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Biomedical subjects

Christopher M Nutting

Publications and source records attributed to Christopher M Nutting.

18 recordsLinked to original sources
PubMed2006

A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor.

PURPOSE: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies. EXPERIMENTAL DESIGN: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7), and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens. RESULTS: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed. CONCLUSIONS: Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.

Adult↗
PubMed2006

Assessment of the formant frequencies in normal and laryngectomized individuals using linear predictive coding.

The objective of this study was to assess the difference in voice quality as defined by acoustical analysis using sustained vowel in laryngectomized patients in comparison with normal volunteers. This was designed as a retrospective single center cohort study. An adult tertiary referral unit formed the setting of this study. Fifty patients (40 males) who underwent total laryngectomy and 31 normal volunteers (18 male) participated. Group comparisons with the first three formant frequencies (F1, F2, and F3) using linear predictive coding (LPC) (Laryngograph Ltd, London, UK) was performed. The existence of any significant difference of F1, F2, and F3 between the two groups using the sustained vowel /i/ and the effects of other factors namely, tumor stage (T), chemoradiotherapy, pharyngectomy, cricothyroid myotomy, closure of pharyngoesophageal segment, and postoperative complication were analyzed. Formant frequencies F1, F2, and F3 were significantly different in male laryngectomees compared to controls: F1 (P<0.001, Mann-Whitney U test), F2 (P<0.001, Student's t test), and F3 (P=0.008, Student's t test). There was no significant difference between females in both groups for all three formant frequencies. Chemoradiotherapy and postoperative complications (pharyngocutaneous fistula) caused a significantly lower formant F1 in men, but showed little effect in F2 and F3. Laryngectomized males produced significantly higher formant frequencies, F1, F2, and F3, compared to normal volunteers, and this is consistent with literature. Chemoradiotherapy and postoperative complications significantly influenced the formant scores in the laryngectomee population. This study shows that robust and reliable data could be obtained using electroglottography and LPC in normal volunteers and laryngectomees using a sustained vowel.

Female↗
PubMed2006

Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels.

PURPOSE: To investigate the potential for intensity-modulated radiotherapy (IMRT) to spare the bowel in rectal tumors. METHODS AND MATERIALS: The targets (pelvic nodal and rectal volumes), bowel, and bladder were outlined in 5 patients. All had conventional, three-dimensional conformal RT and forward-planned multisegment three-field IMRT plans compared with inverse-planned simultaneous integrated boost nine-field equally spaced IMRT plans. Equally spaced seven-field and five-field and five-field, customized, segmented IMRT plans were also evaluated. RESULTS: Ninety-five percent of the prescribed dose covered at least 95% of both planning target volumes using all but the conventional plan (mean primary and pelvic planning target volume receiving 95% of the prescribed dose was 32.8 +/- 13.7 Gy and 23.7 +/- 4.87 Gy, respectively), reflecting a significant lack of coverage. The three-field forward planned IMRT plans reduced the volume of bowel irradiated to 45 Gy and 50 Gy by 26% +/- 16% and 42% +/- 27% compared with three-dimensional conformal RT. Additional reductions to 69 +/- 51 cm(3) to 45 Gy and 20 +/- 21 cm(3) to 50 Gy were obtained with the nine-field equally spaced IMRT plans-64% +/- 11% and 64% +/- 20% reductions compared with three-dimensional conformal RT. Reducing the number of beams and customizing the angles for the five-field equally spaced IMRT plan did not significantly reduce bowel sparing. CONCLUSION: The bowel volume irradiated to 45 Gy and 50 Gy was significantly reduced with IMRT, which could potentially lead to less bowel toxicity. Reducing the number of beams did not reduce bowel sparing and the five-field customized segmented IMRT plan is a reasonable technique to be tested in clinical trials.

Humans↗
PubMed2005

The impact of introducing intensity modulated radiotherapy into routine clinical practice.

