Yttrium-90 Transarterial Radioembolization for Chemotherapy-Refractory Intrahepatic Cholangiocarcinoma: A Prospective, Observational Study.

PURPOSE: To evaluate the safety and efficacy of yttrium-90 transarterial radioembolization (TARE) for the treatment of unresectable, chemotherapy-refractory intrahepatic cholangiocarcinoma (ICC). METHODS: A prospective, observational study was carried out in 10 centers between 2013 and 2017. TARE plus standard care was delivered to patients with unresectable, chemotherapy-refractory or chemotherapy-intolerant ICC. Primary outcome was overall survival. Secondary outcomes included safety, progression-free survival (PFS), and liver-specific progression-free survival (LPFS). RESULTS: Sixty-one patients were treated with TARE. Patients were 53% male; median age was 64 years; 91% had performance status 0/1; 92% had received prior chemotherapy; and 59% had no extrahepatic disease. Median follow-up was 13.9 months (95% confidence interval [CI], 9.6-18.1). Overall survival was 8.7 months (95% CI, 5.3-12.1), and 37% of patients survived to 12 months. PFS was 2.8 months (95% CI, 2.6-3.1), and LPFS was 3.1 months (95% CI, 1.3-4.8). One severe complication (abdominal pain) occurred at the time of the TARE procedure. Thirty patients experienced a total of 49 adverse events, of which 8% were grade ≥3; most common were grade 1-2 fatigue and abdominal pain. A total of 77 abnormal laboratory value events were recorded, of which 4% were grade ≥3. CONCLUSIONS: Patients with advanced ICC have limited therapeutic options and a poor prognosis. This prospective study examined the survival of patients with unresectable, chemotherapy-refractory primary ICC treated with TARE in real-world practice. The results demonstrate that this treatment merits further investigation in this patient cohort in a larger study, including collection of patient-reported outcomes.

Pre-treatment tumour perfusion parameters and initial RECIST response do not predict long-term survival outcomes for patients with head and neck squamous cell carcinoma treated with induction chemotherapy.

OBJECTIVES: Previously, we showed that pre-treatment tumour plasma perfusion (Fp) predicts RECIST response to induction chemotherapy (ICT) in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The aim here was to determine whether the pre-treatment tumour Fp estimate, changes in tumour Fp or RECIST response post 2 cycles of ICT were prognostic for long-term survival outcomes. METHODS: A prospective study enrolled patients with high stage HNSCC treated with docetaxel (T), cisplatin (P) and 5-fluorouracil (F) (ICT) followed by synchronous cisplatin and intensity modulated radiotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before and after two cycles of ICT was used to measure Fp and RECIST response. RESULTS: Forty-two patients were recruited and 37 underwent two scans. The median follow-up was 36 (range 23-49) months. Pre-treatment tumour Fp (stratified by median) was not prognostic for overall survival (p = 0.42), disease specific survival (p = 0.20) and locoregional control (p = 0.64). Neither change in tumour Fp nor RECIST response post two cycles of ICT was prognostic for any outcome (p>0.21). CONCLUSION: DCE-MRI parameters do not predict long-term survival outcomes following ICT and RECIST response to ICT may not be an appropriate endpoint to determine early efficacy of a treatment in HNSCC patients.

Taxane, platinum and 5-FU prior to chemoradiotherapy benefits patients with stage IV neck node-positive head and neck cancer and a good performance status.

