Efficacy and Tolerability of Limited Field Radiotherapy with Concurrent Capecitabine in Locally Advanced Pancreatic Cancer

Efficacy and Tolerability of Limited Field Radiotherapy with Concurrent Capecitabine in Locally Advanced Pancreatic Cancer

Clinical Oncology 22 (2010) 570e577 Contents lists available at ScienceDirect Clinical Oncology journal homepage: www.elsevier.com/locate/clon Origi...

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Clinical Oncology 22 (2010) 570e577 Contents lists available at ScienceDirect

Clinical Oncology journal homepage: www.elsevier.com/locate/clon

Original Article

Efficacy and Tolerability of Limited Field Radiotherapy with Concurrent Capecitabine in Locally Advanced Pancreatic Cancer A.S.N. Jackson *, P. Jain *, G.R. Watkins *, G.A. Whitfield *, M.M. Green *, J. Valle y, M.B. Taylor z, C. Dickinson *, P.M. Price *, A. Saleem * *

Academic Radiation Oncology, The University of Manchester, Manchester, UK Department of Medical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK z Department of Radiology, The Christie Hospital NHS Foundation Trust, Manchester, UK y

Received 8 July 2009; received in revised form 22 March 2010; accepted 11 May 2010

Abstract Aims: Patients with locally advanced pancreatic cancer (LAPC) are most commonly managed with chemotherapy or concurrent chemoradiotherapy (CRT), which may or may not include non-involved regional lymph nodes in the clinical target volume. We present our results of CRT for LAPC using capecitabine and delivering radiotherapy to a limited radiation field that excluded non-involved regional lymph nodes from the clinical target volume. Materials and methods: Thirty patients were studied. Patients received 50.4 Gy external beam radiotherapy in 28 fractions, delivered to a planning target volume expanded from the primary tumour and involved nodes only. Capecitabine (500e600 mg/m2) was given twice daily continuously during radiotherapy. Toxicity and efficacy data were prospectively collected. Results: Nausea, vomiting and tumour pain were the most common grade 2 toxicities. One patient developed grade 3 nausea. The median time to progression was 8.8 months, with 20% remaining progression free at 1 year. The median overall survival was 9.7 months with a 1 year survival of 30%. Of 21 patients with imaged progression, 13 (62%) progressed systemically, three (14%) had local progression, two (10%) had locoregional progression and three (14%) progressed with both local/locoregional and systemic disease. Conclusion: CRT using capecitabine and limited field radiotherapy is a well-tolerated, relatively efficacious treatment for LAPC. The low toxicity and low regional progression rates support the use of limited field radiotherapy, allowing evaluation of this regimen with other anti-cancer agents. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Capecitabine; chemoradiotherapy; limited field; locally advanced pancreatic cancer

Introduction The optimal treatment for unresectable, locally advanced pancreatic cancer (LAPC) remains controversial [1]. Patients can be managed with gemcitabine-based chemotherapy, concurrent chemoradiotherapy (CRT) or radiotherapy alone. CRT is the modality of choice in the USA, and chemotherapy alone is more widely used in the UK, with one retrospective review from a single UK cancer network showing that only 5% of LAPC patients were treated with CRT, compared with 58% who received gemcitabine-based chemotherapy [2]. Author for correspondence: A.S.N. Jackson, Academic Radiation Oncology, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. E-mail address: [email protected] (A.S.N. Jackson).

