Controversies in the Management of Gastric Cancer Update on D1 vs' D2 dissection Is There a Role for

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Controversies in the Management of Gastric
CancerUpdate on D1 vs. D2 dissectionIs There
a Role for Adjuvant Treatment?

• Hernan Bazan, MD
• 1 June 2004
• Team IV Conference

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The problem

• Gastric cancer remains a major worldwide problem
• Despite a decrease in incidence over the last 70
  years
• Still remains one of the most common causes of
  cancer-related deaths worldwide
• Second leading cause of cancer death worldwide
• In 2002
• 800,000 people diagnosed
• 500,000 deaths
• USA
• 21,600 new cases
• 12,400 deaths
• 2 cancer deaths (10th)
• Diagnosed at an advanced stage in Western
  countries
• Present with locally advanced disease

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• GE Junction Tumor/ Distal Esophageal Cancer
• 1930 1976 Esophageal cancer
• 75 ? incidence
• But, gt1976 ? incidence of GE junction tumors
• Major shift in the histologic type has occurred
  in USA and Europe over the past 15 years
• ?Incidence of adenocarcinoma distal esophagus

Devesa SS et al Cancer 1998
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Staging
T1 Invades Submucosa T2 Muscularis
propia T3 Serosa T4 Adjacent organs
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National Cancer Database on 50,169 US patients
who underwent gastrectomies 1985-1996 10-year
survival Stage IA 65 Stages II/III
3-42 Need at least 15 LNs for proper
staging N Regional LNs Perigastric (lesser
and greater curvature, left gastric, common
hepatic, splenic, celiac) Distant
Mets Involvement of hepato- duodenal,
retropancreatic, para-aortic N1 1-6 regional
LNs N2 7-15 LNs N3 gt15 LNs
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Controversies in Management of Gastric Cancer

• Lymphadenectomy

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Controversies in Management of Gastric Cancer

• Japanese advocate radical LN dissection
• Retrospective Japanese studies Stage II/III 5 yr
  survival 60 (vs. 20 in USA)
• D1 Dissection Removal of perigastric LNs
• D2 Dissection Hepatic, gastric, cardiac, splenic
  LNs

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Controversies in Management of Gastric Cancer

• In operable gastric cancer, the extent of surgery
  (node dissection) remains controversial
• Japanese Advocate D2 extended lymphadenectomy
  resection of spleen and distal pancreas
  necessary for removal splenic LNs (Station 10,
  11)
• Dutch and British studies 1999 No survival
  differences in D1 vs. D2 resections higher
  morbidity and mortality associated with D2
  resection involving distal pancreatic and splenic
  resections
• US D1 resection (unfortunately, oftentimes D0
  resection)
• Value of adjuvant therapy also remains
  controversial
• Chemotherapy
• Chemoradiation therapy
• Neoadjuvant?

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• LN group
• 1 R cardiac
• 2 L cardiac
• 3 Lesser curvature
• 4 Greater curvature
• 5 Suprapyloric
• 6 Infrapyloric
• 7 L gastric artery
• 8 Common hepatic artery
• 9 Celiac artery
• 10 Splenic hilar
• 11 Splenic artery
• 12 Hepatic pedicle
• 13 Retropancreatic
• 14 Mesenteric root
• 15 Middle colic artery
• 16 Paraaortic

N1
N2
10

• Distal Tumors
• 35
• Subtotal gastrectomy
• Midbody Tumors
• 15-30
• Total gastrectomy

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Controversies in Management of Gastric Cancer

• In operable gastric cancer, the extent of surgery
  (node dissection) remains controversial
• Japanese Advocate D2 extended lymphadenectomy
  resection of spleen and distal pancreas
  necessary for removal splenic LNs (Station 10,
  11)
• Dutch and British studies 1999 No survival
  differences in D1 vs. D2 resections higher
  morbidity and mortality associated with D2
  resection involving distal pancreatic and splenic
  resections
• US D1 resection (unfortunately, oftentimes D0
  resection)
• Value of adjuvant therapy also remains
  controversial
• Chemotherapy
• Chemoradiation therapy
• Neoadjuvant?