PURPOSE: The benefit of adding docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy to chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC) remains uncertain. We aimed to investigate whether ICT is well tolerated when given with prophylactic treatment against predicted adverse effects and which patients benefit most. METHODS: A single-centre audit identified 132 HNSCC patients with stage IVa/b neck node-positive disease, prescribed TPF followed by CRT. TPF involved three cycles of docetaxel (75 mg/m2 IV) and cisplatin (75 mg/m2 IV) on day 1 plus 5-FU (750 mg/m2 IV) on days 2-5. Planned CRT was 66 Gy in 30 fractions of intensity-modulated radiotherapy with concurrent cisplatin (100 mg/m2 IV) at the beginning of week 1 and 4 (days 1 and 22). All patients received prophylactic antibiotics and granulocyte colony-stimulating factor. RESULTS: Median follow-up was 39.5 months. 92.4% of patients completed three cycles of TPF; 95.5% of patients started chemoradiotherapy. Grade 3/4 adverse events were low (febrile neutropenia 3.0%), with no toxicity-related deaths. 3-year overall survival was 67.2%; disease-specific survival was 78.7%; locoregional control was 78.3%. Distant metastases rate was 9.8% (3.0% in those without locoregional recurrence). Good performance status (p = 0.002) and poor tumour differentiation (p = 0.018) were associated with improved overall survival on multivariate analysis. CONCLUSION: With prophylactic antibiotics and granulocyte colony-stimulating factor TPF was well tolerated with good survival outcomes. TPF should remain a treatment option for stage IV neck node-positive patients with a good performance status. The use of tumour grade to aid patient selection for TPF warrants investigation.

Conventional fractionation should not be the standard of care for T2 glottic cancer.

BACKGROUND: The aim of this study was to report outcomes and late toxicity following hypofractionated accelerated radiotherapy for T2 glottic cancers. We highlight the importance of hypofractionated treatments with shorter overall treatment times, in improving outcomes for T2 glottic cancers. We also compare the biologically effective dose of hypofractionated regimes, with conventional fractionation. METHODS: One hundred twelve patients with T2 glottic cancer were treated between January 1999 and December 2005. All patients were prescribed a hypofractionated accelerated radiotherapy dose of 52.5 Gray in 3.28 Gray per fraction, delivered over 22 days. Radiobiological calculations were used to assess the relationship of fraction size and overall treatment time on local control outcomes and late toxicity. RESULTS: The 5-year overall survival was 67%, the 5-year local control was 82%, and the 5-year disease-specific survival was 90%. The respective 5-year local control for T2a and T2b disease was 88.8 and 70.8% (p = 0.032). Severe late toxicity occurred in two patients (1.8%). Radiobiological calculations showed an increase in local control of nearly 12%, with a 10 Gray increase in biologically effective dose. CONCLUSION: This study has demonstrated that accelerated hypofractionated regimes have improved local control and similar late toxicity compared with conventional fractionation schedules. This supports the use of hypofractionated regimes as the standard of care for early glottic laryngeal cancers.

An automated workflow for patient-specific quality control of contour propagation.

Contour propagation is an essential component of adaptive radiotherapy, but current contour propagation algorithms are not yet sufficiently accurate to be used without manual supervision. Manual review of propagated contours is time-consuming, making routine implementation of real-time adaptive radiotherapy unrealistic. Automated methods of monitoring the performance of contour propagation algorithms are therefore required. We have developed an automated workflow for patient-specific quality control of contour propagation and validated it on a cohort of head and neck patients, on which parotids were outlined by two observers. Two types of error were simulated-mislabelling of contours and introducing noise in the scans before propagation. The ability of the workflow to correctly predict the occurrence of errors was tested, taking both sets of observer contours as ground truth, using receiver operator characteristic analysis. The area under the curve was 0.90 and 0.85 for the observers, indicating good ability to predict the occurrence of errors. This tool could potentially be used to identify propagated contours that are likely to be incorrect, acting as a flag for manual review of these contours. This would make contour propagation more efficient, facilitating the routine implementation of adaptive radiotherapy.

Relative plan robustness of step-and-shoot vs rotational intensity-modulated radiotherapy on repeat computed tomographic simulation for weight loss in head and neck cancer.

