Gray, Joanna L
The role of photodynamic therapy in the treatment of pre-malignant and malignant disease of the oesophagus.
MSc(R) thesis, University of Glasgow.
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The incidence of oesophageal adenocarcinoma is increasing significantly with Scotland having the highest rates in Western Europe. Despite this oesophageal cancer continues to be a late presenting malignancy with treatment options limited to palliative therapy in up to 80% of cases. The identification of patients with Barrett's High Grade Dysplasia (HGD) or early oesophageal cancer therefore remains a priority.
Such patients with HGD in Barrett's oesophagus or early carcinoma often have medical co-morbidity precluding them from radical therapy in the form of surgical resection or chemoradiotherapy. The development of less invasive endoscopic therapy to treat such superficial disease is also therefore a priority. Endoscopic therapies have been shown to be safe with minimal morbidity and mortality and as an alternative potentially curative therapy in early malignant disease and satisfactory palliation in locally advanced disease of the oesophagus. The optimal endoscopic treatment for HGD and early cancer however is not yet fully established.
Photodynamic therapy (PDT) is a new evolving treatment involving administration of a photosensitiser with subsequent endoscopic activation with laser light to treat pre-malignant and malignant disease of the oesophagus.
This thesis aims to explore the role of PDT in the treatment of neoplastic disease of the oesophagus.
Between 1999 and 2011, three patient populations have been assessed:
1) HGD Barrett's oesophagus, 2) early T1 oesophageal cancer and 3) locally advanced inoperable oesophageal cancer.
1) Twenty one patients with HGD in Barrett's oesophagus, 16 male and median age 70 years who were unfit for oesophagectomy due to medical co-morbidity were treated with PDT.
2) Thirty eight patients, 21 male median age 72 years were treated with PDT with curative intent for early T1 oesophageal carcinoma in this surgical unit. These patients were staged with a combination of endoscopy, CT and EUS and were unsuitable for radical treatment due to co-morbidity.
3) Twenty five patients with locally advanced oesophageal cancer with or without metastases, 16 male, median age 79 years were treated with PDT as a palliative therapy for dysphagia. A second group of 25 patients previously treated with self expanding metal stents (SEMS) between 1998 and 2000 were used as a comparative group.
All patients were discussed at the regional MDT and were given visual and written information regarding PDT. All patients were treated as inpatients and received porfimer sodium IV at 2mg/kg bodyweight with laser light activation at 630nm 48 hours later. The laser light dose for HGD patients was 100-200J/cm and 300J/cm for early cancer and palliation. Patients remained on long term high dose proton pump inhibitor post procedure. Patients returned at 6 to 12 weekly intervals for repeat endoscopy and biopsy in the HGD and early cancer cohorts.
Data has been collated prospectively for patients with HGD and early cancer and both retrospectively and prospectively for the palliative patients.
CRP levels pre and post- PDT in the early cancer cohort were evaluated to investigate the inflammatory response after PDT.
Patients treated with PDT for HGD in Barrett's oesophagus had a median follow up of 62 months (2-114 months). Overall twenty of 21 patients were assessed (one died of a non procedure related cause 3 weeks post PDT). Patients had a median number of 1.5 PDT sessions (range 1-2).Overall 17/20 (85%) patients remained free of HGD at a median follow up of 5 years. Three patients developed adenocarcinoma at 47, 48 and 54 months giving a cancer progression rate of 15%. During the treatment period 4/20 developed recurrence of HGD but are now dysplasia free after repeat PDT (three patients) and radiofrequency ablation (RFA) (one patient). There was a significant reduction in length of Barrett's segment pre and post- PDT from median 5 to 3cm (range 0-12cm) p=0.035 respectively.
Patients with early oesophageal cancer had a median follow up of 40 months (1 to 123 months). All patients were staged as T0N0 or T1N0. Twenty six out of 38 (68%) had a complete endoscopic and histological response to treatment 6-8 weeks post- PDT. Overall 50% developed recurrent carcinoma at a median of 8 months. The remaining 50% of patients with initial complete response remain disease free or were disease free until time of death. One third of patients died of non oesophageal cancer related causes.
PDT induced a systemic inflammatory response with a median rise in CRP of 466%. Patients with a baseline CRP<10mgl-1 had a significantly increased length of survival compared to those with a CRP>10mgl-1.
As a palliative therapy PDT had no effect on quality of life despite significant improvement in dysphagia. Such patients however having PDT had improved survival compared to those having self expanding metal stents (SEMS): 132.5 vs 105 days respectively. In health economics terms the cost per day survival however was similar for PDT and SEMS.
Photodynamic therapy successfully ablates HGD in Barrett's oesophagus and may be used with curative intent in early cancer for those patients who have no alternative radical option. PDT improves survival in patients with locally advanced oesophageal cancer compared to SEMS with no alteration in quality of life and similar costs. The survival benefit may be secondary to immune modulation by PDT rather than through a systemic inflammatory response effect.
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