A feasibility study of continuous hyperfractionated accelerated radiotherapy (CHART) and brachytherapy in patients with early oral or oropharyngeal carcinomas.

Overall time is important in the curative treatment of head and neck cancer (Dische, S., Saunders, M.I., Barrett, A., Harvey, A., Gibson, D., Parmar, M., 1997, Radiother. Oncol., 44:123-136). Results are presented on outcome and morbidity in ten patients with head and neck cancer treated with external beam irradiation (CHART protocol) and interstitial implantation, completing treatment in 12 days. Local control and overall survival at 5 years was 67%. Acute and late morbidity was acceptable giving scope for dose escalation.

Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study.

BACKGROUND AND PURPOSE: ARCON (Accelerated Radiotherapy, CarbOgen, Nicotinamide) achieves a large therapeutic gain in rodents. A phase I/II study was therefore undertaken to determine its feasibility in patients with locally advanced head and neck cancer. MATERIALS AND METHODS: The accelerated regime CHART was used in 35 patients given carbogen and/or nicotinamide with 11 small volume fractions. Eight patients received carbogen, 12 received nicotinamide and 15 were treated with ARCON. Treatment compliance, side-effects and acute mucositis were monitored in all cases. RESULTS: All patients underwent CHART as intended. In the 23 patients receiving carbogen, two failed to complete treatment. Compliance with nicotinamide was much lower. Out of 25 patients, only 52% received 10-11 doses of the 80 mg/kg/day of the drug. The most common side-effect was nausea and vomiting, which responded to standard anti-emetics in almost half of the patients. Historical comparisons with the CHART head and neck trials indicate that there was no increase in the severity of acute mucositis in any of these patients. Although the observation period is not sufficiently long to be definitive (median 20 months) there is no evidence of an increase in late normal tissue reactions. CONCLUSIONS: ARCON using CHART as the radiotherapy protocol is feasible in patients with advanced head and neck cancer. However, we are concerned about the low compliance rate in our patients, which is far lower than that reported elsewhere. The implications are discussed together with identifying strategies for increasing compliance.

Finger-prick--an alternative to venipuncture for the assessment of endocrine profiles in women.

Traditionally, there has been a reliance on venipuncture to obtain peripheral blood endocrine levels for the assessment of infertility treatment cycles. We have assessed the viability of a finger-prick capillary blood collection method to provide an alternative to venipuncture, assisting in the treatment of patients for whom venous sampling may be difficult to perform. A direct one-to-one relationship was found between the two collection methods with respect to E2, P, and LH measurement. Finger-prick blood collection is simple and easy to perform and provides a viable alternative to venipuncture. It also alleviates the stress involved with multiple attempts at venous sampling in some patients.

Dynamic contrast enhanced magnetic resonance scanning as a predictor of response to accelerated radiotherapy for advanced head and neck cancer.

Tumour perfusion has been assessed in patients with advanced head and neck cancer using dynamic contrast enhanced MRI prior to and at completion of accelerated radiotherapy, and related to local tumour control. Sequential MRI scans, at 3 s intervals after intravenous injection of gadolinium using a dynamic scan sequence through a tumour region of interest (ROI), were performed in 13 patients with advanced head and neck cancer before and on completion of radiotherapy. The scans have been analysed in terms of maximum tumour enhancement (E), slope of the enhancement versus time curve and the time taken to reach maximum tumour enhancement (Tmax), and these parameters related to tumour outcome after radiotherapy. Local tumour control was related to the value of E on a post-radiotherapy scan and the difference in Tmax between a pre- and post-radiotherapy scan. Durable local control was seen in those tumours with a post-radiotherapy value for E of less than 8 and a mean fall in Tmax of 27.3 s. These results imply that tumours with diminished tumour perfusion at the end of radiotherapy are those most sensitive to treatment and that those tumours which show greater tumour enhancement after accelerated radiotherapy are likely to fail locally. This may reflect the persistence of viable perfused tumour at completion of radiotherapy.

