Neo-adjuvant Therapies for

Gastric Cancer: An Alternative

Approach to an Old Problem

Eduardo A. Guzman MD
 Introduction

• Gastric cancer is the second leading cause of cancer death

worldwide

• US
– 22,280 new case
– 11,430 deaths
 Epidemiology

Marked decline in death rates secondary to

decreasing incidence
Epidemiology
 Etiology
• Low fruits and vegetables
• High salts and nitrates
• Salted fish
• Smoked meats
• H pylori
• Hypochlorhydria
• Polyps
• Genetics (p 53 mutations,
microastellite instability gene
MSI., e-cadherin gene)
• Previous radiation
• Post gastrectomy
• Pernicious anemia
 Tumor location

• Proximal 35 %
• Body 25 %
• Antrum 40 %
 Pathology

• Subtypes
– Intestinal - less aggressive

– Diffuse subtype (linitis

plastica) - More
aggressive
 Lexicon

• Krukenberg tumor – Ovarian metastasis

• Sister Mary Joseph node – Periumbilical node

• Virchow’s node – Left supraclavicular node

• Irish’s node – Axillary lymphadenopathy

• Blummer’s shelf – Tumor in the pelvic cul de sac

 Pathways of spread

• Direct extension

• Lymphatic

• Hematogenous

• Peritoneal involvement
 Clinical findings

• Dysphagia
• Indigestion
• Early satiety
• Loss of appetite
• Nausea
• Abdominal pain
• Weight loss
• Gastric outlet obstruction
• Anemia
• Hematemesis
• Melena
• Lymphadenopathy
 Diagnosis

• Often confused with benign

pathology
– GERD
– Ulcer
• Often diagnosed at an
advance stage
• Endoscopy
• Biopsy
 Staging

• Upper endoscopy
• Chest x ray
• CT scan abdomen and pelvis
• EUS
• Laparoscopy
• Peritoneal cytology
 TNM
Primary tumor (T)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial tumor with invasion of the lamina propria
T1 Tumor invades muscularis propria or submucosa
T2 Tumor invades muscularis propria or subserosa
T3 Tumor penetrates the serosa (visceral involvement) without invasion of
adjacent structures
T4 Tumor invades adjacent structures
Regional lymph nodes (N)
Nx Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–6 regional lymph nodes
N2 Metastasis in 7–15 regional lymph nodes
N3 Metastasis in >15 regional lymph nodes
Distant metastases (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastases
M1 Distant metastases
T stage
 Staging
Stage Grouping 5-Year Survival
Rate (%)
Stage 0 (in situ) Tis N0 M0 >90
Stage IA T1 N0 M0 60–80
Stage IB T1 N1 M0
T2 N0 M0 50–60
Stage II T1 N2 M0
T2 N1 M0
T3 N0 M0 30–40
Stage IIIA T2 N2 M0
T3 N1 M0
T4 N0 M0 20
Stage IIIB` T3 N2 M0 10
Stage IV T4 N1–2 M0
Any T N3 M0
Any T Any N M1 <5
 Endoscopic ultrasound

• Allows for more accurate staging by objectively determining the

depth of invasion and nodal status
• Accuracy is suboptimal
• It is the best we have
Clinical correlation of endoscopic ultrasonography with pathologic stage
and outcome in patients undergoing curative resection for gastric cancer
D Bentrem et al. Ann Surg Onc 2006

• Retrospective review MSKCC

• 225 patients with gastric CA
• Preoperative EUS followed by R0 gastric resection
• Exclusion of patients who received neoadjuvant therapies
• EUS compared with anatomic pathology
• Accuracy
– T stage 57 %
– N stage 50 %
• Conclusion
– Concordance was “lower than expected”
– Difficult to differentiate between T2 and T3
– EUS can identify high risk group of patients. Those with
serosal invasion and positive nodes
 Laparoscopy

• Preoperative laparoscopy is occasionally done as part of the

staging efforts
• Goal is to evaluate for resectability and evidence of peritoneal or
liver metastasis prior to initiation of chemotherapy
• Allows for biopsy of suspicious lesions and peritoneal lavage
• Used in clinical trials
• Not standard of care
 Treatment

• Surgical excision confers the only possibility of cure

Stage Standard Treatment Option

0 Surgery
Ia Surgery
IB Surgery with or without chemoradiation
II Surgery with or without chemoradiation
IIIA Surgery with or without chemoradiation
IIIB Palliative chemotherapy, radiotherapy with or without surgery,
neoadjuvant chemoradiation
IV Palliative chemotherapy, radiotherapy with or without surgery,
neoadjuvant chemoradiation
 Laparotomy and omentectomy