The survival benefit conferred by a 5-fluorouracil (5-FU)based CRT regimen compared with radiotherapy alone was first shown 30 years ago [3,4]. Since then, 5-FU has remained the drug of choice for use in combination with radiotherapy. Of the investigations of other agents in combination with radiotherapy [5e11], only gemcitabinebased CRT has, to date, shown any increased survival benefit compared with 5-FU-based CRT in a randomised trial [6]. Gemcitabine-based CRT has therefore become a treatment option for LAPC, although concerns remain over gastrointestinal toxicity [6,12e14]. One randomised controlled trial in LAPC comparing induction CRT (60 Gy radiotherapy, 5-FU and cisplatin) followed by gemcitabine chemotherapy with gemcitabine chemotherapy alone has shown superiority for chemotherapy alone [15], whereas, conversely, another randomised controlled trial, thus far presented only in

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abstract form, seems to show superiority of gemcitabinebased CRT over gemcitabine alone [16]. Capecitabine is an easily administered oral prodrug of 5-FU. It is thought to preferentially generate 5-FU in pancreatic cancer through a multi-step activation process, with pancreatic tumours shown to have higher expression of thymidine phosphorylase compared with normal tissue [17,18]. A synergistic anti-tumour effect of capecitabine with radiotherapy has also been observed in preclinical studies [19]. These properties have resulted in the replacement of 5-FU by capectabine in other cancers and its subsequent investigation for CRT in LAPC [20e23]. Recent evidence indicates that reducing radiotherapy treatment volumes reduces the toxicity of CRT [24e28]. Particularly in clinical practice outside the UK, treatment fields in patients with LAPC often electively include the regional lymph nodes. However, the resulting large treatment volumes can increase the amount of radiation-sensitive tissue included in the radiation field, particularly bowel, thus constraining both the radiation dose and the ability to add other cytotoxic/biological agents with acceptable toxicity. The use of a limited radiation field, in which radiologically normal locoregional nodes are not included in the clinical target volume (CTV), may potentially overcome this problem. Here, we report our experience of concurrent CRT for LAPC using capecitabine and limited field radiotherapy.

Materials and Methods Patients Local drug and therapeutics committee authorisation was given for the use of radical radiotherapy in combination with capecitabine as a treatment option for LAPC. Thirty consecutive patients, referred between April 2005 and April 2008, were included. All patients had a diagnosis of LAPC and were found to be suitable for CRT. The disease was considered to be locally advanced (inoperable) if abdominal computed tomography or staging laparoscopy revealed a low likelihood of a complete resection and/or any of the following:  superior mesenteric artery/coeliac trunk involvement;  more than 180 contact between the tumour and superior mesenteric/portal vein;  evidence of narrowing of, or thrombus within, the superior mesenteric/portal vein. Patients with limited superior mesenteric/portal vein involvement would have been considered for radical surgery, including venous resection/reconstruction. Patients were required to have no evidence of systemic metastases. Histological confirmation of diagnosis was obtained where possible: otherwise patients were included based on supportive clinical and radiological and serum marker (CA19-9) evidence within a multidisciplinary set-up. Eligibility criteria for CRT included adequate haematological,

