James P Wylie

Phase II Study of Conformal Hypofractionated Radiotherapy With Concurrent Gemcitabine in Muscle-Invasive Bladder Cancer

PURPOSE The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy (RT; GemX). PATIENTS AND METHODS Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival. RESULTS All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%. CONCLUSION Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.

Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer

PURPOSE To determine the relationships between tumor oxygenation and nodal stage in a prospective study of patients with cervix cancer, controlling for other prognostic factors. METHODS AND MATERIALS Between 1994 and 1999, 128 eligible patients with cervix cancer were entered into a prospective study of tumor oxygenation assessed by Eppendorf oxygen electrode before primary radiation therapy. Oxygenation was evaluated using the proportion of pO(2) values < 5 mmHg (HP(5)), and tumors were classified as hypoxic if the HP(5) was > 50%. Patients were assigned to one of three groups: those with no imaging evidence of nodal (pelvic or para-aortic) or distant metastatic disease (N group; n = 67), those with equivocal findings (E group; n = 28), and those with nodal or distant metastatic disease (P group; n = 33). RESULTS The proportion of hypoxic tumors in the P, E, and N groups were 67%, 50%, and 40%, respectively (p = 0.014), with median HP(5) values of 63%, 48%, and 36%, respectively (p = 0.0024). In a multivariate analysis including tumor size, stage, HP(5), and hemoglobin, it was found that tumor size and HP(5) were the only independently significant variables for the finding of metastatic disease (p = 0.009 and 0.017, respectively). CONCLUSION In this patient population, there was a significantly increased risk of nodal or distant metastases in patients with hypoxic tumors, and this finding was independent of tumor size. These results are consistent with the hypothesis that tumor hypoxia is an adverse prognostic factor associated with selection for a metastatic phenotype.

Early prostate cancer – which treatment do men prefer and why?

Study Type – Preference (prospective cohort)
Level of Evidence 1b

Hypofractionated Intensity-Modulated Radiotherapy for Carcinoma of the Prostate: Analysis of Toxicity

PURPOSE Dose escalation for prostate cancer improves biological control but with a significant increase in late toxicity. Recent estimates of low alpha/beta ratio for prostate cancer suggest that hypofractionation may result in biological advantage. Intensity-modulated radiotherapy (IMRT) should enable dose escalation to the prostate while reducing toxicity to local organs. We report late toxicity data of a hypofractionated IMRT regime. METHODS AND MATERIALS Eligible men had T2-3N0M0 adenocarcinoma prostate, and either Gleason score >or= 7 or prostate-specific antigen 20-50 ng/L. Patients received 57-60 Gy to prostate in 19-20 fractions using five-field IMRT. All received hormonal therapy for 3 months before radiotherapy to a maximum of 6 months. Toxicity was assessed 2 years postradiotherapy using the RTOG criteria, LENT/SOMA, and UCLA prostate index assessment tools. RESULTS Acute toxicity was favorable with no RTOG Grade 3 or 4 toxicity. At 2 years, there was 4% Grade 2 bowel and 4.25% Grade 2 bladder toxicity. There was no Grade 3 or 4 bowel toxicity; one patient developed Grade 3 bladder toxicity. UCLA data showed a slight improvement in urinary function at 2 years compared with pretreatment. LENT/SOMA assessments demonstrated general worsening of bowel function at 2 years. Patients receiving 60 Gy were more likely to develop problems with bowel function than those receiving 57 Gy. CONCLUSIONS These data demonstrate that hypofractionated radiotherapy using IMRT for prostate cancer is well tolerated with minimal late toxicity at 2 years posttreatment. Ongoing studies are looking at the efficacy of hypofractionated regimes with respect to biological control.

Analysis of prostate-specific antigen bounce after I125 permanent seed implant for localised prostate cancer

