• Targeted agents in non-small cell lung cancer (NSCLC): Clinical developments and rationale for the combination with thoracic radiotherapy.

      Koh, Pek K; Faivre-Finn, Corinne; Blackhall, Fiona H; De Ruysscher, D; Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. (2011-12-22)
      In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions.
    • Testicular seminoma with mediastinal lymphadenopathy -- a diagnostic pitfall.

      Jegannathen, Apurna; Taylor, Malcolm B; Jones, M; Logue, John P; Departments of Clinical Oncology, Christie Hospital NHS Foundation Trust, Manchester, UK. (2009-05)
      Relapse following adjuvant paraaortic radiation therapy in patients with Stage I seminoma is rare, occurring in approximately 4% of men. The majority of relapses are sited in the pelvis but relapse in the mediastinum is also recognised. As such, radiological imaging using chest radiographs remains commonplace in follow-up. However, there are reports of the association of testicular cancers with sarcoidosis and sarcoid-like processes in the mediastinum, emphasising the importance of making histological diagnosis prior to commencement of any treatment. We report on two men treated for testicular seminoma who on follow-up developed mediastinal lymphadenopathy, which was initially assumed to be metastatic seminoma. Both patients underwent mediastinascopy and biopsy prior to commencement of anti-cancer therapy. In both cases, the biopsies showed sarcoidosis, and unnecessary anti-cancer treatment was avoided.
    • Treatment for advanced cervical cancer: Impact on quality of life.

      Davidson, Susan E; The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. (2010-08-30)
      Cisplatin-based combinations can potentially improve response rates in patients with cervical cancer, but unacceptable toxicity must be avoided. Quality of life (QoL) measures are increasingly used to assess the benefits versus limitations of chemotherapy regimens. A MEDLINE search of English language publications from January 2000 to December 2008 was conducted using the search terms: 'quality of life' OR 'QoL' OR 'HRQoL' AND 'cervical cancer'. Abstracts from the Association of Clinical Oncology meeting, 2008, were also searched. Article inclusion was based on abstract content. Several cervical cancer therapies have shown response rate improvements in combination with cisplatin, including topotecan and paclitaxel. However, only topotecan/cisplatin demonstrates a significant overall survival advantage over cisplatin monotherapy, while both topotecan/cisplatin and paclitaxel/cisplatin demonstrate comparable impact on QoL to cisplatin alone. Few trials of combination chemotherapy for cervical cancer have directly assessed QoL. The combination of topotecan/cisplatin significantly increases overall survival rates without reducing patient QoL.
    • UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan.

      Ferraldeschi, Roberta; Minchell, Laura J; Roberts, Stephen A; Tobi, Simon; Hadfield, Kristen D; Blackhall, Fiona H; Mullamitha, Saifee A; Wilson, Gregory; Valle, Juan W; Saunders, Mark P; et al. (2009-05)
      AIMS: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. MATERIALS & METHODS: Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. RESULTS: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles. CONCLUSION: Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.
    • The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage.

      Howell, Sacha J; Searle, C; Goode, Valerie; Gardener, T; Linton, Kim M; Cowan, Richard A; Harris, Maggie A; Hopwood, Penelope; Swindell, Ric; Norman, Alison; et al. (2009-08-18)
      BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5+/-8.35 years and the mean FU duration for those unaffected by BC was 14.6+/-9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.
    • Ultrasound Imaging to Assess Inter- and Intra-fraction Motion during Bladder Radiotherapy and its Potential as a Verification Tool.

      McBain, Catherine A; Green, M M; Stratford, Julia; Davies, Julie; McCarthy, Claire; Taylor, Benjamin; McHugh, D; Swindell, Ric; Khoo, Vincent S; Price, Patricia M; et al. (2009-06)
      AIMS: Organ motion is the principle source of error in bladder cancer radiotherapy. The aim of this study was to evaluate ultrasound bladder volume measurement as a surrogate measure of organ motion during radiotherapy: (1) to assess inter- and intra-fraction bladder variation and (2) as a potential treatment verification tool. MATERIALS AND METHODS: Twenty patients receiving radical radiotherapy for bladder cancer underwent post-void ultrasound bladder volume measurement at the time of radiotherapy treatment planning (RTP), and immediately before (post-void) and after receiving daily fractions. RESULTS: Ultrasound bladder volume measurement was found to be a simple and acceptable method to estimate relative bladder volume changes. Six patients showed significant changes to post-void bladder volume over the treatment course (P<0.05). The mean inter-fraction post-void bladder volume of five patients exceeded their RTP ultrasound bladder volume by more than 50%. Intra-fraction bladder volume increased on 275/308 (89%) assessed fractions, with the mean intra-fraction volume increases of seven patients exceeding their RTP ultrasound bladder volume by more than 50%. CONCLUSIONS: Both day-to-day bladder volume variation and bladder filling during treatment should be considered in RTP and delivery. Ultrasound may provide a practical daily verification tool by: supporting volume limitation as a method of treatment margin reduction; allowing detection of patients who may require interventions to promote bladder reproducibility; and identifying patients with prominent volume changes for the selective application of more advanced adaptive/image-guided radiotherapy techniques.
    • Use of G-CSF during concurrent chemotherapy and thoracic radiotherapy in patients with limited-stage small-cell lung cancer safety data from a phase II trial.

