Tom Roques
Case history
A 56-year-old man is admitted with an episode of haematemesis and a haemoglobin level of 97g/L. An endoscopy shows a 5cm malignant-looking ulcer in the pre-pyloric region of the stomach. Biopsies from the ulcer confirm a poorly differentiated mucinous type adenocarcinoma. He has type 2 diabetes and hypertension, which are both well controlled on oral medication. He is discharged home with a plan to complete his staging investigations as an outpatient.
Question
1. What staging investigations should be requested and why?
Answer
1. What staging investigations should be requested and why?
A contrast-enhanced CT scan of the chest, abdomen, and pelvis with intravenous contrast and oral water should be performed to assess local extent, lymphadenopathy, and to look for distant metastases. If this scan confirms disease localized to the stomach and adjacent nodes the patient should have a staging laparoscopy. This will assess both the primary tumour (and in particular whether there is invasion of local organs), the number and size of local lymph nodes, and the presence or absence of peritoneal disease and liver metastases. Any suspicious peritoneal or liver nodules should be biopsied. EUS is unlikely to add more information to laparoscopic staging. PET-CT is not routinely recommended as many gastric cancers (particularly those of the mucinous type) do not take up FDG so false negative rates are relatively high.
These tests confirm a T3N2 cancer without clear evidence of peritoneal, liver, or more distant spread. The patient meets a surgeon who feels he has operable disease and is healthy enough to undergo surgery.
Question
2. Assuming he is well enough for all oncological treatments, what two curative approaches could be considered and what is the evidence for each?
Answer
2. Assuming he is well enough for all oncological treatments, what two curative approaches could be considered and what is the evidence for each?
The standard approach in the UK would be to use perioperative chemotherapy—three cycles of epirubicin, cisplatin, and capecitabine (ECX) (or epirubicin, cisplatin, and infusional 5-FU; ECF) before surgery and another three afterwards. The MAGIC study randomized 503 patients, 74% of whom had stomach cancer, to surgery alone or surgery with perioperative ECF chemotherapy. Five-year survival improved from 23 to 36% with the addition of chemotherapy. The REAL-2 study showed that substituting capecitabine for infusional 5-FU produced equivalent results in advanced oesophago-gastric cancers. Extrapolating this to the perioperative setting, ECX has therefore become a standard perioperative chemotherapy regime.
An alternative would be to operate initially and to follow this with adjuvant chemoradiotherapy, an approach favoured in the United States. The evidence for this comes from the Intergroup 0116 trial which randomized 556 patients to surgery alone versus surgery and adjuvant radiochemotherapy (45Gy in 25 fractions plus 5-FU and leucovorin) and showed an improvement in 5-year survival from 23 to 42%. This approach is not usually favoured in the UK, particularly because of concerns about the large numbers of patients having less than D1 resection in the trial and the toxicity of the radiotherapy.
He completes three cycles of preoperative ECF chemotherapy with grade 3 diarrhoea after the second cycle necessitating a 3-day admission to hospital for rehydration. His capecitabine dose is reduced to 75% thereafter. His restaging CT after three cycles shows a reduction in volume of the primary tumour but also a small pulmonary embolus.
Question
3. How should the pulmonary embolus be managed?
Answer
3. How should the pulmonary embolus be managed?
The management of incidental pulmonary emboli on chemotherapy is relatively controversial and without a strong evidence base, but this patient is about to undergo surgery which in itself is a risk factor for further thromboembolic events. He should therefore be anticoagulated with a therapeutic dose of low-molecular-weight heparin or rivaroxaban before surgery and warned about the possibility of further bleeding from his tumour. Assuming that the prothrombotic effect of chemotherapy is partly the cause, treatment dose low-molecular-weight heparin should be continued for the duration of adjuvant treatment and for a total of up to 6 months. There is insufficient evidence to recommend the placement of an inferior vena cava filter prior to surgery in an asymptomatic pulmonary embolus but it should be considered in the event of a symptomatic event.
