Clinical Oncology - Articles in Press

Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review and Practice Guideline - Corrected Proof

2012-01-16

Abstract: After complete resection of melanoma, some patients remain at high risk for recurrence. The efficacy of adjuvant systemic therapy has been inconsistent in randomised trials and remains controversial. An updated systematic review was conducted to identify new evidence on the role of adjuvant interferon therapy in patients with high-risk resected primary melanoma. Outcomes of interest included overall survival, disease-free survival (DFS), adverse effects and quality of life. MEDLINE, EMBASE, Cochrane Library and the proceedings of the American Society of Clinical Oncology were systematically searched to identify new randomised controlled trials, systematic reviews or meta-analyses. An updated meta-analysis of trials comparing high-dose interferon alpha with observation alone was conducted. The new data are presented in this review. Seven randomised controlled trials met the inclusion criteria: six trials of interferon alone and two trials of interferon plus chemotherapy. Two meta-analyses of adjuvant interferon alpha were also identified. Overall survival was not significantly different between adjuvant high-dose interferon and observation alone (hazard ratio 0.93; 95% confidence interval 0.78–1.12; P = 0.45). A meta-analysis of DFS showed a significant benefit for high-dose interferon over control (hazard ratio 0.77; 95% confidence interval 0.65–0.92; P = 0.004). One trial reported a significant DFS benefit for pegylated interferon over observation alone. Our updated literature review indicates that adjuvant interferon therapy does not confer a significant long-term overall survival benefit in patients with high-risk resected primary melanoma; however, a significant DFS benefit for high-dose interferon or pegylated interferon treatment has been shown. An revised practice guideline was developed based on the systematic review.

Intra-fraction Motion during Extreme Hypofractionated Radiotherapy of the Prostate using Pre- and Post-treatment Imaging - Corrected Proof

2012-01-09

Abstract: Aims: To determine intra-fraction displacement of the prostate during extreme hypofractionated radiotherapy using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers.Materials and methods: In total, 265 image pairs were obtained from 53 patients who underwent extreme hypofractionated radiotherapy to a dose of 35 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal X-rays before and after treatment and were used to determine intra-fraction prostate displacement.Results: The mean intra-fraction prostate displacements were −0.03 ± 0.61 mm (one standard deviation), 0.21 ± 1.50 mm and −0.86 ± 1.73 mm in the left–right, superior–inferior and anterior–posterior directions, respectively. The mean intra-fraction displacement during the first two fractions was moderately correlated with the displacement in the remaining three fractions, with correlation coefficients of 0.63 (95% confidence interval 0.43–0.77) and 0.47 (95% confidence interval 0.22–0.65) in the superior–inferior and anterior–posterior directions, respectively. There was no significant correlation in the left–right direction with a coefficient of –0.04 (95% confidence interval −0.31–0.23).Conclusions: The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy is small. A strategy using the first two fractions to predict future displacements >5 mm warrants further validation.

Radionuclide Therapy in Neuroendocrine Tumours: A Systematic Review - Corrected Proof

K.Y. Gulenchyn, X. Yao, S.L. Asa, S. Singh, C. Law — 2012-01-06

Abstract: The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy (111In-DTPAOC, 90Y-DOTALAN, 90Y-DOTATOC, 90Y-DOTATATE, and 177Lu-DOTATATE) and eight focused on 131I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that 177Lu-DOTATATE might be associated with greater clinical outcomes compared with 90Y-DOTATOC or 111In-DTPAOC. The severe toxicities for 177Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of 131I-MIBG in adult NET patients, but the overall tumour response rate from 131I-MIBG was 27–75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after 131I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients’ renal function must be monitored. 131I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic.

