Induction chemotherapy followed by chemoradiation in locally advanced pancreatic cancer: an effective and well-tolerated treatment.

AIMS: The treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone. MATERIALS AND METHODS: Case notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500-5040cGy in 25-28 daily fractions with gemcitabine as a radiosensitiser. RESULTS: Of the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n=26) was 9.2 (6.8-11.9) months and was 15.3 (11.6-upper limit not reached) months for patients who received chemoradiation (n=16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered. CONCLUSIONS: In this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that 'consolidation' chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer.

Prospective cohort comparison of neoadjuvant chemoradiotherapy versus chemotherapy in patients with oesophageal cancer.

BACKGROUND: Chemotherapy and chemoradiotherapy are common neoadjuvant treatments for resectable T3 N0-1 M0 oesophageal carcinoma. The aim of this study was to compare the outcomes of these therapies in consecutive cohorts of patients. METHODS: Between January 1998 and December 2001, 88 patients received neoadjuvant chemoradiotherapy (two cycles of cisplatin and 5-fluorouracil (5-FU), prior to 45 Gy in 25 F concurrent radiotherapy with cisplatin and 5-FU). From 2002, 117 patients received neoadjuvant chemotherapy (76 patients had two cycles of cisplatin and 41 had four cycles of epirubicin, cisplatin and 5-FU). The primary outcome measure was survival, and analysis was by intention to treat. RESULTS: Postoperative morbidity and mortality rates were 56 per cent (40 patients) and 10 per cent (seven patients) respectively in the chemoradiotherapy group, compared with 47 per cent (46 patients) and 1 per cent (one patient) in the chemotherapy group (P = 0.008). The cumulative 5-year survival rate by intention to treat was 35 per cent after chemoradiotherapy versus 21 per cent after chemotherapy (P = 0.188). The cumulative corrected 5-year survival rate after completed treatment was 44 per cent for chemoradiotherapy compared with 25 per cent for chemotherapy (P = 0.032). CONCLUSION: Neoadjuvant chemoradiotherapy should remain an option for patients with satisfactory performance status.

Prospective comparison of transthoracic versus transhiatal esophagectomy following neoadjuvant therapy for esophageal cancer.

Transthoracic esophagectomy (TT) has been championed as a better cancer operation than transhiatal esophagectomy (TH) because the approach facilitates meticulous wide tumor excision and lymphadenectomy. However, neoadjuvant chemoradiotherapy (CRTS) and chemotherapy (CS) have been reported to improve outcomes, and we aimed to compare outcomes after multimodal therapy related to the operative approach. One hundred and fifty-one consecutive patients were studied prospectively. All patients were staged with computed tomography and endoluminal ultrasound, and treatment decisions were related to stage and performance status. One hundred and nineteen TT (median age 58 years, 92 male, 54 CRTS, 65 CS) were performed compared to 32 TH (median age 57 year, 27 male, 14 CRTS, 18 CS). Primary outcome measure was survival. Post-operative morbidity and mortality were 54% and 4%, respectively, after TT compared with 59% and 6% after TH (chi2 0.239 df 1, P=0.625). Recurrent cancer was no less frequent after TT (52%) than after TH (37.5%, chi2 2.151 df=1, P=0.142). Cumulative uncorrected 5-year survival was 34% after TT compared with 53% after TH (log rank 1.44, df=1, P=0.2298). Median survival was also similar in lymph node positive patients (TT vs. TH, 23 months vs. 22 months, respectively, log rank 0.25, df=1, P=0.6199). Despite the fact that patients receiving multimodal therapy and a TH esophagectomy were less fit, operative morbidity, mortality and recurrence were similar, and survival did not differ significantly when compared with multimodal TT esophagectomy.

Small cell oesophageal carcinoma: an institutional experience and review of the literature.

