Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer.

PURPOSE: We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. PATIENTS AND METHODS: NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 µg/L or PSA of 20 to 40 µg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. RESULTS: One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. CONCLUSION: This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.

The effect of pulmonary function of local and loco-regional irradiation for breast cancer.

Eighty-five patients treated with loco-regional radiotherapy to the breast/chest wall and cervico-axillary nodes, and 16 patients treated with local radiotherapy to the breast/chest wall alone for breast cancer were enrolled in a prospective study to measure the effects of treatment on pulmonary function during the acute phase (10 weeks after completing irradiation) and during the late phase (12 months after completing irradiation). Baseline pulmonary function values were obtained from all patients immediately prior to commencing radiotherapy. Twenty-two patients (25.8%) treated with loco-regional radiotherapy developed transient chest symptoms compared with two patients (12.5%) treated with local radiotherapy (P = 0.11). Patients undergoing loco-regional radiotherapy showed a reduction of mean vital capacity of 0.13 litres (4.2%) (P < 0.0001) during the acute phase and at 1 year a further decrease occurred (P = 0.02) so that mean vital capacity was reduced by 0.18 litres (5.8%) (P < 0.0001) compared to pretreatment values. Mean transfer factor for carbon monoxide (TLCO) was reduced by 0.85 mmol.kPa-1.min-1 [11.9%] (P < 0.0001) during the acute phase and remained unchanged at 1 year. Patients undergoing local radiotherapy to the breast/chest wall alone did not show any significant loss of vital capacity but mean TLCO was reduced during the acute phase by 0.65 mmol.kPa-1.min-1 (8.3%) (P < 0.002) which remained unchanged at 1 year. No significant association was found between impairment of ventilation or gas transfer and respiratory history, smoking history, concurrent respiratory symptoms, age, side treated or physiological pulmonary function in either the acute or late phase. This study has quantified some of the physiological sequelae following local and loco-regional radiotherapy for breast cancer. There is no evidence to suggest that any of the above factors are relevant to deciding which patients should, or should not, be offered local or loco-regional radiotherapy for breast cancer.

The value of internal fixation and radiotherapy in the management of upper and lower limb bone metastases.

Fifty-four consecutive patients underwent 61 orthopaedic operations for metastatic bone disease affecting the upper and lower limbs. These patients were subsequently managed using a consistent postoperative radiotherapy (RT) policy. There were 27 prophylactic internal fixations and 34 internal fixations of pathological fractures. There was a marked difference in survival between these groups. The median postoperative survival of the prophylactic (P) group was 15 months whereas that of the fracture (F) group was 2 months (P less than 0.0001). Ninety-three per cent of the P group and 59% of the F group were able to be discharged home following treatment. Subsequent local fracture requiring further surgical intervention occurred in 11% of the P group and in none of the F group. Seventy-eight per cent of the P group and 62% of the F group did not suffer any further sequelae at the operation site until the time of death or last follow-up. Patient mobility following surgery and RT for metastatic lesions occurring in the lower limb was significantly improved in both the P group (P less than 0.05) and in the F group (P less than 0.0001) such that 91% and 58%, respectively, of these patients were subsequently able to walk.

Locally advanced breast cancer: report of phase II study and subsequent phase III trial.

Twenty-four evaluable patients with stage T4 breast cancer were entered into a phase II study and received chemotherapy comprising cyclophosphamide 1,000 mg m-2 i.v., doxorubicin 50 mg m-2 i.v., vincristine 1.4 mg m-2 i.v. and prednisolone 40 mg orally for 5 days, given 3 weekly for four cycles prior to undergoing loco-regional radiotherapy. All patients completed treatment as planned with no major acute toxicity from either chemotherapy or radiotherapy. Subsequently 52 patients with stage T4 breast cancer were randomised in a phase III trial to receive either radiotherapy alone (RT) or this chemotherapy and radiotherapy (CHOP + RT). A significantly higher complete response rate was achieved in the CHOP + RT treatment arm (P = 0.03). However a larger proportion of the RT arm achieved loco-regional control after salvage treatment for relapse such that 50% of the RT arm and 57% of the CHOP + RT arm had no evidence of loco-regional disease at the time of last follow-up or death. There was no statistical difference in time to distant relapse or overall survival. Analysis of the pilot study showed results comparable to the trial CHOP + RT arm. This trial suggests that this cytotoxic therapy used in conjunction with radiotherapy has only marginal value in improving prognosis in locally advanced breast cancer.

A multidisciplinary approach to improving the quality of tangential chest wall and breast irradiation for carcinoma of the breast.

