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Neoadjuvant therapy in gastric cancer.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

September 2001.     Review Article.

Lowy and collegues in their study try to assess the feasibility and toxicity of a regimen of preoperative chemoradiotherapy, surgery, and intraoperative radiotherapy in the treatment of patients with potentially resectable gastric cancer. A secondary objective is to assess pathologic response to chemoradiotherapy in the treated tumours.
In fact in western series less than half of the patients present with localized disease, and of those who undergo surgical resection, 70% recur. The gastric bed and regional nodal basins are frequent site of treatment failure that must be reduced if we are to improve survival rates for patients with gastric cancer.
Preoperative chemoradiotherapy for gastric cancer can be delivered safely and is well tolerated. The rate of surgical complication is consistent with that of other recently reported prospective trial of gastrectomy alone. The pathologic response rate of 73% in resected patients is evidence that chemoradiotherapy has significant activity in the treatment of gastric cancer.The 11% complete pathologic response rate in this trial is less than that seen after chemoradiotherapy for esophageal or rectal cancer but greater than that seen in patients with pancreatic cancer. It is possible that other radiation sensitzers such taxol or cisplatin or gemcitabine used alone or in combination with 5 FU may yeld improved pathologic response.
Longer follow up of this cohort and the treatment of additional patients in a phase II study are required to determine whether this treatment regimen will truly decrease locoregional recurrence and to determine if there is any impact on survival particularly in light of the demonstration of efficacy of postoperative adjuvant chemoradiotherapy ( 1, 2 ).
Ota in a commentary of the above study, provides a rationale for preoperative chemoradiotherapy for patients who are candidates for surgical resection. The first reason is that the recent intergroup gastric adjuvant trial INT-0116 has shown that postoperative adjuvant chemoradiotherapy produces a significant increase in 5 year survival compared with observation alone following gastric resection with curative intent. The second reason in favor of preopearative therapy is that patient tolerance is improved ( 88% of their patients received a full course of chemoradiotherapy, whereas the intergroup trial had a 65% completion rate ). Furthermore one of the main advantages of preoperative therapy is the possibility of increasing the R0 resection rate for gastric cancer.
Improved preoparative staging methods are needed. Lowy et al use endoscopic ultrasonography, CT scanning and laparoscopy. Such a work up is necessary for preoparative therapy because of the high incidence of systemic disease ( 3, 2 ).

Another neoadjuvant approach is the neoadjuvant chemotherapy without radiation that is continuing to be investigated aggressively for the treatment of gastric cancer.
Lowy and collegues treated a total 83 patients with potentially resectable gastric cancer on three consecutives phase II neoadjuvant chemotherapy protocols: etoposide, 5FU and cisplatin; etoposide, adriamycin and cisplatin; and 5FU, alfa interferon and cisplatin (three indipendent, nonrandomized prospectives trials ).
In this study response to neoadjuvant chemotherapy is the single most important predictor of overall survival after neoadjuvant chemotherapy for gastric cancer. Regional nodal basins are a frequent site of failure among patients who recur after neoadjuvant chemotherapy alone.
Thus it may be beneficial to add chemoradiotherapy to a regimen of systemic therapy to optimize locoregional disease control ( 4 ).
Niederhuber riaffirms that chemotherapy-induced tumour downstaging may enhance resectability; patients receive systemic therapy without delay and vitually all patients can receive the prescribed therapy; treatment is administered while there is measurable disease present to assess response, thus allowing therapy to be continued only in patients more likely to benefit; during preoperative chemotherapy, patients with rapidly progressive disease can often be identified and spared a nontherapeutic gastrectomy.
There are potential disadvantages to using neoadjuvant chemotherapy: it is possible that patients who do not require intense and risky treatment would be included in the neoadjuvant group based on clinical staging of their disease. Moreover preoparative treatment has the disadvantage of obscuring the true pathologic stage, thus making it very difficult to accurately assess the benefit of therapy in a clinical trial setting. Finally when an exceptional response occurs to induction therapy, there is the risk that less aggressive surgery will be performed, thus compromising the patient's outcome.
80% of patients who recur initially have locoregional failure and only 5% have isolated metastases. It will therefore be important to evaluate the role of radiation, either in sequence or deliverd concurrently with neoadjuvant chemotherapy ( 5 ).
In fact Ajani and colleagues suggest that a three-step strategy of preoperative pacli-taxel-based induction chemotherapy then chemoradiotherapy followed by surgery is feasible and appears quite active in patients having locoregional carcinoma of the esophagus or gastroesophageal junction. Future investigation should focus on substituting cisplatin with less toxic agents and including more systemic therapy with newer classes of agents ( 13 ).
Weese and colleagues propose that a neoadjuvant multimodality therapy with neoadjuvant 5 fluorouracil, leucovorin, adriamicin and cisplatin, radical resection (comprehensive of extended lymh node dissection) with IORT, and postoperative radiation therapy is safe, can downstage tumours, provides improved locoregional control, and appears to cause significant tumour regression that may result in long-term survival or cure ( 14 ).
Some articles underline the role of intraoperative radiotherapy alone or in combination with external beam radiotherapy in the tratment of gastric cancer (15, 16, 17).
Another approach to the high rate of local recurrence has been the use of intraperitoneal chemotherapy in the immediate postoperative period ( 5, 6, 7, 8, 9 ).