Primary small cell oesophageal carcinoma (SCOC) is rare, prognosis is poor and there is no established optimum treatment strategy. It shares many clinicopathologic features with small cell carcinoma of the lung; therefore, a similar staging and treatment strategy was adopted. Sixteen cases referred to Velindre hospital between 1998 and 2005 were identified. Patients received platinum-based combination chemotherapy if appropriate. Those with limited disease (LD) received radical radiotherapy (RT) to all sites of disease on completion of chemotherapy. Median survival of all patients was 13.2 months. Median survival of patients with LD was significantly longer than those with extensive disease (24.4 vs 9.1 months, P=0.034). This is one of the largest single institution series in the world literature. Combined modality therapy using platinum-based combination chemotherapy and radical RT may allow a nonsurgical approach to management, avoiding the morbidity of oesophagectomy. Prophylactic cranial irradiation is controversial, and should be discussed on an individual basis.

Prognostic significance of body mass indices for patients undergoing esophagectomy for cancer.

The aim of this study was to determine the role of body mass index (BMI) in a Western population on outcomes after esophagectomy for cancer. Two hundred and fifteen consecutive patients undergoing esophagectomy for esophageal cancer of any cell type were studied prospectively. Patients with BMIs > 25 kg/m were classified as overweight and compared with control patients with BMIs below these reference values. Ninety-seven patients (45%) had low or normal BMIs, 86 patients (40%) were overweight, and a further 32 (15%) were obese. High BMIs were associated with a higher incidence of adenocarcinoma versus squamous cell carcinoma (83%vs. 14%, P = 0.041). Operative morbidity and mortality were 53% and 3% in overweight patients compared with 49% (P = 0.489) and 8% (P = 0.123) in control patients. Cumulative survival at 5 years was 27% for overweight patients compared with 38% for control patients (P = 0.6896). In a multivariate analysis, age (hazard ratio [HR] 1.492, 95% CI 1.143-1.948, P = 0.003), T-stage (HR 1.459, 95% CI 1.028-2.071, P = 0.034), N-stage (HR 1.815, 95% CI 1.039-3.172, P = 0.036) and the number of lymph node metastases (HR 1.008, 95% CI 1.023-1.158, P = 0.008), were significantly and independently associated with durations of survival. High BMIs were not associated with increased operative risk, and long-term outcomes were similar after R0 esophagectomy.

Multidisciplinary team management is associated with improved outcomes after surgery for esophageal cancer.

We aim to compare the outcomes of patients undergoing R0 esophagectomy by a multidisciplinary team (MDT) with outcomes after surgery alone performed by surgeons working independently in a UK cancer unit. An historical control group of 77 consecutive patients diagnosed with esophageal cancer and undergoing surgery with curative intent by six general surgeons between 1991 and 1997 (54 R0 esophagectomies) were compared with a group of 67 consecutive patients managed by the MDT between 1998 and 2003 (53 R0 esophagectomies, 26 patients received multimodal therapy). The proportion of patients undergoing open and closed laparotomy and thoracotomy decreased from 21% and 5%, respectively, in control patients, to 13% and 0% in MDT patients (chi2 = 11.90, DF = 1, P = 0.001; chi2 = 5.45, DF = 1, P = 0.02 respectively). MDT patients had lower operative mortality (5.7%vs. 26%; chi2 = 8.22, DF = 1, P = 0.004) than control patients, and were more likely to survive 5 years (52%vs. 10%, chi2 = 15.05, P = 0.0001). In a multivariate analysis, MDT management (HR = 0.337, 95% CI = 0.201-0.564, P < 0.001), lymph node metastases (HR = 1.728, 95% CI = 1.070-2.792, P = 0.025), and American Society of Anesthesiologists grade (HR = 2.207, 95% CI = 1.412-3.450, P = 0.001) were independently associated with duration of survival. Multidisciplinary team management and surgical subspecialization improved outcomes after surgery significantly for patients diagnosed with esophageal cancer.

Definitive chemoradiation in patients with inoperable oesophageal carcinoma.