BACKGROUND AND PURPOSE To report on the incidence of benign prostate-specific antigen bounce following permanent I(125) prostate brachytherapy, to describe the associations in our population and review the relationship of bounce to subsequent biochemical failure. MATERIALS AND METHODS From February 2000 to May 2005, 374 patients with localised prostate cancer were treated with I(125) permanent prostate brachytherapy at a single institution. A prospectively collected database was used to identify cases of prostate-specific antigen (PSA) bounce, defined as a rise of 0.2 ng/ml above an initial PSA nadir with subsequent decline to or below that nadir without treatment. The patients who received neo-adjuvant or adjuvant hormone manipulation were excluded. Biochemical failure was determined using the both the ASTRO consensus definition and Phoenix (nadir +2 ng/mL) definition. RESULTS Two hundred and five patients were identified with a median follow-up of 45 months (24-85). PSA bounce was noted in 79 (37%) men, occurring at a median of 14.8 months (1.7-40.6) following implant. The median peak PSA was 1.8 ng/ml (0.4-7.4) with a bounce magnitude of 0.91 ng/ml (0.2-5.8). When pre- and post-implant factors were assessed for association to bounce, only younger age was statistically significant (p=0.002). The threshold for biochemical failure as defined by the ASTRO consensus definition (1997) was met in 4 (5%) patients after experiencing bounce as opposed to 19 (15%) non-bounce patients (p=0.01). The threshold for Phoenix (nadir +2 ng/mL) was met in 6 (7.5%) patients following bounce versus 22 (17%) of non-bounce patients (p=0.003). Both definitions are prone to false positive calls during bounce. Median PSA velocity during the bounce was 0.08 ng/mL/month (0.02-0.98) and was statistically significantly lower than the median velocity prior to the Phoenix biochemical failure at 0.28 ng/mL/month (0.07-2.04) (p=0.0005). CONCLUSION PSA bounce is a common finding in our population and is associated with a lower rate of subsequent biochemical failure. The noted differences in PSA velocity will require verification in a future analysis to reduce the influence of median follow-up on this finding. Patients should be advised of the potential of bounce in PSA follow-up after permanent I(125) prostate brachytherapy and physicians involved in follow-up of prostate brachytherapy patients should be aware of this phenomenon, allowing them to commit to appropriate PSA surveillance, avoiding the premature and inappropriate initiation of salvage therapy during PSA bounce.

Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation.

PURPOSE To compare postprostatectomy clinical target volume (CTV) delineation before and after the introduction of a contouring protocol and to investigate its effect on interphysician variability METHODS AND MATERIALS Six site-specialized radiation oncologists independently delineated a CTV on the computed tomography (CT) scans of 3 patients who had received postprostatectomy radiotherapy. At least 3 weeks later this was repeated, but with the physicians adhering to the contouring protocol from the Medical Research Councils Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial. The volumes obtained before and after the protocol were compared and the effect of the protocol on interphysician variability assessed. RESULTS An increase in mean CTV for all patients of 40.7 to 53.9 cm(3) was noted as a result of observing the protocol, with individual increases in the mean CTV of 65%, 15%, and 24% for Patients 1, 2, and 3 respectively. A reduction in interphysician variability was noted when the protocol was used. CONCLUSIONS Substantial interphysician variation in target volume delineation for postprostatectomy radiotherapy exists, which can be reduced by the use of a contouring protocol. The RADICALS contouring protocol increases the target volumes when compared with those volumes typically applied at our center. The effect of treating larger volumes on the therapeutic ratio and resultant toxicity should be carefully monitored, particularly if the same dose-response as documented in radical prostate radiotherapy applies to the adjuvant and salvage setting. Prostate cancer, Postprostatectomy, Radiotherapy, Target volume.

Scoring of treatment-related late effects in prostate cancer

BACKGROUND AND PURPOSE To assess the correlation between different general and organ specific quality of life and morbidity scoring methods in a cohort of men treated with radical radiotherapy for prostate cancer. MATERIALS AND METHODS Men who had been treated with radical radiotherapy (50 Gy in 16 fractions over 21 days) for localized prostate cancer more than 3 years previously and who had no evidence of recurrent disease were invited to take part in the study. A total of 101 of 135 invited patients agreed and completed LENT/SOMA, UCLA Prostate Cancer Index, and 36 item RAND Health survey questionnaires. RESULTS The patients had comparable results with other published series with respect to the UCLA and SF-36 indices. There was significant correlation between the corresponding parts of the UCLA and LENT/SOMA scales (P<0.0005). However, for the same symptoms, a patient tended to score lower (worse) on the UCLA scale in comparison to LENT/SOMA. The relationship between the average LENT/SOMA score and maximum score was also not straightforward with each set of data revealing different information. CONCLUSIONS The LENT/SOMA questions were, in the main, more wide-ranging and informative than the UCLA index. It is helpful to give both the overall and maximum LENT/SOMA scores to most efficiently use all of the data. There may need to be a further LENT/SOMA question to allow both symptoms of tenesmus and faecal urgency to be fully addressed.

