MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

AIMS: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies. A pilot trial was conducted to characterise whether these instruments may detect subclinical radiotherapy-induced cardiac damage. MATERIALS AND METHODS: Eligible patients received high cardiac doses defined by either at least 30 Gy to 5% of cardiac volume or a mean dose of 4 Gy. HsTnI and HsTnT were measured before radiotherapy and after 2 and 4 weeks of radiotherapy; three-dimensional echocardiograms were completed before and 1 year after radiotherapy. RESULTS: Of 19 patients, the median 'mean left ventricular dose' was 3.1 Gy and the 'mean cardiac dose' was 8.6 Gy. Significant positive associations between HsTnI and HsTnT were observed at all time points, but there was no significant association with cardiac dose. The mean left ventricular dose and the maximum left ventricular dose were, however, associated with a decrease in ejection fraction (P = 0.054, 0.043) as well as an increase in left ventricular strain (P = 0.058). CONCLUSION: This study suggests that HsTnI and HsTnT are intimately related, but detection of acute cardiac damage was not shown, potentially due to limitations of these markers or low radiotherapy doses using conformal techniques. Our results also suggest subacute damage at 1 year may depend on the dose to the left ventricle. Further studies are needed, as identification of early damage could facilitate the ability to closely monitor and intervene in patients at risk for radiation-induced heart disease.

Natural product MDM2 inhibitors: anticancer activity and mechanisms of action.

The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future.

Poster - Thurs Eve-38: CT Imaging in high dose rate brachytherapy for treatment of cervical cancer: Estimation of dose to bowel.

Treatment of cervical cancer often involves intracavitary high dose rate (HDR) brachytherapy. Dose delivered to the bladder and rectum are typically estimated using the ICRU reference points. Dose to the sigmoid and small bowel are not estimated, yet these organs typically exhibit significant complication rates. The objective of this study was to estimate dose to the small bowel and sigmoid using CT images. Bladder and rectum dose estimates obtained from the reference point method were also compared to those obtained from CT images. Eighteen CT scans taken before or after treatment of women treated with HDR using ring and tandem applicators were included in this study. The small bowel, sigmoid, bladder and rectum were contoured and the ICRU points were digitized. The minimum dose to 2cc (D2cc ) of each organ was calculated and normalized to % prescribed to Point A. Average D2cc bowel dose was 70%. D2cc bowel dose was significantly higher than both D2cc rectal (27%) and D2cc sigmoid (31%) doses. The average D2cc bladder and rectal doses were 68% (p=NS) and 27% (p<0.001) of prescribed Point A dose. D2cc bowel dose, although significantly higher than rectum and sigmoid, is within an acceptable limit. D2cc bladder and rectum values are either not significantly different from or are significantly lower than ICRU reference values. The results of this study suggest that CT imaging is not necessary for determination of dose to organs at risk. However, image guidance is of value for identifying perforations prior to commencing treatment.

Invasive vulvar cancer in a woman with human immunodeficiency virus: case report and review of the literature.

BACKGROUND: : HIV is associated with a decrease in cellular immunity which allows for persistence of high-risk HPV types and this can predispose the woman to dysplasia or cancer of the gynecologic tract. CASE: : We present a case of Stage 3 vulvar cancer in a 33-year-old HIV positive woman. The patient was treated with primary radiation; unfortunately there was persistent disease. Exenterative surgery was planned but abandoned due to a positive presacral node. CONCLUSION: : The optimal treatment of advanced vulvar cancer in HIV positive patients remains unclear given the small number of cases reported in the literature. Lessons from the anal cancer literature may help inform the care of vulvar cancer patients given the comparable high prevalence of this disease in the patients infected with HIV.

Magnetic resonance imaging (MRI) for localization of the prostatic apex: comparison to computed tomography (CT) and urethrography.

