Tom Roques
Case history
A 65-year-old man presents with a 3-month history of increasing dysphagia—initially to solids but increasingly to liquids too. He has lost 15kg in weight (20% of his baseline). He has a background of severe rheumatoid arthritis for which he has been on methotrexate for 7 years. He is referred on a 2-week wait suspected cancer pathway and has an endoscopy which shows a tight malignant-looking stricture from 25 to 29cm. Biopsies show a moderately differentiated squamous cell carcinoma.
Questions
1. What initial staging tests should be performed?
2. How should his weight loss be managed while these tests are carried out?
Answers
1. What initial staging tests should be performed?
Staging investigations are performed to decide whether the tumour is localized to the oesophagus and adjacent nodes and therefore potentially curable and, if there are no metastases, to assess local extent and suitability for resection or radiation. A CT scan of the chest, abdomen, and pelvis with intravenous contrast and oral water is the first imaging test performed. Axial slices should be 2.5–5mm thick to allow multiplanar reformatting which can be particularly helpful in showing/refuting invasion into adjacent organs. If this shows potentially curable disease, a 18FDG PET-CT scan and endoscopic ultrasound (EUS) assessment should also be attempted. EUS may not be possible if the tumour is stricturing. The information from each of these investigations and the diagnostic endoscopy is complementary, but EUS is the most sensitive for assessing local invasion (T stage). A bronchoscopy may be helpful for mid-oesophageal cancers if there is possible invasion of the carina or bronchial tree. EUS is the most sensitive investigation for nodes close to the tumour, but PET-CT has higher specificity and sensitivity for more distant nodal disease. PET-CT will reveal unsuspected metastatic disease in up to 30% of patients at presentation, but it has 5% false positive and false negative rates so solitary hot spots should be correlated with other diagnostic tests.
2. How should his weight loss be managed while these tests are carried out?
This patient has malnutrition (>10% weight loss over 3–6 months) which may compromise his ability to tolerate potentially curative treatment. A dietician should assess him urgently and discuss his calorie intake. A liquidized high-calorie diet and high-protein drinks will be recommended. If, despite these recommendations, he continues to lose weight, nasogastric feeding should be instituted. Careful monitoring of electrolytes in the first few days of nasogastric feeding will help to prevent re-feeding syndrome. A covered plastic stent that could later be removed can also be considered.
The CT scan shows circumferential thickening of the oesophagus over 5cm and an 8mm para-oesophageal lymph node at the superior extent of the tumour. At EUS three suspicious para-oesophageal nodes are seen—all adjacent to the primary tumour which is 4.5cm long and extends into the muscularis but not beyond the oesophagus. The PET-CT scan shows avid uptake of tracer in the mid-oesophagus over 6cm (SUV = 19) but without evidence of nodal spread. None of the investigations show distant metastases.
Questions
3. What stage is the tumour?
4. What are the curative treatment options?
Answers
3. What stage is the tumour?
T3N2M0 using the 7th edition of the AJCC staging manual (the 6th edition is still used in some centres—in which case this tumour would be T3N1 as there are only N0, N1, and Nx nodal staging categories in the older version).
4. What are the curative treatment options?
Several combination treatments are possible for T3N2 disease though there is a paucity of phase III data comparing different options. Clinical trial data are also hampered by broad inclusion criteria (site and histology) and, in the case of radiotherapy, by evidence based on obsolete treatment techniques.
Surgery is the basis for most curative treatments if the patient is fit enough. A two-stage Ivor Lewis oesophagectomy is the usual technique, but minimally invasive oesophagectomy is becoming more widespread. Neoadjuvant chemotherapy with two cycles of cisplatin and 5-FU improves 5-year survival from 17.1% to 23% (Allum et al. 2009). Radiotherapy alone has a small chance of cure, but combined chemotherapy and radiation has cure rates similar to those of surgically based options, although the two approaches have not been compared in adequately powered studies. Whether radiation with concomitant chemotherapy should also be preceded by chemotherapy is uncertain. Triple-modality therapy—chemoradiation followed by surgery—is another option but again there is a paucity of data to support it, though further studies are ongoing. This approach should be considered if the patient is being treated by a multidisciplinary team (MDT) experienced in such therapy. Given all the uncertainties, patients should be offered the chance to participate in clinical trials where possible. The final treatment decision should be taken by the MDT, reflecting local expertise with the involvement of the patient’s perspective, priorities, and wishes. If chemotherapy is used, a dose reduction should be considered in view of his prior treatment with methotrexate which may affect his bone marrow reserve.
