P. Sanghera

Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.

AIMS With the aim of improving locoregional control, the use of preoperative chemoradiotherapy (CRT) for rectal cancer has increased. A pathological complete response (pCR) is often used as a surrogate marker for the efficacy of different CRT schedules. By analysing factors affecting pCR, this analysis aims to guide the development of future trials. MATERIALS AND METHODS Searches of Medline, EMBASE and the electronic American Society of Clinical Oncology abstract databases were carried out to identify prospective phase II and phase III trials using preoperative CRT to treat rectal cancer. Trials were eligible for inclusion if they defined: the CRT drugs, the radiation dose and the pCR rate. Phase I patients were excluded from the analysis. A multivariate analysis examined the effect of the above variables on the pCR rate and in addition the use of neoadjuvant chemotherapy, the type of publication (peer reviewed vs abstract), the year of publication and whether the cancers were stated to be inoperable, fixed or threatening the circumferential resection margin were included. The method of analysis used was weighted linear modelling of the pCR rate. RESULTS Sixty-four phase II and seven phase III trials were identified including a total of 4732 patients. Statistically significant factors associated with pCR were the use of two drugs, the method of fluoropyrimidine administration (with continuous intravenous 5-fluorouracil being the most effective) and a higher radiotherapy dose. Although the use of two drugs was associated with a higher rate of pCR, no single schedule seemed to be more effective. None of the other factors analysed significantly influenced pCR. CONCLUSIONS A higher rate of pCR is seen in studies using two drugs, infusional 5-fluorouracil and a radiotherapy dose of 45 Gy and above.

Patterns of relapse in glioblastoma multiforme following concomitant chemoradiotherapy with temozolomide

OBJECTIVE Different methods for contouring target volumes are currently in use in the UK when irradiating glioblastomas post operatively. Both one- and two-phase techniques are offered at different centres. 90% of relapses are recognised to occur locally when using radiotherapy alone. The objective of this evaluation was to determine the pattern of relapse following concomitant radiotherapy with temozolomide (RT-TMZ). METHODS A retrospective analysis of patients receiving RT-TMZ between 2006 and 2010 was performed. Outcome data including survival were calculated from the start of radiotherapy. Analysis of available serial cross-sectional imaging was performed from diagnosis to first relapse. The site of first relapse was defined by the relationship to primary disease. Central relapse was defined as progression of the primary enhancing mass or the appearance of a new enhancing nodule within 2 cm. RESULTS 105 patients were identified as receiving RT-TMZ. 34 patients were not eligible for relapse analysis owing to either lack of progression or unsuitable imaging. Patterns of first relapse were as follows: 55 (77%) patients relapsed centrally within 2 cm of the original gadolinium-enhanced mass on MRI, 13 (18%) patients relapsed >4 cm from the original enhancement and 3 (4%) relapsed within the contralateral hemisphere. CONCLUSION Central relapse remains the predominant pattern of failure following RT-TMZ. Single-phase conformal radiotherapy using a 2-cm margin from the original contrast-enhanced mass is appropriate for the majority of these patients. ADVANCES IN KNOWLEDGE Central relapse remains the predominant pattern of failure following chemoradiotherapy for glioblastomas.

The role of positron emission tomography/CT imaging in head and neck cancer patients after radical chemoradiotherapy

OBJECTIVES Positron emission tomography with CT (PET/CT) scanning is increasingly being used in head and neck cancer to assess response after radical concomitant chemoradiotherapy. The purpose of this study was to assess the use of PET/CT following chemoradiotherapy at our institution. METHODS All patients receiving radical chemoradiotherapy for head and neck cancer over a 9-year period were retrospectively identified. Outcome data including local control and overall survival were collected for all patients. The negative predictive value of PET/CT for local recurrence was calculated. Of those with a reported positive PET/CT scan the maximum standardised uptake values were compared with the incidence of local recurrence. RESULTS 92 patients were identified having a post-treatment PET/CT from a total of 301 patients receiving radical concomitant chemoradiotherapy. Median time from completion of chemoradiotherapy to PET/CT scan was 3 (range 2-8) months. Median follow-up in surviving patients was 19 and 25 months in the PET/CT and non-PET/CT groups, respectively. The negative predictive value for local recurrence was 91.8%. The median maximum standardised uptake values were 10.2 (range 3.1-33) and 6.89 (range 3.1-30) in those with local recurrence and with no local recurrence, respectively. CONCLUSIONS Post-chemoradiotherapy PET/CT may aid subsequent management decisions. Patients with a negative PET/CT scan after radical chemoradiotherapy have a 91.8% chance of remaining free of local recurrence 19 months post-treatment. A higher maximum standardised uptake value on the post-chemoradiotherapy PET/CT may predict subsequent local recurrence and warrants further investigation. Advances in knowledge Post-chemoradiotherapy PET/CT imaging aids subsequent management decisions.