Physicists, radiotherapists and radiographers have worked together to enhance the quality and accuracy of radiotherapy for tangential irradiation of the chest wall and breast. Each stage of the process has been reassessed and improved. A technique has been developed on the treatment simulator which determines the required beam directions and sizes in a straightforward manner. A computerised tomography facility has also been developed on the simulator and this provides one or more slices for planning through the treatment volume, thus allowing accurate determination of external contour and lung position with the patient in the treatment position. The beam edge entry points and the isocentre position can be seen from radiation opaque markers placed on the skin surface, allowing accurate reproduction of the treatment beam positions as set on the simulator. A photon beam algorithm that corrects for the changes in scatter dose in a 3-dimensional (3-D) inhomogeneous situation has been developed and applied to tangential chest wall irradiation. This has shown large differences (up to 10%) in dose compared to a conventional 2-dimensional algorithm. The changes in dose distribution due to the accurate determination of lung position have also been investigated. A method has been developed of measuring the volume of ipsilateral lung irradiated. Dose-area histograms are used to evaluate the fraction of the lung area irradiated in the central slice, and an estimate of the volume irradiated can be made using a beam's eye radiograph and the simulator CT image.

The risk of occult invasive breast cancer after excisional biopsy showing in-situ ductal carcinoma of comedo pattern.

Between Jan. 1, 1985 and Aug. 31, 1987, 62 in-situ ductal carcinomas with a predominantly comedo pattern were identified in 61 patients in British Columbia from excisional biopsy of a palpable or mammographically demonstrable lesion of a breast. The biopsies were intended to remove the lesion completely. Fifty-seven (92%) of the 61 patients required wide re-excision or total mastectomy, usually within a month of the initial biopsy. Occult invasive disease was demonstrated in 14 of the re-excision specimens (24.5%) and residual in-situ carcinoma was present in a further 24 (42.1%), giving an overall rate of residual disease of 66.6%. Axillary lymph nodes were sampled in 54 cases. Metastases were found in two cases (3.7%) and each was associated with occult infiltrating ductal carcinoma in the breast. This suggests that in-situ ductal carcinoma having a predominant comedo pattern may be more widespread and associated with a higher incidence of invasive ductal carcinoma than is generally believed.

Treatment of small cell lung cancer with induction chemotherapy followed by late intensification.

Seventy-seven patients with small cell lung cancer were entered on a protocol comprising induction chemotherapy with cyclophosphamide 1 g m-2, adriamycin 40 mg m-2 and vincristine 1.4 mg m-2 (CAV) every 21 days for four to six cycles. The overall response rate was 72.8%. Twenty-six patients achieving complete remission received intensification with two further cycles of ifosfamide 5 g m-2, mesna 8 g m-2, methotrexate 30 mg m-2 and etoposide 100 mg m-2 per day for 3 days (IME). Six of the 15 patients in partial remission following CAV achieved a further remission on IME (response rate 40%). Median survival in the limited disease group was 11 months compared with 7 months in the extensive disease patients and four patients are alive at more than 2 yr follow up. There was no significant prolongation of the median survival (11 months) seen in those patients in complete remission who had negative second bronchoscopy examination. This sequential six drug regime produces high response rates in small cell lung cancer, and there is evidence of lack of cross-resistance between CAV and IME.

Familial glioma: a report of glioblastoma in identical twins and oligo-astrocytoma in siblings.

The authors report two pairs of siblings who had intracranial gliomas. One pair of identical twins had glioblastomas and two siblings had mixed oligo-astrocytomas. Genetic influences in the aetiology of glioma are discussed.

Spin-label characterisation of the lamellar-to-hexagonal (HII) phase transition in egg phosphatidylethanolamine aqueous dispersions.

The thermotropic behaviour of egg yolk phosphatidylethanolamine dispersions in excess aqueous phase has been investigated by spin label electron spin resonance spectroscopy and differential thermal analysis. Phosphatidylethanolamine isomers spin-labelled at six different positions along the acyl chain, and steroid spin labels, indicate both gel-fluid lamellar and lamellar-reverse hexagonal (HII) phase transitions, in agreement with complementary calorimetric studies. Analysis of spin label data shows that the transition to the HII phase is accompanied by an increase in conformational freedom of the acyl chain, more pronounced towards the methyl terminus, and representing an increase in the population of gauche isomers which can only be accommodated by a transition to the non-bilayer phase. Raising the bulk pH to, and above, pH 8.5 results in stabilisation of the bilayer phase and no transition to the HII phase is observed. The phosphatidylethanolamine spin labels also indicate a polarity profile which is characteristic of each phase.