C Wratten

Treatment-Related Morbidity in Prostate Cancer: A Comparison of 3-Dimensional Conformal Radiation Therapy With and Without Image Guidance Using Implanted Fiducial Markers

PURPOSEnTo estimate the prevalence of rectal and urinary dysfunctional symptoms using image guided radiation therapy (IGRT) with fiducials and magnetic resonance planning for prostate cancer.nnnMETHODS AND MATERIALSnDuring the implementation stages of IGRT between September 2008 and March 2010, 367 consecutive patients were treated with prostatic irradiation using 3-dimensional conformal radiation therapy with and without IGRT (non-IGRT). In November 2010, these men were asked to report their bowel and bladder symptoms using a postal questionnaire. The proportions of patients with moderate to severe symptoms in these groups were compared using logistic regression models adjusted for tumor and treatment characteristic variables.nnnRESULTSnOf the 282 respondents, the 154 selected for IGRT had higher stage tumors, received higher prescribed doses, and had larger volumes of rectum receiving high dosage than did the 128 selected for non-IGRT. The follow-up duration was 8 to 26 months. Compared with the non-IGRT group, improvement was noted in all dysfunctional rectal symptoms using IGRT. In multivariable analyses, IGRT improved rectal pain (odds ratio [OR] 0.07 [0.009-0.7], P=.02), urgency (OR 0.27 [0.11-0.63], P=<.01), diarrhea (OR 0.009 [0.02-0.35], P<.01), and change in bowel habits (OR 0.18 [0.06-0.52], P<.010). No correlation was observed between rectal symptom levels and dose-volume histogram data. Urinary dysfunctional symptoms were similar in both treatment groups.nnnCONCLUSIONSnIn comparison with men selected for non-IGRT, a significant reduction of bowel dysfunctional symptoms was confirmed in men selected for IGRT, even though they had larger volumes of rectum treated to higher doses.

Comparison of prostate set-up accuracy and margins with off-line bony anatomy corrections and online implanted fiducial-based corrections.

The aim of the study was to determine prostate set‐up accuracy and set‐up margins with off‐line bony anatomy‐based imaging protocols, compared with online implanted fiducial marker‐based imaging with daily corrections. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Pretreatment orthogonal electronic portal images were acquired to determine couch shifts and verification images were acquired during treatment to measure residual set‐up error. The prostate set‐up errors that would result from skin marker set‐up, off‐line bony anatomy‐based protocols and online fiducial marker‐based corrections were determined. Set‐up margins were calculated for each set‐up technique using the percentage of encompassed isocentres and a margin recipe. The prostate systematic set‐up errors in the medial–lateral, superior–inferior and anterior–posterior directions for skin marker set‐up were 2.2, 3.6 and 4.5u2003mm (1 standard deviation). For our bony anatomy‐based off‐line protocol the prostate systematic set‐up errors were 1.6, 2.5 and 4.4u2003mm. For the online fiducial based set‐up the results were 0.5, 1.4 and 1.4u2003mm. A prostate systematic error of 10.2u2003mm was uncorrected by the off‐line bone protocol in one patient. Set‐up margins calculated to encompass 98% of prostate set‐up shifts were 11–14u2003mm with bone off‐line set‐up and 4–7u2003mm with online fiducial markers. Margins from the van Herk margin recipe were generally 1–2u2003mm smaller. Bony anatomy‐based set‐up protocols improve the group prostate set‐up error compared with skin marks; however, large prostate systematic errors can remain undetected or systematic errors increased for individual patients. The margin required for set‐up errors was found to be 10–15u2003mm unless implanted fiducial markers are available for treatment guidance.

Breast Edema in Patients Undergoing Breast‐Conserving Treatment for Breast Cancer: Assessment via High Frequency Ultrasound

Abstract:u2002 To identify factors that can influence breast edema in women undergoing breast‐conserving therapy. Breast edema was assessed clinically and via high frequency ultrasound (HFUS) prior to, during and following radiotherapy. Fifty‐four women were assessed. Breast edema was present prior to radiotherapy in patients who had undergone level 2 node dissection or had wound infection after sentinel node dissection. Edema increased during and after radiotherapy and peaked at 4–6u2003months. The time course of breast edema was related to the extent of nodal dissection, postoperative wound infection and regional radiotherapy. HFUS prior to irradiation was found to be no better than clinical assessment in predicting prolonged parenchymal breast edema but was significantly better at the end of irradiation. Breast edema levels are minimal in patients who do not undergo axillary node dissection or have an uncomplicated sentinel node dissection. Most edema is due to compromise of the draining lymphatics, which relates largely to the extent of axillary node dissection. HFUS appears to be a useful in the research setting in quantifying the effect of techniques that aim to reduce complications such as edema.

Effect of surgery on normal tissue toxicity in patients treated with accelerated radiotherapy.

The aim of this study was to assess the effect of surgery on normal tissue toxicity in head and neck cancer patients treated with accelerated radiotherapy. Toxicity data from two trials of accelerated radiotherapy were compared. The first group was taken from a phase III trial of definitive radiotherapy and the second group from a phase II trial of postoperative radiotherapy. The general eligibility criteria (apart from surgery), data collection and radiotherapy details for both trials were similar. The definitive group included 172 eligible patients and the postoperative group 52 eligible patients. At 3 weeks into treatment, by which time the dose and rate of dose accumulation were identical, there was no difference in acute toxicity. Analysis of late toxicity showed greater subcutaneous fibrosis in the postoperative group.

