J. Armstrong

Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC)

We retrospectively reviewed acute toxicity with cetuximab and radiotherapy, comparing it with a matched cisplatin group. The cetuximab group experienced significantly more toxicity--grade ≥3 oral mucositis (p=0.014), skin dermatitis (p=0.0004), ≥10% weight loss (p=0.03), and enteral feeding requirement (p=0.05). This finding of enhanced toxicity is similar to recent publications.

The impact of three-dimensional radiation on the treatment of non-small cell lung cancer

PURPOSE Non-small cell lung cancer (NSCLC) patients with locally advanced unresectable disease have a grim prognosis. Radiotherapeutic strategies are necessary to improve the permanent eradication of thoracic disease. The poor results achieved with conventional external beam radiation therapy reflect in part, the inadequacy of such therapy in achieving its primary objective of achieving local control. The impact of three-dimensional conformal radiation therapy (3-DCRT) on local disease eradication and its potential role in improving survival is assessed. DESIGN This review addresses aspects of the software and hardware technology of 3-DCRT, the clinical and technical aspects of target volume definition, the use of 3-DCRT to predict radiation pneumonitis, strategies for dose escalation in NSCLC, and analyses the clinical results to date. RESULTS Initially investigators compared the best treatment techniques devised with conventional planning techniques to those devised with 3-DCRT. These analyses showed that 3-DCRT had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Software and hardware developments continue to develop and have the potential to solve evolving clinical issues. Dose-volume-histograms have been used to accurately quantify lung dose and derived parameters have the potential to predict the risk of pneumonitis for individual patients before treatment. Initial clinical results have been promising and strategies for further dose escalation are emerging. CONCLUSION Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced non-small cell lung cancer.

Dose escalation of chart in non-small cell lung cancer: is three-dimensional conformal radiation therapy really necessary?

PURPOSE To evaluate, preclinically, the potential for dose escalation of continuous, hyperfractionated, accelerated radiation therapy (CHART) for non small-cell lung cancer (NSCLC), we examined the strategy of omission of elective nodal irradiation with and without the application of three-dimensional conformal radiation technology (3DCRT). METHODS AND MATERIALS 2D, conventional therapy plans were designed according to the specifications of CHART for 18 patients with NSCLC (Stages Ib, IIb, IIIa, and IIIb). Further plans were generated with the omission of elective nodal irradiation (ENI) from the treatment portals (2D minus ENI plans [2D-ENI plans]). Both sets were inserted in the patients planning computed tomographies (CTs). These reconstructed plans were then compared to alternative, three-dimensional treatment plans which had been generated de novo, with the omission of ENI: 3D minus elective nodal irradiation (3D-ENI plans). Dose delivery to the planning target volumes (PTVs) and to the organs at risk were compared between the 3 sets of corresponding plans. The potential for dose escalation of each patients 2D-ENI and 3D-ENI plan beyond 54 Gy, standard to CHART, was also determined. RESULTS PTV coverage was suboptimal in the 2D CHART and the 2D-ENI plans. Only in the 3D-ENI plans did 100% of the PTV get > or = 95% of the dose prescribed (i.e., 51.5 Gy [51.3-52.2]). Using 3D-ENI plans significantly reduced the dose received by the spinal cord, the mean and median doses to the esophagus and the heart. It did not significantly reduce the lung dose when compared to 2D-ENI plans. Escalation of the dose (minimum > or = 1 Gy) with optimal PTV coverage was possible in 55.5% of patients using 3D-ENI, but was possible only in 16.6% when using the 2D-ENI planning strategy. CONCLUSIONS 3DCRT is fundamental to achieving optimal PTV coverage in NSCLC. A policy of omission of elective nodal irradiation alone (and using 2D technology) will not achieve optimal PTV coverage or dose escalation. 3DCRT with omission of ENI can achieve true escalation of CHART in 55.5% of tumors, depending on their site and N-stage.

