Functional Magnetic Resonance Imaging in Cervical Cancer Diagnosis and Treatment.

Cervical Cancer is the fourth most common cancer in women worldwide. Treatment with chemoradiotherapy followed by brachytherapy achieves high local control, but recurrence with metastatic disease impacts survival. This highlights the need for predictive and prognostic biomarkers identifying populations at risk of poorer treatment response and survival. Magnetic resonance imaging (MRI) is routinely used in cervical cancer and is a potential source for biomarkers. Functional MRI (fMRI) can characterise tumour beyond anatomical MRI, which is limited to the assessment of morphology. This review summarises fMRI techniques used in cervical cancer and examines the role of fMRI parameters as predictive or prognostic biomarkers. Different techniques characterise different tumour factors, which helps to explain the variation in patient outcomes. These can impact simultaneously on outcomes, making biomarker identification challenging. Most studies are small, focussing on single MRI techniques, which raises the need to investigate combined fMRI approaches for a more holistic characterisation of tumour.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Changes in Magnetic Resonance Imaging Radiomic Features in Response to Androgen Deprivation Therapy in Patients with Intermediate- and High-risk Prostate Cancer.

AIMS: The benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT. MATERIALS AND METHODS: Patients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test. RESULTS: Twenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82-105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters. CONCLUSION: Energy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours.

Practical brachytherapy solutions to an age-old quandary.

Cancer is predominantly a disease of the elderly and as population life expectancy increases, so will the incidence of malignant disease. Elderly patients often have other comorbidities and social complexities, increasing the support required to safely deliver all treatment modalities. Brachytherapy is a relatively simple technique by which radiation therapy can be delivered. It offers dosimetric advantages through a highly conformal dose distribution thereby limiting radiation exposure to normal tissues reducing toxicity. Requiring fewer hospital visits, it also offers practical and logistical advantages to the elderly population and in many cases can be performed without the need for general anaesthesia. In tumour streams where brachytherapy forms part of the curative management, it should not be omitted in elderly patients who are medically fit for treatment. In the palliative setting, brachytherapy often offers an excellent means for achieving either local tumour and/or symptom control and should be actively considered in the therapeutic armamentarium of the oncologist in this context.

The Role of Magnetic Resonance Imaging in Brachytherapy.

The application of magnetic resonance imaging (MRI) in image-guided brachytherapy has expanded rapidly over the past two decades. In cervix cancer, significant improvements in overall survival, local control and long-term morbidity have been shown in patients treated with MRI-guided brachytherapy, changing clinical practice and directing an international approach to standardise the technique; unifying adaptive target volume definition and dose reporting. MRI-guided prostate brachytherapy has significantly improved the accuracy of tumour and organ-at-risk delineation, facilitating targeted implantation and dose optimisation. It also has potential to improve clinical outcomes through enhancement of the therapeutic ratio and the identification of dominant lesions that can be the targets of sub-volume boosting and salvage therapy. However, MRI-guided brachytherapy presents a number of logistical and financial challenges in modern healthcare systems, requiring technologically advanced imaging and planning techniques, as well as robust safety and quality assurance procedures. A collaborative, multidisciplinary approach involving clinical oncologists, radiologists, medical physicists, therapy radiographers, nurses and technical staff is therefore critical to its successful incorporation into any clinical brachytherapy workflow. In this overview we evaluate the current role of MRI in image-guided brachytherapy, primarily in cervix and prostate cancer, but also in other tumour sites, and review its potential future developments in the context of both clinical and research spheres.

The changing role of radiation therapy in the management of oligometastatic disease.

It is clear from surgical series that there are selected patients presenting with localised metastatic disease who can be cured by radical ablation of the metastasis. To date this has been limited to surgical resection but the evolution of stereotactic ablative body radiotherapy (SABR) has opened new opportunities. Hypofractionated radiation delivery in 1 to 5 fractions can achieve durable local control with low toxicity. The focus is now to develop robust biomarkers so that those with true oligometastatic and thereby potentially curable disease can be selected for this approach.