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• 1989 1993
• Holland, multi-center (80 hospitals)
• 711 patients randomized
• D1 vs. D2 LN dissection
• All procedures supervised by Japanese surgeons
• 72 month median f/u

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• D2 group had significant higher morbidity and
  mortality compared to D1
• Post-op complications 43 vs. 25
• Mortality 10 vs. 4
• Distal pancreatectomy/ splenectomy
• No difference in 5-year survival
• Conclude Do not support routine D2 LN dissection

Bonenkamp JJ et al NEJM 1999
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• Unclear whether en-bloc removal of regional LNs
  improves survival or refines staging
• Stage migration
• In D2 dissection, splenectomy and distal
  pancreatectomy are required for proximal tumors
• Accounts for morbidity/mortality
• This trial has been extensively scrutinized and
  reanalyzed
• Despite attempts at standardization, deviations
  occur
• In Dutch study, 51 of patients who underwent D2
  dissection No LNs obtained from at least 2 of LN
  stations that were supposed to be dissected
• MRC Trial
• Randomized D1 vs. D2 rsxn
• Found increased mortality D2 rsxn

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• Surgery remains the only chance for cure

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• However, large loco-regional relapse
• Up to 80 patients after gastric resection with
  curative intent
• Gastric bed
• Anastomosis
• Regional LNs
• This high rate of relapse after resection makes
  it important to consider adjuvant treatments
• Chemotherapy
• GI agents
• Novel agents
• Radiation therapy
• Regional radiation
• Meta-analyses 1990s Systemic treatment achieves
  a clinically small but statistically-significant
  reduction in risk of death

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• High rate of locoregional relapse
• Will systemic therapies improve survival after
  curative resection?
• Prevent locoregional and distant recurrence and
  increase the cure rate of patients?

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• Multi-center, randomized trial comparing role of
  post-operative adjuvant therapy
• 13 Centers in Japan
• Starting in 1993, median f/u 69 months
• n252
• Randomly assigned (FMC)
• Surgery plus post-operative 5-fu, mitomycin,
  cytarabine followed by oral 5-fu
• Surgery alone
• 98 gastrectomy, D2 resection
• Early stage (T1/T2) gastric cancer patients

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• Similar frequency of post-operative morbidity and
  mortality

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Overall Survival
No significant difference (91.2 vs. 86.1, p.13)
At median follow-up 69 months, Deaths Surgery
alone 21 patients Chemotherapy 13 patients
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Total Cancer Recurrence

• Surgery alone group was almost double
• (17 13.8 vs. 9 7.1)

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• Though no significant differences in overall
  survival, adjuvant chemotherapy had better 5-year
  survival (91.2 vs. 86.1, p0.13)
• Results show a possible 5 improvement in 5-year
  survival by adjuvant chemotherapy, with the cost
  per patient 5,600 per year.
• Authors do not recommend adjuvant chemotherapy
  (with this regimen, for this early gastric
  cancer/population of patients)
• Future Need to study role of adjuvant
  chemotherapy in more advanced diseased groups (eg
  T3 or more advanced cancers) in order to see a
  significant difference at 5-years
• Post-op chemotherapy in context of clinical
  trials...

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• Adjuvant chemoradiotherapy for gastric cancer?
• Gastric cancer resected with curative intent
• Post-operative chemotherapy and radiation therapy
  may prevent local recurrence and increase the
  cure rate of patients

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• Multicenter trial (Southwest Oncology Group,
  USA), starting in 1991
• n556 patient with resected adenocarcinoma of
  stomach or GE junction
• Randomly assigned to surgery alone or surgery
  plus postoperative chemoradiotherapy
• Surgery Not controlled (just resection of all
  detectable disease)
• Lymphadenectomy/dissection
• 10 D2
• 36 D1
• 54 D0
• 5-fu plus leucovorin
• 4500 cGy of radiation (180 cGy/day) 5 days/wk x 5
  wks

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• Significant side effect profile

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• Median overall survival
• Surgery alone 27 months
• Surgery plus chemoradiotherapy 36 months
• Chemoradiotherapy also improved relapse-free
  survival
• Similar to Dutch and UK studies, found no benefit
  to D2 dissection
• D0 lymphadenectomy is the most common type of LN
  dissection in the US for gastric cancer
• Authors conclude that postoperative
  chemoradiotherapy should be considered for all
  patients at high risk for local and regional
  recurrence after surgery

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• Critiques
• Surgical approach was not uniform in US study
  (2001)
• High proportion of D0 dissections
• Importance of surgical approach
• US study found 3-year relapse-free survival 31
  vs. 60 in the Dutch study (1999), where patients
  underwent D1 or D2 dissections
• Examination of gt15 LNs necessary for adequate
  gastric cancer staging
• D0 lymphadenectomy is an inadequate oncologic
  procedure

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• Meta-analysis Way of providing the cumulative
  evidence from several clinical trials
• 20 randomized, clinical trials
• 1983-1999
• 3,568 patients
• Small benefit in patients with curatively
  resected gastric cancer
• Reassess data with newer chemotherapies

Mari E et al Annals of Oncology 2000
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• No consistent results from multicenter,
  randomized clinical trials assessing similar
  chemotherapy regimen (FAM or FMC) and surgical
  technique (all D1 dissection)
• Await further trials

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• Currently, there are 53 on-going NIH-sponsored
  clinical trials involving gastric cancer and use
  of adjuvant or neoadjuvant chemotherapy,
  radiation therapy, and immunotherapy

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Molecular Markers

• Currently, the use of clinical parameters cannot
  accurately predict which patients may respond
  from preoperative or postoperative chemotherapy
• Are there molecular markers that can predict
  which patients will respond to chemotherapy?
• Markers that can predict which patients
• Will respond to surgery
• Harbor tumors that are more aggressive
• Customize treatment
• High occurrence of p53 abnormalities in gastric
  tumors
• p53 Pleiotropic molecule with numerous functions

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• Inactivation of p53 has been associated with
  resistance of chemotherapy
• Wild type p53 has multiple functions
• in vitro p53-dependent apoptosis modulates the
  cytotoxic effects of some chemotherapy drugs (eg
  5-fu, doxorubicin, cisplatin)
• Cells lacking wild-type p53/inactivation p53 are
  likely to be resistant to some of these
  chemotherapies
• n39 patients
• Evaluated the p53 status patients with locally
  advanced unresectable gastric carcinoma receiving
  chemotherapy
• Cisplatin, doxorubicin, 5-fu, leucovorin

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• Response rate (assessed with EGD and CT scan)
  for patients with wt p53 was significant higher
  than those with alterations/overexpression of p53
• 71 vs. 12, p0.004

Altered p53
Wild-type p53
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• Proof of a molecular marker (p53 alteration) and
  its usefulness in predicting a clinical response
• Inactivation of p53 contributes to cellular
  resistance to chemotherapy
• Gastric cancer
• Ovarian cancer
• NSCLC
• Bladder cancer
• Need to assess other cell cycle regulators that
  act with or independent of p53

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• High-throughput RNA expression
• Combined with improved genomic information
• Robotic
• Simultaneous analysis of thousands of genes at
  once
• Automated, quantitative
• Gene expression profile

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• Clinical Applications
• Development of innovative drugs selectively
  target cancer cells while sparing normal tissues
• STI571 (Gleevac) CML bcr/abl tyrosine kinase
  inhibitors
• mAb against ERBB2 breast cancer
• Only a few molecular markers are used routinely
  in clinical practice
• Reductionist
• A combination of markers is likely to be more
  accurate than a single marker (eg p53) when
  studying tumor classification or response to
  treatment
• Current classifications are insufficient to
  reflect the diversity of cancer
• Ideally, subclasses of tumors defined by common
  mechanisms of malignant transformation
• Using cDNA Microarray
• 8 genes identified that can distinguish between
  malignant pleural mesothelioma and adenocarcinoma
  of the lung
• Two new subclasses of clinically-relevant large
  B-cell lymphoma have been described

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