The patient declines surgery on the basis that a close friend died shortly after an oesophagectomy some years before. A potentially curative regime of two cycles of neoadjuvant chemotherapy with cisplatin and 5-FU followed by definitive chemoradiation is agreed. He tolerates chemotherapy well and has a good response both symptomatically and on imaging. The radiotherapy planning CT scan shows the axial bulk of the tumour to be reduced and that the tumour is now 4cm long.
Questions
5. How should the gross tumour volume (GTV), clinical target volume (CTV), and planning target volume (PTV) be defined?
6. What dose of radiation should be prescribed?
Answers
5. How should the gross tumour volume (GTV), clinical target volume (CTV_, and planning target volume (PTV) be defined?
The tumour GTV (GTV-T) should be defined using the maximum extent of tumour on all available initial investigations (endoscopy, CT, EUS, and PET-CT). In this case the GTV-T should extend over 6cm (the PET-CT length). The nodal GTV (GTV-N) should be defined separately to include all adjacent oesophageal nodes (as highlighted on EUS). Many historical radiotherapy protocols generate a CTV by expanding the GTV with 5cm longitudinal margins for most of the treatment course with a reduced volume for a second phase. There is now good evidence to support the use of a single-phase technique with reduced longitudinal margins as this technique does not seem to produce marginal recurrences.
To define the CTV-T, the GTV-T should initially be extended 20mm superiorly and inferiorly along the plane of the oesophagus. This volume is then isometrically expanded by a 10mm margin in the axial plane. GTV-N is expanded by 10mm in all dimensions to produce a CTV-N. The two CTVs are summed and then edited to reflect likely patterns of tumour spread (e.g. into adjacent para-oesophageal nodes even if not radiologically involved) and natural barriers to local invasion (e.g. edited off the spinal column, aorta, and lungs). The CTV–PTV expansion margin should be defined according to local audit but will be in the region of 5mm axially and 10mm in the longitudinal plane.
6. What dose of radiation should be prescribed?
Several radiation doses have been used in clinical trials: 50Gy in 25 fractions combined with chemotherapy is a UK standard and was used in the recently completed SCOPE trial. Higher doses (up to 65Gy) have been used in some studies but there is no evidence that dose escalation is advantageous.
The patient completes treatment successfully and is eating a soft diet without the need for supplements 2 months later. Eighteen months after radiotherapy he has further difficulty in swallowing.
Questions
7. What are the two most likely diagnoses?
8. How should they be treated?
Answers
7. What are the two most likely diagnoses?
The two most likely diagnoses are a radiation-induced stricture, which occurs in approximately 20% of patients after definitive chemoradiation, or recurrent cancer.
8. How should they be treated?
A radiation-induced stricture is best managed by regular endoscopic dilatations together with nutritional advice from a dietician. Recurrent cancer should be confirmed histologically. The patient should be staged again to see whether this recurrence is local or metastatic. If there is no distant disease salvage surgery could be considered, but the benefit of this is uncertain with the likelihood of cure very low and the complication rate relatively high. Local palliation with brachytherapy or a stent should be considered. Palliative chemotherapy should be discussed with the patient but supportive and palliative care are the most important things to consider.
Treatment and follow-up
At endoscopy a tight stricture at 28cm was seen and successfully dilated. Biopsies of the strictured region did not show cancer. He remains well 35 months after chemoradiation but has needed further dilatation on two occasions.
Further reading
Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. Journal of Clinical Oncology 2009; 27: 5062–5067.
Allum WH, Blazeby JM, Griffin SM, et al. Guidelines for the management of oesophageal and gastric cancer. Gut 2011; 60: 1449–1472.
Button MR, Morgan CA, Crotdon ES, et al. Study to determine adequate margins in radiotherapy planning for esophageal carcinoma by detailing patterns of recurrence after definitive chemoradiotherapy. International Journal of Radiation Oncology Biology Physics 2009; 73: 818–823.
Van Hagen P, Hulshof MC, van Lanschot JJ, et al. (the CROSS Group). Preoperative chemoradiotherapy for esophageal or junctional cancer. New England Journal of Medicine 2012; 366: 2074–2084.