Malignant peripheral nerve sheath tumours in NF1: Improved survival in women and in recent years

BACKGROUND Malignant peripheral nerve sheath tumours (MPNST) are the main soft tissue malignancy associated with neurofibromatosis 1. These uncommon tumours are known to occur at high frequency and lead to poor survival. Our aim was to determine risk of MPNST in NF1 patients, and survival rates. METHODS The incidence of MPNST in NF1 was identified through the NF1 genetic register and The North West Cancer Intelligence Service (NWCIS). Data were used to generate incidence and survival curves. Strict regional boundaries were adhered to avoid ascertainment bias. Kaplan-Meier curves were used to determine five and ten-year survival. RESULTS Of the 1059 NF1 patients 52 developed MPNST (30 cases in females and 22 in males), 43 cases were resident within the strict regional boundary. The risk of MPNST was 10.2% in males and 12.7% in females by age 70 years (p=0.9), with a statistically better survival in females than males (5 and 10 year survival 46% and 41.5% versus 22% and 8.2%; p=0.05). Survival was also significantly improved for patients diagnosed in the last 14 years compared to the previous 13-year period (p=0.03). CONCLUSION With fifteen strict regional MPNSTs in the fourteen years since our previous population study an annual incidence of above 1 per 1000 NF1 patients has now been maintained over a 27-year period. No significant increase in risk of MPNST in females compared to males was found, though the difference in survival is intriguing. Male survival is particularly poor with <10% alive at 10 years.

Development of a patient-reported questionnaire for collecting toxicity data following prostate brachytherapy.

PURPOSE To improve a questionnaire used to collect patient-reported outcomes from patients with early stage prostate cancer treated with brachytherapy. A secondary aim was to adapt the Late Effects of Normal Tissue (LENT) subjective toxicity questionnaire for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data, the current preferred platform for assessing radiation toxicity. MATERIALS AND METHODS Three hundred and seventy-seven patients were treated with permanent iodine-125 seed implant brachytherapy for early prostate cancer. Toxicity data were collected before and at nine time points post-treatment (0-36 months). Compliance rates for patients completing individual items and item-subsection correlation coefficients were calculated. A factor analysis was carried out to analyse responses to the questionnaire and identify less informative questions, which could be removed. Cronbachs α coefficient was used to measure reliability. RESULTS Two thousand one hundred and eighty-eight questionnaires were analysed. There was poor compliance for questions specifically relating to operations and bowel medication. We found that the division of the questionnaire into subsections based on anatomical site was reasonable and that certain items could be safely removed. The high mean value for Cronbachs α across all questionnaires (0.752; 95% CI: 0.726-0.779) indicated that the questionnaire was reliable. Fifteen of the 44 questions were removed from the original questionnaires. Questions on urinary incontinence severity, management of urinary and bowel incontinence, effects of reduced flow of urine and the effects of symptoms on activity of daily living and change in sexual function were required to adapt the LENT subjective questionnaire for use to collect CTCAE data. CONCLUSIONS A questionnaire, validated over 6 years to collect LENT subjective data were adapted and is a reliable approach for collecting CTCAE data after prostate brachytherapy.

Definitive radiotherapy for 114 cases of T3N0 glottic carcinoma: influence of dose-volume parameters on outcome.

BACKGROUND AND PURPOSE Assuming that the dose-response curve for T3N0M0 glottic carcinoma is steep and that the rate of occult lymph node metastases is low, it should be possible to employ high biological tumour doses to modest target volumes and thereby maximise laryngeal control without compromising final neck control. Within the constraints of a retrospective study we aim to examine this policy with respect to local control, incidence of nodal relapse and late complications. MATERIALS AND METHODS One hundred and fourteen patients with T3N0M0 glottic carcinoma who received a 3-week schedule of radical radiotherapy between 1986 and 1994 were analysed. The median age was 67 years (range, 34-85 years) and the median follow-up for living patients was 4.8 years (1.9-8.9 years). There were no strict selection criteria for those patients treated with radiotherapy. RESULTS The 5-year overall survival was 54%. The 5-year local control with radiotherapy and the ultimate loco-regional control following salvage laryngectomy were 68 and 80%, respectively. Nine patients (8%) suffered a regional nodal relapse but only three of these (3% overall) occurred in the absence of local failure. Four patients (3.5%) developed serious late complications requiring surgical intervention (three received 55 Gy and one 52.5 Gy). CONCLUSIONS It is possible to employ maximum tolerable doses to specific target volumes and thereby exploit the dose response demonstrated and minimise major late effects. The use of modest target volumes resulted in only 3% of patients requiring surgery that might have been avoided had prophylactic neck irradiation been employed.