A randomized trial (Irish clinical oncology research group 97-01) comparing short versus protracted neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.

PURPOSE To examine the long-term outcomes of a randomized trial comparing short (4 months; Arm 1) and long (8 months; Arm 2) neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer. METHODS AND MATERIALS Between 1997 and 2001, 276 patients were enrolled and the data from 261 were analyzed. The stratification risk factors were prostate-specific antigen level >20 ng/mL, Gleason score≥7, and Stage T3 or more. The intermediate-risk stratum had one factor and the high-risk stratum had two or more. Staging was done from the bone scan and computed tomography findings. The primary endpoint was biochemical failure-free survival. RESULTS The median follow-up was 102 months. The overall survival, biochemical failure-free survival. and prostate cancer-specific survival did not differ significantly between the two treatment arms, overall or at 5 years. The cumulative probability of overall survival at 5 years was 90% (range, 87-92%) in Arm 1 and 83% (range, 80-86%) in Arm 2. The biochemical failure-free survival rate at 5 years was 66% (range, 62-71%) in Arm 1 and 63% (range, 58-67%) in Arm 2. CONCLUSION No statistically significant difference was found in biochemical failure-free survival between 4 months and 8 months of neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.

A phase II trial for the optimisation of treatment position in the radiation therapy of prostate cancer.

BACKGROUND Patient immobilisation and position are important contributors to the reproducibility and accuracy of radiation therapy. In addition the choice of position can alter the external contour of the treated area and has the potential to alter the spatial relationship between internal organs. The published literature demonstrates variation in the use of the prone and supine position for prostate cancer radiation therapy. Previous investigators using different protocols for patient preparation, imaging and target volume definition have demonstrated changes in the calculated therapeutic ratio comparing the two positions. We did not use rigid immobilisation, laxatives, rectal catheters or bladder voiding and assessed if in the prone position would cause a reduction of the dose to the rectum. We performed a prospective comparison of the two positions in 26 patients to determine if the differences in the spatial relation between the rectum and the planning target volume (PTV) would impact on dose-volume histograms to organs at risk (OAR). We also determined if any such improvement might permit dose escalation. MATERIALS AND METHODS Twenty-six patients with clinically localized prostate cancer consented to participate in this study. All patients underwent a planning CT scan in both the prone and supine treatment positions. The PTV and OAR were drawn on each set of scans by one of the investigators. The PTV included the prostate and seminal vesicles with a 1cm margin except posteriorly where this margin was reduced to 5mm. The outer circumference of the bladder, rectal wall, small bowel (when present) was drawn along with femoral heads. 3D conformal treatment plans were computed using Helax TMS version 6.1B. A 3-field treatment technique was employed with energy of 10/15 MV. The prescribed dose was 70 Gy and the PTV was encompassed by the 95% isodose and the maximum dose was always less than 107%. Cumulative dose-volume histograms were calculated for the PTV, rectum, bladder, femoral heads and small bowel (when present). These non-uniform histograms for both the prone and supine treatment positions were transformed into uniform ones using the effective volume method [Kutcher J, Burman C. Calculation of probability factors for non-uniform normal tissue irradiation: the effective volume method. Med Phys 1987;14:487]. RESULTS Twenty-one of the 26 (80%) patients had a lower effective volume of rectum irradiated if the prone instead of the supine treatment position was used. The median value of the effective volume in the supine treatment position was 31.74 Gy while the median value in the prone position was 22.48 Gy. The dose escalation was applied to the patients in the prone treatment position until the effective volume for the rectum was the same as that in the supine position. The range of dose escalation possible for these patients was 0.1-7.9 Gy. These patients could potentially have the dose escalated from the prescribed dose of 70 Gy for the supine position without any increase in side effects. For the five patients where no potential benefit was found when changing treatment position, only two patients displayed a significant (>1 Gy) advantage for the supine treatment position. Twenty-one of the 26 patients also showed an advantage for the prone treatment position in relation to bladder dose. CONCLUSION The use of the prone position reduced the dose to the unprepared rectum and unvoided bladder in the majority of cases. It should be considered particularly in cases where large posterior seminal vesicles cause significant overlap between the planning target volume and the rectum.