Expression of miR-210 in relation to other measures of hypoxia and prediction of benefit from hypoxia modification in patients with bladder cancer.

BACKGROUND: The addition of hypoxia modifiers carbogen and nicotinamide (CON) to radiotherapy (RT) improved overall survival (OS) in bladder cancer patients in the BCON phase III clinical trial. We investigate whether expression of hsa-miR-210 in BCON patient samples reflects hypoxia and predicts benefit from hypoxia modification. METHODS: In all, 183 T1-T4a bladder cancer samples were available for miR-210 analysis. A total of 86 received RT+CON and 97 received RT alone. TaqMan qPCR plates were used to assess miR-210 expression. Patients were classified as low (

High dose rate brachytherapy for prostate cancer: Standard of care and future direction.

High dose rate brachytherapy is a highly conformal method of radiation dose escalation for prostate cancer and one of several treatment options for men with localised disease. The large doses per fraction exploit the low alpha/beta ratio of prostate cancer cells so that biological radiation dose delivered is substantially greater than that achieved with conventional external beam delivery. This review article presents contemporary data on the rationale for high dose rate brachytherapy including treatment technique and future directions.

Recommendations for Radiotherapy Technique and Dose in Extra-nodal Lymphoma.

Extra-nodal sites may be involved in around 40% of patients with non-Hodgkin lymphoma. The general principles for target volume delineation in this setting are presented, together with specific examples. In general, the entire organ affected should be encompassed in the clinical target volume with an expansion of at least 10 mm, increased in some instances to account for patterns of potential lymphatic flow. Adjacent lymph nodes may be treated using standard techniques for nodal irradiation. Doses for extra-nodal lymphoma follow the same principles as nodal lymphoma, delivering 30 Gy in 15 fractions for Hodgkin and aggressive non-Hodgkin lymphoma and 24 Gy in 12 fractions for indolent lymphomas, with the exception of certain palliative situations, mycosis fungoides, central nervous system lymphoma and natural killer/T-cell lymphoma.

Stereotactic body radiotherapy (SBRT) in the management of extracranial oligometastatic (OM) disease.

OBJECTIVE: A review of stereotactic body radiotherapy (SBRT) for oligometastases defined as three or fewer sites of isolated metastatic disease. The aim was to identify local control, overall survival (OS) and progression-free survival (PFS) of patients receiving SBRT for oligometastatic (OM) disease. METHODS: Data were analysed for SBRT delivered between 01 September 2010 and 31 March 2014. End points included local control, PFS, OS and toxicity. RESULTS: 76 patients received SBRT. The median age was 60 years (31-89 years). 44 were male. Median follow-up was 12.3 months (0.2-36.9 months). Major primary tumour sites included colorectal (38%), the breast (18%) and the prostate (12%). The treatment sites included lymph nodes (42%), the bone and spine (29%) and soft tissue (29%). 42% were previously treated with conventional radiotherapy. 45% were disease free after SBRT. 4% had local relapse, 45% had distant relapse, and 6% had local and distant relapse. Local control was 89%. The OS was 84.4% at 1 year and 63.2% at 2 years. PFS was 49.1% at 1 year and 26.2% at 2 years. Toxicities included duodenal ulcer and biliary stricture formation. CONCLUSION: SBRT can achieve durable control of OM lesions and results in minimal radiation-induced morbidity. ADVANCES IN KNOWLEDGE: This cohort is one of the largest reported to date and contributes to the field of SBRT in oligometastases that is emerging as an important research area. It is the only study reported from the UK and uses a uniform technique throughout. The efficacy and low toxicity with durable control of local disease with this approach is shown, setting the foundations for future randomized studies.

Stereotactic body radiotherapy for spinal and bone metastases.

