A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer.

BACKGROUND: We investigated the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with paclitaxel and carboplatin before radical chemoradiation (CRT) and assessed the response rate to such a regimen. METHODS: CxII is a single-arm phase II trial of 46 patients, with locally advanced cervical cancer (stage Ib2-IVa). Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m⁻²) weekly for six cycles followed by CRT (40 mg m⁻² of weekly cisplatin, 50.4 Gy, 28 fractions plus brachytherapy). The primary end point was response rate 12 weeks post-CRT. RESULTS: Baseline characteristics were: median age at diagnosis 43 years; 72% squamous, 22% adenocarcinoma and 7% adenosquamous histologies; FIGO stage IB2 (11%), II (50%), III (33%), IV (7%). Complete or partial response rate was 70% (95% CI: 54-82) post-NACT and 85% (95% CI: 71-94) post-CRT. The median follow-up was 39.1 months. Overall and progression-free survivals at 3 years were 67% (95% CI: 51-79) and 68% (95% CI: 51-79), respectively. Grade 3/4 toxicities were 20% during NACT (11% haematological, 9% non-haematological) and 52% during CRT (haematological: 41%, non-haematological: 22%). CONCLUSION: A good response rate is achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy (98%).

Recruitment of ethnic minorities into cancer clinical trials: experience from the front lines.

Throughout the world there are problems recruiting ethnic minority patients into cancer clinical trials. A major barrier to trial entry may be distrust of research and the medical system. This may be compounded by the regulatory framework governing research with an emphasis on written consent, closed questions and consent documentation, as well as fiscal issues. The Leicester UK experience is that trial accrual is better if British South Asian patients are approached by a senior doctor rather than someone of perceived lesser hierarchical status and a greater partnership between the hospital and General Practitioner may increase trial participation of this particular ethnic minority. In Los Angeles, USA, trial recruitment was improved by a greater utilisation of Hispanic staff and a Spanish language-based education programme. Involvement of community leaders is essential. While adhering to national, legal and ethnical standards, information sheets and consent, it helps if forms can be tailored towards the local ethnic minority population. Written translations are often of limited value in the recruitment of patients with no or limited knowledge of English. In some cultural settings, tape-recorded verbal consent (following approval presentations) may be an acceptable substitute for written consent, and appropriate legislative changes should be considered to facilitate this option. Approaches should be tailored to specific minority populations, taking consideration of their unique characteristics and with input from their community leadership.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.

BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Gastrointestinal symptoms after pelvic radiotherapy: a national survey of gastroenterologists.

PURPOSE: Seventeen thousand patients receive treatment with radical pelvic radiotherapy annually in the UK. Up to 50% develop significant gastrointestinal symptoms. The National Cancer Survivorship Initiative has identified access to specialist medical care for those with complications after cancer as one of their four key needs. We aimed to determine the current practice of British gastroenterologists with regards to chronic gastrointestinal symptoms after pelvic radiotherapy. METHODS: A questionnaire was developed and sent up to a maximum of five times to all UK consultant gastroenterologists. RESULTS: Eight hundred sixty-six gastroenterologists were approached and 165 (20%) responded. Sixty-one percent saw one to four patients annually with bowel symptoms after radiotherapy. Eighteen percent rate the current treatments as effective "often" or "most of the time". Forty-seven percent of gastroenterologists consider themselves "confident with basic cases", with 11% "confident in all cases". Fifty-nine percent thinks a gastroenterologist with a specialist interest should manage these patients. Although only 29% thinks a specific service is required for these patients, 34% rates the current service as inadequate. The ideal service was considered to be gastroenterology-led, multidisciplinary and regional. Low referral rates, poor evidence-base and poor funding are cited as reasons for the current patchy services. CONCLUSIONS: The low response rate contrasts with that from a parallel survey of clinical oncologists. This may reflect the opinion that radiation-induced bowel toxicity is not a significant issue, which may be because only a small proportion of patients are referred to gastroenterologists. The development of new, evidence-based gastroenterology-led services is considered the optimal way to meet the needs of these patients.

SCOTCERV: a phase II trial of docetaxel and gemcitabine as second line chemotherapy in cervical cancer.