      Sheikh, Hamid Y; Colaco, Rovel J; Lorigan, Paul C; Blackhall, Fiona H; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nick; Faivre-Finn, Corinne; Dept of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK. (2011-10)
      There is paucity of data in the literature regarding the safety of combining granulocyte colony stimulating factor (G-CSF) during chemo-radiotherapy (CTRT) in lung cancer patients. The ASCO 2006 recommendations advise against use of CSFs during concomitant mediastinal CTRT. The only randomised study evaluating CSFs in this context showed significant increase in grade 3/4 thrombocytopenia and an excess of pulmonary toxic deaths. In the context of a phase II trial, 38 patients with limited-stage small cell lung cancer were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy. Radiotherapy (RT) was given concurrently with cisplatin and etoposide. G-CSF was given as primary or secondary prophylaxis or as a therapeutic measure during an episode of febrile neutropenia according to local protocols. Common terminology criteria for adverse events (CTCAE) v3.0 was used to record toxicity. Thirteen (34%) of 38 patients received G-CSF concurrently with RT. With a median follow-up of 16.9 months, there were no treatment related deaths reported. Seven (54%) patients experienced grade 3/4 thrombocytopenia and 5 (38%) experienced grade 3/4 anaemia. Thirty-one percent required platelet transfusions. No episodes of bleeding were observed. There were no cases of grade 3/4 acute pneumonitis. These data suggests that with modern three-dimensional (3D) conformal RT, G-CSF administration concurrently with CTRT does not result in the increase risk of pulmonary toxicity, but does increase the risk of thrombocytopenia. Whether the risks of thrombocytopenia are outweighed by the outcome of timely early concurrent CTRT is being evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563) in which G-CSF is permitted during thoracic irradiation.
    • Use of multiple biological markers in radiotherapy-treated head and neck cancer.

      Silva, Priyamal; Slevin, Nicholas J; Sloan, Philip; Valentine, Helen R; Ryder, W David J; Price, Patricia M; West, Catharine M L; Homer, Jarrod J; School of Cancer & Enabling Sciences, The University of Manchester, Manchester, UK. (2010-06)
      OBJECTIVE: Management of patients with head and neck squamous cell carcinoma is often based on clinical parameters, with little appreciation of the underlying tumour biology. Single biological marker studies fail to acknowledge the complexity of these tumours. Our aim was to define a profile of biological markers associated with outcome. DESIGN: This retrospective study involved consecutive patients with oropharyngeal squamous cell carcinoma treated with primary radiotherapy between 1996 and 2001. Pre-treatment biopsies were used to study the immunohistochemical expression of nine biological markers. Markers were chosen to reflect biologically relevant pathways. RESULTS: Following analysis of nine markers, a profile of two markers was derived (carbonic anhydrase 9 and major vault protein), the co-expression of which conferred a significantly poor probability of locoregional control. The prognostic effect of these biomarkers in combination was greater than their effect individually. CONCLUSION: Biomarker profiles can be established which highlight large differences in locoregional control. Identifying tumours that express both carbonic anhydrase 9 and major vault protein may facilitate patient selection for more aggressive treatment.
    • Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre Phase I study.

      Saunders, Mark P; Wilson, R; Peeters, M; Smith, R; Godwood, A; Oliver, S; Van Cutsem, E; Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK, Mark.Saunders@christie.nhs.uk. (2009-01-29)
      PURPOSE: The safety and tolerability of vandetanib (ZACTIMAtrade mark; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC). METHODS: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI. RESULTS: A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease >/=8 weeks (100 mg, n = 7; 300 mg, n = 2). CONCLUSIONS: Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.
    • What Three Wise Men have to say about diagnosis.

      Mani, Navin; Slevin, Nicholas J; Hudson, Andrew M; Department of Head and Neck Surgical Oncology, Christie Hospital, Manchester M20 4BX, UK. (2011)