The combination of a chemotherapy doublet (gemcitabine and capecitabine) with a biological doublet (bevacizumab and erlotinib) in patients with advanced pancreatic adenocarcinoma. The results of a phase I/II study.

BACKGROUND: Preclinical data support the combined inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways in the treatment of pancreatic cancer. Following a dose finding phase I study the efficacy and toxicity of a four-drug regimen utilising the cytotoxic doublet of gemcitabine and capecitabine (GemCap), with the biological doublet of erlotinib and bevacizumab were further assessed in patients with advanced pancreatic cancer. PATIENTS AND METHODS: In a phase II expansion cohort, patients with chemonaive locally advanced or metastatic pancreatic cancer received gemcitabine (1000mg/m(2) D1, 8, 15), capecitabine (1400mg/m(2) D1-21), erlotinib (100mg daily) and bevacizumab (5mg/kg D1, 15) every 28days. The primary endpoint was radiological response rate by response evaluation criteria in solid tumours (RECIST). Computed tomography (CT) assessment was performed every 8weeks. Consolidation radiotherapy was considered in locally advanced patients following six cycles of treatment. RESULTS: In total 44 patients (phases I & II) were recruited. The median cycles delivered were 6 (range 1-16). Confirmed radiological responses were seen in 23% (95% confidence interval (CI): 11-38%) of patients. The median progression-free and overall survival for the entire cohort was 8.4 and 12.6months, respectively. In patients with metastatic disease the median overall survival was 10.1months. Common grade 3/4 toxicities were; neutropenia 52%, lethargy 32%, diarrhoea 18% and hand-foot syndrome 18%. CONCLUSION: The combination of gemcitabine, capecitabine, erlotinib and bevacizumab was feasible with a manageable toxicity profile and demonstrated encouraging efficacy data in a good performance status population.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection.

BACKGROUND: Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer, but to date, despite extensive research, no predictive or prognostic biomarkers for bevacizumab have been identified. The development of bevacizumab-induced arterial hypertension has recently been suggested as a potential predictive biomarker. METHODS: Blood pressure was recorded during the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. In this analysis, the development of bevacizumab-induced hypertension was correlated with clinical outcomes. RESULTS: Fifteen percent of patients developed ≥grade 1 hypertension while receiving neoadjuvant chemotherapy, and 4% developed grade 3 hypertension. There was no correlation between the development of hypertension and radiological response rate (P=0.642), progression-free survival (P=0.644) or overall survival (P=0.480) in those who developed hypertension compared with those who did not. CONCLUSION: Bevacizumab-induced hypertension did not predict radiological response or survival in our study. The results highlight a number of important issues regarding the use of hypertension as a biomarker.

A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma.

BACKGROUND: Targeting platelet-derived growth factor receptor-ß (PDGFR-ß) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-ß inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2-5) each cycle. RESULTS: Twenty-seven patients received 168 cycles in total. Median age was 61 years (44-74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1-7.0) and 5.6 months (95% CI 2.5-8.7), respectively. CONCLUSION: In gemcitabine-refractory PC, gemcitabine (1000 mg/m(2)) and oxaliplatin (85 mg/m(2)) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.

The prevalence of pain in patients attending sarcoma outpatient clinics.

The prevalence of pain in patients with sarcoma is not well documented. We investigated this in outpatients at a tertiary cancer referral centre, assessing the adequacy of pain control and for risk factors leading to higher prevalence and severity of pain. 149 patients were surveyed. Patients with pain within the previous 7 days completed pain assessment tools (BPI, S-LANSS, PMI). 53% of patients had pain within the previous 7 days, and 25% had significant pain. Of those with pain, 63% was inadequately controlled and neuropathic pain was identified in 36%. Age, gender, tumour type, and the type of cancer treatment were not significant predictors of the prevalence or severity of the pain. Based on our results, patients with sarcoma should be actively screened for pain and have regular reviews of their analgesic requirements.

A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.

BACKGROUND: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. PATIENTS AND METHODS: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). RESULTS: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. CONCLUSION: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction.

BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

Accuracy of multidetector computed tomography in identifying poor prognostic factors in colonic cancer.

