Alastair J. Munro

P53 abnormalities and outcomes in colorectal cancer: a systematic review

We performed a systematic review of studies that investigated the effect of abnormalities of the tumour suppressor gene p53 upon prognosis in patients with colorectal cancer. The methods used to assess p53 status were immunohistochemistry (IHC), indicating abnormal accumulation of p53, and sequence analysis, indicating presence of p53 mutations (mut). We identified 168 reports, with 241 comparisons of relevant end points and survival data on 18 766 patients. We found evidence of both publication bias and heterogeneity of results. Our analysis was hampered by variability in both the assessment of p53 status and the reporting of results. We used a trim and fill method to correct for publication bias and minimised heterogeneity by using well-defined clinical subgroups for the assessment of outcomes. Overall, patients with abnormal p53 were at increased risk of death: relative risk (RR) with IHC 1.32 (95% confidence interval (c.i.) 1.23–1.42) and with mutation analysis 1.31 (95% c.i. 1.19–1.45). The adverse impact of abnormal p53 was greater in patients with lower baseline risk of dying: good prognosis RR (mut) 1.63 (95% c.i. 1.40–1.90) and poor prognosis RR (mut) 1.04 (95% c.i. 0.91–1.19). We found no effect of abnormal p53 on outcome in patients treated with chemotherapy. Abnormal p53 was associated with failure of response to radiotherapy in patients with rectal cancer: RR (mut) 1.49 (95% c.i. 1.25–1.77).

Multidisciplinary team working in cancer: what is the evidence?

Cancer care is increasingly delivered by multidisciplinary teams. Cath Taylor and colleagues argue that stronger evidence is needed of their effectiveness

Carcinoma of the prostate: Results of radical radiotherapy (1970–1985)

PURPOSE To determine the outcome and prognostic factors in patients with localized carcinoma of the prostate treated with external beam radiation therapy. METHODS AND MATERIALS A retrospective review of 999 patients with histologically confirmed adenocarcinoma of the prostate treated radically with megavoltage irradiation at the Princess Margaret Hospital between 1970 and 1985. Prognostic factors were analyzed using recursive partitioning method. RESULTS Overall survival at 5 and 10 years were 69.8% and 40.1% for the whole group. The cause-specific survival rates were 78.9% and 53.5%, respectively. The cause-specific survival rates were significantly different at 10 years by T stage, T1 being 79.0%, T2 66.0%, T3 55% and T4 22%. The overall clinical local control rates was 77% in the first 5 years following treatment. There was no statistically significant difference in the local control rates of T1 and T2 stage disease at 5 years, the combined rate being 88%. Significant differences were observed between other stages, being 76% for T3 and 55% for T4. At 10 years the control rate for T1 tumours was maintained for T1 stage disease (92%) but was significantly reduced for other stages, T2 75%, T3 67% and for T4 37%. In the whole group 33.5% of patients had distant metastases in the first 5 years. The distant relapse rates at 10 years were significantly different by T stage, being 20% for T1, 33% for T2, 55% for T3 and 87% for T4. Multivariate analysis demonstrated that only T stage and histological grade were independent prognostic covariates for cause-specific survival. Age was the only other independent variate in terms of overall survival. The late radiation related morbidity was 2.3% overall; 1.3% affecting rectum and recto-sigmoid and 1.0% arising in the bladder. CONCLUSION In terms of survival the results of radiotherapy of intracapsular disease were excellent, but they were less satisfactory in patients with direct extracapsular extension. The assessment of local control was difficult and may have reflected more the lack of local disease progression rather than true local tumor control. The treatment was well tolerated and there were few serious late complications.

Charged particles in radiotherapy: A 5-year update of a systematic review

Although proton therapy has been used for many decades because of their superior dose distribution over photons and reduced integral dose, their clinical implementation is still controversial. We updated a systematic review of charged particle therapy. Although still no randomised trials were identified, the field is moving quickly and we therefore also formulated ways to move forward. In our view, the aim should be to build enough proton therapy facilities with interest in research to further improve the treatment and to run the needed clinical trials.

