Target volume motion during anal cancer image guided radiotherapy using cone-beam computed tomography.

OBJECTIVE: Literature regarding image-guidance and interfractional motion of the anal canal (AC) during anal cancer radiotherapy is sparse. This study investigates interfractional AC motion during anal cancer radiotherapy. METHODS: Bone matched cone beam CT (CBCT) images were acquired for 20 patients receiving anal cancer radiotherapy allowing population systematic and random error calculations. 12 were selected to investigate interfractional AC motion. Primary anal gross tumour volume and clinical target volume (CTVa) were contoured on each CBCT. CBCT CTVa volumes were compared to planning CTVa. CBCT CTVa volumes were combined into a CBCT-CTVa envelope for each patient. Maximum distortion between each orthogonal border of the planning CTVa and CBCT-CTVa envelope was measured. Frequency, volume and location of CBCT-CTVa envelope beyond the planning target volume (PTVa) was analysed. RESULTS: Population systematic and random errors were 1 and 3 mm respectively. 112 CBCTs were analysed in the interfractional motion study. CTVa varied between each imaging session particularly T location patients of anorectal origin. CTVa border expansions ≥ 1 cm were seen inferiorly, anteriorly, posteriorly and left direction. The CBCT-CTVa envelope fell beyond the PTVa ≥ 50% imaging sessions (n = 5). Of these CBCT CTVa distortions beyond PTVa, 44% and 32% were in the upper and lower thirds of PTVa respectively. CONCLUSION: The AC is susceptible to volume changes and shape deformations. Care must be taken when calculating or considering reducing the PTV margin to the anus. Advances in knowledge: Within a limited field of research, this study provides further knowledge of how the AC deforms during anal cancer radiotherapy.

Magnetic resonance imaging defined mucinous rectal carcinoma is an independent imaging biomarker for poor prognosis and poor response to preoperative chemoradiotherapy.

INTRODUCTION: Mucinous adenocarcinomas represent a potentially poor prognostic subgroup identifiable by imaging. We compared outcomes between magnetic resonance imaging (MRI) detected rectal mucinous carcinoma and adenocarcinomas. The diagnostic performance of MRI compared with initial biopsy in detecting mucinous adenocarcinoma was also assessed. METHODS: The proportion of patients downstaged in the mrMucinous and adenocarcinoma groups was compared. Cox proportional hazard models were used to test independence of mucinous status and baseline MRI and clinical variables on survival. Differences in survival for mucinous versus non-mucinous tumours were tested for significance using the Mantel-Cox log rank test. RESULTS: 60/330 (18%) patients were correctly diagnosed with mucinous rectal cancer based on pre treatment MRI compared with 15/330 (5%) on initial biopsy (diagnostic odds ratio=4.67, p<0.05). All 60 (100%) patients undergoing surgery for mrMucinous tumours were confirmed as such on final histopathology. Significantly fewer mrMucinous tumours showed ypT downstaging when compared with non-mucinous tumours (14/60 (23%) versus 111/270 (40%), p=0.01). Three-year survival outcomes for patients for MRI detected mucinous tumours were significantly worse: disease free survival (DFS) was 48% versus 71%, p=0.006 and OS was 69% versus 79% p=0.04. MRI Mucin was an independent variable for poor DFS (hazard ratios (HR)) 0.58 95% Confidence interval (CI) 0.38-0.89). CONCLUSIONS: MRI diagnosis of mucinous adenocarcinoma is diagnostically superior to preoperative biopsy and occurs in up to 20% of rectal cancer patients. It is an independent imaging biomarker for response to preoperative chemoradiotherapy (CRT) and prognosis. MRI documentation of mucinous status will enable future pursuit of treatment strategies in this poor prognostic subgroup.

Chemoradiotherapy response in recurrent rectal cancer.