Long-term Outcomes and Prognostic Factors of Re-irradiation for Locally Recurrent Nasopharyngeal Carcinoma using Intensity-modulated Radiotherapy - Corrected Proof

2012-01-03

Abstract: Aims: To analyse the outcomes and to evaluate the prognostic factors involved in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT).Materials and methods: A retrospective analysis of 239 NPC patients with local recurrence who were re-irradiated with IMRT between 2001 and 2008 was conducted. The distribution of disease re-staging was 5.4% for stage I, 18.4% for stage II, 29.7% for stage III and 46.4% for stage IV. Cisplatin-based chemotherapy was administered to 117 patients (49.0%) in addition to the IMRT.Results: The mean D95 and the V95 of the gross tumour volume (GTV) were 66.78Gy and 98.61%, respectively. The mean dose to the GTV was 70.04Gy (61.73–77.54Gy). The 5 year overall survival, local recurrence-free survival, distant metastasis-free survival and disease-free survival were 44.9, 85.8, 80.6 and 45.4%, respectively. In a univariate analysis, patient age, recurrent T (rT), recurrent N (rN), recurrent stage, tumour volume, mean dose and mean fractional dose of the GTV were significant prognostic factors for overall survival. In a multivariate analysis, only patient age, rN stage, recurrent stage, mean fractional dose and tumour volume remained significant for overall survival.Conclusions: Re-irradiation using IMRT is available to improve local tumour control and to prolong patients’ survival. A smaller tumour volume, higher fractional dose, younger patient ages, lower rN0 stage and early recurrent stage are all independent prognostic factors for overall survival of recurrent NPC. It is of clinical importance to select the appropriate recurrent NPC cases for salvage re-irradiation by IMRT.

Adaptive Radiotherapy Using Helical Tomotherapy for Head and Neck Cancer in Definitive and Postoperative Settings: Initial Results - Corrected Proof

L. Capelle, M. Mackenzie, C. Field, M. Parliament, S. Ghosh, R. Scrimger — 2011-12-26

Abstract: Aims: To assess whether routine mid-treatment replanning in head and neck squamous cell carcinoma patients results in meaningful improvements in target or normal tissue dosimetry and to assess which patients derive the greatest benefit.Materials and methods: Twenty patients treated with either postoperative chemoradiotherapy or definitive chemoradiotherapy with primary or nodal disease ≥3cm in size were included in this prospective pilot study. Seven patients received adjuvant chemoradiotherapy and 13 received definitive chemoradiotherapy. Patients were planned and treated on a helical tomotherapy system. All patients had a second computed tomography scan after 15 fractions and a new plan based on this was initiated from fraction 20.Results: Relative volume changes between computed tomography scans were: GTV 29%; CTV60 (adjuvant patients) 4%; parotid volume 17.5%; median reduction in neck separation 6–7mm; weight loss 3%. For the group overall and for the definitively treated patient cohort, respectively, adapted plans resulted in reductions in PTV66 D1 (0.3Gy, P=0.01 and 0.5Gy, P=0.01); PTV54 D1 (0.6Gy, P<0.0001 and 0.9Gy, P=0.0002); spinal cord maximum (0.5Gy, P=0.004 and 0.6Gy, P=0.04) and volume of skin receiving ≥50Gy (16cm2, P=0.01 and 19cm2, P=0.001). Definitively treated patients also had a reduction in mean parotid dose (0.6Gy, P=0.046) and volume of normal tissue receiving ≥50Gy (67cm3, P=0.02). Patients with nasopharyngeal carcinoma received the greatest benefits with treatment adaptation with reduction in spinal cord maximum 1.2Gy, mean parotid dose 1.2Gy and parotid V26 6.3%. There was no significant benefit for adjuvant patients. Other factors associated with greater benefits were greater weight loss and greater reduction in neck separation and higher T stage.Conclusions: There is minimal benefit to routine adaptive replanning in unselected patients, and no benefit in adjuvantly treated patients. Patients with nasopharyngeal carcinoma or with greater weight loss or reduction in neck separation did have clinically significant benefits. These patients should be targeted for adaptive strategies.

Evidence-based Guideline Recommendations on the use of Positron Emission Tomography Imaging in Colorectal Cancer - Corrected Proof

K. Chan, S. Welch, C. Walker-Dilks, A. Raifu — 2011-12-23

Abstract: Aims: To provide evidence-based practice guideline recommendations on the use of fluoro-2-deoxy-d-glucose positron emission tomography (PET) for diagnosis, staging, assessing treatment response, liver metastasis and restaging or recurrence of colorectal cancer.Materials and methods: A systematic review by Facey et al. (Health Technology Assessment 2007;11(44):iii–iv, xi–267) was used as the evidence base for recommendation development. As the review was limited to August 2005, the evidence base was updated to May 2010 using the same search strategies for MEDLINE and EMBASE used in the original review. The authors of the current systematic review drafted recommendations, which were reviewed, adapted and accepted by consensus by the Ontario provincial Gastrointestinal Disease Site Group and a special meeting of clinical experts.Results: The results from the Facey et al. review for colorectal cancer included three other systematic reviews and 24 primary studies. The 2005 to 2010 updated search included 10 additional systematic reviews and 28 primary studies. Recommendations were developed based on this evidence and accepted by consensus.Conclusions: The routine use of PET is not recommended for the diagnosis or staging of clinical stage I–III colorectal cancers. PET is recommended for determining management and prognosis if conventional imaging is equivocal for the presence of metastatic disease. PET is also not recommended for routine surveillance in patients with colorectal cancer treated with curative surgery at high risk for recurrence. It is recommended to determine the site of recurrence in the setting of rising CEA when conventional work-up fails to unequivocally identify metastatic disease. Finally, PET is recommended in the preoperative assessment of colorectal cancer liver metastasis before surgical resection.

18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Assessment of Occult Primary Head and Neck Cancers — An Audit and Review of Published Studies - Corrected Proof

2011-12-19

Abstract: 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.

Anatomical and Dose Changes of Gross Tumour Volume and Parotid Glands for Head and Neck Cancer Patients during Intensity-modulated Radiotherapy: Effect on the Probability of Xerostomia Incidence - Corrected Proof

2011-12-06

Abstract: Aims: To quantify the changes in dose as well as in the prediction of parotid gland toxicity due to anatomical changes during therapy of head and neck cancer patients.Materials and methods: Fifteen patients with advanced locoregional head and neck cancer, with no evidence of distant metastasis, were enrolled in a prospective study. All patients were treated with intensity-modulated radiotherapy. Multiple computed tomography scans were repeated at the end of each treatment week. The original treatment plans were copied to the per-treatment scans to create hybrid plans. The normal tissue complication probability (NTCP) was calculated assuming the end point to be grade ≥3 xerostomia according to the Radiation Therapy Oncology Group late toxicity scale.Results: The gross tumour volume dose coverage was slightly affected by the anatomical changes, whereas the mean dose (Dmean) to the parotids changed from 26.1 ± 6.0 to 27.4 ± 7.4 Gy, with a mean increase of 0.22 Gy/treatment week. Consequently, the mean NTCP increased from 0.15 ± 0.06 to 0.18 ± 0.10, primarily due to a few patients exhibiting a marked increase. The absolute gross tumour volume shrinkage and the percentage parotids shrinkage were the best independent predictors for the NTCP variations.Conclusions: On average, the increase in the parotids Dmean as well as in NTCP during treatment is limited, and the observed variations were strongly patient-dependent.

Clinical Correlations and Prognostic Relevance of Tissue Angiogenic Factors in Patients with Gastric Cancer - Corrected Proof

Y. Mohri, C. Miki, K. Tanaka, A. Kawamoto, M. Ohi, T. Yokoe, M. Kusunoki — 2011-11-30

Abstract: Aims: To evaluate the relationship between vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in gastric cancer tissue and clinicopathological features and to determine whether these factors were correlated with survival.Materials and methods: We analysed tissue samples from 58 patients with gastric cancer and used 24 normal gastric mucosae as controls. Tissue levels of VEGF and HGF were measured in tissue extracts by enzyme-linked immunosorbent assay.Results: HGF and VEGF levels were significantly higher in gastric cancer tissue than in matched normal gastric mucosa. VEGF levels were significantly increased in cancer tissue from cases involving lymphatic invasion. HGF levels were significantly increased according to the disease stage. Patients with high levels of VEGF or HGF showed significantly worse survival rates than patients with low levels. Using multivariate analysis, a high level of VEGF or HGF was an independent factor predicting poor survival.Conclusions: Intratumoral levels of HGF and VEGF are an important prognostic determinant in gastric cancer. The current findings suggest that high concentrations of HGF and VEGF may induce aggressive tumour growth and metastasis.