Results of a policy of surveillance in stage I testicular seminoma

PURPOSE To determine what proportion of patients with Stage I testicular seminoma will be cured with orchidectomy alone. METHODS AND MATERIALS From August 1984 to December 1991 148 patients with Stage I testicular seminoma were entered on a prospective study of surveillance following orchidectomy. The eligibility criteria included a normal chest X ray, lymphogram, computed tomography (CT) of the abdomen and pelvis, and normal post-orchidectomy tumor markers (AFP and BHCG). Patients were followed with a clinical assessment (markers, chest X ray and CT abdomen and pelvis) at 4 to 6 monthly intervals. RESULTS With a median follow-up of 47 months (range 7-87 months), the actuarial relapse-free rate was 81% at 5 years. Twenty-three patients have relapsed with a median time to relapse of 15 months (range 2-61 months). Four patients (17%) relapsed at 4 or more years from diagnosis. Twenty-one of the 23 relapses occurred in the paraaortic lymph nodes, one patient relapsed in the mediastinum and ipsilateral inguinal nodes and one patient had an isolated ipsilateral inguinal node relapse. Nineteen patients were treated for relapse with external beam radiation therapy of which three developed a second relapse and were salvaged with chemotherapy. Four patients were treated for first relapse with chemotherapy and one developed a second relapse and died of disease. Age at diagnosis was the only prognostic factor for relapse, with patients age < or = 34 having an actuarial relapse-free rate at 5 years of 70% in contrast to a 91% relapse-free rate in those > 34 years of age. CONCLUSIONS We recommend that surveillance in Stage I testicular seminoma should only be performed in a study setting until further data regarding the risk of late relapse and the efficacy of salvage chemotherapy is available.

Characteristics of patients dying within 30 days of diagnosis of breast or colorectal cancer in Scotland, 2003–2007

Background:Recent research has shown that most of the excess risk of death following breast and colorectal cancer in England compared with Norway and Sweden occurs in older age groups during the first year, and especially in the first month of follow-up. The aim of this study was to explore the characteristics of patients dying within 30 days of being diagnosed with one of these cancers in Scotland during 2003–2007.Methods:Anonymised cancer registry records linked to hospital discharge and death records were extracted. The study population was divided into patients who died within 30 days of diagnosis (cases) and those who survived beyond this threshold (controls). Differences in patient-, tumour-, and health service-related characteristics were assessed using the χ2-test and logistic regression.Results:Patients dying within 30 days were more likely to be elderly and to have experienced emergency admission to non-surgical specialities. Their tumours were less likely to have been verified microscopically, but they appeared more likely to be of high grade and advanced in stage. A substantial number of patients died from causes other than their cancer.Conclusion:These results suggest that early mortality after a diagnosis of breast or colorectal cancer may be partly due to comorbidity and lifestyle factors, as well as due to more advanced disease. Further research is required to determine the precise explanation for these findings and, in particular, if any potentially avoidable factors such as delays in presentation, referral, or diagnosis exist.

Posttraumatic stress disorder after cancer diagnosis in adults: a meta-analysis

Since the introduction of serious illness as a potential traumatic stressor in the fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV), research on the prevalence and predictors of posttraumatic stress disorder (PTSD) after cancer diagnosis has proliferated. Studies have reported widely varying estimates of the number of people with PTSD after cancer. The aim of this review is to synthesize quantitative data from studies reporting the proportion of people with PTSD among groups of cancer survivors.

What is a virtual multidisciplinary team (vMDT)

Background:Multidisciplinary team meetings (MDTs), also known as tumour boards or multidisciplinary case conferences, are an integral component of contemporary cancer care. There are logistical problems with setting up and maintaining participation in these meetings. An ill-defined concept, the virtual MDT (vMDT), has arisen in response to these difficulties. We have, in order to provide clarity and to generate discussion, attempted to define the concept of the vMDT, outline its advantages and disadvantages, and consider some of the practical aspects involved in setting up a virtual MDT.Methods:This is an unstructured review of published evidence and personal experience relating to virtual teams in general, and to MDTs in particular.Results:We have devised a simple taxonomy for MDTs, discussed some of the practicalities involved in setting up a vMDT, and described some of the potential advantages and disadvantages associated with vMDTs.Conclusion:The vMDT may be useful for discussions concerning rare or unusual tumours, or for helping guide the assessment and management of patients with uncommon complications related to treatment. However, the vMDT is a niche concept and is currently unlikely to replace the more traditional face-to-face MDT in the management of common tumours at specific sites.

Differential Contextual Responses of Normal Human Breast Epithelium to Ionizing Radiation in a Mouse Xenograft Model

Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed ΔNp63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of γ-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems.

Bystander effects and their implications for clinical radiation therapy: Insights from multiscale in silico experiments

Radiotherapy is a commonly used treatment for cancer and is usually given in varying doses. At low radiation doses relatively few cells die as a direct response to radiation but secondary radiation effects, such as DNA mutation or bystander phenomena, may affect many cells. Consequently it is at low radiation levels where an understanding of bystander effects is essential in designing novel therapies with superior clinical outcomes. In this paper, we use a hybrid multiscale mathematical model to study the direct effects of radiation as well as radiation-induced bystander effects on both tumour cells and normal cells. We show that bystander responses play a major role in mediating radiation damage to cells at low-doses of radiotherapy, doing more damage than that due to direct radiation. The survival curves derived from our computational simulations showed an area of hyper-radiosensitivity at low-doses that are not obtained using a traditional radiobiological model.