Is community treatment best? a randomised trial comparing delivery of cancer treatment in the hospital, home and GP surgery.

BACKGROUND: Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings. METHODS: Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient-perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics. RESULTS: There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19·5 to +5·2, P=0.25). There was a significant difference between the two community locations in favour of home (+15·2, 1·3 to 29·1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews. INTERPRETATION: Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications.

BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes.

Myasthenia gravis (MG) is caused by helper T cell-dependent autoantibodies against the muscle acetylcholine receptor (AChR). Thymic epithelial tumors (thymomas) occur in 10% of MG patients, but their autoimmunizing potential is unclear. They express mRNAs encoding AChR alpha and epsilon subunits, and might aberrantly select or sensitize developing thymocytes or recirculating peripheral T cells against AChR epitopes. Alternatively, there could be defective self-tolerance induction in the abundant maturing thymocytes that they usually generate. For the first time, we have isolated and characterized AChR-specific T cell clones from two MG thymomas. They recognize extracellular epitopes (alpha75-90 and alpha149-158) which are processed very efficiently from muscle AChR. Both clones express CD4 and CD8alpha, and have a Th-0 cytokine profile, producing IL-4 as well as IFN-gamma. They are restricted to HLA-DP14 and DR52a; expression of these minority isotypes was strong on professional antigen-presenting cells in the donors' tumors, although it is generally weak in the periphery. The two clones' T cell receptor beta chains are different, but their alpha chain sequences are very similar. These resemblances, and the striking contrasts with T cells previously cloned from non-thymoma patients, show that thymomas generate and actively induce specific T cells rather than merely failing to tolerize them against self antigens.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: Comparison of Clinician- versus Patient-reported Outcomes.

AIMS: Breast radiotherapy-associated toxicity is often reported using clinical and photographic assessments. The addition of patient-reported outcome measures (PROMs) is becoming more common. This study investigated the concordance between clinician- and patient-reported outcomes. MATERIALS AND METHODS: The Cambridge Breast Intensity-modulated Radiotherapy (IMRT) trial prospectively collected data on clinician assessment and PROMs at 2 and 5 years after breast radiotherapy. Clinician assessment included physical examination and photographic assessment. PROMs included European Organization for Research and Treatment of Cancer (EORTC) BR23 questionnaire and four breast radiotherapy-specific questions. The correlation between patient and clinician scores were analysed on an independent patient basis using percentage agreement, Cohen's kappa coefficient (k) and Bowker's test of symmetry. The analysis was repeated after stratifying patients based on age, baseline Hospital Anxiety and Depression Score (HADS) and baseline body image score. RESULTS: At 2 and 5 years, a weak level of concordance was seen between the clinician-based assessment and PROMS for all the five toxicity end points (k = 0.05-0.21), with individual patient-based agreement of 32.9-78.3% and a highly discordant Bowker's test of symmetry (P < 0.001). The most frequently reported moderate-severe toxicity by patients was change in breast appearance (14% at both 2 and 5 years), whereas it was breast induration (36% and 25% at 2 and 5 years, respectively) by the clinicians. The lack of concordance was not affected by patient's age, baseline HADS and baseline body image score. CONCLUSIONS: This study found that moderate-severe toxicity reported by patients is low and the overall concordance between clinicians and patients is low. This could be due to methodological limitations or alternatively reflects the subjective nature of PROMs. Incorporation of a patient's perception on treatment-related toxicity will have important implications for treatment decisions and follow-up care.

Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part II--Radiotherapy strategies to reduce radiation-induced late effects.

Radiotherapy after conservation surgery has been proven to decrease local relapse and death from breast cancer, and is now firmly established in the management of early breast carcinoma. Currently, the challenge is to optimise the therapeutic ratio by minimising treatment-related morbidity, while maintaining or improving local control and survival. The second part of this review examines the role of two approaches: intensity-modulated radiation therapy (IMRT) and partial breast irradiation, as means of improving the therapeutic ratio. Discussion of IMRT includes both inverse- and forward-planned methods: the breast usually requires minimal modulation to improve dose homogeneity, and therefore lends itself to simpler forward-planned IMRT techniques; whereas inverse-planned IMRT may be useful in selected cases. There are many dosimetry studies reporting the superiority of IMRT over conventional breast radiotherapy, but there is still a paucity of clinical data regarding patient benefit from these techniques. A critical literature review of clinical partial breast radiotherapy studies focuses on the influence of irradiated breast volume, dose and fractionation, and patient selection on normal tissue side-effects and local control. Clinical reports of partial breast irradiation show several encouraging, but some concerning results about local recurrence rates. Therefore, mature results from randomised trials comparing partial breast irradiation with whole-breast radiotherapy are required. Accurate localisation of the tumour bed and application of appropriate clinical target volumes and planning target volumes are discussed in detail, as these concepts are fundamental for partial breast irradiation.

Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part I--normal tissue complications.