A phase I/II study of CHARTWEL with concurrent chemotherapy in locally advanced, inoperable carcinoma of the oesophagus.

AIM: To evaluate the feasibility, efficacy and toxicity of concurrent chemotherapy and continuous, hyperfractionated, accelerated radiotherapy weekend less (CHARTWEL) in the treatment of locally advanced, inoperable oesophageal cancer. METHODS: A prospective study of 19 patients with histologically confirmed, locally advanced, inoperable carcinoma of the oesophagus. CHARTWEL was prescribed from day 1 to doses of 40.5 Gy (three patients), 42 Gy (five patients), 45 Gy (four patients), 46.5 Gy (three patients) and 49.5 Gy (four patients). Cisplatin 75 mg/m2 was administered on day 1 of radiotherapy, followed by 5-fluorouracil (5-FU) 1000 mg daily for 4 days. RESULTS: All patients completed radiotherapy, with two requiring modification of their chemotherapy dose. Acute toxicity was acceptable, with no interruptions to treatment. The median dysphagia free time was 9.6 months with 38% of patients being dysphagia free at 42 months. The median time to locoregional relapse was 13.2 months with 50% being free at 1 year and 35% at 3.5 years. There was a trend towards greater control when the higher doses (45-49.5 Gy) were compared with the lower doses (40.5-42 Gy), P = 0.07. The median survival time was 10.7 months with 1- and 2-year survival rates of 50 and 26%, respectively. Strictures developed in seven out of 18 patients (38%), but five were found on biopsy to be due to recurrent disease. There was no other long-term toxicity and no treatment-related death occurred. CONCLUSIONS: CHARTWEL with concomitant cisplatin/5-FU chemotherapy is a feasible treatment option in these patients. It is well tolerated, achieves a high rate of local control and effectively palliates the symptoms of dysphagia, all with relatively rapid resolution of treatment-related toxicity. The results warrant continued dose escalation to 51 Gy.

Management of "brittle" diabetes with a preprogrammable implanted insulin pump delivering intraperitoneal insulin.

OBJECTIVE: Glycaemic control in a young woman with "brittle" diabetes. DESIGN: Use of a preprogrammable fully implanted pump (Infusaid) to deliver insulin intraperitoneally at variable rates, giving a total dose of about 60 units/24 h. SETTING: Endocrinology department in a teaching hospital. PATIENT: Thirty year old woman with 15 years' history of "brittle" diabetes. MAIN OUTCOME MEASURES: Glycated haemoglobin concentration; plasma glucose concentration. RESULTS: After implantation of the pump there was an immediate and sustained improvement in diabetic control. The patient's glycated haemoglobin concentration decreased from 15.2% to 9.2% over seven months. Her daily glucose concentrations were in the range 3.5-12 mmol/l. She has not been admitted to hospital since implantation of the pump, which was eight months before the time of writing. CONCLUSION: The implanted programmable intraperitoneal insulin pump may be of value in the management of patients with "brittle" diabetes in whom other attempts at glycaemic control have failed.

18F-fluorodeoxyglucose positron emission tomography/computed tomography in the assessment of occult primary head and neck cancers--an audit and review of published studies.

AIMS: To assess the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with squamous cell and undifferentiated cancer neck nodes and no primary site on conventional assessment. MATERIALS AND METHODS: Seventy-eight patients with neck nodal metastases from an unknown primary cancer were studied. PET/CT was carried out in all patients, 1h after FDG injection. RESULTS: Uptake suspicious of an occult primary cancer was found in 46/78 (59.0%) patients. Subsequent investigations confirmed a primary site in the base of the tongue in 14, pharyngeal palatine tonsil in 14, post cricoid in one, lung in one. PET/CT diagnosed primary cancers in 30/78 patients (38.5%); sensitivity, specificity, positive predictive value, negative predictive value: 30/30 (100.0%), 32/48 (66.7%), 30/46 (65.2%), 32/32 (100.0%), respectively. PET/CT detected additional disease in four patients: contralateral nodal disease in two, mediastinal nodal disease in one and liver metastases in one. CONCLUSIONS: FDG PET/CT is of value in the assessment of patients with occult head and neck primary cancers. However, false-positive results remain a limitation of the investigation.