BACKGROUND AND PURPOSE: Intensity modulated radiotherapy (IMRT) at the Royal Marsden Hospital London was introduced in July 2001. Treatment delivery was dynamic using a single-phase technique. Concerns were raised regarding increased clinical workload due to introduction of new technology. The potential increased use of resources was assessed. PATIENTS AND METHODS: IMRT patient selection was within guidelines of clinical trials and included patients undergoing prostate plus pelvic lymph node (PPN) irradiation and head and neck cancer (HNC) treatment. Patient planning, quality assurance and treatment times were collected for an initial IMRT patient group. A comparative group of patients with advanced HNC undergoing two- or three-phase conventional radiotherapy, requiring matched photon and electron fields, were also timed. RESULTS: The median overall total planning time for IMRT was greater for HNC patients compared to the PPN cohort. For HNC the overall IMRT planning time was significantly longer than for conventional. The median treatment time for conventional two- or three-phase HNC treatments, encompassing similar volumes to those treated with IMRT, was greater than that for the IMRT HNC patient cohort. A reduction in radiographer man hours per patient of 4.8h was recorded whereas physics time was increased by 4.9h per patient. CONCLUSIONS: IMRT currently increases overall planning time. Additional clinician input is required for target volume localisation. Physics time is increased, a significant component of this being patient specific QA. Radiographer time is decreased. For HNC a single phase IMRT treatment has proven to be more efficient than a multiple phase conventional treatment. IMRT has been integrated smoothly and efficiently into the existing treatment working day. This preliminary study suggests that IMRT could be a routine treatment with efficient use of current radiotherapy resources.

Cohort Studies↗
PubMed2005

Assessment of a customised immobilisation system for head and neck IMRT using electronic portal imaging.

PURPOSE: To evaluate set-up reproducibility of a cabulite shell and determine CTV-PTV margins for head and neck intensity-modulated-radiotherapy. MATERIALS AND METHODS: Twenty patients were entered into the study. A total of 354 anterior and lateral isocentric electronic portal images (EPIs) were compared to simulator reference images. RESULTS: About 94% of all translational displacements were < or =3 mm, and 99% < or =5 mm. The overall systematic error was 0.9 mm (+/-1.0SD) in the Right-Left, 0.7 mm (+/-0.9SD) in the Superior-Inferior and -0.02 mm (+/-1.1SD) in the Anterior-Posterior directions. The corresponding SDs of the random errors were +/-0.4, +/-0.6 and +/-0.7 mm. The estimated margins required from CTV-PTV were calculated according to the Van Herk formula was 2.9, 2.6 and 3.3 mm, respectively. CONCLUSIONS: This head and neck immobilisation system is of sufficient accuracy for its use with IMRT treatments and a 3 mm CTV-PTV margin has been adopted.

Dose-Response Relationship, Radiation↗
PubMed2005

Gene therapy for head and neck cancer.

The prognosis of patients with advanced head and neck cancer has not changed significantly in the last twenty years, despite concerted efforts to optimize treatment using conventional modalities such as surgery, radiotherapy and chemotherapy. Novel therapeutic approaches based on our increasing understanding of the molecular changes that underlie the development of cancer have the potential to alter this situation. Gene therapy involves the delivery of genetic sequences in to tumour or normal cells for a therapeutic purpose. A number of viral and non-viral vectors have been developed that have the ability to deliver therapeutic genes specifically to tumours. These therapeutic genes can exert their effects by correcting existing genetic abnormalities, by killing cells directly or indirectly through recruitment of the immune system. In this review, the various gene therapy strategies that are under development are presented with particular reference to the treatment of head and neck cancer.

Animals↗
PubMed2005

Initial patient imaging with an optimised radiotherapy beam for portal imaging.

BACKGROUND AND PURPOSE: To investigate the feasibility and the advantages of a portal-imaging mode on a medical accelerator, consisting of a thin low-Z bremsstrahlung target and a thin Gd2O2S/film detector, for patient imaging. PATIENTS AND METHODS: The international code of practice for high-energy photon dosimetry was used to calibrate dosimetry instruments for the imaging beam produced by 4.75 MeV electrons hitting a 6mm thick aluminium target. Images of the head and neck of a humanoid phantom were taken with a mammography film system and the dose in the phantom was measured with TLDs calibrated for this beam. The first head and neck patient images are compared with conventional images (taken with the treatment beam on a film radiotherapy verification detector). Visibility of structures for six patients was evaluated. RESULTS: Images of the head and neck of a humanoid phantom, taken with both imaging systems showed that the contrast increased dramatically for the new system while the dose required to form an image was less than 10(-2)Gy. The patient images taken with the new and the conventional systems showed that air-tissue interfaces were better defined in the new system image. Anatomical structures, visible on both films, are clearer with the new system. Additionally, bony structures, such as vertebrae, were clearly visible only with the new system. The system under evaluation was significantly better for all features in lateral images and most features in anterior images. CONCLUSIONS: This pilot study of the new portal imaging system showed the image quality is significantly improved.