Radiotherapy after conservation surgery has been proven to decrease local relapse and death from breast cancer, and is now firmly established in the management of early breast carcinoma. Currently, the challenge is to minimise the morbidity caused by this treatment without losing its efficacy. This review will be divided into two parts, with Part I focusing on the radiation factors contributing to late normal tissue complications after radiotherapy for early breast cancer. Three major normal tissue side-effects will be discussed: cosmetic outcome, cardiac complications and pulmonary side-effects.

Reduction of plasma aldosterone and arterial stiffness in obese pre- and stage1 hypertensive subjects after aerobic exercise.

Obesity-related hypertension is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52±3.2 years, body mass index=33.5±1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4-week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4±75 to 215.8±66 pg ml(-1), P=0.001), SBP (140±12 to 136±10.4 mm Hg; P=0.02), DBP (89±4.2 to 85±6.3 mm Hg; P=0.03) and central PWV (11.2±0.6 to 9.8±0.8 m s(-1); P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions.

The influence of breast size on late radiation effects and association with radiotherapy dose inhomogeneity.

A prospective assessment of late changes in breast appearance in 559 patients after tumour excision and radiotherapy for early breast cancer noted a strong association with breast size. Only 3/48 (6%) patients with small breasts developed moderate or severe late changes compared with 94/423 (22%) with medium sized breasts and 34/88 (39%) patients with large breasts (p < 0.001). One possibility is that greater radiation changes are related to greater dose inhomogeneity in women with large breasts. To explore this hypothesis, radiation dose distributions were assessed in a separate group of 37 women in whom three-level transverse computer tomographic images of the breast in the treatment position were available. A significant correlation was found between breast size and dose inhomogeneity which may account for the marked changes in breast appearance reported in women with large breasts.

Approaches for studying the pathogenic T cells in autoimmune patients.

Our provisional conclusions from this work are as follows. (1) For screening responses of established lines, native human AChR is not prohibitively scarce, especially if it is concentrated onto beads, and class II-transfected TE671 cells may be useful too; both may give vital evidence of AChR-specificity, but it is still crucial to confirm that with synthetic peptides. (2) For mapping epitopes, panels of full-length and shorter recombinant human polypeptides, and of synthetic peptides, are invaluable complementary material: longer peptides tend to stimulate particularly strongly. (3) Initial selection with pooled synthetic peptides can easily generate interesting lines from both patients and controls, but they may depend on the artificial processing sites that are an inevitable consequence of arbitrarily chosen start and stop points. Of course, these might conceivably be employed in unusual antigen-presenting cells (such as thymic myoid cells), so we cannot totally dismiss such "cryptic" epitopes. This system can sometimes select T cells responding to "natural" epitopes too, as now reported for tetanus toxin. Nevertheless, for these and other reasons, at present, we strongly favor using the longest human recombinant material possible, because it is apparently processed more naturally. This must be combined with rigorous screening for reactivity to E. coli-derived contaminants plus concomitant mapping of epitopes as above. Use of intact AChR for initiating lines may yet become feasible. (4) The T cells thus isolated and characterized so far are proving to be heterogeneous in the epitopes and presenting class II molecules they recognize, and in their T-cell receptor gene usage. It is premature to claim key myasthenogenic epitopes or clonotypes, but HLA-DR3 and the linked -DQw2 do not appear to monopolize presentation. (5) Assessing the disease-relevance of these T cells is a separate problem, highlighted by their apparent similarity in healthy controls. In the meantime, to test their potential pathogenicity, we are assaying their cytokine profiles and ability to help specific antibody production in vitro. In the hope that they do prove to be relevant, we are also using some of them to test possible therapeutic strategies that might prove applicable in the patients.

Medullary carcinoma of the thyroid misdiagnosed as differentiated thyroid carcinoma.

Four patients are presented, who were initially diagnosed and treated for differentiated thyroid carcinoma, but subsequently discovered to have medullary carcinoma. We suggest that tumour histopathology needs to be carefully reviewed in all cases of thyroid cancer, especially those having atypical clinical or pathological features. This should be completed prior to further therapeutic intervention, such as the administration of ablative radioactive iodine.

Renin-producing leiomyosarcoma originating in the uterus.

We present a case of uterine leiomyosarcoma in a 60-year-old woman, who had severe hypertension with hypokalaemia and metabolic alkalosis. Investigation revealed an elevated serum renin level; the tumour stained for renin on immunocytochemistry. The serum renin level fell on successful treatment of the primary. We suggest that this is the first reported case of uterine leiomyosarcoma shown to be producing renin.

Giving patients a choice improves quality of life: a multi-centre, investigator-blind, randomised, crossover study comparing letrozole with anastrozole.