INTRODUCTION: Interfractional anatomical alterations may have a differential effect on the dose delivered by step-and-shoot intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). The increased degrees of freedom afforded by rotational delivery may increase plan robustness (measured by change in target volume coverage and doses to organs at risk [OARs]). However, this has not been evaluated for head and neck cancer. MATERIALS AND METHODS: A total of 10 patients who required repeat computed tomography (CT) simulation and replanning during head and neck IMRT were included. Step-and-shoot IMRT and VMAT plans were generated from the original planning scan. The initial and second CT simulation scans were fused and targets/OAR contours transferred, reviewed, and modified. The plans were applied to the second CT scan and doses recalculated without repeat optimization. Differences between step-and-shoot IMRT and VMAT for change in target volume coverage and doses to OARs between first and second CT scans were compared by Wilcoxon signed rank test. RESULTS: There were clinically relevant dosimetric changes between the first and the second CT scans for both the techniques (reduction in mean D95% for PTV2 and PTV3, Dmin for CTV2 and CTV3, and increased mean doses to the parotid glands). However, there were no significant differences between step-and-shoot IMRT and VMAT for change in any target coverage parameter (including D95% for PTV2 and PTV3 and Dmin for CTV2 and CTV3) or dose to any OARs (including parotid glands) between the first and the second CT scans. CONCLUSIONS: For patients with head and neck cancer who required replanning mainly due to weight loss, there were no significant differences in plan robustness between step-and-shoot IMRT and VMAT. This information is useful with increased clinical adoption of VMAT.

Tumor plasma flow determined by dynamic contrast-enhanced MRI predicts response to induction chemotherapy in head and neck cancer.

OBJECTIVES: Non-response to induction chemotherapy (IC) occurs in 30% of head and neck squamous cell carcinoma (HNSCC) and has been predicted by tumor plasma flow (Fp) derived by perfusion computed tomography. The present study was designed to test whether baseline tumor Fp determined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) would predict IC response. MATERIALS AND METHODS: A prospective open study powered to test the relationship between tumor Fp and response to IC (docetaxel, cisplatin, 5-fluorouracil) enrolled 50 patients with stage IV HNSCC. Response after two IC cycles was measured by MRI using Response Evaluation Criteria in Solid Tumors in 37 patients. Tumor Fp (primary end point) and multiple parameters in tumors and lymph nodes (secondary end points) were generated at baseline. Differences in baseline DCE-MRI parameters according to IC response were assessed by the Mann-Whitney U test, and predictive value by receiver operating characteristic (ROC) analysis. RESULTS: Median baseline tumor Fp was 53.2ml/100ml/min in 25 responders and 23.9 in 12 non-responders (U 82; P=0.027; area under ROC curve (AUC) 0.73). Median baseline Fp in lymph nodes was 25.8ml/100ml/min for 37 nodes in 25 responders and 17.1 for 15 nodes in 12 non-responders (U 186, P=0.066; AUC 0.67). Frequency of IC response in 37 patients was 68% overall, 83% for tumor Fp above the median (40.6ml/100ml/min) and 45% below the median. Other DCE-MRI parameters were not associated with IC response. CONCLUSION: Pre-treatment tumor Fp determined by DCE-MRI predicts IC response in HNSCC.

Dose intensified hypofractionated intensity-modulated radiotherapy with synchronous cetuximab for intermediate stage head and neck squamous cell carcinoma.