OBJECTIVE: The aim of the study was to determine the response rate and response duration of cervical cancer previously treated by cisplatin (with or without radiation) to a combination of docetaxel and gemcitabine. Secondary endpoints were assessment of toxicity and quality of life (QoL) of patients receiving the treatment. METHODS: This was a multicentre phase II trial of 3 weekly docetaxel 75 mg/m(2) day 1 (reduced to 60 mg/m(2) after 32 cycles had been administered) and gemcitabine 1000 mg/m(2) (days 1 and 8). A two stage Gehan design was used initially. Twenty-nine patients recruited had disease outside the irradiated pelvis (Group 1), and 21 had disease confined to the irradiated pelvis (Group 2). The target response for the Gehan 2 design was 25% (Group 1) and 10% (Group 2). RESULTS: The overall response rate for Group 1 was 21.4% (95% CI 8.3-41.0%). Amongst those who had at least 3 cycles of chemotherapy the response rate was 27.3% (95% CI 10.7-50.2%). The median survival was 7.3 months (95% CI 5.4 to 9.2 months) with 39.3% (95% CI 21.7-56.5%) alive at 1 year. In Group 2 the overall response rate was 9.5% (95% CI 1.2%-30.4%). The response rate for those who had at least 3 cycles of chemotherapy was 12.5% (95% CI 1.6-38.4%). The median survival was 7.9 months (95% CI 2.2-13.6 months). Toxicity was mainly haematological with 51% developing grade 3 or 4 neutropenia after at least 1 cycle of chemotherapy. QoL showed a significant deterioration from baseline for physical and role function but there was an improvement in emotional function during treatment. CONCLUSION: Response rates and survival duration were similar to those reported following treatment with platinum based doublets. In view of the relatively poor response rates (no more than 36%) to conventional chemotherapy future developments should be a combination of chemotherapy and biological agents such as VEGFR inhibitors.

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

BACKGROUND: Overall, approximately 5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. METHODS: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. RESULTS: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). INTERPRETATION: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association.

Concomitant (without adjuvant) temozolomide and radiation to treat glioblastoma: a retrospective study.

Between November 2004 and August 2006 we treated 35 patients with concomitant temozolomide (TMZ) and radiotherapy. Twelve patients had very large or multicentric glioblastoma multiforme with a poor performance status and received TMZ plus radiation doses of 45-50.4 Gy. The median survival of these patients was only 3.8 months. Twenty-three patients would have been eligible for randomisation in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial comparing combined and adjuvant TMZ plus radiation against radiotherapy alone. This group of patients received 60 Gy in 30 fractions plus concomitant TMZ (75 mg/m(2)) but no adjuvant chemotherapy. At a median follow-up of 26 months, five of 23 patients are alive. The median survival time was 17 months (1.43 years; 95% confidence interval 0.96-1.55). Eighteen per cent were alive at 2 years. Toxicity from TMZ was infrequent. This series adds to indirect evidence that the concomitant rather than the adjuvant is the more efficacious part of the EORTC/NCIC schedule for this type of patient. Further trials should include a concomitant chemoradiotherapy regimen as well as concomitant plus adjuvant chemotherapy.

Genetic Variants Predict Optimal Timing of Radiotherapy to Reduce Side-effects in Breast Cancer Patients.

AIMS: Radiotherapy is an important treatment for many types of cancer, but a minority of patients suffer long-term side-effects of treatment. Multiple lines of evidence suggest a role for circadian rhythm in the development of radiotherapy late side-effects. MATERIALS AND METHODS: We carried out a study to examine the effect of radiotherapy timing in two breast cancer patient cohorts. The retrospective LeND cohort comprised 535 patients scored for late effects using the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. Acute effects were assessed prospectively in 343 patients from the REQUITE study using the CTCAE v4 scales. Genotyping was carried out for candidate circadian rhythm variants. RESULTS: In the LeND cohort, patients who had radiotherapy in the morning had a significantly increased incidence of late toxicity in univariate (P = 0.03) and multivariate analysis (P = 0.01). Acute effects in the REQUITE group were also significantly increased in univariate analysis after morning treatment (P = 0.03) but not on multivariate analysis. Increased late effects in the LeND group receiving morning radiotherapy were associated with carriage of the PER3 variable number tandem repeat 4/4 genotype (P = 6 × 10-3) and the NOCT rs131116075 AA genotype (P = 5 × 10-3). CONCLUSION: Our results suggest that it may be possible to reduce toxicity associated with breast cancer radiotherapy by identifying gene variants that affect circadian rhythm and scheduling for appropriate morning or afternoon radiotherapy.