BACKGROUND: Recent neoadjuvant strategies for high-risk colonic tumours have renewed interest in accurate preoperative staging. The aim of this study was to validate prospectively the accuracy of multidetector computed tomography (MDCT) in stratifying patients into good and poor prognostic groups in a multicentre setting. METHODS: Staging MDCT scans of 84 patients with colonic cancer were reviewed by two independent radiologists and stratified into low-risk (T1/T2 and T3 with extramural tumour depth (EMD) of less than 5 mm) and high-risk (T3 with EMD of at least 5 mm and T4) tumours. Nodal status and extramural venous invasion (EMVI) were also assessed. RESULTS: The accuracy, sensitivity, specificity and positive predictive value of stratification by CT compared with histological examination was 74 (95 per cent confidence interval 64 to 82), 78 (65 to 87), 67 (49 to 81) and 81 (68 to 89) per cent respectively. Accuracy for detecting malignant lymph nodes and EMVI was 58 and 70 per cent respectively. The agreement for predicting prognostic stratification was moderate (kappa = 0.54). CONCLUSION: As the ability of CT to identify node status is poor, the depth of tumour invasion beyond the muscularis propria is the most accurate way to identify patients with a poor prognosis who may be suitable for neoadjuvant treatment.

The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice.

BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.

Prevalence of pain in head and neck cancer out-patients.

BACKGROUND: This study aimed to determine the prevalence of pain, and the adequacy of its treatment, amongst patients with head and neck cancer, and to determine whether specific groups could be identified as being at risk of pain. METHODS: Consecutive patients attending head and neck oncology out-patient services were surveyed. RESULTS: The prevalence of pain was 34 per cent, lower than that found in systematic reviews. No specific risk factors for pain were identified. Particular pain problems in this population comprised a high incidence of neuropathic pain, breakthrough pain and pain of non-malignant origin. CONCLUSION: The prevalence of unrelieved pain was high in this study population, although no specific risk factors were found. A further study is planned to determine the effect of using a routine screening tool and an immediate pain treatment protocol in this group of patients.

Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.

PURPOSE: The aim of this study was to investigate prospectively the weekly volume changes in the target volumes and organs at risk and the resulting dosimetric changes during induction chemotherapy followed by chemoradiotherapy with intensity-modulated radiation therapy (C-IMRT) for head-and-neck cancer patients. METHODS AND MATERIALS: Patients receiving C-IMRT for head-and-neck cancer had repeat CT scans at weeks 2, 3, 4, and 5 during radiotherapy. The volume changes of clinical target volume 1 (CTV1) and CTV2 and the resulting dosimetric changes to planning target volume 1 (PTV1) and PTV2 and the organs at risk were measured. RESULTS: The most significant volume differences were seen at week 2 for CTV1 and CTV2. The reductions in the volumes of CTV1 and CTV2 at week 2 were 3.2% and 10%, respectively (p = 0.003 and p < 0.001). The volume changes resulted in a significant reduction in the minimum dose to PTV1 and PTV2 (2 Gy, p = 0.002, and 3.9 Gy, p = 0.03, respectively) and an increased dose range across PTV1 and PTV2 (2.5 Gy, p < 0.001, and 5.1 Gy, p = 0.008, respectively). There was a 15% reduction in the parotid volumes by week 2 (p < 0.001) and 31% by week 4 (p < 0.001). There was a statistically significant increase in the mean dose to the ipsilateral parotid only at week 4 (2.7 Gy, p = 0.006). The parotid glands shifted medially by an average of 2.3 mm (p < 0.001) by week 4. CONCLUSION: The most significant volumetric changes and dosimetric alterations in the tumor volumes and organs at risk during a course of C-IMRT occur by week 2 of radiotherapy. Further adaptive radiotherapy with replanning, if appropriate, is recommended.

Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers.

Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.

The impact of carcinoembryonic antigen flare in patients with advanced colorectal cancer receiving first-line chemotherapy.

BACKGROUND: Carcinoembryonic antigen (CEA) flare may have a favourable response to chemotherapy, but its impact on survival is unknown. This study aimed to evaluate the incidence of CEA flare and its impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with histologically proven advanced colorectal cancer undergoing first-line chemotherapy with three or more serial CEA measurements (one at baseline and two or more during treatment) were included. Patients were grouped according to CEA kinetic as flare (F), decreasing CEA, normal baseline CEA, stable CEA and increasing CEA (I). RESULTS: From January 2000 to February 2008, 837 patients were screened of whom 670 were eligible. CEA flare occurred in 78 (11.6%) patients. On multivariate analysis, compared with patients with increasing CEA, patients with CEA flare had a significantly better ORR [I versus F: 11% versus 73%; risk ratio (RR): 27.96; 95% confidence interval (CI): 9.55-81.88; P < 0.001], PFS (median 3.1 versus 8.3 months; RR: 0.38; 95% CI: 0.26-0.56; P < 0.001) and OS (median 10.9 versus 17.7 months; RR: 0.53; 95% CI: 0.34-0.82; P < 0.001). CONCLUSIONS: Compared with patients with rising CEA, flare was an independent favourable predictive and prognostic factor for tumour response and survival.

Frequency of screening magnetic resonance imaging to detect occult spinal cord compromise and to prevent neurological deficit in metastatic castration-resistant prostate cancer.