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hepatic and renal function. Blood biochemistry was required to conform to the following limits: haemoglobin 10 g/dl; white blood cells 3.0  109/l; absolute neutrophil count 1.5  109/l; platelet count 100  109/l; total bilirubin 1.5  upper limit of normal (ULN); alanine transaminase, aspartate transaminase and alkaline phosphatase 1.5  ULN; serum urea and creatinine 1.5  ULN. Creatinine clearance levels were subsequently calculated and a baseline 99Tcm-mercaptoacetyltriglycine (MAG3) renogram was also carried out before radiotherapy. Radiotherapy A computed tomography-planned three-dimensional conformal technique was used. The gross tumour volume (GTV) comprised the visualised pancreatic tumour plus any peri-pancreatic lymph nodes considered by the reporting radiologist to be radiologically abnormal. In general, this included adjacent nodes >1 cm short axis diameter or clusters of suspicious nodes. The GTV was expanded by 5 mm in all directions to account for microscopic disease and to generate the CTV. Regional lymph nodes with no sign of abnormality were not electively included. Standard departmental margins of 2 cm in the cranio-caudal direction and 1 cm anteroposteriorly and laterally (since changed) were then added to account for motion and to obtain the planning target volume (PTV). The liver, spinal cord and both kidneys were outlined and treated as organs at risk. No more than 50% of the total liver volume was planned to receive more than 30 Gy (V30 < 50%), and the maximum radiation dose to the spinal cord was 40 Gy. No more than 50% of one kidney (normally the right for pancreatic head tumours, and the left for tumours of the tail) was planned to receive more than 20 Gy (V20 < 50%) and no more than 30% of the other kidney was planned to receive more than 20 Gy (V20 < 30%). The results of the MAG3 renogram were analysed in conjunction with calculated creatinine clearance levels and estimated radiation doses to the kidneys to confirm adequate overall and individual renal function before CRT. Treatment was planned using three or four isocentric beams, ensuring that the PTV was covered by the 95% isodose curve. A radiation dose of 50.4 Gy in 28 fractions of 1.8 Gy, delivered 5 days per week, was prescribed to the isocentre. Chemotherapy The first cohort of 11 consecutively treated patients received capecitabine 500 mg/m2 twice daily continuously (including weekends) starting on the first day of radiotherapy and continuing until the end of radiotherapy. This chemotherapy dose was associated with minimal toxicity. With the emergence of further safety data on capecitabine dosage, subsequent patients were treated with an increased dose of 600 mg/m2 twice daily. The capecitabine dose was rounded to allow for standard dosing with 500 and 150 mg tablets. A dose reduction was instituted in the presence of reduced calculated creatinine clearance, with patients

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receiving 75% of the dose if the creatinine clearance was 30e50 ml/min.

(range) of 149 (5e6676) U/ml. The corresponding median serum bilirubin level was 11 (5e87) mmol/l.

Toxicity Assessment

Treatment Parameters

Patients were assessed weekly during CRT, again at 6 weeks after the completion of treatment and thereafter at 3 monthly intervals. Clinical toxicity was recorded and blood was collected for haematology and biochemistry assays at each assessment. The European Organisation for Research and Treatment of Cancer Common Toxicity Criteria version 3.0 was used to score toxicity.

The median (range) PTV volume was 387 (145e860) cm3. The median (range) percentage of the left and right kidneys receiving 20 Gy (V20) was 0% (0e30%) and 15% (0e45%), respectively. The median (range) V30 for the liver was 10% (0e33%).

Efficacy and Assessment of Progression

Of the 30 patients who commenced treatment, only one was unable to complete the intended treatment. This patient had undergone a previous trial dissection, which was aborted due to local infiltration of small bowel mesentery. CRT was stopped after seven fractions (12.6 Gy) delivered to an average size PTV (390 cm3), when the patient developed nausea, vomiting, right upper quadrant pain and diarrhoea. These symptoms were attributed to radiation-induced toxicity of the underlying adherent bowel. The remaining 29 patients complied well with treatment and received the planned radiation dose. Treatment was generally well tolerated. The most common reported grade 1 toxicities were nausea, vomiting, anorexia, fatigue and tumour pain. Sixteen patients developed grade 2 toxicity effects, predominantly nausea or vomiting (see Table 1). One patient experienced grade 3 nausea. Four patients were unable to receive the full dose of capecitabine due to elevated aspartate transaminase (one patient), grade 2 thrombocytopenia (one patient) or intercurrent cholangitis (two patients). In one patient, capecitabine was started a week into treatment to allow resolution of jaundice after a biliary stent insertion. One patient took a reduced dose of capecitabine in error. Six patients (21%) developed symptoms of gastric outlet obstruction at a median (range) time of 3.8 (3.4e8.0)