Stereotactic body radiotherapy (SBRT) can deliver high radiation doses to small volumes with very tight margins, which has significant advantages when treating tumours close to the spinal cord or at sites of retreatment. When treating spinal tumours, meticulous quality control is essential with effective immobilisation, as dose gradients at the edge of the spinal cord will be steep and excessive movements can be catastrophic. A range of dose-fractionation schedules have been used from single doses of 15-24 Gy to fractionated schedules delivering 15-35 Gy in three to five fractions. Indications include solitary or up to three vertebral metastases and primary tumours, in particular chordomas or bone sarcomas. Pain relief from metastatic disease is seen in over 80%, with similar rates of objective local control. Local control can be achieved in primary tumours of the spine in up to 95% and similar response rates are seen in non-spinal bone metastases. Toxicity rates are low, even in series that have delivered re-irradiation with myelopathy in <1%, although later vertebral fracture may occur. Further prospective studies are required to formally evaluate patient selection and optimal dose and fractionation alongside an evaluation of cost-effectiveness.

Combination external beam radiotherapy and intraluminal brachytherapy for non-radical treatment of oesophageal carcinoma in patients not suitable for surgery or chemoradiation.

AIMS: This single-centre retrospective study evaluated combination external beam radiotherapy and high dose rate brachytherapy for patients in whom radical treatment was appropriate but comorbidity or frailty excluded this as an option. MATERIALS AND METHODS: In total, 59 patients were selected for a combined approach and treated between October 2000 and October 2011; 68% were male. The median age was 77 years (range 53-88 years); 66% had adenocarcinoma, 31% squamous cell carcinoma. Tumour stage: I: 20%, II: 43%, III: 32% and IV: 3%. External beam radiotherapy doses of either 27 Gy/six fractions or 30 Gy/10 fractions were delivered, followed by high dose rate brachytherapy at doses of either 10 or 15 Gy utilising an iridium 192 source at 1 cm. RESULTS: The median overall survival of all treated patients was 12.3 months; 1, 2 and 3 year survival rates were 51, 19 and 7%, respectively. Patients with stage I disease had a median survival of 16 months compared with 10 months for patients with stage III disease (P = 0.036). The pretreatment dysphagia score was associated with survival (P = 0.021). CONCLUSIONS: This study shows the value of a purely radiation-based approach in a selected population. Treatment is deliverable with excellent compliance and the median survival compares favourably with unselected patients treated palliatively in our institution.

Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.

BACKGROUND: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON. METHODS: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON). HIF-1α expression was studied in 137 tumours using tissue microarrays and immunohistochemistry. Data were available from other studies for carbonic anhydrase IX and glucose transporter 1 protein and gene expression and tumour necrosis. RESULTS: Patients with high HIF-1α expression had improved 5-year local relapse-free survival with RT+CON (47%) compared with RT alone (21%; hazard ratio (HR) 0.48, 95% CI 0.26-0.8, P=0.02), no benefit was seen with low HIF-1α expression (HR 0.81, 95% CI 0.43-1.50, P=0.5). Combinations of markers including necrosis also predicted benefit but did not improve on prediction using necrosis alone. CONCLUSIONS: HIF-1α may be used to predict benefit from CON in patients with bladder cancer but does not improve on use of necrosis.

Image-guided high-dose-rate brachytherapy in inoperable endometrial cancer.

Inoperable endometrial cancer may be treated with curative aim using radical radiotherapy alone. The radiation techniques are external beam radiotherapy (EBRT) alone, EBRT plus brachytherapy and brachytherapy alone. Recently, high-dose-rate brachytherapy has been used instead of low-dose-rate brachytherapy. Image-guided brachytherapy enables sufficient coverage of tumour and reduction of dose to the organs at risk, thus increasing the therapeutic ratio of treatment. Local control rates with three-dimensional brachytherapy appear better than with conventional techniques (about 90-100% and 70-90%, respectively).

Pre-treatment haemoglobin and peripheral blood lymphocyte count as independent predictors of outcome in carcinoma of cervix.