The Patient Perspective on Radiogenomics Testing for Breast Radiation Toxicity.

AIMS: In the field of radiogenomics, several potential predictive genetic markers have been identified that are associated with individual susceptibility to radiation toxicity. Predictive models of radiation toxicity incorporating radiogenomics and other biomarkers are being developed as part of the ongoing multicentre REQUITE trial. The purpose of this study was to explore patient attitudes towards future predictive radiogenomics testing for breast radiation toxicity. PATIENTS AND METHODS: Twenty-one semi-structured interviews were conducted with breast cancer patients taking part in the REQUITE study at one centre. We used inductive thematic analysis to generate common themes. RESULTS: We identified three emerging themes describing attitudes and feelings towards a predictive radiogenomics test for breast radiation toxicity: theme 1 - willingness to undergo a test (subthemes - information, trusted expert); theme 2 - implications of a test (subthemes - preparation and planning, anxiety without recourse); theme 3 - impact on treatment decision-making (subthemes - prioritising cancer cure, preserving breast integrity, patient preferences). CONCLUSIONS: Results from the present study indicate that patients support and have confidence in the validity of a radiogenomics test for breast radiation toxicity, but they would prefer the result be provided to healthcare professionals. Except in cases of significant chronic symptoms and pain or significant end-organ damage, participants in this study rarely felt that advance knowledge of their personal risk of breast radiation toxicity would influence their treatment decision-making. These findings provide a number of insights that will allow us to anticipate how patients are likely to engage with predictive radiogenomics testing in the future.

Carbonic anhydrase IX expression and outcome after radiotherapy for muscle-invasive bladder cancer.

AIMS: Carbonic anhydrase IX (CA IX) expression has been described as an endogenous marker of hypoxia in solid neoplasms. Furthermore, CA IX expression has been associated with an aggressive phenotype and resistance to radiotherapy. We assessed the prognostic significance of CA IX expression in patients with muscle-invasive bladder cancer treated with radiotherapy. MATERIALS AND METHODS: A standard immunohistochemistry technique was used to show CA IX expression in 110 muscle-invasive bladder tumours treated with radiotherapy. Clinicopathological data were obtained from medical case notes. RESULTS: CA IX immunostaining was detected in 89 ( approximately 81%) patients. Staining was predominantly membranous, with areas of concurrent cytoplasmic and nuclear staining and was abundant in luminal and perinecrotic areas. No significant correlation was shown between the overall CA IX status and the initial response to radiotherapy, 5-year bladder cancer-specific survival or the time to local recurrence. CONCLUSIONS: The distribution of CA IX expression in paraffin-embedded tissue sections seen in this series is consistent with previous studies in bladder cancer, but does not provide significant prognostic information with respect to the response to radiotherapy at 3 months and disease-specific survival after radical radiotherapy.

Dermatomyositis as a paraneoplastic syndrome in carcinosarcoma of uterine origin.

Paraneoplastic syndromes are a collection of disorders affecting an organ or tissue caused by cancer but occurring at a site distant from the primary or metastases. Dermatomyositis can occur in association with malignancy as a paraneoplastic phenomenon. We present a case of a patient presenting simultaneously with an advanced carcinosarcoma of the uterus and dermatomyositis. The diagnoses, pathophysiology and treatment of these two conditions are discussed and current published studies reviewed.

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer.

AIMS: Epidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status. MATERIALS AND METHODS: Archived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression. RESULTS: Of 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (chi(2) test, P = 0.05). Kaplan-Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively). CONCLUSIONS: EGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours. Colquhoun, A. J.

Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial.

