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treatment of Oesophageal and Gastric Cancers



treatment of esophageal and gastric cancers
treatment of esophageal and gastric cancers


1.Oesophageal Cancer


Oesophageal cancer aetiologically, therapeutically and prognostically should be
divided into two common histological types, rather than considered together,
although many of the treatments overlap. Squamous cancers can affect the entire
oesophagus, whereas adenocarcinomas are confi ned to the distal oesophagus and gastro-oesophageal junction. Most tumours present at stage T3 or greater and/or are node positive, and cure with multimodality therapy is only around 15 %.

2.1 Oesophageal Cancer Treatment

2.2 Curative


Early tumours, namely, those confi ned to the mucosa (T1a), can be treated by endoscopic mucosal resection (EMR), of which there is considerable experience, or by ablative modalities, including photodynamic therapy (PDT), argon plasma coagulation (APC), radiofrequency ablation (RFA) and laser therapy where there is less data [ 2 ]. More advanced tumours need surgical or combined modality treatments.

Squamous Carcinoma


Oesophageal squamous carcinoma typically has a worse prognosis compared to
adenocarcinoma. It has a tendency to spread early. Because of this, it is common
practice to consider only T1–T2 stage tumours for initial surgery. T3 and T4 tumours have often spread either submucosally or along lymphatics so that surgery at this stage is rarely curative [ 3 ]. Hence affected patients are treated with chemoradiotherapy.
The effects of chemoradiotherapy and surgery on survival rates are similar
[ 4 ], although signifi cant number of tumours do not respond fully to chemoradiotherapy.These patients are considered for salvage surgery.

Adenocarcinoma


Patients with T2 N0 disease or less proceed directly to surgery. Patients with more advanced or with nodal disease receive preoperative chemotherapy, typically two to three cycles of a platinum plus fl uoropyrimidine-containing regimen. This is associated with an absolute survival benefi t at 5 years of at least 6 % [ 5 , 6 ]. Whether combined chemoradiotherapy before surgery for adenocarcinoma is superior to chemotherapy is controversial. There have been no adequate comparisons between the two modalities. A recent Cochrane review suggested a trend to greater survival for chemoradiotherapy as compared to chemotherapy in oesophageal and oesophagogastric junction tumours [ 7 ].

3.Palliative Therapies



Local therapies are directed at relieving obstruction or other local symptoms. This typically involves either stenting or radiotherapy. Systematic therapies comprise the same chemotherapy regimens as used in gastric cancer and are discussed below.


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4.Gastric Cancer

Staging and Preoperative Evaluation


The TNM staging for gastric cancer is similar to oesophageal carcinoma.
Preoperative staging is most effectively done by CT scans of the chest, abdomen
and pelvis. Although CT is not specifi cally accurate for assessing the depth of
tumour invasion of the stomach wall or regional nodal involvement, it is useful for staging distant spread. Staging laparoscopy is standard for any medically fi t
patient with beyond a T1 tumour. These modalities obviate the role of EUS, which is not routine in many centres unless the tumour involves the oesophagogastric junction.
The role of FDG-PET/CT in the preoperative staging of gastric adenocarcinoma
is evolving. Signet-ring carcinomas are not FDG avid [ 8 ], and the sensitivity of
FDG-PET for peritoneal carcinomatosis is only approximately 50 % [ 9 ]. Hence
PET scanning is not as utilised as it is for oesophageal cancer, although signifi cant upstaging rates of approximately 10 % have been described in patients with ≥ T3 or ≥ N1 disease [ 10 ].

5.Gastric Cancer Treatment


EMR is feasible for early gastric cancers (T1a) if well differentiated, ≤ 2 cm, and not ulcerated [ 11 ]. Surgery alone is recommended for any < T2 N0 disease.

6.Chemotherapy


Patients with more advanced stages should receive preoperative adjuvant chemotherapy.This is associated with an absolute survival increase of 9 % at 5 years [ 7 ].Typically this comprises three cycles of a platinum and fl uoropyrimidine combination with or without epirubicin. Postoperative adjuvant chemotherapy also reduces recurrence rates [ 12 ]; however, frequently there is considerable delay in patients receiving postoperative treatment, and many fail to complete. Hence preoperative chemotherapy is the preferred option.

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7.Palliative Chemotherapy


Systemic chemotherapy is used for inoperable or metastatic oesophagogastric
cancer.Meta-analysis comparing chemotherapy to the best supportive care shows an improvement in median survival from 4.3 to 11 months [ 13 ]. Fluoropyrimidine-/platinum-containing or other doublet regimens are associated with improved survival in comparison to single-agent fl uoropyrimidine regimens [ 13 ].
In general, response rates to primary chemotherapy are between 35 and 50 %
with a further signifi cant proportion achieving disease stabilisation. There is no
consensus on which regimen to use as fi rst-line treatment. Commonly used
regimens include epirubicin, oxaliplatin and capecitabine (EOX) and docetaxel,
cisplatin, and infusional 5-FU (DCF) combinations. These are relatively toxic
regimens, particularly DCF [ 14 ], and since combination regimens probably only modestly improve survival compared to single-agent regimens, it is appropriate to use single- agent regimens in elderly patients or those with reduced performance status.
Second-line chemotherapy can modestly (by around 8 weeks) prolong survival
compared to the best supportive care, and both irinotecan and docetaxel have efficacy, probably with improved quality of life [ 15 , 16 ].

8.Biological Agents


There is a limited place for biological agents. The addition of the HER2-targeted
antibody trastuzumab in patients with oesophagogastric adenocarcinomas expressing HER2 (about 20 % of tumours) [ 17 ] improved response rates and overall survival by approximately 10 weeks in patient receiving fi rst-line combination of platinum and fl uoropyrimidine chemotherapy [ 18 ].
Recently, ramucirumab, a monoclonal antibody which binds VEGFR-2, was
reported to produce a modest survival prolongation (approximately 6–8 weeks) in patients with previously treated oesophagogastric adenocarcinoma [ 19 ].
Key Points
• Early tumours confi ned to the mucosa (T1a) can be treated by endoscopic
mucosal resection (EMR) or by ablative modalities (PDT, APC, RFA) and
laser therapy.
• More advanced tumours need surgical or combined modality treatments.
• Oesophageal squamous carcinoma has a worse prognosis compared to
adenocarcinoma.
• Oesophageal squamous carcinoma: Only stages T1 and T2 are considered
for initial surgery and T3/T4 stages for chemoradiotherapy.
• The role of FDG-PET/CT in the preoperative staging of gastric adenocarcinoma
is evolving.
• EMR is feasible for early gastric cancers (T1a) if well differentiated,
≤ 2 cm, and not ulcerated [ 11 ]. Surgery alone is recommended for any
< T2 N0 disease.
• Patients with more advanced gastric cancer stages should receive preoperative
adjuvant chemotherapy.
• Systemic chemotherapy is used for inoperable or metastatic oesophagogastric
cancer.
• There is a limited place for biological agents.

References:

2. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a)
esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology. 2009;137(3):815–23.
3. Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same disease?
Semin Radiat Oncol. 2007;17(1):38–44.
4. Allum WH, Blazeby JM, Griffi n SM, et al. Guidelines for the management of oesophageal and gastric cancer. Gut. 2011;60(11):1449–72.
5. 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. J Clin Oncol.
2009;27(30):5062–7.
6. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715–21.
7. Ronellenfi tsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction,and lower esophagus. Cochrane Database Syst Rev. 2013;5:CD008107.
8. Stahl A, Ott K, Weber WA, et al. FDG PET imaging of locally advanced gastric carcinomas:correlation with endoscopic and histopathological fi ndings. Eur J Nucl Med Mol Imaging.2003;30(2):288–95.
9. Yoshioka T, Yamaguchi K, Kubota K, et al. Evaluation of 18F-FDG PET in patients with
advanced, metastatic, or recurrent gastric cancer. J Nucl Med. 2003;44(5):690–9.
10. Smyth E, Schoder H, Strong VE, et al. A prospective evaluation of the utility of 2-deoxy-2-[(18) F]fl uoro-D-glucose positron emission tomography and computed tomography in staging locally advanced gastric cancer. Cancer. 2012;118(22):5481–8.
11. Tada M, Tanaka Y, Matsuo N, et al. Mucosectomy for gastric cancer: current status in Japan.J Gastroenterol Hepatol. 2000;15(Suppl):D98–102.
12. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet.2012;379(9813):315–21.
13. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer.
Cochrane Database Syst Rev. 2010;(3):CD004064.
14. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fl uorouracil compared with cisplatin and fl uorouracil as fi rst-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7.
15. Kang JH, Lee SI, do Lim H, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30(13):1513–8.
16. Park SH, Lee WK, Chung M, et al. Quality of life in patients with advanced gastric cancer
treated with second-line chemotherapy. Cancer Chemother Pharmacol. 2006;57(3):289–94.
17. Tanner M, Hollmen M, Junttila TT, et al. Amplifi cation of HER-2 in gastric carcinoma: association with Topoisomerase II alpha gene amplifi cation, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16(2):273–8.
18. 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 gastrooesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lancet. 2010;376(9742):687–97.
19. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international,randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9

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