• Upper midline or subcostal

incision
• Separate greater omentum
from transverse colon
• Dissect lesser omental bursa
• Avoid injuring the colon
 Gastric resection

• 5 cm margin if possible
• Frozen section evaluation of
margins
• En Bloc resections
• Proximal = Total
gastrectomy
• Distal = Subtotal
gastrectomy
 Extent of resection

• Gastrectomy
– Subtotal gastrectomy has been shown to have an equivalent
oncologic result with significantly fewer complications
– For proximal tumors total gastrectomy is preferred over
proximal gastrectomy
• Splenectomy
– Routine performance of splenectomy has been associated
with increased morbidity without improvement in long term
survival
– Indicated if involved lymph nodes in splenic hylum
• En bloc resection
– should be done for local invasion into other organs
 Lymphadenectomy

• 70 % of specimens have nodal

metastasis
• D0 - No lymphadenectomy
• D1 - LN included in the greater and
lesser omentum
• D2 - LN along the splenic and
hepatic arteries, omental bursa and
front leaf of the transverse
mesocolon. Splenectomy in proximal
cancers
• D3 - Removal of para-aortic and
retroperitoneal LN
 Randomized comparison of morbidity after D1 and D2 disection for
gastric cancer in 996 Dutch patients
JJ Bonenkamp et al, Lancet 1995

• Dutch gastric cancer study

• Randomized controlled trial
• Resectable gastric cancer
• 711 patients who underwent curative resection
• D1 380 D2 331
• Supervising surgeons were proctored by expert Japanese
surgeon experienced in gastric CA surgery
• Supervising surgeons attended every D2 dissection
• Significantly higher morbidity and mortality in D2
 Randomized comparison of morbidity after D1 and D2 disection for
gastric cancer in 996 Dutch patients
JJ Bonenkamp et al, Lancet 1995

D1 D2 P value
Mortality 4% 10 % 0.004
Complications 25 % 43 % < 0.001

• Conclusion:
– Routine D2 lymphadenectomies should not be used as a
standard treatment
• Critiques
– Inexperienced surgeons
– Very high postoperative morbidity
 D1 Vs D2 lymphadenectomy

• Similar trial from England (Medical research council trial) showed

equivalent results

• Due to this trials the routine performance of a distal

pancreatectomy and splenectomy has been eliminated

• A D2 lymphadenectomy is viewed as a superior oncologic

operation and it should continue to be performed by experienced
oncologic surgeons with minimal morbidity
 Reconstruction

Billroth I Billroth II Total gastrectomy

 Anastomosis

Hand sewn
gastrojejunostomy

Stapled
esophagojejunostomy
 Minimally invasive surgical therapies
• Endoscopic mucosal resection
– T1 tumors, less than 3 cm, no
ulceration, no invasive findings
– Very poor operative candidates

• Laparoscopic wedge resection

– Small tumors
– Negative nodes

• Problems
– No lymphadenectomy
– Narrow margins
– Higher local recurrences
– Not a cancer operation
 “R” status

• R0: No macroscopic or microscopic cancer at

resection margin ( - margins)

• R1: Microscopic residual cancer (+ margin)

• R2: Gross residual cancer

 Nutrition

• Feeding catheher jejunostomy

• Aggressive nutritional supplementation
• Vitamin deficits
• Postgastrectomy diet
 Post-gastrectomy syndromes

• Dumping
– Very common
– Due to absence of pylorus and rapid entry of hyperosmolar
solutions into the small bowel
– Early - 20 min
• GI symptoms nausea, vomiting, fullness
• Cardiovascular symptoms, palpitations, tachycardia, diaphorsesis
• Secondary to the release of hormones (bradykinin, serotonin)
– Late 2 hours
• Caused by rapid delivery of carbohydrates into the small intestine
• Hyperinsulinemia with resultant hypoglycemia
• Recommendation is to eat frequent small meals
 Post-gastrectomy syndromes

• Metabolic disturbances
– Worse with Billroth 2

– Megaloblastic anemia
• B12 deficiency – Due to lack of intrinsic factor

– Steatorrhea
 Post-gastrectomy syndromes

• Afferent loop syndrome

– Caused by partial obstruction of the afferent limb
– Kinking , adhesions, stenosis
– Limb distention > Cramping > Bilious vomiting
– Acute or chronic
– Blind loop syndrome
 Post-gastrectomy syndromes