All patients had diagnostic computed tomography about 3 months after the completion of CRT. Responses were assessed using the response evaluation criteria for solid tumours (RECIST). Sites of progression were classified as local when growth of the gross primary tumour plus involved draining lymph nodes (i.e. as contained in the original GTV) was observed, locoregional when progressive disease included previously uninvolved regional lymphatic areas, and systemic where disease was seen in distant organ sites, e.g. liver, lung, peritoneum. The term ‘progression’ was chosen here instead of ‘recurrence’, as radiologically, complete responses are not often seen in this setting, partly because complete sterilisation of disease may never be truly achieved, but also because of post-treatment fibrotic reaction, which often gives the appearance of a persistent mass. Statistical Analysis Statistical analyses were carried out using StataÒ version 9.2. Progression-free and overall survival were analysed by the KaplaneMeier method. Survival times were calculated from the first day of CRT treatment to the date of progression or date of death for progression-free survival, and to the date last seen or date of death for overall survival. Censored patients are denoted by a tick on the survival curves.

Results

Compliance and Toxicity

Table 1 Grade 2 acute chemoradiotherapy

toxicity

Toxicity

Patients The median age of the patients was 65 years (range 45e83). Twenty (67%) patients were men and 10 (33%) were women. Tumours were located in the pancreatic head in 26 (87%) patients. Tumour diagnosis was histologically confirmed in 20 (67%) patients. A combination of clinical plus radiological and serological (CA19-9) findings was used for diagnosis in the other 10 patients. Of the 30 patients treated, 10 (33%) had a failed trial dissection and/or palliative surgical bypass before referral for CRT. Twenty-nine patients had a CA19-9 measurement at baseline. Of these, 23 (79%) were above the ULN of 30 U/ml, with a median

Nausea Vomiting Tumour pain Bloating Diarrhoea Fatigue Gastritis Palmar plantar erythema Anorexia Dermatitis Dry skin Gastro-oesophageal reflux Oesophagitis

for

29

patients

completing

Number of patients (%) Grade 2

Grade 3

5 4 3 2 2 2 2 2 1 1 1 1 1

1 (3.4) 0 0 0 0 0 0 0 0 0 0 0 0

(17.2) (13.8) (10.3) (6.9) (6.9) (6.9) (6.9) (6.9) (3.4) (3.4) (3.4) (3.4) (3.4)

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Efficacy A planned post-treatment computed tomography scan was available in 24 of the 29 patients who completed CRT. This was acquired at a median time (range) of 3 (2e5) months after the completion of treatment. Based on RECIST criteria, four patients (17%) showed a partial response and a further 12 patients (50%) achieved disease stabilisation. The remaining eight patients (33%) had progressive disease on the post-treatment computed tomography scan. Later follow-up imaging showed subsequent disease progression in a further 13 patients. Five patients died without any post-treatment radiological documentation of disease progression. This was due to their poor clinical condition and because the clinical diagnosis of progression was not in doubt. For survival analysis purposes for these patients, the date of progression was taken to be the date of death. For the 21 patients in total with progression demonstrated on imaging, this progression was systemic alone in 13 patients (62%), local alone in three patients (14%), locoregional alone in two (10%) patients, and both systemic and local/locoregional in three patients (14%) (see Table 2). Eleven patients who developed progressive disease after CRT went on to receive chemotherapy consisting of singleagent gemcitabine in eight patients and gemcitabine in combination with cisplatin in three patients. Progression-free and overall survival analysis charts are shown in Figs 1 and 2, respectively. With a median follow-up of 8.3 months, the median time to progression was 8.8 months, and the progression-free survival rate at 1 year was 20%. At the time of analysis, 28 (93%) of the 30 patients had died. Overall, the median survival for all 30 patients included in this analysis was 9.7 months, with a 1 year survival rate of 30%. For the 11 patients who received palliative chemotherapy at disease progression, the median survival time was 12.6 months and the 1 year survival rate 45%.

100

Progression-free survival (%)

months after finishing CRT. Late toxicity cannot be excluded as a cause of these symptoms. However, as five patients also showed simultaneous evidence of disease progression with a median time to progression of 4.5 months, progressive disease was probably responsible for the symptoms in most of these instances.

