Controversies in the Management of Gastric Cancer

Update on D1 vs. D2 dissection

Is There a Role for Adjuvant Treatment?

Hernan Bazan, MD1 June 2004

Team IV Conference

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

• Overall, 5 year survival is <20%

GE Junction Tumor/ Distal Esophageal Cancer

• 1930 – 1976: Esophageal cancer– 75% ⇩ incidence

• But, >1976 ⇧ 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

Staging

T1 Invades Submucosa

T2 Muscularis propiaT3 SerosaT4 Adjacent organs

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 andgreater curvature, leftgastric, common hepatic,splenic, celiac)

Distant Mets:Involvement of hepato-duodenal, retropancreatic,para-aortic

N1 1-6 regional LNs; N2 7-15 LNs N3 >15 LNs

Controversies in Management of Gastric Cancer

Lymphadenectomy

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

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?

LN group1 R cardiac2 L cardiac3 Lesser curvature4 Greater curvature5 Suprapyloric6 Infrapyloric7 L gastric artery8 Common hepatic artery9 Celiac artery10 Splenic hilar11 Splenic artery12 Hepatic pedicle13 Retropancreatic14 Mesenteric root15 Middle colic artery16 Paraaortic

N1

N2

Distal Tumors35%-Subtotal gastrectomy

Midbody Tumors15-30%-Total gastrectomy

Proximal Tumors35-50%Siewert ClasssificationType I: Barrett’s esophagus Ivor-Lewis

Type II: GE junction tumor (2 cm squamocolumnar junction) Roux-en-Y total gastrectomy

Type III: Subcardial region tumor Roux-en-Y total gastrectomy

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?

• 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

• 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

• 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

Surgery remains the only chance

for cure

• However, large loco-regional relapseUp 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

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?

• Multi-center, randomized trial comparing role of post-operative adjuvant therapy

• 13 Centers in Japan

• Starting in 1993, median f/u 69 months

• n=252

• 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

Similar frequency of post-operative morbidity and mortality

No significant difference(91.2% vs. 86.1%, p=.13)

At median follow-up 69 months, Deaths:Surgery alone: 21 patientsChemotherapy: 13 patients

Overall Survival

Surgery alone group was almost double

(17 [13.8%] vs. 9 [7.1%])

Total Cancer Recurrence

• Though no significant differences in overall survival, adjuvant chemotherapy had better 5-year survival (91.2% vs. 86.1%, p=0.13)

– 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...

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

• Multicenter trial (Southwest Oncology Group, USA), starting in 1991

• n=556 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% D236% D154% D0

– 5-fu plus leucovorin– 4500 cGy of radiation (180 cGy/day) 5

days/wk x 5 wks

Significant side effect profile

• 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

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 >15 LNs necessary for adequate gastric cancer staging

– D0 lymphadenectomy is an inadequate oncologic procedure

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

No consistent results from multicenter, randomized clinical trials assessing similar chemotherapy regimen (FAM or FMC) and

surgical technique (all D1 dissection)

Await further trials

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

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

• 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

• n=39 patients

• Evaluated the p53 status patients with locally advanced unresectable gastric carcinoma receiving chemotherapy

• Cisplatin, doxorubicin, 5-fu, leucovorin

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%, p=0.004

Altered p53 Wild-type p53

• 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

• High-throughput RNA expression

• Combined with improved genomic information

• Robotic

• Simultaneous analysis of thousands of genes at once

• Automated, quantitative

• “Gene expression profile”

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

• Two subclasses of melanoma that have distinct aggressive potential identified

• New, more specific (less false positive) markers for screening – Osteopontin and ovarian cancer– Multiple markers for breast cancer

• Prognosis

• Predicting adjuvant therapy response

Await Clinical trials