Linear accelerator stereotactic radiosurgery for vestibular schwannomas: a UK series.

AIMS To evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas. MATERIALS AND METHODS The institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage. RESULTS Ninety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve. CONCLUSIONS SRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

Neurocognitive Effects Following Cranial Irradiation for Brain Metastases

About 90% of patients with brain metastases have impaired neurocognitive function at diagnosis and up to two-thirds will show further declines within 2-6 months of whole brain radiotherapy. Distinguishing treatment effects from progressive disease can be challenging because the prognosis remains poor in many patients. Omitting whole brain radiotherapy after local therapy in good prognosis patients improves verbal memory at 4 months, but the effect of higher intracranial recurrence and salvage therapy rates on neurocognitive function beyond this time point is unknown. Hippocampal-sparing whole brain radiotherapy and postoperative stereotactic radiosurgery are investigational techniques intended to reduce toxicity. Here we describe the changes that can occur and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice.

The use of MuGard™, Caphosol® and Episil® in patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck

IntroductionOral mucositis is common for patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). Despite the significant detrimental sequelae associated, there is no consensus on the optimum mouth care regimen. This prospective audit aims to record mucositis and dysphagia toxicity and the level of analgesia prescribed when recent products: MuGard™, Caphosol® and Episil® are compared with our standard departmental mouth care regimen.MethodsPatients undergoing concurrent chemoradiotherapy for locally advanced SCCHN at University Hospital Birmingham, UK were prospectively audited weekly for 8 consecutive weeks starting from week 1 of chemoradiotherapy from June 2009 until January 2011. Patients received either standard oral care regimen of aspirin, glycerin and sucralfate, or, MuGard™, Caphosol® or Episil®. Grade of mucositis, dysphagia and analgesia score were prospectively recorded using the common toxicity criteria v3·0.ResultsOne hundred and four patients were included. There was no difference in the grade and duration of mucositis (p = 0·82), dysphagia (p = 0·99) or analgesia score (p = 0·61) for either MuGard™, Caphosol® or Episil® compared with standard oral care.ConclusionThere is no evidence from this audit that Mugard™, Caphosol® or Episil® improves mucositis and dysphagia toxicity or the level of analgesia prescribed compared with our standard departmental mouth care regimen. Randomised trials comparing these approaches are required to detect any meaningful clinical benefit.

Can radiobiological parameters derived from squamous cell carcinoma of the head and neck be used to predict local control in anal cancer treated with chemoradiation

OBJECTIVES Parameters have been derived in head and neck cancer to account for the additional biological effective dose provided by synchronous chemotherapy. The purpose of this study was to establish whether such parameters could be used to predict local control differences in anal cancer. METHODS In anal cancer two randomised trials of radiotherapy vs chemoradiotherapy and two trials randomising between different synchronous chemotherapy regimens were identified. To predict differences in local control between the arms of the first two studies, a global value of 9.3 Gy for the chemotherapy biologically effective dose was employed. For the last two trials, values specific to differing chemotherapy schedules were derived. These values were added to the calculated biological effective dose for the radiotherapy component in order to predict local control outcomes in anal cancer trials. RESULTS The predicted difference in local control using the global value of 9.3 Gy for the addition of synchronous chemotherapy in the trials of radiotherapy vs radiotherapy and synchronous chemotherapy was 24.6% compared with the observed difference of 21.4%. Using schedule-specific values for the contribution of chemotherapy, the predicted differences in local control in the two trials of differing synchronous chemotherapy schedules were 7.2% and 12% compared with the observed 18% and 0%. CONCLUSION The methods initially proposed require modification to result in adequate prediction. If the decreased cisplatin dose intensity employed in anal cancer is modelled, more satisfactory predictions for such trials can be achieved. ADVANCES IN KNOWLEDGE This revised modelling may be hypothesis generating.