Adaptive 18fluoro-2-deoxyglucose positron emission tomography/computed tomography-based target volume delineation in radiotherapy planning of head and neck cancer.

AIMS: This study investigated an adaptive threshold-based method to delineate the target volume using (18)fluoro-2-deoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) before and during a course of radical radiotherapy or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Ten patients were enrolled between March 2006 and May 2008. (18)FDG PET/CT scans were carried out 72h before the start of radiotherapy and then at three time points during radiotherapy (8-18, 36-50 and 66Gy). Functional volumes were delineated using an adaptive iterative algorithm weighted according to the mean standard uptake value (SUV(mean)) within the region of interest. The background (18)FDG uptake, maximum standard uptake value (SUV(max)) and SUV(mean) within the volumes were assessed. RESULTS: There was no significant reduction in the primary target volumes defined by the adaptive threshold during radiotherapy. However, the SUV(max) significantly reduced within the primary (P=0.003-0.011) and lymph node (P<0.0001) target volume at 36-50 and 36-66Gy compared with 0Gy. The SUV(mean) was negatively correlated to radiation dose (P<0.0001-0.014). The ratio between the background uptake of (18)FDG and the SUV(mean) significantly reduced for both the lymph node target volume at 36-50Gy and the primary volume at 66Gy. The lack of significant correlation between the defined volume and radiation dose was because the SUV(mean) within the region of interest used to define the edge of the volume was equal to or less than the background (18)FDG uptake and the software was unable to effectively differentiate between tumour and background uptake. CONCLUSIONS: The adaptive threshold method may be of benefit when used to define the target volume before the start of radiotherapy. This method was not beneficial during radiotherapy because the software is not sensitive enough to distinguish tumour from background and define a volume. (18)FDG PET/CT-guided volumes delineated by automatic adaptive thresholding methods should only be used for dose escalation with the pretreatment imaging.

Chemoradiotherapy with or without induction chemotherapy for locally advanced pancreatic cancer: a UK multi-institutional experience.

AIMS: The optimal management for patients with unresectable locally advanced adenocarcinoma of the pancreas (LAPC) is unclear. The aim of this study was to determine the outcome of patients treated with chemoradiotherapy (CRT) with or without induction chemotherapy. MATERIALS AND METHODS: We conducted a multi-centre retrospective analysis of 48 patients with biopsy-proven LAPC treated with CRT in four regional oncology centres in the UK between March 2000 and October 2007. The prescribed radiotherapy dose was 4500-5040 cGy in 25-28 fractions and was given concurrent with gemcitabine (n=37), gemcitabine/cisplatin (n=9), 5-fluorouracil (n=1) or capecitabine (n=1). RESULTS: Four patients (8.3%) did not complete the intended treatment due to CRT-related toxicities. The disease control rate (Objective response rate (ORR) and stable disease (SD)) was 81.3%. The median overall survival was 17 months (range 5-66 months). In subgroup analysis, a trend towards improved survival was seen in patients who completed the intended treatment (17.1 months vs 11.0 months, P=0.06) and in patients undergoing surgery (27 months vs 16 months, P=0.023). CONCLUSIONS: This is the largest reported series from the UK focussing on patients who received CRT for pancreas cancer. It shows that it is possible to deliver pancreatic CRT with acceptable toxicity. Induction chemotherapy followed by gemcitabine-based CRT shows promising activity and should be evaluated in phase III studies.

FaFEC: a novel regimen for advanced ovarian cancer.