Two hundred eleven patients with advanced breast cancer were randomized to receive either epirubicin (E) 50 mg/m2 and prednisolone (LEP) or E 100 mg/m2 and prednisolone (HEP). The intended treatment consisted of 16 courses of LEP or eight courses of HEP given at 3-weekly intervals. Reasons for stopping treatment early included progressive disease, stable disease without symptomatic improvement, or severe toxicity deemed intolerable by either the patient or physician. Toxicity was recorded at 3-weekly and response at 9-weekly intervals using the World Health Organization (WHO) criteria of response and toxicity. Two hundred nine patients were eligible for analysis, 98% of whom have been followed for more than a year. One hundred four patients received LEP and 105 HEP. Significantly worse myelosuppression, alopecia, nausea and vomiting, and mucositis were seen in the high-dose arm (P less than or equal to .001). More patients in the LEP arm stopped treatment before the fourth course than in the HEP arm, and the commonest reason for stopping was progressive disease. A similar median number of courses was given in each arm. There was a significantly higher response in the HEP arm (HEP - complete response [CR] + partial response [PR] = 41%, LEP - CR + PR = 23%). Despite this, no statistically significant differences was seen in overall survival or progression-free interval. The median survival for HEP and LEP was 44 and 46 weeks, respectively.

Docetaxel and cisplatin in combination as first-line chemotherapy for advanced epithelial ovarian cancer. Scottish Gynaecological Cancer Trials Group.

PURPOSE: A prospective, nonrandomized, multicenter, open feasibility study of cisplatin and docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV epithelial ovarian cancer was conducted. The primary end point was the incidence of severe fluid retention that necessitated treatment withdrawal. PATIENTS AND METHODS: Cisplatin and docetaxel were administered every 3 weeks for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg two times per day). One hundred patients (median age, 53 years; range, 24 to 71 years) received a total of 512 cycles of chemotherapy in two cohorts: cohort 1, 49 patients, 258 cycles (cisplatin 75 mg/m(2) and docetaxel 75 mg/m(2)); cohort 2, 51 patients, 254 cycles (cisplatin 75 mg/m(2) and docetaxel 85 mg/m(2)). RESULTS: No patients were taken off study because of fluid retention. Sixty-six patients completed six cycles of protocol therapy; 16 stopped early because of toxicity (neurotoxicity in six patients, nephrotoxicity in three, neutropenia in two, and hypersensitivity, diarrhea and vomiting, skin rash, clinical deterioration, and patient's wishes in one patient each). Grade 3/4 neutropenia was observed in more than 75% of patients and seemed to be cumulative. Patients in cohort 2 had significantly more severe neutropenia and lethargy than those in cohort 1. In addition, there were five treatment-related deaths in cohort 2 (three neutropenia and two upper gastrointestinal hemorrhage). Neurotoxicity (mainly sensory, > grade 1) was observed in 23 patients. The overall clinical response rate was 69% (complete response, 38%; partial response, 31%); CA-125 response rate was 73%. Median progression-free survival for the group was 12 months. CONCLUSION: Cisplatin and docetaxel can be administered at doses of 75 mg/m(2) and 75 mg/m(2), respectively, every 3 weeks, and the utility of this regimen is not limited by fluid retention. However, 33 of 100 patients were unable to complete the planned six cycles, which may explain, in part, the poor overall progression-free survival. Increasing the docetaxel dose to 85 mg/m(2) adds unacceptable hematologic toxicity and potential risks to the patient.

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Radiotherapy to patients with artificial cardiac pacemakers.

BACKGROUND: The in vitro studies show that the modern cardiac pacemakers utilising the complementary metal-oxide semi-conductor (CMOS) circuitry can be adversely affected by therapeutic radiation. However, the published clinical data are sparse regarding the safety of radiotherapy delivery to patients with artificial pacemakers. Despite the potential risk of life threatening complications, there are no national guidelines and most radiotherapy departments have no formal clinical risk management strategy in place. A literature review was performed to assess the risks involved in irradiating patients with pacemakers and to identify strategies, which minimise the risk of pacemaker malfunction. Recommendations for radiotherapy departments are made. CONCLUSION: Modern multi-programmable pacemakers are very sensitive to therapeutic megavoltage irradiation. There is no safe radiation threshold for megavoltage radiation. The low energy kilovoltage X-rays used for radiotherapy simulation cause no pacemaker malfunction. Megavoltage radiation can be safely delivered to patients with cardiac pacemakers provided direct irradiation of pacemakers is avoided, adequate monitoring is done during and after irradiation, and the dose to the pacemaker generator is kept below 2 Gy. Close liaison with cardiologists and a pacemaker clinic is essential and radiotherapy departments should have protocols in place to identify and care for cancer patients with pacemakers.