Implementing Head and Neck Contouring Peer Review without Pathway Delay: The On-demand Approach

AIMS Peer review of contour volume is a priority in the radiotherapy treatment quality assurance process for head and neck cancer. It is essential that incorporation of peer review activity does not introduce additional delays. An on-demand peer review process was piloted to assess the feasibility and efficiency of this approach, as compared with a historic scheduled weekly approach. MATERIALS AND METHODS Between November 2016 and April 2017 four head and neck clinicians in one centre took part in an on-demand peer review process. Cases were of radical or adjuvant intent of any histology and submitted on a voluntary basis. The outcome of contour peer review would be one of unchanged (UC), unchanged with variation or discretion noted (UV), minor change (M) or significant change (S). The time difference between the completion of the on-demand peer review was compared with the time difference to a hypothetical next Monday or Tuesday weekly peer review meeting. The time taken to review each case was also documented in the latter period of the pilot project. RESULTS In total, 62 cases underwent peer review. Peer review on-demand provided dosimetrists with an average of an extra two working days available per case to meet treatment start dates. The proportion of cases with outcomes UC, UV, M and S were 45%, 16%, 26% and 13%, respectively. The mean peer review time spent per case was 17 min (12 cases). The main reason for S was discrepancy in imaging interpretation (4/8 cases). A lower proportion of oropharyngeal cases were submitted and had S outcomes. A higher proportion of complex cases, e.g. sinonasal/nasopharynx location or previous downstaging chemotherapy had S outcomes. The distribution of S outcomes appears to be similar regardless of clinician experience. The level of peer review activity among individuals differed by workload and job timetable. CONCLUSION On-demand peer review of the head and neck contour volume is feasible, reduces delay to the start of dosimetry planning and bypasses the logistical barriers of weekly meetings. An audit of participation will be required to ensure successful implementation.

Can Synchronous Chemotherapy be Added to Accelerated Hypofractionated Radiotherapy in Patients with Base of Tongue Cancer

AIM To evaluate the tolerability of synchronous chemotherapy and accelerated hypofractionated radiotherapy in patients with locally advanced squamous cell carcinoma of the base of the tongue. MATERIALS AND METHODS Between 1999 and 2004, 43 patients with stage II-IV squamous cell carcinoma of the base of the tongue were treated with a combined modality of radiotherapy (prescribed 55 Gy in 20 fractions), synchronous chemotherapy and in some cases surgical neck dissection. End points were acute and late toxicity, 3 year locoregional control, overall survival, cancer-specific survival and compliance. RESULTS The median follow-up for surviving patients was 3.9 years. All patients completed radiotherapy and 30% received neoadjuvant chemotherapy. The median time for the completion of treatment was 27 days (range 25-36). Overall, only 42% completed the prescribed synchronous chemotherapy. However, compliance increased to 60% in patients who did not receive neoadjuvant chemotherapy. Grade 3 mucositis developed in 90% of patients. Prolonged grade 3 mucositis (>4 weeks) was seen in 24/43 (56%) and none developed grade 4 mucositis. There were no toxic deaths. Feeding tube dependency at 1 year was 14%. The 3 year locoregional control, overall survival and cancer-specific survival were 70, 60 and 60%, respectively. Clinical T staging was most significantly associated with poor overall survival, cancer-specific survival and local control. Distant metastases occurred in 6/43 patients (14%), 5/6 without locoregional recurrence. CONCLUSION The addition of synchronous chemotherapy to accelerated hypofractionated radiotherapy consistently led to grade 3 mucositis. Tumour control rates compare well with published outcomes. Higher mucosal toxicity and lower synchronous chemotherapy compliance compared with other series may suggest that this approach is at the limit of patient tolerability. However, the tumour site investigated and the choice of synchronous chemotherapy agent may also be important. Compliance may be improved using intensity-modulated radiotherapy and agents that do not enhance mucosal toxicity. Longer fractionation will probably increase compliance with chemotherapy, particularly when induction is used before synchronous treatment.

The effect of silver sulfadiazine and zinc oxide creams on dose distribution during radiotherapy.

Introduction The use of metallic containing creams to prevent and treat radiodermatitis is controversial and lacking evidence base. We compare the dose effect of two metallic-based skin creams, which could be used for treating radiodermatitis, to a control. Methodology Universal containers of silver sulfadiazine cream, zinc oxide cream and aqueous cream were examined using a computed tomography scanner to assess their electron densities relative to water. Second, each cream was exposed to 100 kV and 6 MV photons. The relative doses were measured using an X-ray chamber. Results The relative electron density measured was similar for the silver sulfadiazine and aqueous creams. Zinc oxide was 40% higher. The relative dose measurements showed that silver sulfadiazine behaved in a similar way to aqueous cream; however, zinc oxide cream exhibited a dose difference of 11·0% in kV photons and −4·1% in MV photons. Conclusion Application of silver sulfadiazine appears unlikely to bring about significant changes in the dose distribution when compared with aqueous during MV or kV radiotherapy. While zinc oxide cream brought about more significant dose changes.