A palliative combination chemotherapy regimen (FaFEC) was developed for patients with relapsed epithelial ovarian cancer in particular patients relapsing after, or ineligible to enter, phase II trials, usually due to lack of evaluable disease. Forty-six patients were enrolled. Patients had received a mean of 2.3 previous drug regimens and nine (19%) had intestinal obstruction at the start of FaFEC. The majority of patients were inevaluable by WHO criteria so objective response data was obtained from serial serum CA125 evaluations. A serological response was demonstrated in 8/44 (18%). The responders included 6/27 women who had a prior relapse-free interval of less than 3 months, four who were resistant to platinum chemotherapy and three patients who had previously received paclitaxel. The major (WHO grade 3/4) toxicities included leucopenia (six patients), anemia (three patients), thrombocytopenia (two patients), nausea and vomiting (four patients) and severe infections (five patients). Following FaFEC the median time to failure was 0.48 years and the median survival was 0.66 years. FaFEC was effective in this group of very poor prognosis patients. The serological response rate of 18% is noteworthy considering the multiple prior treatments that patients had received and the short treatment free intervals. FaFEC may be useful second line therapy in epithelial ovarian cancer patients ineligible for phase II studies and should be considered for a randomized comparison with paclitaxel.

Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy.

Carbogen and nicotinamide have been evaluated in a phase II study as hypoxia-modifying agents during radical radiotherapy for bladder cancer using a standard daily 20-fraction schedule. Three groups of patients have received (a) nicotinamide alone, given orally in a dose of 80 mg kg(-1) daily with 52.5 Gy in 20 fractions over 4 weeks, (b) carbogen alone, with 50 Gy in 20 fractions over 4 weeks, and (c) carbogen and nicotinamide, with 50-52.5 Gy in 20 fractions over 4 weeks. Ten patients were treated in each group. All patients completed carbogen and radiotherapy as prescribed, but only 45% completed daily nicotinamide over the 4-week treatment period. The end points of this study were acute bowel and bladder morbidity and local control at cystoscopy 6 months after treatment. An expected level of acute bowel and bladder morbidity was seen that reverted to normal in most patients by 12 weeks with no difference between the three treatment groups. Complete response rates at 6 months were seven out of ten (100%) in the nicotinamide alone group, nine out of ten (90%) in the carbogen alone group and seven out of ten (70%) in the carbogen and nicotinamide group. It is concluded that carbogen and nicotinamide may improve the results of daily fractionated radiotherapy in bladder cancer and that further evaluation is required.

Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer.

Results from the multicentre randomized trial of CHART (continuous, hyperfractionated, accelerated radiotherapy) in non-small-cell lung cancer (NSCLC) showed a significant increase in survival (P=0.004) compared with conventional radiotherapy and a therapeutic benefit relative to late radiation-induced morbidity. However, 60% of patients died because of failure to control locoregional disease. These findings have stimulated interest in assessing the feasibility of dose escalation using a modified CHART schedule. Acute and late morbidity with a CHARTWEL (CHART WeekEnd Less) schedule of 54 Gy in 16 days was compared with that observed with 60 Gy in 18 days in patients with locally advanced NSCLC. The incidence and severity of dysphagia and of analgesia were scored using a semiquantitative clinical scale. Late radiation-induced morbidity, namely pulmonary, spinal cord and oesophageal strictures, were monitored using clinical and/or radiological criteria. Acute dysphagia and the analgesia required to control the symptoms were more severe and lasted longer in patients treated with CHARTWEL 60 Gy (P< or = 0.02). However, at 12 weeks, oesophagitis was similar to that seen with 54 Gy and did not lead to consequential damage. Early radiation pneumonitis was not increased but, after 6 months, there was a higher incidence of mild pulmonary toxicity compared with CHARTWEL 54 Gy. No cases of radiation myelitis, oesophageal strictures or of grade 2 or 3 lung morbidity have been encountered. CHARTWEL 60 Gy resulted in an enhancement of oesophagitis and grade 1 lung toxicity compared with CHARTWEL 54 Gy. These were of no clinical significance, but may be important if CHARTWEL is used with concomitant chemotherapy. These results provide a basis for further dose escalation or the introduction of concurrent chemotherapy.

BOLD MRI of human tumor oxygenation during carbogen breathing.

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). T2*-weighted gradient-echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5-82.4%), and one decreased (-26.5 +/- 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4-14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 +/- 3.7%, range 5.0-11.7%). T2*-weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization.