C.B. Wilson

A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: baseline characteristics and dosimetry results.

BACKGROUND AND PURPOSE This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results. MATERIALS AND METHODS Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy. RESULTS Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol>107) and less than 95% (Vol<95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm(3) (95% CI 26.4-41.6; P<0.0001) and 48.1 cm(3) (95% CI 34.4-61.9; P<0.0001), respectively. In this study, 90% of patients who had a breast separation greater > or = 21 cm had Vol>107>2 cm(3) on standard radiotherapy plans. CONCLUSION This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: Results from the Cambridge Breast IMRT trial

AIMS There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications

Background:Pyridoxine is frequently used to treat capecitabine-induced hand–foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes.Methods:A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/ 35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily.Results:Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15–1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival.Conclusion:Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

The Cambridge post-mastectomy radiotherapy (C-PMRT) index: A practical tool for patient selection

BACKGROUND AND PURPOSE Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ⩾ 4 positive lymph nodes (LN). The role of PMRT in 1-3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index. MATERIALS AND METHODS The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy. RESULTS From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively. CONCLUSION Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.

Audit of local recurrence following breast conservation surgery with 5-mm target margin and hypofractionated 40-Gray breast radiotherapy for invasive breast cancer

INTRODUCTION The risk of ipsilateral breast tumour recurrence (IBTR) following breast conservation surgery (BCS) for invasive breast cancer (IBC) and radiotherapy is dependent on patient-, tumour- and treatment-related variables. In the Cambridge Breast Unit, breast conserving surgery has been performed with a target radial margin of 5 mm for IBC, in combination with 40-Gy hypofractionated (15 fractions) breast radiotherapy, since 1999. PATIENTS AND METHODS An audit was performed of cases treated between 1999 and 2004. A total of 563 patients underwent BCS for invasive breast cancer with 90.4% receiving radiotherapy (RT) and 60.4% of patients receiving boost RT (3 fractions of 3-Gy). RESULTS After a median follow-up of 58 months, five of the 563 (0.9%) patients developed IBTR. The 5-year actuarial IBTR rate was 1.1%. In terms of distant disease recurrence (DDR), 29 of the 563 (5.2%) had DDR during follow-up, giving a 5-year actuarial DDR rate of 5.4%. The 5-year breast cancer specific survival was 95%, with the poorer NPI groups having worse breast cancer specific survival (Log-rank, P<0.0001). More importantly, patients with IBTR had a shorter breast cancer-specific survival than those who were IBTR-free (Log-rank, P<0.0001). CONCLUSIONS Our treatment regimen, combining BCS with a 5-mm target margin and hypofractionated 40-Gy RT, results in an extremely low rate of IBTR, and compares favourably with the target IBTR rate of <5% defined by the Association of Breast Surgeons (ABS) at BASO guidelines.

A Randomised Controlled Trial of Forward-Planned Intensity Modulated Radiotherapy (IMRT) for Early Breast Cancer: Interim Results at 2 Years Follow-Up.

Background: This large single centre trial was designed to investigate whether correction of dose inhomogeneities using IMRT reduces late toxicity and improves quality of life in patients with early breast cancer. We report interim results at 2 years follow-up. Materials and Methods: Standard tangential breast radiotherapy plans of 1145 trial patients were assessed for dose inhomogeneity as defined by ICRU recommendations. Patients with inhomogeneous plans were randomised to either IMRT or standard radiotherapy. Patients with homogenous plans were treated with standard radiotherapy, but were followed up within the trial as per randomised patients. The primary endpoint of the trial was photographic assessment of breast shrinkage. Secondary endpoints included photographic assessment of final cosmesis, clinical assessment of toxicity, and patient-reported symptoms and quality of life. All endpoints were scored using validated assessment methods. Data were collected on potential confounding factors which included: age at randomisation, smoking history, body mass index, co-morbidity such as diabetes mellitus, cardiovascular and peripheral vascular disease, use of hormones and/or chemotherapy, treated breast volume, and presence or absence of breast boost. Results: 330/1145 (29%) of patients had adequate dosimetry with standard 2D radiotherapy and were not randomised. In the 815 randomised patients, dosimetry was significantly improved in the interventional (IMRT) arm compared to the control. Currently, data from 632 randoimsed patients who have reached 2 years of follow up have been analysed. This interim analysis demonstrates that the incidence of telangiectasia in the control arm was significantly greater than in the interventional group (P = 0.024). Pre-radiotherapy surgical cosmesis significantly affected photographic assessment of final cosmesis, and clinical assessment of breast shrinkage and induration (P Discussion: This trial shows that the use of forward-planned IMRT can significantly improve dose homogeneity, and suggests that this translates into improvements in late toxicity at only 2 years from completion of radiotherapy. Surgical cosmesis appears to be a very important determinant of overall final cosmesis after 2 years of follow-up, and may mask any beneficial effects of IMRT at this early stage. It is highly likely that these trial patients will have not expressed their final level of toxicity at 2 years post-radiotherapy, and re-analysis is planned at 5 years from completion of radiotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 71.

Improved long-term survival after resection of colorectal liver metastases following staging with FDG positron emission tomography.

Actual long‐term survival of patients with colorectal liver metastases staged by PET CT has not been reported. Objectives were to investigate whether PET CT staging results in actual improved long‐term survival, to examine outcome in patients with ‘equivocal’ PET CT scans, and those excluded from hepatectomy by PET CT.

Laparoscopic salpingo-oophorectomy for ovarian ablation in women with hormone-sensitive breast cancer

To evaluate institutional experiences regarding laparoscopic salpingo‐oophorectomy in breast cancer patients and to compare the technique with gonadotropin‐releasing hormone (GnRH) analogs among premenopausal women with hormone‐sensitive breast cancer.

A radiotherapy technique to improve dose homogeneity around bone prostheses.

Purpose. Following limb conserving surgery for bone or soft tissue sarcoma, patients may require post-operative radiotherapy to minimise the risk of local recurrence. In such circumstances the metal prosthesis reduces the dose in its shadow by approximately 10% when using opposed fields. We describe a technique to boost the underdosed area to overcome this problem. Patients or subjects. Seven sequential patients presenting between 1995 and 2001 had their treatment individualised because they had metal prosthesis in the treatment volume. Methods. To improve the target dose homogeneity we used a custom-made keyhole cutout to boost the area in the shadow of the prosthesis. The degree of attenuation caused by the metal prosthesis was estimated and a boost dose calculated. Exit thermoluminescent dosimetry (TLD) was used to confirm the estimates made. Results and discussion. Variation between patients was seen, demonstrating the need for exit TLD to individualise the treatment plan. The use of a boost field provides a method to overcome under-dosage in the shadow of a metal prosthesis. It improves dose homogeneity throughout the target volume and ensures adequate dose intensity around the prosthesis, the site most at risk of local recurrence.