Altered amino acid homeostasis and the development of fatigue by breast cancer radiotherapy patients: A pilot study.

OBJECTIVESnTo examine altered amino acid homeostasis as a predisposing factor of fatigue in female radiotherapy breast cancer patients.nnnDESIGN AND METHODSnParticipants underwent breast-conserving surgery and adjuvant breast irradiation and were free from significant fatigue pre-radiotherapy. The Functional Assessment of Cancer Therapy fatigue subscale was used to assess fatigue pre- and post-radiotherapy. Blood biochemistry factors and urinary and plasma amino acid levels were measured.nnnRESULTSnOne third of 27 patients developed fatigue and were designated as the fatigued cohort. It was possible to differentiate between fatigued subjects pre- and post-radiotherapy based upon their urinary amino acid profiles. Univariate analysis supported altered amino acid homeostasis within the fatigued cohort. Urinary levels of histidine and alanine were increased pre-radiotherapy whilst threonine, methionine, alanine, serine, asparagine and glutamine levels were higher after 5weeks of radiotherapy for the fatigued cohort.nnnCONCLUSIONSnFatigue was accompanied by altered amino acid homeostasis with increased amino acid excretion suggestive of a catabolic response.

The GOFURTGO Study: AGITG Phase II Study of fixed dose rate gemcitabine–oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer

Background:Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine–oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established.Methods:A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000u2009mgu2009m−2 d1 + d15 q28) and oxaliplatin (100u2009mgu2009m−2 d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200u2009mgu2009m−2 per day over 6 weeks during 3DCRT 54u2009Gy.Results:Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity.Conclusion:Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.

Pilot study of high-frequency ultrasound to assess cutaneous oedema in the conservatively managed breast.

Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high‐frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast‐conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High‐frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High‐frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 295–301 (2000).

Assessment of a daily online implanted fiducial marker-guided prostate radiotherapy process

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software‐predicted set‐up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in‐plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in‐plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5u2003mm (1 standard deviation) in all directions (range 0.2–3.9u2003mm). The random prostate errors ranged from 0.8 to 3.3u2003mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set‐up error of more than 10u2003mm for one fraction. In 14 of 35 fractions, the postalignment prostate set‐up error was greater than 5u2003mm in the anterior–posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2° to 20° for the patients. The differences between set‐up shifts determined by the online software without in‐plane rotations to align markers, and with rotations applied, was less than 1u2003mm (root mean square), with a maximum difference of 4.1u2003mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set‐up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in‐plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.

Thrombin generation as a predictor of radiotherapy induced skin erythema

BACKGROUND AND PURPOSEnBiological mechanisms underlying radiation induced erythema remain largely unknown, with no simple way to accurately predict or prevent extreme cases. Based on the recent findings in patients suffering from chronic urticaria, we sought to determine if similar mechanisms of hypercoagulation contributed to comparable skin reactions during radiotherapy.nnnMATERIALS AND METHODSnPlasma levels of prothrombin factor 1+2 (F1+2), D-dimers and plasminogen activator inhibitor-1 (Pai-1) were tested in 32 women undergoing irradiation following breast conserving surgery for early breast cancer. Reflectance spectrophotometry was used to objectively assess erythema throughout the treatment by measuring the amount of light reflected from the skin surface as a function of wavelength. Correlations between peak levels of erythema and plasma biomarkers were then assessed.nnnRESULTSnIndividual peak reflectance readings generally occurred between day 29 of treatment and 2 weeks post radiotherapy, and represented a median increase of 66% (range: 11-146%; p<0.001) from baseline. Peak reflectance correlated with F1+2 and Pai-1 levels measured both at baseline and day 29 of treatment, and multivariate analysis indicated that these two baseline measurements were the best predictors of peak reflectance, accounting for 59% of the variability in erythema (p=0.000004).nnnCONCLUSIONSnPatients with signs of intravascular thrombin generation are at higher risk of radiotherapy-induced skin reactions, providing a new therapeutic avenue for possibly predicting and preventing this side effect of cancer treatment.

Sci—Sat AM(1): Planning — 05: Feasibility of Atlas‐Based Organ Segmentation and Electron Density Mapping for MRI‐Based Prostate Radiation Therapy Planning

This project develops atlas‐based deformable image registration methods to map electron densities and automatically segment organs on MRI scans. This will enable dose calculations to be performed using the MRI scan without the requirement for an additional CT scan. The method developed uses atlas‐based deformable image registration. An MRI atlas was developed based on whole pelvic MRI scans for 39 patients. The atlas is then registered to an individual patient MRI scan. The registration of the atlas organ contours gives the automatically segmented organs on that patient scan. A CT or electron‐density atlas was also developed that corresponds to the MRI atlas. The deformation vectors that register the MRI‐atlas to the patient MRI scan are applied to the CT‐atlas to produce a pseudo‐CT scan for the patient. This can then be used for dose planning and digitally reconstructed radiographs. The feasibility of the entire workflow has been tested for one patient. The rectum, bladder, prostate and bone were automatically segmented on the MRI scan with Dice coefficient results of 0.82, 0.59, 0.62 and 0.81. The patients plan was applied to the pseudo‐CT using a commercial treatment planning system. Dose at the normalisation point was 2.9% lower than on the full density CT plan. This method will improve the workflow of prostate radiotherapy planning and will reduce systematic uncertainties introduced by MRI‐CT registration.