a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer.

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.

Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules.

AIMS: To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2). MATERIALS AND METHODS: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. RESULTS: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P < 0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197). CONCLUSIONS: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

The effect of laryngeal irradiation on pharyngoesophageal motility.

The upper esophageal sphincter (UES) receives the full radiation dose during external beam radiotherapy to the adjacent larynx. The aim of the study was to assess the effects, if any, of radical laryngeal radiotherapy on motility patterns in the pharyngoesophageal segment. A strain gauge assembly and a digital manometric recorder were used to assess 19 patients 13 to 71 months after irradiation of T1 to T3 glottic cancer to a central dose of 52.5 to 55.7 Gy in 20 daily fractions. Results were compared with those of 23 healthy controls. Tonic lower esophageal sphincter (LES) pressure, distal peristaltic contraction, tonic UES pressure, and eight parameters of pharyngoesophageal dynamics during water and bread swallows were studied. No difference was found between the two groups in tonic LES pressure, peristaltic amplitude, or tonic UES pressure. Water swallow pharyngoesophageal wave velocity was significantly lower in patients than in controls, and the irradiated group also showed a trend toward increased duration of the distal esophageal peristaltic wave. The reduction in upper esophageal wave velocity was associated with the interval following irradiation. The post-treatment interval was also inversely related to the amplitude of UES after-contraction, and associated with an increase in wave duration throughout the pharyngoesophageal segment. A study of 23 laryngectomy specimens, 5 of which had been removed following radiotherapy, failed to identify pathological features in nerves or muscle which characterised previous laryngopharyngeal irradiation. We conclude that laryngeal irradiation has no effect on upper or lower esophageal sphincter tone but causes an increase in wave duration and a reduction in wave velocity in the pharyngoesophageal segment. These changes are independent of age and sex and are not associated with pathological features like the neural degeneration described in the myenteric plexus of irradiated rectum.

An analysis of the radiation related morbidity observed in a randomized trial of neutron therapy for bladder cancer.

This report is an analysis of the morbidity in the bladder and bowel observed in a randomized trial of d(15)+Be neutrons versus megavoltage photons in the treatment of bladder cancer. Acute reactions in the bladder and bowel were significantly worse after photon therapy. Of the patients treated with photons 45.7% had severe reactions in the bladder compared with 10.6% after neutron therapy (p less than 0.001). Severe acute bowel reactions were observed in 8.5% of the patients after photon therapy compared with 3.8% after neutron therapy (p less than 0.05). Late reactions were significantly worse after neutrons. Severe late reactions in the bladder were seen in 58.5% of patients after neutron therapy and in 40.5% after photon therapy (p less than 0.05). In the bowel they were observed in 53.3% of patients after neutron therapy compared with 8% after photon therapy (p less than 0.0001). The disparity in the degree of early and late complications makes assessment of RBE values difficult. It is estimated that for bladder morbidity the RBE value, for photon dose fractions of 2.75 Gy, is less than 3.3 for early reactions and equal to 3.4 for late effects. The respective RBE values for early and late effects in the bowel are less than 3.4 and 3.8.

A report of a randomized trial of d(15)+Be neutrons compared with megavoltage X ray therapy of bladder cancer.

The results of a randomized trial of d(15)+Be neutrons compared with 4 or 6 MV photons for the treatment of transitional cell carcinoma of the bladder. Between December 1978 and December 1981, 113 patients were accrued, 53 allocated to be treated by neutrons and 60 by photons. Complete local tumor regression was observed in 64% of patients treated by neutrons and 62% treated by photons. Recurrent cancer was subsequently confirmed in 31% of patients, similar in both treatment groups. There was no significant difference in the control rates by T stage between the two treatment groups. Late morbidity was significantly worse in patients treated by neutrons. Following neutron therapy, 78% of patients had serious late morbidity in at least one tissue compared with 38% in the group treated by photons. Survival was significantly better in the photon treated group 45.3% (+/- 11%) at 5 years compared with 12% (+/- 6%) after neutron therapy.

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers.

PURPOSE: Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS: Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS: T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS: Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.

Adverse effect of treatment gaps in the outcome of radiotherapy for laryngeal cancer.