Hypofractionation in Breast Cancer: Is it Fair to Generalise the Data? - Corrected Proof

S. Chatterjee, I. Mallick, R. Achari — 2011-11-28

Sir — Recent studies have confirmed the safety and efficacy of hypofractionated radiotherapy in the adjuvant treatment of breast cancer. Appropriate adjustments to the total dose allow 15- or 16-fraction schedules to be delivered over 3 weeks that are at least as safe and effective as standard 5-week regimens. A reduction in the overall treatment time has significant benefits, not only for the patient, but also saves resources in busy departments and has been adopted widely in many European and Canadian centres.

Concurrent Chemotherapy and Intensity-modulated Radiation Therapy for Anal Carcinoma — Clinical Outcomes in a Large National Cancer Institute-designated Integrated Cancer Centre Network - Corrected Proof

2011-11-10

Abstract: Aims: To report the clinical outcomes of patients with anal carcinoma treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy in a large integrated academic-community cancer centre network.Materials and methods: Seventy-eight patients were treated with IMRT for anal carcinoma at 13 community cancer centres. IMRT planning for all centres was carried out at one central location. Sixty-five patients (83%) were T1–T2, 64% were N0, 9% were M1; five patients were HIV positive. All but one patient received concurrent chemotherapy. The median dose to the pelvis including inguinal nodes was 45Gy. The primary site and involved nodes were boosted to a median dose of 55.8Gy. All acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0.Results: The median follow-up for the entire cohort was 16 months (range 0–72 months). Acute grade ≥3 toxicity included 27.7% gastrointestinal and 29.0% dermatological. Acute grade 4 haematological toxicity occurred in 12.9% of patients. Sixty-four (88.9%) patients experienced a complete response. The 2 year colostomy-free survival, overall survival, freedom from local failure and freedom from distant failure rates were 81.2, 86.9, 83.6 and 81.8%, respectively.Conclusions: Early results seem to confirm that IMRT used concurrently with chemotherapy for treatment of anal carcinoma is effective and well tolerated. This complex treatment can be safely and effectively carried out in a large integrated healthcare network.

UK Guidance Document: Treatment of Metastatic Breast Cancer - Corrected Proof

2011-11-10

Abstract: Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.

The Role of Autophagy in Clinical Practice - Corrected Proof

A.L. Swampillai, P. Salomoni, S.C. Short — 2011-10-28

Abstract: Resisting cell death is one of the six hallmarks of cancer. Autophagy is a highly adaptable metabolic process that plays an important role in stressful conditions, such as nutrient deprivation and hypoxia. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. In tumourigenesis, autophagy plays a dual role, which may be related to the different stages in cancer development. The autophagy-mediated removal of damaged proteins and organelles may prevent cancer initiation by limiting tissue inflammation. In contrast, autophagy has been shown to allow established tumours to survive in nutrient-deprived or hypoxic conditions during cancer progression. Key regulators of the autophagy pathway are modulated or aberrantly expressed in cancer and modulating autophagy is an attractive concept for cancer therapy. The difficulties, however, lie in the complexity of the crosstalk between apoptosis and autophagy and the lack of robust tissue biomarkers and in vivo assessment of autophagic flux. Currently there are 19 clinical trials in both solid and haematogenous cancers investigating the efficacy and toxicity of adding an autophagy inhibitor to standard treatment. Hydroxychloroquine, a drug routinely used in the treatment of malaria and autoimmune disorders, is the most common autophagy inhibitor under investigation due to its more favourable toxicity profile. This overview summarises the role of autophagy in cancer initiation, progression and resistance to treatment and thereby the therapeutic benefit that may be gained by modulating its effects.