573

75

50

25

0 0

3

6

9

12

Time from start of chemoradiotherapy (months)

Fig. 1. KaplaneMeier progression-free survival curve.

Discussion This is the first report of a capecitabine-based CRT study carried out in the UK. Our experience showed that pancreatic radiotherapy to a limited target volume with concurrent capecitabine is well tolerated and relatively efficacious. The key advantages were the simple oral administration of chemotherapy and low toxicity. The good tolerability observed indicates that concurrent CRT with limited field radiotherapy may allow intensification or supplementation of treatment. The low rates of locoregional relapse and the prevalence of systemic progression support intensification of systemic therapy rather than including non-involved locoregional nodes in the CTV. Although comparisons with other data should be made cautiously, in general, similar efficacy was obtained compared with other CRT studies in LAPC using 5-FU, gemcitabine or capecitabine [4e7,9,10,13,14,24,26,27,29e33]. Post-treatment disease control rates and the median time to progression tend to compare favourably, and median survival rates were similar to most reports at w10 months. The median survival data were also similar to subgroup analysis of locally advanced disease in chemotherapy studies that report a range of 7.5e11.7 months [34e37], and a study

100

Site of progression

Patients (%)

Peritoneum Liver Liver and peritoneum Local Locoregional Local and liver Locoregional and peritoneum Local, locoregional, peritoneum and lung

6 4 3 3 2 1 1 1

(28.5) (19) (14.3) (14.3) (9.5) (4.8) (4.8) (4.8)

Overall survival (%)

75

Table 2 First sites of disease progression for 21 patients with follow-up imaging

50

25

0 0

3

6

9

Time from start of chemoradiotherapy (months)

Fig. 2. KaplaneMeier overall survival curve.

12

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of escalated radiotherapy treatment only [38]. Survival was also similar to that described in a retrospective review of all LAPC patients receiving treatment within a single UK cancer network. [2]. However, the median survival and overall survival at 1 year was not as high as some CRT reports, with up to 14.5 months and 41% reported, respectively [4e6,10,29,32]. The capecitabine dose used in this study was chosen for its radiosensitising properties rather than for a systemic effect, and was based on previous investigations of capecitabine when used in combination with radiotherapy for pancreatic cancer (Table 3). A dose of 1600 mg/m2 was previously recommended, divided into two daily doses given 5 days per week [23,39]. This equates to an average daily dose of 1143 mg/m2 when using a 7 day regimen. A later study used a daily dose with an increased dose intensity of up to 1330 mg/m2/day, and reported good tolerability when combined with radiotherapy [22]. The good tolerability with relative efficacy is in line with more recent publications using capectabine-based CRT with doses of 850 mg/m2 twice daily [20,21], demonstrating capectabine CRT as an attractive platform upon which to integrate other cytotoxic/biological agents. Of the 29 patients who completed treatment, only one patient (<4%) experienced grade 3 toxicity, with most patients demonstrating grade1/2 toxicity effects. These acute toxicities are substantially lower than those observed in CRT regimens with irradiation to regional nodal volumes [5,6,10,13,30,31], reflecting that expected from the use of a limited radiation field [24,27]. The gastric symptoms observed in six patients after treatment could be attributed to late toxicity effects, but simultaneous disease progression seems a more probable cause in at least five cases. With 1 year survival rates for LAPC typically in the range of 30e40%, reports of late toxicity for LAPC are limited for