• Efferent loop obstruction

– Limb obstruction caused by retroanastomotic herniation

• Alkaline reflux gastritis

– Epigastric pain, bilious vomiting
– More common with B2

• Retained antral syndrome

– Retained antrum in duodenal side
– Hypergastrinemia > Increased gastric acid
– Document duodenal mucosa on frozen section
 Neo-adjuvant Therapies for
Gastric Cancer: An Alternative
Approach to an Old Problem

Eduardo A. Guzman MD
 Status quo

• Gastric cancer still has a high mortality

– Overall 5 yr survival 10 % to 20 %
– Overall 5 yr survival after curative resection 24 % to 57 %
• High rates of recurrences
– 40 to 80 %
– Locoregional failure
• 38 – 45%
– Peritoneal metastasis
• 54 %
• Low rates of R0 resection < 50 % of patients
• Significant delays in initiation of adjuvant therapy
– 1/3 of patients do not recover quickly enough
 Survival

5 yr overall

• 10 % to 20 %

5 yr after curative resection

• 24 % to 57 %
Is there anything we can do about it?

Adjuvant therapies
 Adjuvant radiation

• Not much data

• RCT by British stomach cancer group 1989
• 436 patients randomized
– Surgery
– Surgery + radiation
• No survival difference
• Depressed locoregional failure rates
– Surgery 27 %
– Surgery + radiation 10 %

• Radiation is helpful in improving local control rates

 Adjuvant chemotherapy

• Multiple studies
• Phase III RCT by EORTC - Lise M et al JCO 1995
• 314 patients with resected gastric CA
• FAM2 regimen = 5 Fu + doxorubicin + mitomycin
• Randomized
– Surgery
– Surgery + FAM2
• No difference in overall survival
• Highly toxic regimen

• Adjuvant chemotherapy alone has failed to demonstrate

significant improvements in survival
 Adjuvant intraperitoneal chemotherapy

• HR Rosen JCO 1998

• Phase III multicentric trial
• 91 patients 1994 1997
• Gastric adenocarcinoma s/p R0 resection
• Randomized intraoperatively
– Intraperitoneal mitomycin C
– No further tx
• Median follow up 597 days
• Complications
– Mitomycin C 35 %
– Control 16 %
• Mortality
– Mitomycin C 11 %
– Control 2 %
• Conclusion
– Adjuvant Mitomycin C is associated with an increased rate of
postoperative complications without improvements in long
term survival

• Currently there is no role for IP chemotherapy outside of a clinical

trial
 Adjuvant chemoradiation

• John S. MacDonald NEJM 2001

• To investigate the effect of surgery + adjuvant
chemoradiotherapy on survival
• 556 selected patients with resected gastric cancer
• 66 %T3 T4 85 % nodal metastasis
• Postoperative randomization
– Surgery alone
– Surgery > 5 FU + Leucovorin > 4500 cGy > 5 FU +
Leucovorin
• R0 resection
• D2 lymphadenectomy 10 % pts
• Median follow up 5 years
 Surgery Surgery + P value
chemo+
rads
Median 27 mo 36 mo
survival
3 year 41 % 50 % 0.005
overall
survival
Overall survival
3 year 31 % 48 % < 0.001
disease free
survival
Local 29 % 19 %
recurrence

Significant improvement in survival

Disease free survival

• Conclusion:
– Adjuvant chemoradiotherapy should be considered in all
patients at high risk of recurrence of gastric cancer who have
undergone a curative resection

• Critiques
– Considerable toxicity (41 % grade 3, 32 % grade 4)
– Incomplete lymphadenectomies (D2 10 %)
– These findings suggest that the main effect of chemoradiation
was to compensate for inadequate surgery

• Based on this trial, adjuvant chemoradiation has become “standard

of care” on patients with completely resected gastric cancer other
than T1
Can we do any better?