BACKGROUND AND PURPOSE: A correlation has been demonstrated between unplanned prolongation of radiotherapy and increased local relapse. This review was performed to assess the importance of overall time on the outcome of curative radiotherapy of larynx cancer. MATERIALS AND METHODS: Retrospective analysis was performed of 383 patients with laryngeal cancer managed by elective radiotherapy between 1976-1988 in the Department of Clinical Oncology, University of Edinburgh, Western General Hospital, Edinburgh All cancers were confirmed histologically to be squamous cell carcinomas. All subjects received radiotherapy in 20 daily fractions (except Saturdays and Sundays), employing individual beam direction techniques and computer dose distribution calculations. Main outcome measures were complete resolution of the cancer in the irradiated volume; local relapse; survival and cause-specific survival rates. RESULTS: Radiotherapy was completed without any unplanned interruption (28 +/- 2 days) in 230/383 (60%) of patients. A statistically significant two-fold increase in local relapse rates was observed when treatment was given in 31 days or more. There also was a statistically significant four-fold increase in laryngeal cancer deaths when the treatment time exceeded 30 days. CONCLUSIONS: In patients with laryngeal cancer, accelerated repopulation of cancer cells probably occurs after the start of radiotherapy. When the overall treatment time is 4 weeks or less, gaps at weekends are not detrimental. However, long holiday periods or gaps in treatment longer than 4 days increase the risk of laryngeal cancer relapse and cancer-related mortality. Significant gaps in treatment should be avoided. If treatment has to be prolonged, additional radiation dose should be prescribed to compensate for increased tumour cell proliferation.

Effect of gap length and position on results of treatment of cancer of the larynx in Scotland by radiotherapy: a linear quadratic analysis.

PURPOSE: This paper reports on the analysis of the effect of the length and position of unplanned gaps in radiotherapy treatment schedules. MATERIALS AND METHODS: Data from an audit of the treatment of carcinoma of the larynx are used. They represent all newly diagnosed cases of glottic node-negative carcinoma of the larynx between 1986 and 1990, inclusive, in Scotland that were referred to one of the five Scottish Oncology Centres for primary radical radiotherapy treatment. The end-points are local control of cancer of the larynx in 5 years and the length of the disease-free period. The local control rates at > or =5 years, Pc were analyzed by log linear models and Cox proportional hazard models were used to model the disease-free period. RESULTS: Unplanned gaps in treatment are associated with poorer local control rates and an increased hazard of a local recurrence through their effect on extending the treatment time. A gap of 1 day is potentially damaging but the greatest effect is at treatment extensions of 3 or more days, where the hazard of a failure of local control is increased by a factor of 1.75 (95% confidence interval 1.20-2.55) compared to no gap. The time factor for the actual time was imprecisely estimated at 2.7 Gy/day with a standard error of 13.2 Gy/day. Among those cases who had exactly one gap resulting in a treatment extension of 1 day, there is no evidence that gap position influences local control (P = 0.17). The treatment extension as a result of the gap is more important than the position of the gap in the schedule. CONCLUSIONS: Gaps in the treatment schedule have a detrimental effect on the disease-free period. A gap has a slightly greater effect than an increase in the prescribed treatment time. Any gap in treatment is potentially damaging. The position of the gap in the schedule was shown to be not important.

A patient with Rothmund-Thomson syndrome and tongue cancer--experience of radiation toxicity.

We describe a male patient with Rothmund-Thomson syndrome (RTS) given postoperative radiotherapy for squamous carcinoma of the tongue. This was well tolerated. This is only the second reported case of oral cancer and radiotherapy in RTS.

Fast neutron treatment for squamous cell carcinoma of the head and neck: final report of Edinburgh randomised trial.

OBJECTIVE: To compare neutron treatment and megavoltage (photon) radiotherapy in locally advanced squamous cell carcinoma of the head and neck. DESIGN: Randomised trial of patients stratified by site of primary tumour and presence or absence of lymph node metastases. Follow up of patients after treatment. SETTING: Department of clinical oncology, Western General Hospital, Edinburgh. PATIENTS: 165 Patients with untreated, histologically proved squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. All patients completed treatment, and no patient was lost to follow up. INTERVENTION: Treatment with either neutrons or photons. MAIN OUTCOME MEASURES: Disease state and morbidity (scored with the system of the European Organisation for Research on Treatment of Cancer) at each visit during follow up. RESULTS: Of the 165 patients, 85 were randomised to receive neutron treatment and 80 to receive photon treatment. Minimum follow up was five years. Local control of cancer remained similar in the two groups, being achieved in 37 (44%) patients after neutron treatment and 36 (45%) after photon treatment. Five year and actuarial 10 year survival rates were 24% (20/85) and 14% respectively in the group treated with neutrons and 34% (27/80) and 30% respectively in the group treated with photons. Five year survival rates without local disease were 19% (16/85) and 30% (24/80) respectively. Necrosis was more common after neutron treatment than after photon treatment. Seven patients in the neutron group who developed necrosis died whereas no deaths were associated with photon treatment. CONCLUSION: Rates of long term local control were similar in the two groups. Necrosis related to radiation was more common in patients treated with neutrons, and the mortality related to treatment was significantly higher in these patients.