BACKGROUND AND PURPOSE: It is necessary to include the entire prostate in the high dose treatment volume when planning radical radiation for patients with prostate cancer. We prospectively compared magnetic resonance imaging (MRI) to computed tomography (CT) and urethrography as means of localizing the prostatic apex. MATERIALS AND METHODS: Thirty patients with clinically localized prostate cancer had a sagittal T2-weighted MRI scan and a conventional axial CT scan performed in the treatment position prior to the start of radiotherapy. Twenty of these patients had a static retrograde urethrogram performed at simulation. The position of the MRI and CT apices were localized independently by two radiation oncologists. In addition, the MRI apex was localized independently by a diagnostic radiologist. The urethrogram apex, defined as the tip of the urethral contrast cone, was easily identified and was therefore localized by only one observer. RESULTS: There was good interobserver agreement in the position of the MRI apex. Interobserver agreement was significantly better with MRI than with CT. There were no systematic differences in the position of the MRI and CT apices. However, the MRI apex was located significantly above and behind the urethrogram apex. There was poor correlation between MRI and CT and between MRI and urethrogram in the height of the apex above the ischial tuberosities. There was 83% agreement between MRI and CT and 80% agreement between MRI and urethrogram in the identification of patients with a low-lying apex. The apex, as determined by MRI, was <2 cm above the ischial tuberosities and therefore potentially under-treated in 17% of the patients. CONCLUSIONS: MRI is superior to CT and urethrography for localization of the prostatic apex. All patients undergoing radiotherapy for prostate cancer should have localization of the apex using MRI or a technique of equal precision to assure adequate dose delivery to the entire prostate and to minimize the unnecessary irradiation of normal tissues.

Does delay in breast irradiation following conservative breast surgery in node-negative breast cancer patients have an impact on risk of recurrence?

PURPOSE: This retrospective review was conducted to determine if delay in the start of radiotherapy after definitive breast surgery had any detrimental effect on local recurrence or disease-free survival in node-negative breast cancer patients. METHODS AND MATERIALS: A total of 568 patients with T1-T2, N0 breast cancer were treated with breast-conserving surgery and breast irradiation, without adjuvant systemic therapy between January 1, 1985 and December 31, 1992, at the London Regional Cancer Centre. Adjuvant breast irradiation consisted either of 50 Gy in 25 fractions or 40 Gy in 15 or 16 fractions, followed by a boost of 10 Gy or 12.5 Gy to the lumpectomy site. The time intervals from definitive breast surgery to breast irradiation used for analysis were 0-8 weeks (201 patients), > 8-12 weeks (235 patients), > 1216 weeks (91 patients), and > 16 weeks (41 patients). The time intervals of 0-12 weeks (436 patients) and > 12 weeks (132 patients) were also analyzed. Kaplan-Meier estimates of time to local recurrence and disease-free survival rates were calculated. The association between surgery-radiotherapy interval, age (< or = 40, > 40 years), tumor size (< or = 2, > 2cm), Scharf-Bloom-Richardson (SBR) grade, resection margins, lymphatic vessel invasion, extensive intraductal component, and local recurrence and disease-free survival were investigated using Cox regression techniques. RESULTS: Median follow-up was 63.5 months. Patients in all 4 time intervals were similar in terms of age and pathologic features. There was no statistically significant difference between the 4 groups in local recurrence or disease-free survival with surgery-radiotherapy interval (p = 0.189 and p = 0.413, respectively). The 5-year freedom from local relapse was 95.4%. The crude local recurrence rate was 6.9% (7.8% for 436 patients treated within 12 weeks (median follow-up 67 months) and 3.8% for 132 patients treated > 12 weeks from surgery (median follow-up 52 months). In a stepwise multivariable Cox regression model for disease-free survival, allowing for entry of known risk factors, tumour size (p < 0.001), grade (p < 0.001), and age (p = 0.048) entered the model, but the surgery-radiotherapy interval did not enter the model. CONCLUSION: This retrospective study suggests that delay in start of breast irradiation beyond 12 and up to 16 weeks does not increase the risk of recurrence in node-negative breast cancer patients. The certainty of these results are limited by the retrospective nature of this analysis and the lack of information concerning the late local failure rate.

A comparison of manual and remote afterloading in the treatment of carcinoma of the cervix: increasing dose rate with a flexible applicator.

A historical cohort design was used to assess the effect of introducing a remote afterloading system with a flexible applicator for the intracavitary treatment of cervical cancer. One hundred and sixty-eight patients treated for the 5 years prior to its introduction were compared to 84 patients treated for the first 3 years of its use. Patients were comparable with respect to age and stage. Treatment policies and techniques remained the same during the study period. Average dose rate to point A increased from 0.46 Gy/hr to 0.67 Gy/hr. The 3-year actuarial survival was equivalent between the two treatment modalities: 67.7% (manual), and 60.6% (remote). Patterns of local recurrence and distant failure were also equivalent between the two groups. Severe complication rates were comparable (8.3% manual, 6.3% remote) despite the increase in dose rate, confirming that the remote afterloading system can be safely adapted to a flexible applicator. The introduction of the remote afterloading system resulted in a 72% reduction in radiation exposure to staff.