We performed a retrospective study of 90 consecutive cases with inoperable carcinoma of the oesophagus treated with definitive chemoradiation at a single cancer centre between 1995 and 2002. For the last 4 years, 73 patients have received therapy according to an agreed protocol. This outpatient-based regimen involves four cycles of chemotherapy, cycles 3 and 4 given concurrently with 50 Gy external beam radiotherapy (XRT) delivered in 25 fractions over 5 weeks. Cisplatin 60 mg m(-2) day(-1) is given every 3 weeks together with continuous infusional 5-fluorouracil 300 mg m(-2) day(-1), reduced to 225 mg m(-2) day(-1) during the XRT. In all, 45 (50%) patients suffered one or more WHO grade 3/4 toxicity, grade 3 in 93% cases. Patients received more than 90% of the planned chemoradiation schedule. The median overall survival was 26 (15, >96) months, 51% (41, 64) and 26% (13, 52) surviving 2 and 5 years, respectively. Advanced stage, particularly T4 disease, was associated with a worse prognosis. Patients considered not suitable for surgery for reasons other than their disease, mainly co-morbidity, had a significantly better outcome, median survival 40 (26, >96) months, 2- and 5-year survivals 67% (54, 84) and 32% (13, 79), respectively (P<0.001). This schedule is a feasible, tolerable and effective treatment for patients with oesophageal cancer considered unsuitable for surgery.

The significance of cardiac doses received during chemoradiation of oesophageal and gastro-oesophageal junctional cancers.

AIM: Although radiation-induced cardiotoxicity has been described in patients with breast cancer and Hodgkin's disease, the effect of oesophageal radiotherapy on the heart has not been evaluated. This study was designed to evaluate the dose received by the heart during chemoradiotherapy (CT-RT) for oesophageal cancer, to assess its impact on cardiac function, and explore methods of reducing this dose. METHODS: Cardiac doses were calculated from dose-volume histograms in 15 patients with carcinoma of mid and lower oesophagus undergoing combined technique treatment, in whom pre- and post-treatment multigated acquisition scans were available. Chemotherapy consisted of cisplatin and 5-fluorouracil with or without paclitaxel. The radiotherapy was delivered in two phases to a total dose of 45-50 Gy in 25 fractions. RESULTS: There was a significant reduction in median ejection fraction after CT-RT (63% to 58%, P = 0.003). The median dose received by the heart using three-dimensional conformal technique was 27.4 Gy (interquartile range 25.8-34.2 Gy). If shielding blocks were not used, as would be the case with conventional planning, the median dose would have been 35 Gy (interquartile range 28.2-37.7 Gy), which is significantly higher (P = 0.002). The use of a three-field technique throughout treatment also reduced the median cardiac dose from 27.4 Gy to 22.7 Gy (P = 0.001) and the volume of heart receiving 70% of total dose from 63.8% to 25% (P = 0.001). CONCLUSION: This study highlights the significant dose of radiation received by the heart during oesophageal CT-RT, with consequent reduction in cardiac ejection fraction. Conformal radiotherapy reduces cardiac doses received. The cardiac, as well as the pulmonary, side effects of CT-RT needs to be borne in mind, especially when using this treatment before radical surgery.

331 cases of clinically node-negative supraglottic carcinoma of the larynx: a study of a modest size fixed field radiotherapy approach.