comparison, with only one study specifically investigating late toxicity after capectibine CRT [40]. Table 4 lists reported late toxicities for the references used herein. Gastrointestinal bleeding and gastric/duodenal ulceration/perforation are the most common late toxicities described. The predominant pattern of progression seen in 13 of 21 assessable patients (62%) was distant metastatic disease, most often in the absence of local/locoregional progression. Only two patients (9.5%) had isolated locoregional progression and, overall, 17/21 (81%) patients did not show any locoregional (nodal) disease progression. These results are similar to those obtained in other CRT studies using limited radiation fields [24,25,27]. In one of these comprising 26 patients and using small field radiotherapy, again distant relapses were most commonly seen, local failure occurred in 36% of patients, but no progression was seen locoregionally outside the radiation field, indicating no loss of benefit with smaller radiation fields [27]. In another CRT study of 33 patients, after limited field radiotherapy that excluded normal regional lymphatics from the CTV, the most frequent site of disease progression was the liver, 9% of patients experienced local failure alone, but again no regional lymph node progression outside the treatment field was seen [24]. Taken in context with the patterns of disease relapse observed in these studies, our results support the use of limited field radiotherapy to increase the tolerability of CRT for all patients. A limitation of this study is the lack of histological or cytological proof of diagnosis in around one-third of patients. However, the presence of supportive clinical and radiological features at presentation in all patients, the presence of an elevated CA19-9 in most patients, and/or subsequent disease progression of a pattern in keeping with pancreatic carcinoma would seem to confirm that the initial diagnosis was correct. Nevertheless, despite the difficulty in

Table 3 Previous capectabine chemoradiotherapy (CRT) studies. Study and reference

CRT regimen

Results

Capecitabine CRT in gastrointestinal malignancies [23]

Capecitabine 1200e2500 mg/m2 5 days per week during radiotherapy 45e64 Gy over 4e6 weeks

Well tolerated Overall response rate 36% Recommended capectabine dose 1600 mg/m2/day/5 days per week

IMRT and concurrent capecitabine for pancreatic cancer [39]

Capecitabine 1600 mg/m2 5 days per week during radiotherapy 54e55 Gy in 25 fractions IMRT Adjuvant gemcitabine before and/or after CRT

Well tolerated 1 year survival 69%

Phase I study of capecitabine CRT in LAPC [31]

Capecitabine 600e1250 mg/m2 5 days per week during radiotherapy 50.4 Gy in 28 fractions Adjuvant capecitabine 2000 mg/m2 for 14 days every 21 days after CRT for stable and responding patients

20% partial response rate Recommended phase II dose 1600 mg/m2/day/5 days per week

Capecitabine CRT with combination chemotherapy before and after CRT in advanced pancreatic cancer [22]

Capecitabine 1330 mg/m2 daily during radiotherapy 50.4 Gy in 28 fractions Adjuvant gemcitabine and cisplatin before and after CRT

CRT well tolerated Median survival 12.8 months

IMRT, intensity-modulated radiotherapy; LAPC, locally advanced pancreatic cancer.

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Table 4 Late toxicities reported for locally advanced pancreatic cancer treatment Reference

Treatment

Late toxicity reported

[38]

70e72 Gy radiotherapy alone

Of 40 patients studied: 3 (7.5%) grade 3 gastrointestinal bleeding 2 (5%) grade 4 duodenal obstruction 3 (7.5%) grade 5 (fatal) gastrointestinal bleeding

[25]

Escalated radiotherapy (24e42 Gy) to limited field plus gemcitabine (1000 mg/m2)

Of 37 treated patients: 2 (5.4%) gastrointestinal bleeding due to ulceration 1 (2.7%) renal artery stenosis 1 (2.7%) gastric/duodenal ulceration recurrence 1 (2.7%) transverse colon stricture

[8]

50.4 Gy radiotherapy plus cisplatin (5 mg/m2/day) Adjuvant maintenance 5-fluorouracil (500 mg/m2)

Of 41 patients studied: 1 (2.4%) massive gastrointestinal bleed due to gastric ulceration

[6]

50.4e61.2 Gy radiotherapy plus gemcitabine (600 mg/m2) or 5-fluorouracil (500 mg/m2) Adjuvant gemcitabine (1000 mg/m2/week)

Of 34 patients: 2 (5.6%) gastrointestinal bleeding due to gastritis/gastric erosion

[27]