AIMS: Although the third-generation aromatase inhibitors are generally well tolerated, side-effects still occur in up to 40% of women. As more women are taking these drugs for longer, the issue as to which version is better tolerated is now a significant patient concern. This study aimed to assess whether tolerance for either letrozole or anastrozole can differ for each individual in terms of early quality of life (QoL), whether patients welcome being given a preference and whether this correlated with formal toxicity scoring. MATERIALS AND METHODS: A single-blind, crossover trial, with 72 women with breast cancer who had experienced tamoxifen failure. Randomised to either letrozole 2.5 mg or anastrozole 1 mg, for 4 weeks, 1 week off, then crossover for 4 weeks. RESULTS: Patients were confidently able to choose which drug suited them best (letrozole 68%, anastrozole 32%; P < 0.01). Fewer patients, when taking letrozole, experienced adverse events than when taking anastrozole (43% vs 65%; P = 0.0028). QoL was better when patients were taking letrozole than when they took anastrozole (P = 0.02). CONCLUSIONS: As toxicity and QoL strongly correlated with patient preference for either drug, albeit with a tendency towards letrozole, this suggests that patient preference is now a legitimate and useful end point for future crossover studies. In routine practice, women would warmly welcome extra involvement in the decision-making process via a crossover manoeuvre if side-effects develop, whichever aromatase inhibitor is prescribed initially.

British National Lymphoma Investigation: pilot studies of neoadjuvant chemotherapy in clinical stage Ia and IIa Hodgkin's disease.

In order to improve treatment in early Stage IA and IIA Hodgkin's disease, the British National Lymphoma Investigation (BNLI) has evaluated two neoadjuvant chemotherapy regimens with involved field radiotherapy. This article reports the results of the methotrexate, vinblastine and prednisolone (MVP) study in 39 patients and updates the previous report on vinblastine, bleomycin and methotrexate (VBM) in 30 patients. Both studies recruited clinical Stage IA or IIA Hodgkin's disease patients with intermediate risk of relapse into a prospective multicentre Phase II study. They received two cycles of chemotherapy followed by involved field radiotherapy and then four further cycles of chemotherapy. For MVP the 5-year survival is 97% and for VBM it is 93%. The 5-year event-free survival rates are 71% and 87% respectively. The acute pulmonary and haematological toxicity occurring with VBM was not acceptable and therefore the MVP study was performed. There was less toxicity with this regimen although modest acute pulmonary toxicity was still observed. However, in view of the length of treatment with MVP (9 months) and the excellent results reported by the Manchester group, future efforts of the BNLI are to be directed towards a new short course chemotherapy regimen, VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin).

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial.

AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS: The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS: Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS: On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS: In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

Paediatric tumours in the adult population: the experience of the Royal Marsden Hospital 1974-1990.

Adult patients (greater than 18 years), referred to the Royal Marsden Hospital between 1974 and 1990 with embryonal tumours, have been reviewed. The aim of the study was to document the presentation, management and outcome for this group of patients and to compare these parameters with those of tumours of the same histology arising in the paediatric population. The study population consisted of 15 patients with medulloblastoma, 15 with Ewing's sarcoma, three with neuroblastoma, seven with rhabdomyosarcoma and two with nephroblastoma. Actuarial survival, at 5 years, for adults with medulloblastoma was 80%, which compares very favourably with the outcome for children treated over the same time span. In addition, salvage therapy after relapse was in some cases successful. In the Ewing's sarcoma group the outcome was less favourable, with 5-year actuarial survival of 50%. This is disappointing in view of the lack of tumours with poor prognostic features and may be an area in which these tumours differ from those that arise in children. The number of patients with the diagnosis of neuroblastoma, rhabdomyosarcoma and Wilms' tumour was too small for statistical analysis and they are presented as case reports. Embryonal tumours arising in adults provide an opportunity to study clinical behaviour and biology from an extreme standpoint. This may provide useful information with regard to aetiology, natural history and treatment response. The establishment of registers facilitate the collection of relevant data and also offers the opportunity to improve the treatment received by patients with these rare tumours.

The CD8alphabeta co-receptor on double-positive thymocytes binds with differing affinities to the products of distinct class I MHC loci.

The CD8 co-receptor is essential for TCR-dependent immune recognition and T cell development involving peptides bound to MHC class I (MHCI) molecules. The dominant interaction of CD8 alpha alpha and alpha beta co-receptors is with the alpha3 domain of an MHCI molecule. Whether this interaction is different for the products of various MHCI loci is currently unknown. Here we examine the interaction between H-2K(b) and H-2D(b), the two MHCI molecules in the C57BL / 6 mouse, and CD8 using H-2K(b) and H-2D(b) tetramers. The MHCI molecules bind to the CD8alpha beta co-receptor on double-positive thymocytes with different avidities (H-2K(b) > D(b)). The differences are linked to their respective alpha3 domains. Hence, an H-2D(b)K(b) tetramer comprising D(b)alpha1--alpha2 and K(b)alpha3 domains shows more binding than H-2D(b). We also quantitated the monomeric affinities of CD8alpha alpha and CD8alpha beta for H-2K(b) and H-2D(b). The H-2K(b) interaction with CD8alpha alpha and CD8alpha beta is stronger than that of H-2D(b). Given that T cell repertoire selection of DP thymocytes is a function of both TCR-pMHCI and CD8alpha beta-pMHCI avidities, these differences may explain the dominant role of H-2K(b) as compared to H-2D(b) in CD8 T cell development of C57BL / 6 mice. The influence of allelic and non-allelic alpha3 polymorphisms on thymic selection processes are discussed.