Fluorodeoxyglucose Detected by Positron Emission Tomography Scanning After Radiation Therapy for Non–Small-Cell Lung Cancer and Radiation Pneumonitis

PURPOSE To study the relationship between fluorodeoxyglucose (FDG) uptake in pulmonary tissue after radical radiation therapy (RT) and the presence and severity of radiation pneumonitis. METHODS AND MATERIALS In 88 consecutive patients, (18)F-FDG-positron emission tomography was performed at a median of 70 days after completion of RT. Patients received 60 Gy in 30 fractions, and all but 15 had concurrent platinum-based chemotherapy. RT-induced pulmonary inflammatory changes occurring within the radiation treatment volume were scored, using a visual (0 to 3) radiotoxicity grading scale, by an observer blinded to the presence or absence of clinical radiation pneumonitis. Radiation pneumonitis was retrospectively graded using the Radiation Therapy Oncology Group (RTOG) scale by an observer blinded to the PET radiotoxicity score. RESULTS There was a significant association between the worst RTOG pneumonitis grade occurring at any time after RT and the positron emission tomograph (PET) radiotoxicity grade (one-sided p = 0.033). The worst RTOG pneumonitis grade occurring after the PET scan was also associated with the PET radiotoxicity grade (one-sided p = 0.035). For every one-level increase in the PET toxicity scale, the risk of a higher RTOG radiation pneumonitis score increased by approximately 40%. The PET radiotoxicity score showed no significant correlation with the duration of radiation pneumonitis. CONCLUSIONS The intensity of FDG uptake in pulmonary tissue after RT determined using a simple visual scoring system showed significant correlation with the presence and severity of radiation pneumonitis. (18)F-FDG-PET may be useful in the prediction, diagnosis and therapeutic monitoring of radiation pneumonitis.

The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non-small cell lung cancer: Results of a prospective study with mature survival data

BACKGROUND AND PURPOSE This prospective study investigated the impact of radiotherapy (RT)-planning FDG-PET/CT on management of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Patients still eligible for radical RT after conventional staging underwent RT-planning PET/CT and, if disease was still treatable to 60 Gy, they entered our planning study, where visually-contoured tumour volumes derived with and without PET information were compared. If PET/CT detected advanced disease, palliative therapy was given. Overall survival (OS) for palliative and curative patients was compared. RESULTS Of 76 eligible patients, only 50 (66%) received radical chemoRT after PET/CT while 26 (34%) received palliative therapies because PET/CT detected advanced disease. Without PET, FDG-avid tumour would reside outside the planning target volume (PTV) in 36% of radical cases and in 25% <90% of the PTV would have received >95% prescribed dose. OS for all patients was 56.8% and 24.9% at 1 and 4 years, respectively. OS for patients given chemoRT was 77.5% and 35.6% at 1 and 4 years, respectively and was 32% for stage IIIA patients at 4 years. OS for patients treated palliatively was inferior (P<0.001); 16.3% and 4.1% at 1 and 4 years, respectively. CONCLUSIONS Planning PET/CT frequently changed management and was associated with excellent survival. Survival data from this study were presented in part at the 2011 World Lung Cancer Conference, Amsterdam and planning data at the 2010 Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Chicago.

Differential 18F-FDG and 18F-FLT Uptake on Serial PET/CT Imaging Before and During Definitive Chemoradiation for Non–Small Cell Lung Cancer

We aimed to prospectively observe cellular metabolism and proliferation in patients with non–small-cell lung cancer (NSCLC) during radical chemoradiation therapy using serial PET/CT with 18F-FDG and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT). Methods: Twenty patients with stage I–III NSCLC and candidates for radical chemoradiation therapy (60 Gy in 30 fractions over 6 wk) were recruited. 18F-FDG and 18F-FLT PET/CT were performed at baseline and during therapy (weeks 2 and 4). Tumor response was assessed semiquantitatively and using visual response criteria. Results: The median and range for primary tumor volume (cm3) at baseline on 18F-FDG were 28 and 2–241, respectively, and on 18F-FLT 31 and 2–184, respectively. At week 2, 18F-FDG was 26 (range, 2–164), and 18F-FLT was 11 (range, 0–111). At week 4, 18F-FDG was 19 (1–147), and 18F-FLT was 7 (0–48). The median and range of maximum standardized uptake value (SUVmax) at baseline on 18F-FDG were 14 and 4–31, respectively, and on 18F-FLT 6 and 2–12, respectively. Week 2 18F-FDG median SUVmax was 10 (2–31), and 18F-FLT median SUVmax was 3 (1–15); week 4 18F-FDG median SUVmax was 10 (2–15), and 18F-FLT median SUVmax was 2 (2–9). There was fair agreement between visual tumor response on 18F-FDG and 18F-FLT during therapy (Cohens unweighted κ statistic, 0.27 at week 2 and 0.355 at week 4). Cerebral metastases were detected on 1 baseline 18F-FLT scan, resulting in palliative management. Progressive disease was detected on week 2 scans in 3 patients, resulting in changes to radiation therapy (2 patients) and treatment intent (1 patient). Conclusion: This study demonstrates that 18F-FLT PET/CT is a more sensitive tracer of early treatment response than 18F-FDG PET/CT. The ability of these tracers to detect distinct biologic processes may lead to their use as biomarkers for personalized radiation therapy and prognosis in the future.