Peter Jenkins

Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer

BACKGROUND Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. METHODS In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). CONCLUSIONS Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).

Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004)

Purpose To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. Methods and Materials In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Results Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population. Conclusions In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.

Computed Tomography Appearance of Early Radiation Injury to the Lung: Correlation With Clinical and Dosimetric Factors

PURPOSE To systematically assess the spectrum of radiologic changes in the lung after radiation therapy for non-small-cell lung cancer. METHODS AND MATERIALS We reviewed the cases of 146 patients treated with radical radiotherapy at our institution. All patients had computed tomography (CT) scans performed 3 months after completion of therapy. Radiographic appearances were categorized using a standard grading system. The association of these abnormalities with pretreatment factors and clinical radiation pneumonitis (RP) was investigated. RESULTS New intrapulmonary abnormalities were seen in 92 patients (63%). These were ground-glass opacity in 16 (11%), patchy consolidation in 19 (13%), and diffuse consolidation in 57 (39%). Twenty-five patients (17%) developed clinical symptoms of RP. Although 80% of the patients with RP had areas of consolidation seen on the posttreatment CT scan, the majority (74%) of patients with such radiographic changes were asymptomatic. For patients with lung infiltrates, the minimum isodose encompassing the volume of radiologic abnormality was usually ≥27 Gy. Traditional dose-volume metrics, pulmonary function tests, and the coadministration of angiotensin converting enzyme inhibitors (ACE-I) were all strongly correlated with the presence of radiologic injury on univariate analysis (p≤0.002). There was also an inverse correlation between prior smoking history and CT scan changes (p=0.02). On multivariate analysis, dosimetric parameters and the use of ACE-I retained significance (p=0.005). CONCLUSIONS Our findings suggest that there is substantial interindividual variation in lung radiosensitivity. ACE-I prevented the radiologic changes seen after high-dose radiation therapy, and their role as radioprotectants warrants further investigation.

AN IMPROVED MODEL FOR PREDICTING RADIATION PNEUMONITIS INCORPORATING CLINICAL AND DOSIMETRIC VARIABLES

PURPOSE Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. METHODS AND MATERIALS The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. RESULTS Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS(5)). The area under the receiver operator characteristic curve for TFS(5) was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS(5) <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS(5) ≥ 2.17. CONCLUSIONS TFS(5) represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.

Re-evaluating the role of palliative radiotherapy in malignant pleural mesothelioma

PURPOSE To determine the objective response rate of malignant pleural mesothelioma (MPM) to short course radiation therapy. METHODS We reviewed the cases of 54 patients with advanced MPM who were treated with palliative radiotherapy according to a standardised institutional policy. Pre- and post-treatment computed tomography scans were used to assess response. RESULTS Fifty-seven percent of patients reported some improvement in their symptoms following radiotherapy. The radiology response rate was 43% (22 patients had a partial response and 1 patient a complete response). Response to treatment was correlated with the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (p=0.001), performance status (p=0.02) and histological subtype (p=0.04). In the EORTC good prognosis group 56% of patients responded, compared with only 7% in the poor prognosis group (p=0.001). The median survivals from diagnosis and from the start of radiotherapy were 11.3 months and 5.2 months, respectively. Survival following treatment was correlated with the EORTC prognostic index (p<0.001), histological subtype (p<0.001), performance status (p=0.001), treatment response (p=0.002) and haemoglobin level (0.02). The EORTC good and poor prognostic groups had survivals of 7.1 and 2.1 months, respectively (p<0.001). Neither tumour volume nor stage were associated with prognosis. CONCLUSIONS Palliative radiotherapy produces a response rate in MPM that is equivalent to chemotherapy. The EORTC prognostic index can be used to select patients who are most likely to benefit from this treatment.

Defining the clinical target volume for bladder cancer radiotherapy treatment planning.

PURPOSE There are currently no data for the expansion margin required to define the clinical target volume (CTV) around bladder tumors. This information is particularly relevant when perivesical soft tissue changes are seen on the planning scan. While this appearance may reflect extravesical extension (EVE), it may also be an artifact of previous transurethral resection (TUR). METHODS AND MATERIALS Eighty patients with muscle-invasive bladder cancer who had undergone radical cystectomy were studied. All patients underwent preoperative TUR and staging computed tomography (CT) scans. The presence and extent of tumor growth beyond the outer bladder wall was measured radiologically and histopathologically. RESULTS Forty one (51%) patients had histologically confirmed tumor extension into perivesical fat. The median and mean extensions beyond the outer bladder wall were 1.7 and 3.1 mm, respectively. Thirty five (44%) patients had EVE, as seen on CT scans. The sensitivity and specificity of CT scans for EVE were 56% and 79%, respectively. False-positive results were infrequent and not affected by either the timing or the amount of tissue resected at TUR. CT scans consistently tended to overestimate the extent of EVE. Tumor size and the presence of either lymphovascular invasion or squamoid differentiation predict a greater extent of EVE. CONCLUSIONS In patients with radiological evidence of extravesical disease, the CTV should comprise the outer bladder wall plus a 10-mm margin. In patients with no evidence of extravesical disease on CT scans, the CTV should be restricted to the outer bladder wall plus a 6-mm margin. These recommendations would encompass microscopic disease extension in 90% of cases.