BACKGROUND: For stage II and III head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy alone, loco-regional recurrence is the main cause of treatment failure. Strategies to improve loco-regional control should not be at the expense of increased late normal tissue toxicity. We investigated dose-intensified hypofractionated intensity-modulated radiotherapy (IMRT) with synchronous cetuximab. MATERIAL AND METHODS: In a phase I/II trial, 27 patients with stage III or high risk stage II HNSCC were recruited. They received three dose level simultaneous integrated boost IMRT, 62.5 Gy in 25 daily fractions to planning target volume one over five weeks with synchronous cetuximab. The primary endpoint was acute toxicity. Secondary endpoints included: late toxicity and quality of life; loco-regional control, cause-specific and overall survival. RESULTS: Radiotherapy was completed by 26/27 patients; for one (4%) the final fraction was omitted due to skin toxicity. All cycles of cetuximab were received by 23/27 patients. Grade 3 acute toxicities included: pain (81%), oral mucositis (78%) and dysphagia (41%). There were few grade 3 physician-recorded late toxicities, including: pain (11%), problems with teeth (8%) and weight loss (4%). At 12 months, only one (4%) patient required a feeding tube, inserted prior to treatment due to dysphagia. The maximal/peak rates of patient-reported late toxicities included: severe pain (11%), any dry mouth (89%) and swallowing dysfunction that required a soft/liquid diet (23%). At 12 months, all quality of life and most symptoms mean scores had resolved to baseline or were only a little worse; dry mouth, sticky saliva and dentition scores remained very much worse. At a median follow-up of 47 months, there were five (18.5%) loco-regional recurrences and the overall cause-specific survival was 79% (95% CI 53-92). CONCLUSIONS: This regimen is safe with acceptable acute toxicity, low rates of late toxicity and impact on quality of life at 12 months following treatment. Further evaluation is recommended.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Anaplastic thyroid cancer: the addition of systemic chemotherapy to radiotherapy led to an observed improvement in survival--a single centre experience and review of the literature.

INTRODUCTION: Anaplastic thyroid carcinoma (ATC) is rare yet accounts for up to 50% of all thyroid cancer deaths. This study reviews outcomes of patients with confirmed ATC referred to a tertiary oncology centre plus reviews the literature to explore how poor outcomes may be improved. MATERIALS AND METHODS: The management and outcomes of 20 patients with ATC were reviewed. RESULTS: Median age at diagnosis was 69.5 years. 19 patients died due to ATC, 40% of whom died from asphyxiation. Median survival for all cases was 59 days. Patients who had previous surgery prior to other treatment modalities had a longer median survival overall compared to those who had not had previous surgery (142 days compared to 59 days) and produced the one long-term survivor. Chemotherapy followed by radiotherapy (without previous surgery) was associated with longer median survival (220 days). Palliative radiotherapy alone did not decrease the rate of death by asphyxiation when compared to other single modality treatments. CONCLUSION: Multimodality treatment including surgery when feasible remains the best strategy to improve survival and prevent death from asphyxiation in the management of ATC. The addition of chemotherapy to our institutional protocol led to improved survival but prognosis remains very poor.

The impact of radiotherapy on swallowing and speech in patients who undergo total laryngectomy.

OBJECTIVES: Quality of life studies have shown no detrimental effect with radiotherapy (RT) in patients who have a total laryngectomy. We wished to determine the effect of RT (initial or postoperative) specifically on the swallowing and voice function in patients treated by total laryngectomy (TL) for carcinoma of the larynx. DESIGN: Multicenter chart review. SETTING: Multicenter study in the Greater Manchester and Lancashire area. PARTICIPANTS: A total of 121 postlaryngectomy patients all of whom had completed definitive treatment at least 6 months before this study. Twenty-six patients had total laryngectomy as a single modality treatment and 95 had total laryngectomy and radiotherapy. MAIN OUTCOME MEASURES: Swallowing (solid food, soft diet or fluid/PEG) and voice development. RESULTS: Swallowing was better in the group who had no radiotherapy (P = 0.0037). There was no difference in voice function between the two groups. We also demonstrated that females had a worse swallowing outcome (P = 0.0101), as did advanced nodal stage (P = 0.001). CONCLUSIONS: RT adversely affects the swallowing results but not the speech results after TL when given either as initial treatment or postoperatively. This should be kept in mind in the decision-making process in the treatment of patients with carcinoma of the larynx.

A systematic review of honey uses and its potential value within oncology care.