Gefitinib Compared with Systemic Chemotherapy as First-line Treatment for Chemotherapy-naive Patients with Advanced Non-small Cell Lung Cancer: A Meta-analysis of Randomised Controlled Trials - Corrected Proof

F. Wang, L.D. Wang, B. Li, Z.X. Sheng — 2011-10-24

Abstract: To define the efficacy of gefitinib in chemotherapy-naive patients with advanced non-small cell lung cancer, we carried out a meta-analysis of randomised controlled trials. Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched. Seven trials were identified, covering a total of 4656 subjects. As compared with chemotherapy, gefitinib was effective in the selected patients: the corresponding summary hazard ratios (gefitinib versus chemotherapy) for progression-free survival were 0.43 (0.32, 0.58) (P < 0.001) for the subgroup of patients with epidermal growth factor receptor (EGFR) mutant treated with gefitinib monotherapy, 0.71 (0.60, 0.83) (P < 0.001) for the subgroup of patients with lung adenocarcinoma; but was detrimental for the patients without EGFR mutant treated by gefitinib monotherapy [hazard ratio = 2.16 (1.17, 3.99), P = 0.01]. Significantly improved survival was found in the gefitinib group compared with the control in the subgroup of patients with lung adenocarcinoma [hazard ratio = 0.89 (0.81, 0.99); P = 0.03], but not found in the subgroup of patients with EGFR mutant [hazard ratio = 0.87 (0.68, 1.12); P = 0.28]. In conclusion, first-line treatment with gefitinib conferred prolonged progression-free survival than treatment with systemic chemotherapy in a molecularly or histologically defined population of patients with non-small cell lung cancer, and improved survival in the subgroup of patients with lung adenocarcinoma.

Single Agent Weekly Paclitaxel as Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer: A Feasibility Study - Corrected Proof

2011-10-20

Abstract: Aim: To study the toxicity profile and response rates of weekly paclitaxel given as neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer.Materials and methods: The study was planned as a single arm, prospective phase II study. Twenty-six patients with locally advanced breast cancer were enrolled in the study from December 2006 to October 2007. These patients underwent NACT with weekly paclitaxel at 100 mg/m2 for 8 consecutive weeks followed by surgery. This was followed by anthracycline-based chemotherapy for three to four cycles followed by radiation. The patients received standard adjuvant hormonal therapy. The patients were carefully monitored for side-effects using common toxicity criteria. The clinical and pathological response rates were documented. The response rates were descriptively stated.Results: The median age of the patients was 52 years (30–67 years) and the median tumour size was 7 cm (2.5–15 cm). Of the 208 planned weekly cycles, 207 could be given. The rates of grade 3–4 neutropenia, thrombocytopenia and neuropathy were 4, 12 and 4%, respectively. A complete clinical response was observed in 10 patients (38.5%) and a completed pathological response, defined as the absence of invasive cancer from the breast and axillary nodes, was seen in 11.5% of patients. Breast-conserving surgery was possible in 23% of patients.Conclusion: The regimen of weekly single agent paclitaxel is feasible in patients with locally advanced breast cancer with acceptable toxicity. It resulted in a pathological response rate that was comparable with other regimens in this group of advanced stage patients. Considering the efficacy and low toxicity of this regimen, it is worth exploring in larger studies.

Expression of HER2neu in Ductal Carcinoma in situ is Associated with Local Recurrence - Corrected Proof

2011-09-28

Abstract: Aims: Determination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS.Materials and methods: We reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu–), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER–, PR–, HER2neu+), triple negative (ER–, PR–, HER2neu–)]. We evaluated the association between the molecular subtype and the development of local recurrence.Results: In total, 180 cases of DCIS were included in the study (luminal A, n=113; luminal B, n=25; HER2neu type, n=29; triple negative, n=13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio=1.98; 95% confidence interval: 1.11, 3.53, P=0.02).Conclusion: HER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence.