AIMS: To evaluate pre-treatment haemoglobin and peripheral blood lymphocyte (PBL) counts as predictors of treatment outcome in cervix carcinoma treated with radical chemoradiation. MATERIALS AND METHODS: Pre-treatment PBL counts and haemoglobin concentrations were retrieved from full blood count examinations from 111 patients who received concurrent chemoradiotherapy. Overall survival and relapse-free survival were obtained using the Kaplan-Meier method by ranking the data by median haemoglobin and PBL, singly and then in association. Their independence and significance as predictors of outcome were analysed using the Cox proportional hazard model. RESULTS: Survival rates were significantly higher in patients whose haemoglobin level or PBL counts were at or above the corresponding median value. At 5 years, rates of overall survival were 77% versus 41% (P = 0.0003) and 75% versus 42% (P = 0.002), when dichotomised around median haemoglobin and PBL, respectively. In multivariate and univariate analyses, both PBL and haemoglobin were independent and significant predictors for risk of death and relapse. Their predictive power was dramatically enhanced when the data were stratified into four groups by associating patients with haemoglobin ≥ median or < median with those whose PBL was ≥ or < median. CONCLUSION: Baseline PBL and haemoglobin seem to be strong, independent predictors of treatment outcome in carcinoma of the cervix, particularly if patient response is ranked using the predictors simultaneously. The hypothesis needs to be tested and, if confirmed, the markers should be used in combination to identify those at greater risk of failure who may benefit from additional therapy, with further validation in prospective trials offering treatment modification.

Biochemical outcomes for patients with intermediate risk prostate cancer treated with I-125 interstitial brachytherapy monotherapy.

BACKGROUND AND PURPOSE: Routine use of I-125 interstitial brachytherapy (BT) alone in intermediate risk (IR) prostate cancer is controversial. It is often combined with external beam radiotherapy (EBRT). The biochemical outcome of a large cohort of only IR disease treated with BT monotherapy is reported. MATERIALS AND METHODS: Between 2003 and 2007, 615 patients with Memorial Sloan-Kettering Cancer Centre (MSKCC) defined IR disease (one risk factor only-T2b, or Gleason score (GS) 7, or raised initial PSA (iPSA) 10.1-20ng/ml) were treated with BT monotherapy. ASTRO (3 consecutive rises) and Phoenix (nadir plus 2) criteria defined biochemical failure. Potential prognostic factors (pre- and post-implant dosimetric indices, GS 3+4 versus 4+3, androgen deprivation therapy (ADT)) were analysed. RESULTS: Median follow-up was 5.0years. Forty-three patients had stage T2b, 180 had raised iPSA, 392 had GS 7 disease. ADT was received by 108 patients. The 5-year biochemical no evidence of disease (bNED) rates are 87.3% (by ASTRO), 88.6% (by Phoenix). Stratification by risk factor (T2b, GS7, raised iPSA) demonstrated raised iPSA to have poorer outcome only by Phoenix criteria (p=0.0002). Other potential prognostic variables were non-significant. CONCLUSION: Good rates of biochemical control can be achieved in the medium term with BT monotherapy in IR disease. Raised iPSA correlated with a poorer outcome.

Brachytherapy: current status and future strategies -- can high dose rate replace low dose rate and external beam radiotherapy?

Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10-15 Gy is commonly combined with EBRT to a dose of 40-50 Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is now being investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer.

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

Variations in radiotherapy delivery in England - evidence from the national radiotherapy dataset.

AIMS, MATERIALS AND METHOD: Data in the national radiotherapy dataset for England for 2009-2011 is based upon downloads of activity from every linear accelerator in the country through its oncology management system linked to the local patient administration system to give a full overview of each patient episode. RESULTS: An analysis of this dataset shows that there is still a considerable variation in radiotherapy activity across the country, with a two-fold variation between the most and least active networks. Lower activity is seen in London and the southeast compared with the rest of the country, but when the data are split between the north and south of the country, no such variation is seen. Activity is higher in smaller centres and non-teaching centres. About half of all treatment is palliative and this proportion does not vary with geography, although there is considerable variation between individual centres in the proportion of radical radiotherapy given. There is a trend towards less use of radiotherapy, both radical and palliative, in the more deprived population groups, although no change in the relative use of palliative and radical treatment. CONCLUSION: It is important to emphasise that these data currently reflect activity patterns only and do not reflect quality of care or treatment outcomes, which will be achieved by linkage with cancer registry data in the future.