Concomitant chemoradiotherapy for muscle-invasive bladder cancer: the way forward for bladder preservation?

Muscle-invasive bladder cancer is a common malignancy with a high mortality rate. Despite ongoing debates about the optimal primary intervention, radical cystectomy remains the cornerstone of first-line therapy in many institutions. Over the past decade, bladder-preserving strategies involving transurethral resection (TUR), chemotherapy and radiotherapy have evolved. However, the advantage of these approaches over radiation treatment as monotherapy has yet to be fully evaluated. In other tumour models, most notably cervical and anal cancer, radiation and chemotherapy delivered concomitantly have resulted in significant survival advantages. Here, we consider the potential value of this approach in the treatment of invasive bladder cancer. Concomitant chemoradiotherapy is currently the mainstay of several bladder-preserving programmes reported in the medical literature. Overall, local control and survival rates compare favourably with contemporary cystectomy series; however, difficulties in drawing valid conclusions are highlighted. Concomitant chemoradiotherapy may have a role in the management of certain patient subgroups, and the debate should remain open. Further large-scale randomised trials are needed, and information regarding bladder function and quality of life after treatment is lacking at present. The importance of close follow-up and prompt salvage cystectomy is emphasised.

Concomitant hydroxyurea plus radiotherapy versus radiotherapy for carcinoma of the uterine cervix: a systematic review.

We identified eight randomised control trials of hydroxyurea and radiation versus radiotherapy alone (six published in full and two abstracts). Most concluded that outcomes were improved by use of hydroxyurea. However, methodological problems associated with these trials included small sample size, a large number of patient exclusions post randomisation, differing outcome definitions, subgroup analyses of already small numbers of patients and questionable rules for censoring, particularly a failure to include treatment related deaths in the survival analysis. All but two studies were of less than 50 patients. Patients were excluded from some analyses for treatment related reasons. The exclusion of such patients undoubtedly altered the conclusions of the studies. Even if there was a survival advantage attributed to hydroxyurea, overall survival was somewhat poor. We found the evidence regarding the use of hydroxyurea and radiotherapy to be inadequate for assessing its role in the treatment of cervical cancer.

The effect of differing radiotherapeutic schedules on the response of glottic carcinoma of the larynx.

Laryngeal tumours, especially T1N0M0 and T2N0M0 lesions, are readily controlled by radiotherapy. Studies have shown that control varies with the dose of radiotherapy delivered to the tumour. Other factors, including the dose per fraction and the time over which the treatment schedule is delivered are also important. The varying biological effectiveness of a number of different dose fraction time schedules used in the management of laryngeal tumours of different stages are considered, the end points being tumour control and associated morbidity. Special attention has been given to the length of time over which the schedule is delivered. Of the schedules examined the results would suggest that a dose of 60 Gy given in 25 fractions over a period of 35 days is the best of the six schedules studied for T1, T2, T3 and T4 lesions with minimal associated morbidity. It is possible, however, that the poor results shown on the Kaplan-Meier curves for patients treated with the schedule of 60 Gy in 30 fractions over a period of 42 days could be due to geographical misses of the tumours as 56% were treated without a beam directed shell. The poor result obtained when patients were treated with the schedule of 60 Gy given in 30 fractions over 49+ days may be due to tumour repopulation occurring during the rest period though the possibility of geographical misses may contribute to the poor tumour control results. Mathematical modelling using linear quadratic analysis suggests that the shorter the period of time over which the treatment is given the better chance of achieving tumour control irrespective of the stage of the disease. These models were developed for patients treated with a beam directed shell thus excluding those patients who are most likely to be at risk from a geographic miss of the tumour. Linear quadratic analysis of the treatment data suggests that the ratio alpha/beta for tumour cells is estimated in the region of 13 Gy. For T1 lesions the tumour doubling time is in the order of 6 days, with longer doubling times for the more advanced stages. The analysis provides some support for investigative use of accelerated treatment schedules. This analysis also shows the importance of using beam directed shells when treating small fields especially in the head and neck region.