Accuracy and Completeness of Pathology Reporting — Impact on Partial Breast Irradiation Eligibility - Corrected Proof

J.-P. Pignol, E. Rakovitch, J. Zeppieri, W. Hanna — 2011-09-21

Abstract: Aims: Accelerated partial breast irradiation (APBI) is an alternative to whole breast irradiation that is delivered over a shorter period of time with less toxicity. Appropriate patient selection is critical to its success and the American Society for Radiation Oncology (ASTRO) has published detailed selection criteria for ‘suitable’ patients. This study evaluated the effect of those selection criteria on APBI eligibility based on pathology reports.Materials and methods: From March 2004 to March 2007 all patients referred to a single cancer centre for breast radiotherapy were screened for participation in a phase I/II trial of permanent breast seed implant brachytherapy. Eligible patients underwent a computed tomography simulation and those referred from an outside institution had a secondary expert breast pathology assessment. Initial and expert pathology reports were compared regarding completeness and accuracy.Results: In total, 143 patients were eligible for the trial; 79 patients had surgery carried out outside our institution. In the initial pathology report, the most frequently missing critical information was the resection margin width (29.1%) and the presence of extensive in situ carcinoma (11.4%). Comparing initial and reviewed pathology, the agreement was higher than 90% for most features. The main source of disagreement was the width of the negative resection margin, with 34.4% disagreement (P=0.016), although it changed eligibility in only 3.6%. There was major disagreement in the evaluation of lymphovascular invasion. Overall, pathology review changed the eligibility for a patient from ‘suitable’ for APBI to ‘cautionary’ in 18.6% of the cases.Conclusion: Using stringent eligibility criteria has a direct effect on patient screening for APBI. The use of synoptic pathology reporting and a quality assurance programme with secondary expert assessments are recommended.

The Management of Neuroendocrine Tumours: Current and Future Medical Therapy Options - Corrected Proof

K.E. Öberg — 2011-09-12

Abstract: Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.

Image-guided Radiotherapy for Rectal Cancer — A Systematic Review - Corrected Proof

S. Gwynne, R. Webster, R. Adams, S. Mukherjee, B. Coles, J. Staffurth — 2011-08-19

Abstract: Radiotherapy for rectal cancer is becoming more conformal. Both the rectum and the mesorectum are mobile structures and the use of image-guided radiotherapy techniques may improve treatment delivery. Studies up to 2008 have previously been reviewed; rectal motion was mostly studied in bladder and prostate cancer cases. Large variations were seen in both the rectal volume and rectal wall displacement during the treatment course. We reviewed the literature on primary rectal cancer. A systematic review was conducted using Medline and Embase databases using the keywords ‘rectal, radiotherapy, IGRT, image guided, organ motion, internal margin, target shape/volume’. Nine studies looked at both inter- and intrafractional motion of the gross tumour volume, rectum, mesorectum and the clinical target volume using a variety of imaging modalities. There was significant movement in the upper mesorectum. There was a strong relationship between rectal filling and mesorectal motion. Differences according to gender and body mass index have been reported. One study showed adequate dose to the rectum despite rectal motion and deformation. Current margin recipes may not apply to deformable structures. Suggested margins for the clinical target volume to planning target volume expansion are between 1 and 3.5cm. There may be a role for re-imaging and re-planning during a treatment course. From the available data, electronic portal imaging devices should continue to be used to match for bony anatomy. Additional information on internal motion can be obtained by cone beam computer tomography or tomotherapy and if available its use should be considered. Individualised anisotropic margins may be required. Further work is required to assess the optimal imaging modality, whether to match to bone or soft tissue, and to assess if internal motion affects treatment outcome.

Volumetric Modulated Arc Therapy with Simultaneous Integrated Boost for Locally Advanced Rectal Cancer - Corrected Proof