50.4 Gy radiotherapy to small field plus 5-fluorouracil (200 mg/m2) or cisplatin (5 mg/m2)

No late toxicity observed in 53 (100%) patients

[41]

Intensity-modulated radiotherapy to 25 patients with pancreatic and bile duct malignancies plus concurrent 5-fluorouracil in 23 patients

Of 14 assessable patients: 3 (21.4%) grade 1 nausea and/or abdominal pain 1 (7.1%) grade 1 liver toxicity (probably metastases) 1 (7.1%) grade 4 liver toxicity and grade 2 small bowel obstruction

[26]

36 Gy radiotherapy plus gemcitabine (1000 mg/m2) plus cisplatin (30e50 mg/m2)

Of 18 assessable patients:1 (5.6%) partial gastric outlet obstruction due to ulceration 1 (5.6%) fatal thrombosis of superior mesenteric artery

[31]

50.4e54 Gy radiotherapy plus capecitabine (1200e1600 mg/m2/day) Adjuvant/maintenance capectabine (1000e1250 mg/m2 twice daily)

Of 25 patients with gastrointestinal malignancies: 3 (12%) serious gastrointestinal bleeding within radiation field (2 fatal)

[42]

50.4 Gy radiotherapy to limited field plus capecitabine (1300e1650 mg/m2/day) Bevacizumab (2.5e10 mg/kg) before, during and after chemoradiotherapy

Of 30 patients studied: 3 (10%) grade 3 tumour-associated gastrointestinal bleeding (1 fatal) 1 (3.3%) grade 3 duodenal perforation

[28]

50 Gy radiotherapy to limited field plus gemcitabine (1000 mg/m2)

Of 22 assessable patients:1 (4.5%) gastric ulceration

obtaining cytological or histological proof of diagnosis in this group of patients, it should be considered good practice to attempt to obtain it, and considered mandatory for patients entering clinical trials. The margins used to expand the CTV to the PTV for the patients reported here was 2 cm in the superior and inferior directions and 1 cm in other directions. This choice of margin was largely historical. However, recent data [43], including data from our own cone-beam computed tomography research (Jain et al., submitted), has shown a need for larger margins to account for the substantial pancreatic tumour inter- and intra-fraction motion observed. A minority of patients may still benefit from prophylactic irradiation of regional lymph nodes, but it is more likely that most patients would benefit from intensification/

supplementation of the systemic therapy component of CRT to improve control of subclinical disseminated disease. Intensity-modulated radiotherapy (IMRT) has also been reported as a means of including non-involved regional lymph nodes in the treatment volume while limiting treatment toxicity [39,41,44]. Here, where the PTV may be a complex shape, the improved conformality achievable with IMRT has the advantage of significantly reducing the organs at risk doses as compared with a conventional radiotherapy technique [41,45] and IMRT can also be used to boost dose to specific tumour regions. If non-involved lymph nodes are not included in the CTV, then the PTV will tend to be less complex in shape, and IMRT will probably have less advantage over conventional techniques in terms of organs at risk dose sparing.

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Other recent studies have shown that reduced radiotherapy fields allow the intensification of CRT, with fulldose gemcitabine, escalated radiotherapy and supplemental chemotherapy agents used, while still retaining treatment tolerability and no loss of benefit to locoregional control reported [28,42].

Conclusion CRT using capecitabine and limited field radiotherapy for LAPC is a well-tolerated treatment with comparable efficacy to chemotherapy and CRT with more extended field radiotherapy. The low toxicity and patterns of disease progression observed support the use of limited field radiotherapy, which would potentially allow radiotherapy dose escalation and/or intensification/supplementation of the systemic treatment component to improve disease control.

Acknowledgements AS was supported by CRUK grant number C153/A4331, PJ was supported by funding from Elekta, Crawley, UK. GRW and CD are supported by Department of Health/CRUK ECMC grant number C1467/A7286. GAW is supported by a CRUK McElwain Clinical Research Fellowship.

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