Is routine chest radiography a useful test in the follow up of all adult patients with soft tissue sarcoma?

Following treatment for localized soft tissue sarcoma the risk of relapse is either locally or in the lungs. In Edinburgh patients are reviewed every 6 months with a chest X-ray (CXR). The radiation exposure over a 10 year follow up remains small, but it is unclear if all patients, irrespective of the initial grade of their primary tumour, require this. To determine the pick up rate of lung metastases by routine CXR over a 10 year period and to review the primary histology. Adult patients on routine follow up between 1994 and 2004 were identified and the notes of those with lung metastases reviewed. Data was collected on their initial histology, and date and method of diagnosis of lung metastases. 179 patients were under follow up. 24 (13%) developed lung metastases. For 2, notes were not found. 6 (27%) had metastases diagnosed by routine CXR, 9 (41%) had metastases diagnosed by non routine CXR and 7 (32%) had metastases diagnosed by CT. On review of histology none were grade 1, 4 (18%) were grade 2 and 18 (82%) were grade 3. 155 patients received. 6 monthly CXR for 10 years with no detection of lung metastases. Lung metastases occurred in a minority of patients (13%) and most (82%) occurred in patients with grade 3 tumours. No patients with grade 1 tumours developed lung metastases. Thus routine CXR may be appropriate on grade 3 tumours, but not on lower grade tumours where other risk factors are absent.

Salvage laryngectomy after radical radiotherapy for laryngeal carcinoma.

Of 376 patients who were treated by radical radiotherapy for squamous carcinoma of the larynx, 56 subsequently underwent total laryngectomy. Residual or recurrent tumour was identified in 43 of the resection specimens, and necrosis alone in 13 cases, although a positive biopsy had been obtained in 3 of these prior to salvage laryngectomy. No disease related factors such as site or stage of the original tumour, or treatment related factors such as radiation type or dose, were found to be predictive of whether or not tumour was present. The clinical opinion of an experienced surgeon was found to have a positive predictive value of 0.86 for the presence of tumour. The fistula rate of salvage laryngectomy, 15 out of 56, was similar to that of other series. The actuarial cause specific 5-year survival for patients with tumour was 0.589, and for patients with necrosis only was 0.923. Intercurrent, smoking related disease was the cause of death in 16 of the 33 patients who have died.

Cis-platin and methotrexate in the treatment of transitional cell carcinoma of the urinary tract.

Nineteen patients with recurrent or metastatic transitional cell carcinoma of the urinary tract were treated with a 3-weekly combination of methotrexate 200 mg/m2 as a 24-h infusion with folinic acid rescue and cis-platin 100 mg/m2. An objective response rate of 68% was obtained, with 4 patients (21%) achieving complete remission. Pulmonary disease and lymph node metastases were particularly sensitive to this therapy. The median duration of response was 21 weeks with a median survival of 54 weeks in the responding patients. This regimen warrants further investigation in the treatment of invasive bladder carcinoma.

Monoclonal antibody assay of serum placental alkaline phosphatase in the monitoring of testicular tumours.

A monoclonal antibody (H17E2) recognising both placental alkaline phosphatase (PLAP) and testicular PLAP-like alkaline phosphatase was incorporated in a solid phase immunoassay. This was used to measure levels of PLAP in 257 sera from 148 patients with germ cell neoplasms of the testis. High levels of PLAP were found in all patients with active seminomas (mean 0.85 O.D.) compared to those in clinical remission (mean 0.20 O.D.) (P less than 0.0001). More importantly, changing levels of PLAP correlated with the course of disease in 79 samples from 33 patients with seminoma (P less than 0.0001). Elevated PLAP levels were also noted in patients in remission who were smokers (mean 0.32 O.D.) compared to non-smokers (mean 0.15 O.D.) (P less than 0.001). These data demonstrate that determination of PLAP levels using this sensitive immunoassay is an important new adjunct in the monitoring of the response to treatment in patients with seminoma.