PURPOSE: For node-negative supraglottic carcinoma of the larynx, radiotherapy with surgery in reserve commonly provides very good results in terms of both local control and survival, while preserving function. However uncertainty exists over the treatment of the node-negative neck. Elective whole neck radiotherapy, while effective, may be associated with significant morbidity. The purpose of this study was to examine our practice of treating a modest size, fixed field to a high biologically effective dose and compare it with the patterns of recurrence from other centers that use different dose/volume approaches. METHODS AND MATERIALS: Over a 10-year period 331 patients with node-negative supraglottic carcinoma of the larynx were treated with radiotherapy at the Christie Hospital Manchester. Patients were treated with doses of 50-55 Gy in 16 fractions over 3 weeks. Data were collected retrospectively for local and regional control, survival, and morbidity. RESULTS: Overall local control, after surgical salvage in 17 cases, was 79% (T1-92%, T2-81%, T3-67%, T4-73%). Overall regional lymph node control, after surgical salvage in 13 cases, was 84% (T1-91%, T2-88%, T3-81%, T4-72%). Five-year crude survival was 50%, but after correcting for intercurrent deaths was 70% (T1-83%, T2-78%, T3-53%, T4-61%). Serious morbidity requiring surgery was seen in 7 cases (2.1%) and was related to prescribed dose (50 Gy-0%, 52.5 Gy-1. 3%, 55 Gy-3.4%). DISCUSSION: Our results confirm that treating a modest size, fixed field to a high biologically effective dose is highly effective. It enables preservation of the larynx in most cases, with acceptable regional control and no loss of survival compared to whole neck radiotherapy regimes.

Single fraction prophylactic cranial irradiation for small cell carcinoma of the lung.

The effectiveness of a single 8-Gy fraction prophylactic cranial irradiation regime was assessed in 106 patients with small-cell carcinoma of the lung. All patients had limited stage disease and received combination chemotherapy consisting of either cisplatin or carboplatin with ifosfamide, etoposide, and vincristine (VICE). Cranial irradiation was administered 48 h after the first cycle of chemotherapy and was well tolerated. Actual 2-year survival was 35% and cranial relapse occurred in 22% of those patients who achieved complete remission. This compares favourably with a cranial relapse rate of 45% incomplete remitters previously reported with the same chemotherapy regime after a minimum follow-up of 2 years where PCI was not used. Formal psychometric testing was performed retrospectively on a series of 25 long-term survivors of whom 14 were taken from this reported series. Whilst 75% of patients were impaired on at least one test with 68% performing badly in the most complex task, this was not associated with clinically detectable neurological damage and the patients did not complain of memory or concentration difficulties. In conclusion, single fraction PCI, when used with platinum based combination chemotherapy, appears to be equally effective but may be less neurotoxic than the more standard fractionated regimes.

Intraluminal brachytherapy using the high dose rate microSelectron in the palliation of carcinoma of the oesophagus.

A total of 197 patients, who presented to the Christie Hospital with advanced carcinoma of the oesophagus, were treated with the high dose rate microSelectron between June 1988 and June 1992. In 54%, a single intraluminal brachytherapy treatment resulted in useful palliation, which was sustained for a substantial part of the patient's remaining life. The simplicity of the treatment, which could be completed as a day case procedure and did not cause significant morbidity, commends itself in the palliation of these patients who have poor overall survival and quality of life. Approaches that might improve the response rate in those patients who did not gain significant palliation after a single treatment are discussed.

The influence of radiotherapy treatment time on the control of laryngeal cancer: a direct analysis of data from two British Institute of Radiology trials to calculate the lag period and the time factor.

This study analyses node-negative laryngeal tumour control data from two clinical trials conducted by the British Institute of Radiology in order to determine the time factors and the presence or absence of a lag period before the time factor takes effect. A direct maximum likelihood approach is used to fit a double-logarithmic model including a repopulation term which commences after an initial lag period, Tk. The analysis yields a time factor of 0.8 Gy per day (95% confidence interval 0.5-1.1 Gy per day) as the extra dose required to counteract the reduction in tumour control probability (TCP) with extension of the treatment time. The latter reduction amounted to between 5 and 12% TCP per week, depending on the stage and time period. With this dataset, where few patients were treated for short times, no statistically significant lag phase can be demonstrated. However, the best estimate of Tk is 21 days (95% confidence interval 0-27 days), which is consistent with estimates from other studies on other datasets. If a lag phase exists, this study would indicate that the duration is less than 27 days. Other studies have used retrospective data and are subject to a number of potential biases. The present study, using data from multicentre prospective randomized clinical trials, is free from some of these sources of bias. The fact that very similar estimates of the radiobiological parameters are obtained lends credence to these other studies and suggests that the potential biases may be small in practice.