2011-08-05

Abstract: Aims: To report the feasibility of volumetric modulated arc therapy (VMAT) for neoadjuvant radiotherapy in locally advanced rectal cancer in a dose-escalation protocol and simultaneous integrated boost (SIB) approach. Moreover, the VMAT technique was compared with three-dimensional conformal radiotherapy (3D-CRT) and fixed-field intensity modulated radiotherapy (IMRT), in terms of target coverage and irradiation of organs at risk.Materials and methods: Eight patients with locally advanced rectal cancer were treated with the SIB-VMAT technique. The VMAT plans were compared with 3D-CRT and IMRT techniques in terms of several clinically dosimetric parameters. The number of monitor units and the delivery time were analysed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a two-dimensional array of ionisation chambers.Results: All techniques meet the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformality. VMAT is associated with 40, 53 and 58% reduction in the percentage of volume of small bowel irradiated to 30, 40 and 50Gy, compared with 3D-CRT. No significant differences were found with respect to SIB-IMRT. VMAT plans showed a significant reduction of monitor units by nearly 20% with respect to IMRT and reduced treatment time from 14 to 5min for a single fraction.Conclusions: SIB-VMAT plans can be planned and carried out with high quality and efficiency for rectal cancer, providing similar sparing of organs at risk to SIB-IMRT and resulting in the most efficient treatment option. SIB-VMAT is currently our standard approach for radiotherapy of locally advanced rectal cancer.

The Concepts, Diagnosis and Management of Early Imaging Changes after Therapy for Glioblastomas - Corrected Proof

2011-07-25

Abstract: Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with ‘pseudoprogression’ and ‘pseudoresponse’ are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies.

Dual Arc Volumetric-modulated Arc Radiotherapy (VMAT) of Nasopharyngeal Carcinomas: A Simultaneous Integrated Boost Treatment Plan Comparison with Intensity-modulated Radiotherapies and Single Arc VMAT - Corrected Proof

T.-F. Lee, H.-M. Ting, P.-J. Chao, F.-M. Fang — 2011-07-13

Abstract: Aims: To compare the performance of volumetric-modulated arc radiotherapy (VMAT) by dual arc with fixed beam intensity-modulated radiotherapies (IMRTs) and single arc VMAT on nasopharyngeal carcinomas (NPC).Materials and methods: Twenty NPC cases were re-planned using the planning system of the Pinnacle3®SmartArc (SA) module to compare the performance of the following four techniques: seven-field (7F) and 18-field (18F) fixed beam IMRT, and single (SA1) and dual arc VMAT (SA2). The plan was delivered on an Elekta Synergy™ Linac equipped with an 80-leaf 1cm multileaf collimator. Three dose levels of planning target volumes (PTVs) with 70/59.4/54.0Gy in 33 fractions were prescribed and delivered as a simultaneous integrated boost. The conformity index and homogeneity index of the PTVs, the comprehensive quality index (CQI), the normal tissue complication probability for the organs at risk (OARs), and the planning time, delivery efficiency and accuracy were analysed.Results: A significantly inferior conformity index at the three dose levels of PTV and homogeneity index of PTV70 were observed in SA1 compared with the other techniques. Comparable conformity index and homogeneity index of the PTV were observed among 7F/18F IMRT and SA2. Based on the CQI of the 11 OARs, the most efficient dose reduction was observed in 18F IMRT followed in order by SA2, 7F IMRT and SA1. The planning time was on average 13.2/24.9/40.1/42.8min for 7F/18F IMRT/SA1/SA2, respectively. With regards to the delivery efficiency compared with 7F IMRT, a 51 and 41% reduction in delivery time was achieved by SA1 and SA2, respectively. All techniques presented a high quality assurance pass rate (>98%) of the Γ3mm,3% criterion.Conclusion: In NPC cases, SA2 gave superior results in terms of PTV coverage and OAR sparing compared with SA1 and approached the performance achieved by 18F IMRT, but without sacrificing the delivery efficiency.

A Dosimetric Planning Study Comparing Intensity-modulated Radiotherapy with Four-field Conformal Pelvic Radiotherapy for the Definitive Treatment of Cervical Carcinoma - Corrected Proof