Early Salvage Hormonal Therapy for Biochemical Failure Improved Survival in Prostate Cancer Patients After Neoadjuvant Hormonal Therapy Plus Radiation Therapy—A Secondary Analysis of Irish Clinical Oncology Research Group 97-01

PURPOSE To assess the survival benefit of early vs late salvage hormonal therapy (HT), we performed a secondary analysis on patients who developed recurrence from Irish Clinical Oncology Research Group 97-01, a randomized trial comparing 4 vs 8 months neoadjuvant HT plus radiation therapy (RT) in intermediate- and high-risk prostate adenocarcinoma. METHODS AND MATERIALS A total of 102 patients from the trial who recurred were analyzed at a median follow-up of 8.5 years. The patients were divided into 3 groups based on the timing of salvage HT: 57 patients had prostate-specific antigen (PSA)≤10 ng/mL and absent distant metastases (group 1, early), 21 patients had PSA>10 ng/mL and absent distant metastases (group 2, late), and 24 patients had distant metastases (group 3, late). The endpoint analyzed was overall survival (OS) calculated from 2 different time points: date of enrolment in the trial (OS1) and date of initiation of salvage HT (OS2). Survival was estimated using Kaplan-Meier curves and a Cox regression model. RESULTS The OS1 differed significantly between groups (P<.0005): OS1 at 10 years was 78% in group 1, 42% in group 2, and 29% in group 3. The OS2 also differed significantly between groups (P<.0005): OS2 at 6 years was 70% in group 1, 47% in group 2, and 22% in group 3. Group 1 had the longest median time from end of RT to biochemical failure compared with groups 2 and 3 (3.3, 0.9, and 1.7 years, respectively; P<.0005). Group 1 also had the longest median PSA doubling time compared with groups 2 and 3 (9.9, 3.6, and 2.4 months, respectively; P<.0005). On multivariate analysis, timing of salvage HT, time from end of RT to biochemical failure, and PSA nadir on salvage HT were significant predictors of survival. CONCLUSION Early salvage HT based on PSA≤10 ng/mL and absent distant metastases improved survival in patients with prostate cancer after failure of initial treatment with neoadjuvant HT plus RT.

Development of a label-free LC-MS/MS strategy to approach the identification of candidate protein biomarkers of disease recurrence in prostate cancer patients in a clinical trial of combined hormone and radiation therapy

Combined hormone and radiation therapy (CHRT) is one of the principle curative regimes for localised prostate cancer (PCa). Following treatment, many patients subsequently experience disease recurrence however; current diagnostics tests fail to predict the onset of disease recurrence. Biomarkers that address this issue would be of significant advantage.

Duration of Short-Course Androgen Suppression Therapy and the Risk of Death As a Result of Prostate Cancer

PURPOSE We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories. PATIENTS AND METHODS Between February 2, 1996, and December 27, 2001, 761 men with unfavorable-risk PC were treated in Australia, New Zealand, Ireland, or the United States in a randomized trial with radiotherapy and 3, 4, or 6 months of AST (the study cohort). Competing risks regression was used to evaluate whether the duration of AST interacted with GS and was significantly associated with the risk of PCSM, adjusting for age, trial site, and PC prognostic factors. RESULTS After a median follow-up of 10.9 years, 263 men died, 111 (42%) from PC. For all men, 6 versus 3 or 4 months of AST was associated with a reduced risk of PCSM (adjusted hazard ratio [AHR], 0.55; 95% CI, 0.36 to 0.82; P = .004). AHRs evaluating the impact of the duration of AST on the risk of PCSM were 0.67 (95% CI, 0.29 to 1.56; P = .35), 0.47 (95% CI, 0.25 to 0.85; P = .01), and 0.59 (95% CI, 0.30 to 1.19; P = .14) for men with GS ≤ 6, 7, and 8 to 10 PC, respectively. Therefore, the strongest evidence for this benefit was in men with GS 7 PC. CONCLUSION AST durations of no less than 6 months should be considered when treating GS 7 PC with conventional dose RT.