The efficacy of response to preoperative chemoradiotherapy (CRT) in recurrent versus primary rectal cancer has not been investigated. We compared radiological downsizing between primary and recurrent rectal cancers following CRT and determined the optimal size reduction threshold for response validated by survival outcomes. The proportional change in tumor length for primary and recurrent rectal cancers following CRT was compared using the independent sample t-test. Overall survival (OS) was calculated using the Kaplan-Meier product limit method and differences between survival for tumor size reduction thresholds of 30% (response evaluation criteria in solid tumors [RECIST]), 40%, and 50% after CRT in primary and recurrent rectal cancer groups. A total of 385 patients undergoing CRT were analyzed, 99 with recurrent rectal cancer and 286 with primary rectal cancer. The mean proportional reduction in maximum craniocaudal length was significantly higher for primary rectal tumors (33%) compared with recurrent rectal cancer (11%) (P < 0.01). There was no difference in OS for either primary or recurrent rectal cancer when ≤30% or ≤40% definitions were used. However, for both primary and recurrent tumors, significant differences in median 3-year OS were observed when a RECIST cut-off of 50% was used. OS was 99% versus 77% in primary and 100% versus 42% in recurrent rectal cancer (P = 0.002 and P = 0.03, respectively). Only patients that demonstrated >50% size reduction showed a survival benefit. Recurrent rectal cancer appears radioresistant compared with primary tumors for tumor size after CRT. Further investigation into improving/intensifying chemotherapy and radiotherapy for locally recurrent rectal cancer is justified.

Cone beam CT verification for oesophageal cancer - impact of volume selected for image registration.

PURPOSE: Oesophageal cancers are difficult to visualise on volumetric imaging and reliable surrogate are needed for accurate tumour registration. The aim of this investigation is to evaluate the effect of a user defined volume with automated registration techniques using commercially available software with the on-board volumetric imaging for treatment verification of oesophageal cancer and determine the optimum location of this volume. MATERIAL AND METHODS: In 20 patients four 'clipbox'(C) volumes were defined: C-planning target volume (PTV), C-carina, C-vertebrae, C-thorax. The set-up corrections (translational and rotational) for C-PTV were compared to the corrections using C-carina, C-vertebrae and C-thorax. RESULTS: Six hundred and eight registrations were performed. The best concordance in set-up corrections was found in the superior/inferior direction between C-PTV and C-carina (76%). In the right/left and anterior/posterior direction, better agreement was found between C-PTV and C-thorax with 80% and 76% agreement, respectively. Automatic 'bone' registration using C-vertebrae failed in 28% of scans. The correlation ratio between C-PTV and C-carina (n = 4) for mid-oesophageal tumours was 0.88, 0.79, and 0.95 in the right/left, superior/inferior and anterior/posterior directions, respectively. CONCLUSION: The defined volume for matching is important for oesophageal tumours. The alignment 'clipbox' and registration method selected can affect the displacements obtained. This may best be determined by tumour location and highlights the need to diversify protocols within one tumour treatment site. Further analysis is required to validate carina as a tumour surrogate for mid-oesophageal tumours.

Set-up errors in radiotherapy for oesophageal cancers--is electronic portal imaging or conebeam more accurate?

PURPOSE: To compare kV computed tomography (CBCT) with electronic portal imaging (EPI) and evaluate set-up variations in the anterior-posterior (AP), right-left (LR) and cranio-caudal (CC) directions and rotational variations: pitch, roll, and yaw, for oesophageal cancer patients treated with radical radiotherapy. METHODS AND MATERIALS: Twenty patients with locally advanced oesophageal cancer treated with chemoradiation were consented for this prospective ethics approved protocol. Patients were positioned using skin marks/tattoos, kV-CBCT scans (XVI) and EPI's were performed prior to treatment and registered to the planning CT scans and digitally reconstructed radiographs, respectively. XVI data was used to adjust patient setups before treatment delivery. A total of 122 EPI pairs and 207 CBCT scans were analysed. The systematic and random errors were calculated. RESULTS: The systematic and random errors (mm) for XVI were 1.3, 1.7, 1.4 and 2.6, 3.9, 2.0 in RL, CC and AP direction, respectively, with EPI of similar magnitude. There was no correlation between the 2 modalities of imaging as 31.7% of all image pairs were discordant >3 mm and 12.5% >5 mm. XVI identified rotations >3° in 44 images. CONCLUSIONS: EPI results in different position correction for verification of radiotherapy in oesophageal malignancies when compared with CBCT. CBCT verification offers adequate 3D volumetric image quality to improve the accuracy of treatment delivery for oesophageal malignancies in radiotherapy and should be used for image guidance.