J. Forrest, J. Presutti, M. Davidson, P. Hamilton, A. Kiss, G. Thomas — 2011-07-13

Abstract: Aims: To compare the dose to organs at risk (OAR) between a conventional four-field whole pelvis radiotherapy (4F-WPRT) plan and an initial single intensity-modulated WPRT (IM-WPRT) plan for definitive treatment of cervical cancer. The magnitude of potential dose sparing of OAR is unknown when planning target volumes are defined to include potential organ motion and microscopic disease extent.Materials and Methods: Planning computed tomography scans of 50 consecutive, previously treated patients were re-planned using 4F-WPRT and IM-WPRT. Margins compatible with the literature on organ motion were used to create the planning target volume. Dose–volume histograms for target and OAR were compared for each patient with paired t-tests and waterfall plots.Results: The mean target volume covered by 95% (V47.8) was 99.7% for 4F-WPRT and 98.8% for IM-WPRT (P>0.05, ns). Intensity-modulated radiotherapy (IMRT) was associated with a significant reduction in the dose to OAR at the V50, V45, V40 and V30 level. There was a >20% difference in V50 in most patients: 84% (bladder), 58% (small bowel), 54% (sigmoid) and 84% (rectum).Conclusions: A single, initial IMRT plan with appropriate margins encompassing initial gross and potential microscopic pelvic disease leads to a reduction in the dose to OAR without compromising target coverage. This offers a potential ‘class solution’ for definitive treatment of patients with cervical cancer. Clinical outcome data are still needed to verify this planning study.

Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T, A1298C and G1793A Polymorphisms: Association with Risk for Clear Cell Renal Cell Carcinoma and Tumour Behaviour in Men - Corrected Proof

M.R. Safarinejad, N. Shafiei, S. Safarinejad — 2011-04-14

Abstract: Aims: Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels.Materials and methods: A case–control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined.Results: The MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31–3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21–2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75–8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72–6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22–5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55–6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times increased risk of developing CCRCC than their control counterparts (odds ratio=4.40, 95% confidence interval=2.41–6.72; P=0.0001). There was not a significant interaction between MTHFR polymorphisms and serum levels of total Hcy and folate in increasing the risk of CCRCC.Conclusions: Our results provide evidence that the MTHFR polymorphisms might contribute to increased CCRCC risk in men.

Clinical Outcome of Low-risk Differentiated Thyroid Cancer Patients after Radioiodine Remnant Ablation and Recombinant Human Thyroid-stimulating Hormone Preparation - Corrected Proof

2011-03-16

Abstract: Aim: Recombinant human thyroid-stimulating hormone (rhTSH) has been approved in Europe as a preparation tool for radioiodine ablation of post-surgical thyroid remnants in patients with low-risk differentiated thyroid cancer (DTC). Published studies report that, both thyroid hormone withdrawal and rhTSH preparation result in similar rates of successful remnant ablation, but few studies have determined the effectiveness of rhTSH preparation on disease recurrence. We sought to determine the clinical outcome, considering both ablation success and disease recurrence, of low-risk DTC patients who underwent 131I ablation.Materials and methods: This retrospective study describes the clinical outcome of 100 patients treated with 131I remnant ablation after preparation with rhTSH. After ablation, patients were classified as in complete remission, as having no evidence of persistent disease, or as having clinical recurrence on the basis of a subsequent diagnostic whole body scan with 131I, stimulated thyroglobulin and cross-sectional imaging studies.Results: Overall assessment of ablation success was verified and obtained in 75% of patients (75/100). Considering only patients who underwent a diagnostic whole body scan and stimulated thyroglobulin without interfering anti-thyroglobulin antibody, complete ablation was obtained in 96% of patients (75/78). After a follow-up of about 4 years, 78 patients are in complete remission: 75 with initial ablation success and three who achieved a complete remission during subsequent follow-up. Among the remaining 22 patients, 21 have no clinical evidence of disease (NCED), indicating the inability to verify the complete remission or to detect residual disease, as in patients with positive thyroglobulin antibody, whereas one has persistent disease demonstrated only by stimulated thyroglobulin. No recurrences were observed. Of four patients initially classified as having persistent disease, one obtained a complete remission and two are now considered NCED.Conclusion: Our data confirm the favourable outcome, with low rates of recurrence and persistent disease, of patients with low-risk DTC who underwent 131I ablation after rhTSH. Moreover, our results compare favourably with those reported in the literature in patients prepared with rhTSH, but also in patients prepared with hormone withdrawal.

WITHDRAWN: Recent Advances in Angiopoietin Biology in Cancer — A Review - Corrected Proof

Suhasini Joshi, Ashish Tiwari — 2011-02-09

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy