The first decision is to decide whether a tumour is operable or not. Inoperability depends on patient and tumour factors:
- Patient Factors
- Unfit for surgery
- Refuse surgery
- Tumour Factors
- Encasement of vascular structures
- Extensive involvement of adjacent structures
Operable Tumours
Subtotal gastrectomy is used except when:
- 5 cm margins are not possible to obtain
- 5 cm margins are necessary to to achieve microscopically clear margins; this is due to frequent (20-30%) involvement of margins
- This often occurs for tumours in the middle part of the stomach where the amount of residual stomach after a 5 cm expansion means that subtotal gastrectomy is not anatomically possible
- This may also occur for diffuse tumours of the stomach
- Tumours of the cardia or gastrooesophageal junction are a special case:
- Proximal subtotal gastrectomy is associated with higher rates of gastro-oesophageal reflux compared to total gastrectomy with Roux-en-Y reconstruction
- Proximal subtotal gastrectomy poorly assesses the lymph nodes of the lesser curvature
- Gastro-oesophageal tumours need a distal oesophagectomy to obtain clear margins (eg. Ivor Lewis oesophagectomy); tumours of the cardia may also need this; tumours in these sites are usually considered as distal oesophageal tumours
Surgery alone is suitable for T1 N0 patients, where it gives 90% 5 year survival. This group of patients is small in Western countries (< 5%). For more advanced lesions, failure may occur:
- Locally (ie. tumour bed, remaining stomach or adjacent structures)
- In lymph nodes (relating to site of primary)
- Lesions invading the gastro-oesophageal junction may recur in perioesophageal or mediastinal nodes
- Proximal stomach lesions may recur in perigastric or coeliac nodes
- Middle and distal stomach lesions may recur in perigastric, coeliac, suprapancreatic, pancreato-duodenal, splenic or porta hepatis nodes
- Due to haematogenous spread (liver, lungs)
- Due to transcoloemic spread (ovary, peritoneum)
- Ovarian metastasis from a gastric carcinoma are known as Krukenberg's tumour
The extent of surgical resection is defined as D1, D2 or D3.
- D1
- D2
- D3 is the most extensive dissection and is performed more frequently in Japan
There are numerous randomised studies demonstrating similar outcomes but higher morbidity with D1 vs D2 resection. In contrast, the number of lymph nodes removed (rather than the extent of lymph node dissection) seems to affect prognosis.
The spleen is only removed if it is macroscopically invaded by tumour.
In these patients, neo-adjuvant or adjuvant therapy may improve control of tumour.
- Radiotherapy aims to reduce local and lymph node recurrences
- Chemotherapy aims to reduce all recurrences
Neoadjuvant Therapy
Patients undergoing neoadjuvant therapy often need enteral feeding. It is essential that these patients receive a percutaneous jejunostomy rather than gastrostomy as the stomach is either to be removed or used for reconstruction. This also applies to oesophageal tumours that require enteral feeding.
Radiotherapy
Neoadjuvant radiotherapy alone has been evaluated in trials based in Russia and China. This is not routinely used in Australian practice although those studies suggest a survival benefit to radiotherapy alone.
Chemotherapy
The MAGIC trial[1] is the most important chemotherapy trial for gastric carcinoma currently and many patients are treated according to its protocol. The schedule is:
- Epirubicin (50 mg/m2)/Cisplatin(60 mg/m2)/5-fluorouracil(200 mg/m2) (ECF) x 3 cycles
- Surgery (partial/total gastrectomy)
- ECF x 3 cycles (adjuvant)
5 year overall survival improves from 23% to 39% with the trial. There is significant shrinkage of the primary tumour.
Criticisms: Only 40% of patients completed 6 cycles of chemotherapy and only 50% of patients received adjuvant chemotherapy at all.
Chemoradiotherapy
There are no randomised studies exploring the use of concurrent neoadjuvant chemoradiotherapy for gastric cancer.
Data may be extrapolated from studies of adenocarcinoma of the gastro-oesophageal junction.
- The POET study showed non-significant improvement of overall survival
- Other studies have shown improvements in R0 resections with neoadjuvant chemoradiotherapy for oesophageal cancers
- These results are not easily translatable to pure gastric tumours but suggest that neoadjuvant chemoradiotherapy in gastric cancer is a topic for further research
The TOPGEAR randomised trial will evaluate neoadjuvant ECF (3 cycles) with neoadjuvant ECF (2 cycles) and radiotherapy, then continuing on with 3 cycles ECF adjuvantly (as per MAGIC). This may make radiotherapy an important option for neoadjuvant treatment in the future. TOPGEAR provides modern contouring guidelines for neoadjuvant chemoradiotherapy.
