Adaptive radiotherapy for virally mediated head and neck cancer

Introduction: Clinical investigation has revealed a subgroup of head and neck cancers that are virally mediated. The relationship between nasopharyngeal cancer and Epstein Barr Virus (EBV) has long been established and more recently, the association between oropharyngeal cancer and Human Papillomavirus (HPV) has been revealed1,2 These cancers often present with nodal involvement and generally respond well to radiation treatment, evidenced by tumour regression1. This results in the need for treatment plan adaptation or re-planning in a subset of patients. Adaptive techniques allow the target region of the radiotherapy treatment plan to be altered in accordance with treatment-induced changes to ensure that under or over dosing does not occur3. It also assists in limiting potential overdosing of surrounding critical normal tissues4. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Method: Between 2005-2010, 121 patients with virally mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent radiotherapy treatment were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories to determine the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into risk categories; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with virally mediated head and neck cancer and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of curative radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study. ‘Real World’ Implications: This research identifies predictive factors for those patients with virally mediated head and neck cancer that will benefit most from treatment adaptation. This will assist in minimising the side effects experienced by these patients thereby improving their quality of life after treatment.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for a re-planning CT during radiotherapy (RT) in a subset of patients. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive RT trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent RT were reviewed. Patients were analysed based on maximum size of the dominant node with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Sample size did not allow statistical analysis to detect a significant difference or exclusion of a lack of difference between the 3 groups. Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive RT study.

Impact of a novel nurse-led prechemotherapy education intervention (ChemoEd) on patient distress, symptom burden, and treatment-related information and support needs : results from a randomised, controlled trial

Background: High levels of distress and need for self-care information by patients commencing chemotherapy suggest that current prechemotherapy education is suboptimal. We conducted a randomised, controlled trial of a prechemotherapy education intervention (ChemoEd) to assess impact on patient distress, treatment-related concerns, and the prevalence and severity of and bother caused by six chemotherapy side-effects. Patients and methods: One hundred and ninety-two breast, gastrointestinal, and haematologic cancer patients were recruited before the trial closing prematurely (original target 352). ChemoEd patients received a DVD, question-prompt list, self-care information, an education consultation ≥24 h before first treatment (intervention 1), telephone follow-up 48 h after first treatment (intervention 2), and a face-to-face review immediately before second treatment (intervention 3). Patient outcomes were measured at baseline (T1: pre-education) and immediately preceding treatment cycles 1 (T2) and 3 (T3). Results: ChemoEd did not significantly reduce patient distress. However, a significant decrease in sensory/psychological (P = 0.027) and procedural (P = 0.03) concerns, as well as prevalence and severity of and bother due to vomiting (all P = 0.001), were observed at T3. In addition, subgroup analysis of patients with elevated distress at T1 indicated a significant decrease (P = 0.035) at T2 but not at T3 (P = 0.055) in ChemoEd patients. Conclusions: ChemoEd holds promise to improve patient treatment-related concerns and some physical/psychological outcomes; however, further research is required on more diverse patient populations to ensure generalisability.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for a re-planning CT during radiotherapy (RT) in a subset of patients. We sought to identify a high-risk group based on nodal size to be evaluated in a future prospective adaptive RT trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal (EBV positive) or oropharyngeal (HPV positive) cancers, receiving curative intent RT were reviewed. Patients were analysed based on maximum size of the dominant node with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups; ≤35mm (Group 1), 36-45mm (Group 2), ≥46mm (Group 3). Re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Sample size did not allow statistical analysis to detect a significant difference or exclusion of a lack of difference between the 3 groups. Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of re-planning during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive RT study.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for plan adaptation during radiotherapy in a subset of patients. We sought to identify a high-risk group based on pre-treatment nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal or oropharyngeal cancers, receiving definitive radiotherapy were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups defined by pre-treatment nodal size; ≤ 35mm (Group 1), 36-45mm (Group 2), ≥ 46mm (Group 3). Applying these groups to the patient cohort, re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of plan adaptation during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study.

Growth of confined cancer spheroids : a combined experimental marker, critical modelling approach

A critical step in the dissemination of ovarian cancer is the formation of multicellular spheroids from cells shed from the primary tumour. The objectives of this study were to apply bioengineered three-dimensional (3D) microenvironments for culturing ovarian cancer spheroids in vitro and simultaneously to build on a mathematical model describing the growth of multicellular spheroids in these biomimetic matrices. Cancer cells derived from human epithelial ovarian carcinoma were embedded within biomimetic hydrogels of varying stiffness and grown for up to 4 weeks. Immunohistochemistry, imaging and growth analyses were used to quantify the dependence of cell proliferation and apoptosis on matrix stiffness, long-term culture and treatment with the anti-cancer drug paclitaxel. The mathematical model was formulated as a free boundary problem in which each spheroid was treated as an incompressible porous medium. The functional forms used to describe the rates of cell proliferation and apoptosis were motivated by the experimental work and predictions of the mathematical model compared with the experimental output. This work aimed to establish whether it is possible to simulate solid tumour growth on the basis of data on spheroid size, cell proliferation and cell death within these spheroids. The mathematical model predictions were in agreement with the experimental data set and simulated how the growth of cancer spheroids was influenced by mechanical and biochemical stimuli including matrix stiffness, culture duration and administration of a chemotherapeutic drug. Our computational model provides new perspectives on experimental results and has informed the design of new 3D studies of chemoresistance of multicellular cancer spheroids.

Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment

High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.

Multilevel determinants of breast cancer survival : association with geographic remoteness and area-level socioeconomic disadvantage

A major priority for cancer control agencies is to reduce geographical inequalities in cancer outcomes. While the poorer breast cancer survival among socioeconomically disadvantaged women is well established, few studies have looked at the independent contribution that area- and individual-level factors make to breast cancer survival. Here we examine relationships between geographic remoteness, area-level socioeconomic disadvantage and breast cancer survival after adjustment for patients’ socio- demographic characteristics and stage at diagnosis. Multilevel logistic regression and Markov chain Monte Carlo simulation were used to analyze 18 568 breast cancer cases extracted from the Queensland Cancer Registry for women aged 30 to 70 years diagnosed between 1997 and 2006 from 478 Statistical Local Areas in Queensland, Australia. Independent of individual-level factors, area-level disadvantage was associated with breast-cancer survival (p=0.032). Compared to women in the least disadvantaged quintile (Quintile 5), women diagnosed while resident in one of the remaining four quintiles had significantly worse survival (OR 1.23, 1.27, 1.30, 1.37 for Quintiles 4, 3, 2 and 1 respectively).) Geographic remoteness was not related to lower survival after multivariable adjustment. There was no evidence that the impact of area-level disadvantage varied by geographic remoteness. At the individual level, Indigenous status, blue collar occupations and advanced disease were important predictors of poorer survival. A woman’s survival after a diagnosis of breast cancer depends on the socio-economic characteristics of the area where she lives, independently of her individual-level characteristics. It is crucial that the underlying reasons for these inequalities be identified to appropriately target policies, resources and effective intervention strategies.

New players for advanced prostate cancer and the rationalisation of insulin-sensitising medication

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of “old players” for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer.

Numerical solution of an optimal control model of dendritic cell treatment of a growing tumour

A new optimal control model of the interactions between a growing tumour and the host immune system along with an immunotherapy treatment strategy is presented. The model is based on an ordinary differential equation model of interactions between the growing tu- mour and the natural killer, cytotoxic T lymphocyte and dendritic cells of the host immune system, extended through the addition of a control function representing the application of a dendritic cell treat- ment to the system. The numerical solution of this model, obtained from a multi species Runge–Kutta forward-backward sweep scheme, is described. We investigate the effects of varying the maximum al- lowed amount of dendritic cell vaccine administered to the system and find that control of the tumour cell population is best effected via a high initial vaccine level, followed by reduced treatment and finally cessation of treatment. We also found that increasing the strength of the dendritic cell vaccine causes an increase in the number of natural killer cells and lymphocytes, which in turn reduces the growth of the tumour.

Predicting fitness for chemotherapy in older cancer patients

Background: The Vulnerable Elders Survey-13 (VES-13) is increasingly used to screen for older patients who can proceed to intensive chemotherapy without further comprehensive assessment. This study compared the VES-13 determination of fitness for treatment with the oncologist's assessments of fitness. Method: Sample: Consecutive series of solid tumour patients ≥65 years (n=175; M=72; range=65-86) from an Australian cancer centre. Patients were screened with the VES-13 before proceeding to usual treatment. Blinded to screening, oncologists concurrently predicted patient fitness for chemotherapy. A sample of 175 can detect, with 90% power, kappa coefficients of agreement between VES-13 and oncologists’ assessments >0.90 ("almost perfect agreement"). Separate backward stepwise logistic regression analyses assessed potential predictors of VES-13 and oncologists’ ratings of fitness. Results: Kappa coefficient for agreement between VES-13 and oncologists’ ratings of fitness was 0.41 (p<0.001). VES-13 and oncologists’ assessments agreed in 71% of ratings. VES-13 sensitivity = 83.3%; specificity = 57%; positive predictive value = 69%; negative predictive value = 75%. Logistic regression modelling indicated that the odds of being vulnerable to chemotherapy (VES-13) increased with increasing depression (OR=1.42; 95% CI: 1.18, 1.71) and decreased with increased functional independence assessed on the Bartel Index (OR=0.82; CI: 0.74, 0.92) and Lawton instrumental activities of daily living (OR=0.44; CI: 0.30, 0.65); RSquare=.65. Similarly, the odds of a patient being vulnerable to chemotherapy, when assessed by physicians, increased with increasing age (OR=1.15; CI: 1.07, 1.23) and depression (OR=1.23; CI: 1.06, 1.43), and decreased with increasing functional independence (OR=0.91; CI: 0.85, 0.98); RSquare=.32. Conclusions: Our data indicate moderate agreement between VES-13 and clinician assessments of patients’ fitness for chemotherapy. Current ‘one-step’ screening processes to determine fitness have limits. Nonetheless, screening tools do have the potential for modification and enhanced predictive properties in cancer care by adding relevant items, thus enabling fit patients to be immediately referred for chemotherapy.