AIMS: Neurological deficit from malignant spinal cord compression (SCC) is a major complication of metastatic castration-resistant prostate cancer (CRPC). The aims of the present study were to determine the incidence of neurological deficit in metastatic prostate cancer patients and to determine the optimal frequency of screening magnetic resonance imaging (MRI) spine required to detect clinically occult radiological SCC (rSCC). MATERIALS AND METHODS: A retrospective analysis of the clinical data of 130 consecutive patients with CRPC, with no functional neurological deficit, who had screening MRI spine from January 2001 to May 2005, was undertaken. Patients found to have rSCC received radiotherapy. All patients were followed-up to document the incidence of neurological deficit. RESULTS: Thirty-seven (28.4%) patients had rSCC on MRI. The proportion of patients free from neurological deficit at 3, 6, 12, 18 and 24 months was 94, 80, 59 and 43%, respectively, in patients who had rSCC on initial MRI and 97.5, 89, 75 and 63%, respectively, in patients who had no rSCC. A high prostate-specific antigen (PSA) level at initial MRI (P = 0.035) and a short PSA doubling time < 3 months (P = 0.009) significantly predicted for neurological deficit on univariate analysis, whereas back pain (P = 0.059), although an important predictive factor, did not attain statistical significance. On multivariate analysis, only rapid PSA doubling time (<3 months) independently predicted for future neurological deficit (P = 0.042). CONCLUSION: MRI spine can be used to detect asymptomatic rSCC in patients with CRPC and serial estimations are required to maintain a low incidence of clinical SCC. If serial screening MRI spine is used to detect rSCC in 90% of patients before the development of neurological signs, the optimum frequency depends on the subset of patients studied. The results of our study suggest that the optimum frequency would be every 4-6 months for patients with previous SCC, rapid or high PSA or back pain and annually for asymptomatic patients.

Prospective assessment of MRI for imaging retroperitoneal metastases from testicular germ cell tumours.

AIM: To determine the sensitivity of magnetic resonance imaging (MRI) in the detection of retroperitoneal lymph nodes in patients with testicular germ cell tumours (TGCT). METHODS AND MATERIALS: A prospective study of 52 patients (mean age 34 years, range 18-54 years) was performed. Imaging of the retroperitoneum was performed using multidetector computed tomography (CT) and 1.5 T MRI systems. The CT and MRI images were read independently by three observers. The number, size, and site of enlarged nodes (> or =10 mm maximum short axis diameter) were recorded. Retroperitoneal nodal detection on MRI was compared to CT. RESULTS: Twenty-two (42%) of the 52 patients had no retroperitoneal disease; in remaining 30 patients 51 enlarged nodes were identified. On a per patient basis readers 1, 2, and 3 identified nodal disease in 28 of 29, 29 of 30, and 24 of 30 patients, respectively, using MRI compared to CT. Thus for experienced radiologists (readers 1 and 2) MRI is comparable to CT for nodal detection (i.e., this study excludes MRI being inferior to CT with 80% power and 5% type 1 error). CONCLUSION: MRI offers an alternative method for staging the retroperitoneum in young patients being followed for TGCT and has the major advantage of avoiding exposure to ionizing radiation.

Radical radiotherapy for treatment of malignant parotid tumours: a single centre experience 1995-2005.

Radiotherapy is commonly used to reduce the risk of recurrence of malignant parotid gland tumours. We report our experience with radiotherapy for parotid malignancies at the Royal Marsden Hospital. We retrospectively reviewed the case notes of 90 patients with malignant parotid tumours who were treated with megavoltage irradiation between 1995 and 2005 at the Royal Marsden Hospital, and obtained details about age, sex, pathology, type of operation, type of radiotherapy, and outcome. Outcome data included date of recurrence, whether local or metastatic, date of death, and cause of death. Outcome for patients who had definitive operations compared with those who did not were analysed separately. Forty-three patients (54%) had superficial parotidectomy, 26 (33%) had total parotidectomy, and 11 (13%) had fine needle aspiration (FNA). Adenocarcinoma, squamous cell carcinoma (SCC), and mucoepidermoid carcinoma were the most prevalent histologically confirmed tumours. Radiation was given most often by the lateral wedged pair field technique. Five-year locoregional control was better for patients who had definitive operations and postoperative radiotherapy than for those who did not (82% compared with 21%), disease-free survival was 58% compared with 29%, and overall survival was 68% compared with 0%, respectively.

Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery.