Head and Neck Neoplasms↗
PubMed2004

Clinical implementation of dynamic and step-and-shoot IMRT to treat prostate cancer with high risk of pelvic lymph node involvement.

BACKGROUND AND PURPOSE: Two systems have been developed for treating patients with locally advanced prostate cancer using intensity-modulated radiotherapy (IMRT): one using dynamic multi-leaf collimator delivery and the other using step-and-shoot. This paper describes the clinical implementation of these two techniques, and presents results from the first 14 patients treated in a clinical setting (nine dynamic, five step-and-shoot). PATIENTS AND METHODS: Dynamic treatments were planned using Corvus, and step-and-shoot using Helax-TMS; all were delivered using Elekta accelerators. Prior to the first clinical treatments, validation measurements were carried out for each system, including measurements for a complete IMRT treatment. The reproducibility of dynamic delivery and the characteristics of the accelerator for low-monitor-unit (MU) deliveries were also assessed. An extensive quality assurance (QA) program was performed for each of the patients. Additionally, timing measurements were carried out to assess the practicalities of the technique. RESULTS: The planning objectives were met in most cases. Absolute doses for complete IMRT treatments were within 2%, on average, with dose distributions generally showing agreement within 3% or 3 mm. Beam modulation measurements made throughout each patient's treatment indicated that both delivery methods were reproducible. The dynamic plans required an average of 765 MU per beam, with a treatment delivery time of 14 min; corresponding results for step-and-shoot plans were 105 MU and 10 min. CONCLUSIONS: Two IMRT techniques for this group of patients have been successfully implemented in the clinic. The more complex dynamic treatments showed no advantages over the step-and-shoot approach. QA results have shown accurate and reproducible delivery for both techniques, giving increased confidence in the techniques and allowing a reduction in the QA program.

Humans↗
PubMed2004

Intensity-modulated radiotherapy improves target coverage, spinal cord sparing and allows dose escalation in patients with locally advanced cancer of the larynx.

BACKGROUND AND PURPOSE: An investigation has been carried out into the potential of intensity-modulated radiotherapy (IMRT) to improve the coverage of the targets and the sparing of the spinal cord (SC) in radiotherapy treatment of the larynx and bilateral cervical lymph nodes, in patients with advanced larynx cancer. PATIENTS AND METHODS: Conventional radiotherapy (CRT) and IMRT plans were produced for six patients to treat the larynx (PTV1) and lymph nodes (PTV2) to 50 Gy (phase 1). A second plan was created to treat the PTV1 to 65 Gy and PTV2 to 50 Gy (phases 1 and 2). The potential to escalate the dose to both the larynx (to 67 Gy) and the nodes (to 56 Gy) was investigated for the IMRT plans. RESULTS: The phase 1 treatment gave average minimum doses (dose received by 99% volume) of 38.1 (+/-8.2) and 48.5 (+/-0.2)Gy for PTV1, treated by CRT and IMRT, respectively, and 35.9 (+/-2.9) and 46.2 (+/-1.8)Gy for PTV2. For the two phase treatment the average minimum doses to PTV1 were 51.6 (+/-8.2) (CRT) and 62.1 (+/-0.7)Gy (IMRT) (p=0.028) and for PTV2 were 36.2 (+/-2.9) (CRT) and 46.8 (+/-0.5)Gy (IMRT) (P=0.0004). The average maximum doses (dose received by 1% volume) to the SC were 42.5 (+/-1.9) (CRT) and 37.9 (+/-1.4)Gy (IMRT) (P=0.01). For the dose escalated IMRT plans the minimum dose to PTV1 was 64.6 (+/-0.5) and 50.8 (+/-1.8)Gy to PTV2. The average SC maximum was 41.5 (+/-1.6)Gy. CONCLUSIONS: IMRT offers improved target homogeneity and reduces irradiation of the SC. This sparing of normal tissue structures is sufficient that significant dose escalation of both the larynx and lymph nodes may be possible.