Cone beam computed tomography-derived adaptive radiotherapy for radical treatment of esophageal cancer.

PURPOSE: To investigate the potential for reduction in normal tissue irradiation by creating a patient specific planning target volume (PTV) using cone beam computed tomography (CBCT) imaging acquired in the first week of radiotherapy for patients receiving radical radiotherapy. METHODS AND MATERIALS: Patients receiving radical RT for carcinoma of the esophagus were investigated. The PTV is defined as CTV(tumor, nodes) plus esophagus outlined 3 to 5 cm cranio-caudally and a 1.5-cm circumferential margin is added (clinical plan). Prefraction CBCT are acquired on Days 1 to 4, then weekly. No correction for setup error made. The images are imported into the planning system. The tumor and esophagus for the length of the PTV are contoured on each CBCT and 5 mm margin is added. A composite volume (PTV1) is created using Week 1 composite CBCT volumes. The same process is repeated using CBCT Week 2 to 6 (PTV2). A new plan is created using PTV1 (adaptive plan). The coverage of the 95% isodose of PTV1 is evaluated on PTV2. Dose-volume histograms (DVH) for lungs, heart, and cord for two plans are compared. RESULTS: A total of 139 CBCT for 14 cases were analyzed. For the adaptive plan the coverage of the 95% prescription isodose for PTV1 = 95.6% +/- 4% and the PTV2 = 96.8% +/- 4.1% (t test, 0.19). Lungs V20 (15.6 Gy vs. 10.2 Gy) and heart mean dose (26.9 Gy vs. 20.7 Gy) were significantly smaller for the adaptive plan. CONCLUSIONS: A reduced planning volume can be constructed within the first week of treatment using CBCT. A single plan modification can be performed within the second week of treatment with considerable reduction in organ at risk dose.

Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer.

The past decade has seen pronounced changes in the treatment of locally advanced rectal cancer. Historically, the standard of care involved surgery followed by adjuvant radiotherapy or chemoradiotherapy. More recently, the emergence of neo-adjuvant chemoradiotherapy has fundamentally changed the management of patients with locally advanced disease. In clinical trials, pathological complete responses of up to 25% have raised the question as to whether surgery can be avoided in a select cohort of patients. A trial of omission of surgery for selected patients with complete response after preoperative chemoradiotherapy has shown favourable long-term results. In this article, we outline emerging factors for achieving pathological complete response, non-operative strategies to date, methods for prediction of response to chemoradiotherapy, and future directions with the addition of MRI as a radiological guide to complete response.

Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels.

PURPOSE: To investigate the potential for intensity-modulated radiotherapy (IMRT) to spare the bowel in rectal tumors. METHODS AND MATERIALS: The targets (pelvic nodal and rectal volumes), bowel, and bladder were outlined in 5 patients. All had conventional, three-dimensional conformal RT and forward-planned multisegment three-field IMRT plans compared with inverse-planned simultaneous integrated boost nine-field equally spaced IMRT plans. Equally spaced seven-field and five-field and five-field, customized, segmented IMRT plans were also evaluated. RESULTS: Ninety-five percent of the prescribed dose covered at least 95% of both planning target volumes using all but the conventional plan (mean primary and pelvic planning target volume receiving 95% of the prescribed dose was 32.8 +/- 13.7 Gy and 23.7 +/- 4.87 Gy, respectively), reflecting a significant lack of coverage. The three-field forward planned IMRT plans reduced the volume of bowel irradiated to 45 Gy and 50 Gy by 26% +/- 16% and 42% +/- 27% compared with three-dimensional conformal RT. Additional reductions to 69 +/- 51 cm(3) to 45 Gy and 20 +/- 21 cm(3) to 50 Gy were obtained with the nine-field equally spaced IMRT plans-64% +/- 11% and 64% +/- 20% reductions compared with three-dimensional conformal RT. Reducing the number of beams and customizing the angles for the five-field equally spaced IMRT plan did not significantly reduce bowel sparing. CONCLUSION: The bowel volume irradiated to 45 Gy and 50 Gy was significantly reduced with IMRT, which could potentially lead to less bowel toxicity. Reducing the number of beams did not reduce bowel sparing and the five-field customized segmented IMRT plan is a reasonable technique to be tested in clinical trials.

Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma.

PURPOSE: To analyze the impact of radiotherapy (RT) parameters on outcome in a randomized study of pre-RT chemotherapy for M0-M1 medulloblastoma. METHODS AND MATERIALS: Patients were randomized to RT alone or RT preceded by chemotherapy with vincristine, etoposide, carboplatin, and cyclophosphamide. RT consisted of craniospinal RT, 35 Gy in 21 fractions, followed by a posterior fossa (PF) boost of 20 Gy in 12 fractions. The accuracy of cribriform fossa, skull base, and PF field placement was assessed. RESULTS: Between 1992 and 2000, 217 patients were randomized, of whom 179 were eligible for analysis. At a median follow-up of 5.4 years, the 3- and 5-year overall survival rate was 79.5% and 70.7%, respectively. The 3- and 5-year event-free survival (EFS) rate was 71.6% and 67.0%, respectively. EFS was significantly better for the chemotherapy plus RT group (3-year EFS rate 78.5% vs. 64.8%, p = 0.0366). Overall survival and EFS were significantly better for patients completing RT within 50 days compared with those taking >50 days to complete RT (3-year overall survival rate 84.1% vs. 70.9%, p = 0.0356, 3-year EFS rate 78.5% vs. 53.7%, p = 0.0092). Multivariate analysis identified the use of chemotherapy (p = 0.0248) and RT duration (p = 0.0100) as predictive of better EFS. Planning films were reviewed for 131 (74.4%) of 176 patients. Sixty-five (49.6%) had no targeting deviations and 58 (44.3%) had one or more deviations. PF recurrence occurred in 11 (34.4%) of 32 with a PF targeting deviation compared with 13 (16.3%) of 80 without (p = 0.043). No statistically significant impact of other targeting deviations on recurrence risk or EFS were found. CONCLUSION: The results of this study have confirmed the importance of the duration of RT for medulloblastoma. Also, attention to detail when planning RT is important, as illustrated in the case of PF field placement.

Can the irradiated uterus sustain a pregnancy? A literature review.

A significant number of adult pre- menopausal women are offered pelvic radical radiotherapy as part of the management of their malignancy. Advances in human reproductive research are making pregnancy a possibility for these women, but ovarian function, however, is not the only requirement for establishing and maintaining a pregnancy that will result in the delivery of a normal infant. The processes of implantation, fetal and placental development and labour require normal cervical structure and function. Radiation induces acute and late changes in the uterus that have a permanent impact. This article aims to summarise the published data on this complex subject. To date, the majority of reports of successful pregnancies refer to women who had hemi-pelvis or abdominal irradiation suggesting that partial volume irradiation of the uterus may not preclude pregnancy. However, with the current available information, women receiving a radical dose of radiotherapy to the whole uterus are very unlikely to have a successful pregnancy even if ovarian function is maintained. Systematic studies and, in particular, studies looking at modern radiotherapy techniques are required, as well as a register of pregnancies and outcomes to be able to provide answers for this group of patients.

Molecular pharmacology of cancer therapy in human colorectal cancer by gene expression profiling.

Global gene expression profiling has potential for elucidating the complex cellular effects and mechanisms of action of novel targeted anticancer agents or existing chemotherapeutics for which the precise molecular mechanism of action may be unclear. In this study, decreased expression of genes required for RNA and protein synthesis, and for metabolism were detected in rectal cancer biopsies taken from patients during a 5-fluorouracil infusion. Our observations demonstrate that this approach is feasible and can detect responses that may have otherwise been missed by conventional methods. The results suggested new mechanism-based combination treatments for colorectal cancer and demonstrated that expression profiling could provide valuable information on the molecular pharmacology of established and novel drugs.

Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.

PURPOSE: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.