Pilomatrix carcinoma presenting as an extra axial mass: clinicopathological features

Pilomatrix carcinoma is the rare malignant counterpart of pilomatrixoma, a skin adnexal tumour originating from hair matrix cells. Pilomatrix carcinoma can arise as a solitary lesion de novo, or through transformation of a pilomatrixoma. Pilomatrixoma was first described erroneously as being of sebaceous gland origin but was later discovered to be derived from hair matrix cells. They are rare, slow growing tumours of the skin found in the lower dermis and subcutaneous fat and are predominantly found in the neck and the scalp. While known to be locally aggressive, no malignant form was thought to exist until it was described relatively recently. Since then, approximately ninety cases of pilomatrix carcinoma have been reported.We report the case of a 41 year old mentally retarded male who had a longstanding lesion in the left neck for approximately fifteen years previously diagnosed as a pilomatrixoma. He presented with severe headache, falls and visual disturbance and a biopsy showed pilomatrix carcinoma of the occipital region which, on computed tomography ( CT ) invaded the occipital bone, the cerebellum and the left temporal lobe. At his initial presentation he had a craniotomy and subtotal excision of the lesion but received no adjuvant therapy. After an early intracranial recurrence he had further debulking and adjuvant external beam radiotherapy. He has had no further intracranial recurrence after three and a half years of follow-up. Here we present the pathological features of this uncommon tumour.

The effect of short term neo-adjuvant androgen deprivation on erectile function in patients treated with external beam radiotherapy for localised prostate cancer: An analysis of the 4- versus 8-month randomised trial (Irish Clinical Oncology Research Group 97-01)

BACKGROUND AND PURPOSE Erectile dysfunction is a common consequence of external beam radiotherapy (EBRT) for prostate cancer. The addition of neo-adjuvant androgen deprivation (NAD) has an indeterminate additive effect. We examined the long-term effect on erectile function (EF) of two durations (4 months: arm 1 and 8 months: arm 2) of NAD prior to radiation (RT) for patients with localised prostate cancer from the Irish Clinical Oncology Research Group (ICORG 97-01) 4- versus 8-month trial. In this study we aimed to (1) analyse the overall effect on EF of NAD in an EBRT population, (2) compare the probability of retained EF over time in an EBRT population treated with either 4 or 8 months of NAD and (3) identify any variables such as risk group and age which may have an additive detrimental effect. This analysis provides unique long term follow up data. MATERIALS AND METHODS From 1997 to 2001, 276 patients with adenocarcinoma of the prostate were randomised to 4 or 8 months of NAD before RT. EF data were recorded at baseline and at each follow-up visit by physician directed questions, using a 4-point grading system. RESULTS Two hundred and thirty patients were included in the analysis of EF and were followed for a median of 80 months. One hundred and forty-one patients had EF at baseline. Neo-adjuvant androgen deprivation in addition to radiation therapy caused a significant reduction in EF. The most significant reduction in EF happens within the first year. The median time to grade 3-4 EF toxicity was 14.6 months, 17.6 months in arm 1 and 13.7 in arm 2. Freedom from late EF toxicity did not differ significantly between arms, overall or at 5 years (n=141). The cumulative probability of EF preservation at 5 years was 28% (22-34) in arm 1 and 24% (19-30) in arm 2. Age was a significant predictor of post-treatment EF. CONCLUSIONS The first year post ADT and EBRT poses the greatest risk to sexual function and a continued decline may be expected. However, 26% of men can expect to retain sexual function at 5 years.