AIM: To synthesise the evidence regarding honey's role in health care and to identify whether this evidence applies more specifically to cancer care. DESIGN: Systematic review. METHODS: The inclusion and exclusion criteria were agreed by two reviewers and a keyword strategy was developed. EMBASE, CINAHL, AMED, MEDLINE, COCHRANE and PUBMED databases were screened to identify suitable articles. The citation list from each included study was also screened for potentially suitable papers. The key findings from each study were entered onto a data extraction sheet. RESULTS: In total, 43 studies were included in the systematic review, which included studies in relation to wounds (n = 19), burns (n = 11), skin (n = 3), cancer (n = 5) and others (n = 5). In addition, a systematic review regarding honey use in wound care was also included. While the majority of studies noted the efficacy of honey in clinical use, five studies found honey to be equally as effective as the comparator and three found honey to be less effective than the comparator treatment. Other research did not illustrate any significant difference between standard treatment regimes vs. honey treatment. Studies were generally poor in quality because of small sample sizes, lack of randomisation and absence of blinding. CONCLUSIONS: Honey was found to be a suitable alternative for wound healing, burns and various skin conditions and to potentially have a role within cancer care. RELEVANCE TO CLINICAL PRACTICE: In the cancer setting, honey may be used for radiation-induced mucositis, radiotherapy-induced skin reactions, hand and foot skin reactions in chemotherapy patients and for oral cavity and external surgical wounds.

Patterns of relapse following radiotherapy for differentiated thyroid cancer: implication for target volume delineation.

INTRODUCTION: Post-operative residual disease in differentiated thyroid cancer is an indication for external beam radiotherapy (EBRT) especially if there is poor radioiodine uptake by the residual disease. There are no standardized guidelines or consensus in target delineation for radiotherapy in thyroid cancer. AIMS: To determine the pattern of recurrence in patients with well differentiated thyroid cancer who received adjuvant or definitive radiotherapy as well as radioiodine ablation following surgery or biopsy with a view to better defining future target volume delineation for radiotherapy. MATERIALS AND METHODS: Forty-nine patients with differentiated thyroid cancer received radical external beam radiotherapy and radioiodine ablation (3.5GBq) following thyroidectomy or biopsy between 1990 and 2000. Nineteen patients had macroscopic residual (11) or inoperable disease (8), whilst 30 patients had clear (5) or microscopic positive resection margin (24), and 1 patient the resection margin status was unknown. All the patients were deemed high risk for local recurrence or progressive disease. The thyroid bed and regional nodes were irradiated using two radiotherapy techniques: (1) non co-planar lateral fields (NCLF) in coronal plane using 6MV photons to a dose of 45-50Gy in 16 fractions over 22 days and (2) anterior-posterior parallel pair of 6MV photons to a dose of 40-42.5Gy in 16 fractions over 22 days. There was no attempt to irradiate the lymph nodes in that part of the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina. RESULTS: The median follow-up was 5.4 years (range 0.9-12.4 years). The actuarial 5-year cause-specific survival and local control for the whole group was 75.7% and 81.4%, respectively. Of the 4 patients with mediastinal recurrence, all had neck recurrences and two had distant metastases. All the medisastinal recurrences occurred in superior mediastinum (level VII) and all were treated with NCLF in coronal plane radiotherapy technique. Furthermore, mediastinal recurrences did not occur in isolation. The 5-years loco-regional control rate was 89.1% for those with clear or microscopic positive margins and 69.2% for those with macroscopic residual or inoperable disease. Five-year cause specific survival was 58.3% for patients with macroscopic residual or inoperable disease and 91.4% for those with clear or microscopic positive margins. CONCLUSION: The status of postoperative margin relating to bulk of disease influences local control and cause specific survival. Surgical resection in locally advanced thyroid cancer should be performed by an experienced surgeon to achieve macroscopic clearance where possible. The majority of recurrences were loco-regional. The few superior mediastinal recurrences did not occur in isolation. All the mediastinal recurrences occurred in the superior mediastinum (level VII). We recommend the target volume should encompass the thyroid bed and regional neck nodes and the superior mediastinum level VII excluding the lymph nodes on both sides of the trachea within the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina (compartment 4). Thus, this should facilitate dose escalation to improve loco-regional control and avoiding radiation induced mediastinal toxicity.