Differences in Epidural and Analgesic Use in Patients with Apparent Stage I Endometrial Cancer treated by open versus laparoscopic surgery: results from the randomised LACE trial

Objectives: We compared post-operative analgesic requirements between women with early stage endometrial cancer treated by total abdominal hysterectomy (TAH) or total laparoscopic hysterectomy (TLH). Methods: 760 patients with apparent stage I endometrial cancer were treated in the international, multicentre, prospective randomised trial (LACE) by TAH (n=353) or TLH (n=407) (2005-2010). Epidural, opioid and non-opioid analgesic requirements were collected until ten months after surgery. Results: Baseline demographics and analgesic use were comparable between treatment arms. TAH patients were more likely to receive epidural analgesia than TLH patients (33% vs 0.5%, p<0.001) during the early postoperative phase. Although opioid use was comparable in the TAH vs TLH groups during postoperative 0-2 days (99.7% vs 98.5%, p 0.09), a significantly higher proportion of TAH patients required opioids 3-5 days (70% vs 22%, p<0.0001), 6-14 days (35% vs 15%, p<0.0001), and 15-60 days (15% vs 9%, p 0.02) post-surgery. Mean pain scores were significantly higher in the TAH versus TLH group one (2.48 vs 1.62, p<0.0001) and four weeks (0.89 vs 0.63, p 0.01) following surgery. Conclusion: Treatment of early stage endometrial cancer with TLH is associated with less frequent use of epidural, lower post-operative opioid requirements and better pain scores than TAH.

A study of post diagnosis breast cancer concerns for women living in rural and remote Queensland. Part I : Personal concerns

The findings presented in this paper are part of a research project designed to provide a preliminary indication of the support needs of postdiagnosis women with breast cancer in remote and isolated areas in Queensland. This discussion will present data that focuses on the women’s expressed personal concerns. For participants in this research a diagnosis of breast cancer involves a confrontation with their own mortality and the possibility of a reduced life span. This is a definite life crisis, creating shock and needing considerable adjustment. Along with these generic issues the participants also articulated significant issues in relation to their experience as women in a rural setting. These concerns centred around worries about how their partner and families cope during their absences for treatment, the additional burden on the family of having to cope with running the property or farm during the participant’s absence or illness, added financial strain brought about by the cost of travel for treatment, maintenance of properties during absences, and problems created by time off from properties or self-employment. These findings accord with other reports of health and welfare services for rural Australian and the generic literature on psycho-oncology studies of breast cancer.

A study of postdiagnosis breast cancer concerns for women living in rural and remote Queensland. Part II : support issues

This paper presents the recent findings from a study on the postdiagnosis support needs of women with breast cancer living in rural and remote Queensland. The findings presented in this discussion focus on support needs from the perspective of the women experiencing breast cancer as well as health service providers. The tyranny of distance imposes unique hardships, such as separation from family and friends, during a time of great vulnerability for treatment, the need to travel long distances for support and follow-up services, and extra financial burdens, which can combine to cause strains on the marital relationship and family cohesion. Positive indications are, however, that the rural communities operate on strong, informal networks of support. This network of family, friends and community can, and does, play an active role in the provision of emotional and practical support.

Patients with terminal cancer who use alternative therapies: their beliefs and practices

This paper examines the extent to which patients who have been diagnosed as having terminal cancer choose to use non-medical therapies. In particular it is concerned with the illness behaviour of patients who are receiving conventional cytotoxic drug and radiation treatments, who also decide to use a wide range of ‘alternative’ medications and therapies. The paper discusses the findings of a study of 152 patients with metastatic cancer that examined the extent to which they used alternative cancer therapies, as well as the beliefs and attitudes they have about their cancer, its treatment, and the practitioners providing that treatment. Four groups of users of alternative therapies, who differ according to their commitment to and the type of therapies they use, were identified. Results of logistic regression analyses indicate that those using alternative therapies were different in range of social attitudes. These differences were primarily their greater reported ‘will to live’ and desire for control over treatment decisions, and the differing beliefs they hold about their disease.