Dose Fractionation, Radiation↗
PubMed2004

Combination epidermal growth factor receptor inhibition and radical radiotherapy for NSCLC.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death in the developed world. Despite advances in therapy with conventional modalities, over 85% of patients will die from their disease within 5 years of diagnosis. For patients with inoperable lung cancer, the addition of chemotherapy to radical radiotherapy yields a small but significant 10% survival benefit at 3 years. However, the systemic toxicity of chemotherapy is common and may be severe. Over the past 20 years, dramatic improvements in our understanding of the molecular etiology of cancer have enabled the development of novel targeted therapies. Overexpression of the epidermal growth factor receptor (EGFR) in lung cancer correlates with an aggressive disease course and poor tumor response to radiotherapy. Strategies to inhibit this molecular switch have become a focus for drug development. Preclinical efficacy has been repeatedly demonstrated with anti-EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors, and responses have been documented in the clinic with acceptable toxicity. Phase III trials combining EGFR tyrosine kinase inhibitors with radical chemoradiation are recruiting at present. This review addresses the current challenges of discovering how best to use these new anticancer therapies, with particular emphasis on the enhancement of existing therapeutic strategies such as radical radiotherapy, factors relating to patient selection and prediction of clinical response.

Antibodies, Monoclonal↗
PubMed2003

Le Fort I osteotomy and low-dose rate Ir192 brachytherapy for treatment of recurrent nasopharyngeal tumours.

BACKGROUND: Treatment of recurrent nasopharyngeal carcinoma is a difficult clinical problem. External beam re-irradiation is associated with a long-term cure in a proportion of cases but this may be associated with severe radiation injury. METHODS: Eighteen patients with post-nasal space tumours were treated between 1986 and 2001 with surgical excision and nasopharyngeal brachytherapy via a Le Fort I osteotomy approach. Low-dose rate (LDR) and high-dose rate (HDR) brachytherapy was used. Data was prospectively collected. Local control and overall survival were measured. Acute and late complications were assessed using the RTOG system. RESULTS: The overall survival was 67% at 2 years and 33.5% at 5 years. The corresponding local control rates were 42 and 31.5%, respectively. The T stage at relapse was a significant prognostic factor for local control (P=0.004) but not overall survival. Acute toxicity was mild. RTOG grade >/=3 late complications occurred in 40% of patients treated with the HDR, and 0% treated with LDR. CONCLUSIONS: The results of the Le Fort osteotomy, tumour debulking and post-operative brachytherapy gives local control rates similar to those achieved with wide-field re-irradiation. Complication rates are acceptable and are lower than that reported with other methods of radiation therapy. The surgical technique was well tolerated. HDR brachytherapy with this technique had a high complication rate. This approach is a viable option in the treatment of recurrent nasopharyngeal tumours.

Adult↗
PubMed2003

A systematic study of techniques for elective cervical nodal irradiation with anterior or opposed anterior and posterior beams.

PURPOSE: To assess target coverage and dose homogeneity using conventional radiotherapy (RT) and intensity-modulated RT (IMRT) with anterior and posterior beams for elective irradiation of the cervical lymph nodes in patients with head and neck cancer. MATERIALS AND METHODS: A planning study was performed in six patients who had undergone radical RT for head and neck cancer. RT plans to irradiate the cervical lymph nodes using a single anterior field, or opposed anterior and posterior fields, with 6 or 10 MV photons were compared. Plans using IMRT for missing-tissue compensation were also studied. An algorithm was developed to guide clinicians to the most appropriate treatment technique depending on the nodal groups to be irradiated. RESULTS: With 6 MV single field (SF) irradiation significant under-dose (minimum dose <70% of prescription dose) was seen in nodal groups II and V, due to their posterior position. With SF 10 MV the mean dose to level II was higher (p<0.001) and dose homogeneity to levels Ib and II was improved. Using opposed fields (OF), minimum doses to the nodes in levels II and V were improved. OF using 10 MV showed significant advantage over 6 MV with reduction of maximum doses to levels II, III and V. SF 10 MV IMRT improved maximum doses to levels Ib and II compared to SF 6 MV IMRT. OF IMRT gave the best dose distributions with optimal mean dose and dose homogeneity. Beam energy made no difference with OF IMRT. CONCLUSIONS: The optimal technique for elective cervical node irradiation depends on the lymph node levels within the PTV. If irradiation of the level II or V nodes is required, then the OF IMRT technique with either 6 or 10 MV gives the best dose distributions. In the absence of IMRT, then OF conventional techniques are best. If the aim is to irradiate levels III and IV or level IV only, then 6 MV SF non-IMRT is the simplest technique.

Algorithms↗