For these types of neoadjuvant therapy the surgeon must be sure that such patients are optimally staged and selected for appropriate clinical trial partecipation ( 5 ).
Weese and colleagues confirm that current methods of staging that include spiral computed tomography scans, endoscopic ultrasound, conventional radiographs, and magnetic resonance imaging have not yielded consistent staging that correlates with the pathologic examination. Laparoscopy with ultrasound assisted laparoscopy has been forwarded as techniques to improve staging information, but it carries risks and potential immunologic depression that may no benefit the patient. As a result it is difficult to assess true clinical response to neoadjuvant therapy other than histologic review of the specimen. Until better diagnostic tools are devised, true assessment of tumour response will be imprecise ( 14 ).
The use of molecular markers is clearly the hope of the future both for pretrial selection and for treatment monitoring and therapeutic endpoint guidance ( 10 ).
Anatomic imaging is notoriously poor for following tumor response during induction chemotherapy and studies using functional imaging should provide significant improvement in this regard. Changes in tumour FDG uptake are seen in all tumours after chemotherapy. FDG-PET may have a role to play in the assessment of patients with upper gastrointestinal malignancy receiving chemotherapy ( 11 ).
Nakata and colleagues underline that changes in the serum levels of CEA, Ca 19-9, and sialyn-Tn antigen after chemotherapy may be an excellent prognostic indicator for patients with gastric carcinoma ( 12 ).

Schumacher and colleagues stress that on the basis of an accurate staging, including endoscopic ultrasound and the EDL, neoadjuvant chemotherapy in a highly selected patient set with gastric adenocarcinoma appears to result in short term and long term survival benefit for a subgroup of patients compared with historic data.
Phase III studies comparing results from patients who undergo noadjuvant chemotherapy followed by surgery with results from patients who undergo surgery alone should stress the value of adequate pretherapeutic staging and must be accomplished by studies of potential methods for predicting tumour response.
The authors define the possibility of introduction of other treatment options, for example radiation therapy combined with chemotherapy or perhaps innovative methods using monoclonal antibodies ( 18 ).
A previous study from the Siewert's institution shows that the rate of tumour cell microinvolvement is markedly lower in patients who are treated with preoperative chemotherapy compared with patients who are primarily resected ( 19 ).


1) A M Lowy, BW Feig, N Janjan, TA Rich, PWT Pisters, JA Ajani, and P Mansfield. A pilot study of preoperative chemoradiotherapy for respectable gastric cancer. Annals of Surgical Oncology 2001, 8 (6): 519-524.

2) MacDonald JS, Smalley s, Benedetti J et al. Postoperative combined radiation and chemotherapy improves disease-free survival (DFS) and overall survival (OS) in resected adenocarcinoma of the stomach and GE junction. Proc Am Soc Clin Oncol 2000; 19: 1a.

3) David M Ota. A pilot study of preoparative chemoradiation for gastric cancer. Annals of Surgical Oncology 2001, 8 (6): 482-483.

4) A M Lowy, P F Mansfield, S D Leach, R Padzur, P Dumas and JA Ajani. Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Annals of Surgery, vol 229, n 3, 303-308, 1999.

5) J E Niederhuber. Neoadjuvant therapy. Annals of Surgery 1999, 229, n 3, 309-312.

6) Crookes P et al.Systemic chemotherapy for gastric carcinoma followed by postoperative intraperitoneal therapy: a final report. Cancer 1997; 79: 1767-1775.

7) Kelsen D et al. Neoadjuvant therapy of high risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil. J Clin Oncol 1996; 14: 1818-1828.

8) Yu W et al. Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjunt to resectable gastric cancer. Ann Surg 1998; 228: 347-354.

9) W YU, I Whang, Ho Young Chung, Andrew Averbach, Paul H Sugarbaker. Indications for early postoperative intraperitoneal chemotherapy of advanced gastric cancer: results of a prospective randomized trial. World J Surg. 25, 985-990, 2001.

10) Chung HC et al. P- glycoprotein as an intermidiate end point of drug resistance to neoadjuvant chemotherapy in locally advanced gastric cancer. Yonsei Med J 1996; 37: 397-404.

11) GW Couper et al. Detection of response to chemotherapy using positron emission tomography in patients with oesophageal and gastric cancer. British Journal of Surgery 1998, 85, 1403-1406.

12) B Nakata et al. Changes in tumour marker levels as a predictor of chemotherapeutic effect in patients with gastric carcinoma. Cancer 1998; 83: 19-24.

13) J A Ajani. A three step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastoesophageal junction. Cancer 2001;92: 279-86.

14) JL Weese et al. Neoadjuvant chemotherapy, radical resection with intraoperative radiation therapy (IORT) : improved treatment for gastric adenocarcinoma. Surgery 2000; 128: 564-71.

15) Glehen O et al. Intraoperative radiotherapy and external beam radiation therapy in gastric adenocarcinoma with R0-R1 resection. Eur J Surg Oncol 2000; 26 suppl.

16) Skoropad VY et al. A prospective randomized trial of preoperative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer. Eur J Surg Oncol 2000; 26:773-779.

17) T Lehnert et al. Intraoperative radiotherapy for gastrointestinal cancer. Seminars in Surgical Oncology 2001; 20: 40-49.

18) CP Scuhmacher, U Fink, K Becker, R Busch, H-J Dittler, James Mueller and J R Siewert. Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin and cisplatin. Cancer 2001; 91:918-27.

19) K Becker et al. Neoadjuvant chemotherapy for patients with locally advanced gastric carcinoma. Cancer 1999; 85: 1484-9.

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