Synergistic effects of imatinib (STI 571) in combination with chemotherapeutic drugs in head and neck cancer.

The tyrosine kinase inhibitor imatinib (STI 571; glivec) is a potent inhibitor of bcr-abl, c-kit and platelet-derived growth factor receptors. Imatinib was evaluated both alone and in combination with established chemotherapeutic agents in adenoid cystic carcinoma (ACC) primary cultures and established cell lines representing squamous cell carcinoma of the head and neck (HNSCC). Over 90% of ACC tumors are c-kit-positive, and these primary cultures proved to be of short-term usefulness in assessing chemosensitivity. Interaction was determined over a wide range of drug combinations using a statistical three-dimensional analysis model. Both ACC short-term cultures and HNSCC cell lines were demonstrated to have a response ranging from additive to synergistic when imatinib and cisplatin were combined. The interaction of imatinib on cisplatin-induced DNA cross-linking was further investigated using the comet-X assay. In contrast, significant antagonism was observed when imatinib and gemcitabine were combined. Since gemcitabine is activated by deoxycytidine kinase (dCK), the effect of imatinib on this enzyme was investigated. A dose-dependent inhibition of dCK was observed, highlighting this kinase as a possible additional secondary molecular target for imatinib. This work demonstrates a synergistic interaction between cisplatin and imatinib, which may prove to be clinically relevant in the future management of both ACC and HNSCC.

Radiotherapy for head and neck cancer in elderly patients.

BACKGROUND AND PURPOSE: Elderly patients with head and neck cancer may not be treated aggressively with radiotherapy, due to concerns regarding tolerance of treatment and toxicity. A retrospective study was undertaken of patients aged 80 years and over, treated by definitive radiotherapy for head and neck cancer. MATERIAL AND METHODS: 98 patients aged 80-92 received radiotherapy for carcinoma of the head and neck between 1991 and 1995. All patients received beam directed radiotherapy with radical intent using an immobilisation shell. RESULTS: Cancer specific survival was 59% and overall local control was 70% at 5 years. Both were significantly affected by T stage and site of disease. Cancer specific survival was comparable to that of patients aged below 80 years. Seven patients died within 6 months of the treatment. Three patients developed severe late toxicity. Metastatic disease occurred in eight patients. CONCLUSIONS: Radiotherapy is a beneficial and well tolerated treatment in elderly patients with carcinoma of the head and neck.

Three weeks radiotherapy for T1 glottic cancer: the Christie and Royal Marsden Hospital Experience.

BACKGROUND AND PURPOSE: Radiotherapy for laryngeal carcinoma is conventionally given over a 6-7-week period. However, in a number of UK centres early lesions are treated over 3 weeks. We review recent results of this policy and discuss the reasons why short treatment times may be advantageous. MATERIALS AND METHODS: Two hundred patients (100 from each centre) with T1 glottic invasive squamous cell carcinoma treated with definitive radiotherapy between 1989 and 1997 were analysed. The median age was 68 years. All patients received once daily fractionation, 5 days a week to a total tumour dose of 50.0-52.5 Gy in 16 fractions over 21 days; the fraction size ranged from 3.12 to 3.28 Gy. The median follow-up period was 5 years and 10 months. RESULTS: The 5-year local control rates with radiotherapy for the whole group was 93%; there were 14 recurrences of which seven were salvaged by laryngectomy giving an ultimate local control of 96%. The 5-year overall survival was 80% and cause specific survival at 5 years was 97%. Univariate analysis revealed that T1 substaging (P=0.82) and anterior commissure involvement (P=0.47) did not significantly influence local control. A severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment. There were no severe acute complications. CONCLUSIONS: Once daily radiotherapy over 3 weeks gives excellent local control in patients with T1 glottic squamous-cell carcinoma and has a low rate of severe complications. The short overall treatment time and large fraction size may be advantageous in radiotherapy of these well-differentiated tumours.