Adjuvant Therapy
Radiotherapy
Radiotherapy alone is not frequently used and has only been studied alone in a few trials. It improves local control but not overall survival.
Chemotherapy
Chemotherapy has been studied extensively in the post-operative setting. Meta-analysis demonstrates an 18% survival benefit but individual trials often show no significant effect.
Chemoradiotherapy
INT 0116
The landmark trial for chemoradiotherapy is the INT 0116 trial run in the US([[bibcite 2]]). It is also referred to as the MacDonald Trial or the MacDonald Protocol. It demonstrated that median survival increased from 27 to 36 months (33% greater) when patients were treated with concurrent chemoradiotherapy. The protocol is:
- Chemotherapy with 5-fluorouracil and leucovorin on day 1
- Concurrent chemoradiotherapy starting day 28
- 5-FU 400 mg/m2 and leucovorin 20 mg/m2 on days 1-4 and days 23-25 of radiotherapy (first 4 and last 3 days).
- 45 Gy in 25 fractions delivered to the tumour bed, regional nodes, and 2 cm on each side of resection.
- Chemotherapy with 5-FU and leucovorin (5 day cycle) 1 month and 2 months after completion of radiotherapy.
Guidelines for the delineation of target volumes is discussed in the radiotherapy subtopic.
The INT 0116 trial is criticised for poor rates of lymph node dissection (10% D2, 30% D1, 50% D0!) and poor radiotherapy quality assurance. In an updated analysis of INT 0116, the survival advantage persists with extended follow up.
TROG 03.02
A phase II trial performed by TROG (TROG 03.02) was a feasibility study evaluating combined chemotherapy and chemoradiotherapy prior to surgery. Patients received 1 cycle of ECF, a course of radiotherapy + 5-FU, followed by 2 further cycles of ECF. Grade 3/4 haematological toxicity was seen in 65% of patients, usually with the 2nd and 3rd cycles of ECF. Gastrointestinal toxicity occured in 10-20% of patients. Central review of treatment plans prior to commencing radiotherapy was found to be essential for accurate radiotherapy delivery.
The TROG 03.02 study provides contouring guidelines for stomach radiotherapy post-operatively.
Adjuvant Therapy Summary
Additional treatment to surgery is recommended for patients with stage T2 and above disease. The timing of treatment, and use of radiotherapy, are the subject of ongoing research. In patients able to tolerate it, the MAGIC protocol seems to be standard of care in Australia. Patients with resected gastric cancers, stage T2 and above, should receive adjuvant chemoradiotherapy if they are not on the MAGIC trial. If radiotherapy is not possible then chemotherapy has shown a more modest survival benefit in meta-analysis. Adjuvant radiotherapy alone improves local control but not survival.
Locally Advanced Gastric Cancer
Some tumours are not surgically resectable, or at best questionably resectable, at diagnosis - without distant metastases. Long term survival is unlikely. Unfortunately, there are no randomised controlled trials in this area. Chemotherapy has been used to downstage tumours to allow for resection and chemoradiotherapy may have even greater down staging impact; whether this translates to long term survival is unknown.
In Summary, individualised approach is required for every patient, taking into account patient, tumour and treatment factors. Young, fit patients with tumours that are borderline resectable may be most suitable for neoadjuvant down staging treatment. Other patients should be treated palliatively (as below).
Palliative Management
Palliative management involves local control of symptoms (obstruction, pain, bleeding) and improvement in survival (usually with systemic chemotherapy).
Local Control
Surgery can be used to palliate symptoms. It requires an individual approach per patient, considering the potential benefits (reduced pain, bleeding, bypass of stomach) with risks and recovery times. If obstruction is the main problem, and lesions are proximal, stenting may be appropriate.
Radiotherapy is a potential option in these patients, particularly if stenting is not possible. A dose of 37.5 Gy in 15 fractions is standard. Concurrent 5-fluorouracil may be used.
Systemic Therapy
Systemic therapy was shown to triumph over best supportive care in the 1990s. Meta-analysis shows survival is improved from 4 to 11 months. In patients able to tolerate systemic cytotoxic therapy, this should be used.
The REAL Study demonstrated equivalence of capecitabine and oxaliplatin to 5-fluorouracil and cisplatin (both in combination with etoposide). Indeed, EOX showed improved survival over ECF and there are moves to making EOX the treatment of choice. Single agents are less effective but may be better tolerated, particularly by older patients.
More recently, a study evaluating trastuzumab, cisplatin, and capecitabine or 5-fluorouracil has shown a further improvement in median overall survival to 16-17 months, for patients who have ERBB2 amplification.
Links
Bibliography
- 2
- MacDonald