Transfer of healthy autologous tissue as a microvascular free flap facilitates reconstruction during ablative cancer surgery. In addition to filling surgical defects, free flaps might concentrate viral vectors at the tumour bed and mediate local therapeutic effects. We evaluated the magnitude, topography and duration of luciferase gene expression after plasmid and adenoviral delivery in rat superficial inferior epigastric (SIE) flaps. For plasmid delivery, luciferase expression was significantly increased by all transduction routes (topical, intraflap injection, intravascular) (P<0.01) at day 1, but not at day 7. The spread of luciferase expression was significantly different between the 4 groups at 1 day (P=0.026) and was greatest for flaps transduced by intravascular injection. For adenoviral transduction, total radiance was significantly different between the transduced groups at 1, 14 and 28 days (P<0.05 for all comparisons). The highest levels of radiance were seen in the intravascular group. There was a statistically significant difference in the spread of light emission between the 3 groups at 1 (P=0.009) and 14 (P=0.013) days, but this was no longer evident at 28 days. Intravascular adenoviral delivery yields high-level, diffuse and durable gene expression in rat SIE flaps and is suitable for examination in therapeutic models.

Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer.

We describe a retrospective series of patients with advanced head-and-neck cancer who were treated with induction chemotherapy followed by radical chemo-radiation. Patients treated with two cycles of induction chemotherapy followed by definitive chemo-radiation for squamous cell carcinoma of the head-and-neck region, from 2001 - 2006 at the Royal Marsden Hospital, formed the basis of this study. Cisplatin (75 mg m(-2)) on day 1 and 5-FU (1000 mg m(-2)) day 1 - 4 was the standard regimen used for induction treatment. Cisplatin (100 mg m(-2)) on day 1 and day 29 was used for concomitant treatment. The radiation was delivered using conformal technique. Tissues containing macroscopic and microscopic disease were treated to doses of 65 Gray (Gy) in 30 fractions and 50 Gy in 25 fractions, respectively. Data on patterns of relapse and acute toxicity (NCICTCv.3.0) were collected. A total of 129 patients were included, median age was 58 (range: 27 - 78). The site of tumour was: oropharynx 70 (54%), larynx 30 (23%), hypopharynx 24 (19%) and other 5 (4%). The median follow-up was 19 months (range: 4 - 58). Local control, disease-specific survival and overall survival at 2 years were 71%, 68% and 63%, respectively. The distant recurrence rate at 2 years was 9%. Ten patients required dose reduction during induction chemotherapy due to toxicity. The dose of 5-FU was reduced in six patients and that of cisplatin in four patients. The incidence of grade 3/4 toxicity was: neutropenia 5%, thrombocytopenia 1%, nausea and vomiting 3%. One cycle of concurrent cisplatin was omitted in 23 patients due to toxicity. Full-dose radiotherapy was administered to 98% of patients. The incidence of grade 3/4 toxicity was: skin 20%, dysphagia 65%, mucositis 60%, neutropenia 3%, anaemia 1%, nausea and vomiting 4%, nephrotoxicity 1%. Induction chemotherapy followed by radical chemo-radiation is a safe and tolerable regimen in the treatment of advanced head-and-neck cancer. Distant recurrence rates are lower with equivalent local control and survival compared to chemo-radiation alone (historical controls).

Experience in a UK cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and primary peritoneal cancer.

OBJECTIVES: Weekly paclitaxel (WP) has been reported to have significant activity in patients with ovarian and primary peritoneal cancer patients while retaining a favorable toxicity profile. This study assessed the current usage of WP in routine clinical practice in a tertiary cancer center. METHODS: We conducted a retrospective audit in 53 patients with recurrent ovarian or primary peritoneal cancer treated with WP (80-100 mg/m(2)) over a 2-year period (Nov 2003-Nov 2005). Toxicity was assessed using Common Toxicity Criteria, and response was evaluated using radiological and CA-125 criteria. RESULTS: Patients had a median age of 69 (36-86) and previously received a median of 3 treatments (range 1-7). A median of 13 weekly doses of paclitaxel (range 1-39) were given. The response rate was 48% by radiological criteria and 69% by CA-125 assessment. Grade 3 toxicities were fatigue (13% of patients), peripheral neuropathy (11%) and neutropenia (8%) and there were no grade 4 toxicities. The median progression-free survival was 4. 8 months and median survival was 13. 5 months. There was no significant difference in efficacy between those 24 patients previously treated with taxanes (radiol. response 43%/CA-125 response 63%) and those 29 patients who had not received prior taxanes (radiol. response 52%/CA-125 response 76%). There was also no difference in efficacy for patients with platinum-free or treatment-free intervals of less than 6 months compared to 6 months or longer. CONCLUSIONS: WP is a well tolerated and active regimen in patients with pre-treated ovarian cancer and its use in recurrent disease is likely to increase. Further studies should aim to assess the importance of the "paclitaxel-free interval" in predicting response in relapsed disease, along similar lines as are now established for platinums.