Neoadjuvant therapies
 Benefits of preoperative therapies

• Increased patient compliance

• Specially postgastrectomy patients who suffer from long
postoperative recovery periods
• Avoidance of curative surgery in patients who rapidly develop
metastatic disease (10 – 15 % of T3 pts)
• Selection of patients with not so aggressive disease
• Tumor downstaging – Improved resectability
• Early initiation of systemic therapy
• Better tissue oxygenation
• Easier to define radiation fields ( removal of surgeon effect
 Neoadjuvant chemotherapy

• H Hartgrink European Journal of Surgical Oncology 2004

• To evaluate the effect of preoperative chemotherapy on
resectability and survival
• FAMTX = 5-flouroracil + doxorubicin + methotrexate
• 59 patients 1993 -1996
• Randomization
– 4 cycles FAMTX >> Surgey
– Surgery alone
• Median survival • 5 year survival
– FAMTX 18 mo – FAMTX 32 %
– Surgery 30 mo – Surgery 53 %
• Conclusion
– No beneficial effect of preoperative FAMTX chemotherapy

• Critiques
– Trial was closed prematurely due to lack of tumor downstaging
combined with no survival diference.
– Poor trial
 Neoadjuvant chemotherapy

• MAGIC trial D Cunningham NEJM 2006

• Regimen of epirubicin, cisplatin and infused fluorouracil has been
shown to improve survival in patients with locally advanced and
metastatic gastric adenocarcinoma
• Evaluate whether the addition of this regimen to surgery improves
outcomes
• Prospective Randomized multi-center
• 453 patients were randomized
– ECF > Surgery > ECF
– Surgery
• Median follow up 4 years
• Perioperative morbidity and mortality were similar between groups
 Overall survival Disease free survival

•5 year overall survival

–Surgery 23 %
–Chemotherapy + surgery 36 %
• Conclusion: Perioperative ECF decreases tumor size and stage and
improves both overall and disease free survival
• Critiques
– Tumor heterogeneity
• 25 % of patients had esophageal and GE junction tumors
– Treatment toxicity
• Only 42 % of the patients in the perioperative group completed all
protocol treatments
• 34 % of the patients who completed preoperative chemotx + surgery did
not undergo postop chemotx
– Inadequate staging
• Only 70 % of the patients had their tumor size recorded prior to surgery
• No EUS, no laparoscopy
– No radiation, older generation drugs
• Despite the impressive results of the trial, neoadjuvant chemotherapy
with an ECF regimen has not been adopted as standard of care
What else is coming down the
pipeline?

Phase II trials
Investigational treatments
 Neoadjuvant chemoradiation

• Phase II clinical trial J Ajani JCO 2006

• Primary aim: Achievement of a 20 % pathologic complete
response in a multinstitutional setting
• Rigorous staging: EUS, laparoscopy, peritoneal lavage
• 20 institutions 43 patients
• 5FU + Cisplatin >>> 4500 cGY + 5fu >>> Surgery
• 50 % had a D2 Lymphadenectomy
• Median follow up 21.6 months
• Path Cr 26 %
• R0 resection 77 %
• Grade 4 toxicity 21%
 72% 82%

69%

Median survival 23.2 months Patients who had a pathologic

Overall survival 72% at one complete response had an
year Improved survival
 71%

38%

Patients who underwent an R0

resection had an improved
survival
• Conclusion
– A preoperative chemoradiotherapy strategy proved to be
succesful in a cooperative group setting with acheivement of a
pathological complete response rate of over 20 %

• Critiques
– Small number of patients
– Phase II trial
– No comparison arm

• Based on this results, a preoperative chemoradiation strategy is to

be compared with adjuvant chemoradiation in a phase III clinical
trial
 What is the future?
• Neoadjuvant therapies vs adjuvant chemoradiation
• Trial CALGB (Cancer and Leukemia Group B) 80101
– Assessing the role of a potentially more active postoperative
chemoradiation regimen

• Magic B study
– Examine the role of adding bevacizumab to perioperative
chemotherapy

• CRITICS
– Evaluate the role of postoperative chemoradiation in combination with
preoperative chemotherapy

• Immunotherapy
 Summary
• Gastric cancer remains a challenging disease to treat
– High mortality
– High rates of locoregional recurrences
– Low R0 resection
• Extended lymphadenectomies have not proven beneficial,
although still being performed by advanced centers
• Adjuvant chemoradiotherapy remains standard of care
• Neoadjuvant therapy approaches have not been proven to be
superior to adjuvant chemoradiation
• Neoadjuvant chemoradiation awaits it evaluation under a
randomized clinical trial
Current treatment recommendations
 Conclusion

• The introduction of neoadjuvant therapy protocols appears likely

to favorably impact tumor resectability, local control and overall
survival

• Phase III randomized controlled trials are required to prove its

efficacy