He has a resection of his tumour and recovers well from his surgery. Pathology shows a good response to chemotherapy (Mandard grade 3; see Box 9.1) and he commences post-operative chemotherapy but is admitted with neutropenic sepsis after his second cycle and does not complete a third. He remains well for 17 months until he presents with abdominal pain and weight loss of 5kg in a month. A re-staging CT confirms the presence of peritoneal metastases and moderate-volume ascites as well as multiple liver metastases measuring up to 23mm in diameter. His original tumour is tested for HER2 by immunohistochemistry and found to be 3+. His ECOG performance status is 1.
Box 9.1 Pathological assessment of tumour regression after preoperative chemotherapy
Mandard tumour regression grades (TRG)
TRG 1: Complete regression—absence of residual cancer and fibrosis extending through the different layers of the oesophageal/stomach wall.
TRG 2: Presence of rare residual cancer cells scattered through the fibrosis.
TRG 3: An increase in the number of residual cancer cells, but fibrosis still predominates.
TRG 4: Residual cancer outgrowing fibrosis.
TRG 5: Absence of regressive changes.
Reproduced from Madard AM, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma: clinicopathologic correlations. Cancer 1994; 73(11): 2680–2686. Copyright © 1994 American Cancer Society, with permission from John Wiley and Sons, Inc. All Rights Reserved.
Question
4. Which chemotherapy regimen would you recommend and why?
Answer
4. Which chemotherapy regimen would you recommend and why?
Trastuzumab, cisplatin, and capecitabine (TCX), based on evidence from the ToGA trial (Bang et al. 2010) (though this study recruited chemo-naïve patients), National Institute for Health and Care Excellence (NICE) guidance, and the relatively long disease-free interval from ECX and previous response to this regime. Up to six cycles should be given depending on response. This should be followed by maintenance trastuzumab until disease progression.
Question
5. What regular monitoring, in addition to standard pre-chemotherapy blood tests, should be performed?
Answer
5. What regular monitoring, in addition to standard pre-chemotherapy blood tests, should be performed?
Echocardiogram to assess left ventricular ejection fraction in view of treatment with trastuzumab and CT scan of the chest, abdomen, and pelvis to assess response, each every 3 months.
He has stable disease on imaging after three cycles of chemotherapy but is admitted after the fifth cycle with increasing abdominal distension. A CT confirms large-volume ascites and progression of his liver metastases. Five litres of ascitic fluid is drained and his chemotherapy is stopped. On review 3 weeks later the ascites has reaccumulated.
Question
6. What are the options for management of his ascites?
Answer
6. What are the options for management of his ascites?
The ascites is likely to continue to reaccumulate quickly and need management for the rest of his life. A peritoneal drain could be inserted as and when it becomes symptomatic, but this would mean repeated hospital visits. A permanent tunnelled peritoneal catheter could be inserted under ultrasound control. This could then be drained by the patient or his carer at home using a vacuum bottle, reducing the need for recurrent hospital attendances. The patient should be offered entry into early phase clinical trials if he is well enough, but there is no standard chemotherapy option with an evidence base in this situation.
Treatment and follow-up
A tunnelled catheter was inserted and palliated his ascites to good effect. He continued to deteriorate at home and died there 10 weeks later.
Further reading
Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet 2010; 376: 687–697.
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New England Journal of Medicine 2006; 355: 11–20.
Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophago-gastric cancer. New England Journal of Medicine 2008; 358: 36–46.
Hurt CN, Nixon LS, Griffiths GO, et al. SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus. BMC Cancer2011; 11: 466.
Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. New England Journal of Medicine2001; 345: 725–730.
NICE. Gastric cancer (HER2-positive metastatic) – trastuzumab. NICE Technology Appraisal Guidance 208, November 2010.
NICE. The PleurX peritoneal catheter drainage system for vacuum assisted drainage of treatment-resistant recurrent malignant ascites. NICE Medical Technology Guidance 9, March 2012.