Controversies in the Management of Gastric Cancer Update

Controversies in the Management of Gastric Cancer Update on D1 vs. D2 dissection Is There a Role for Adjuvant Treatment? Hernan Bazan, MD 1 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 T2 T3 T4 Invades Submucosa Muscularis propia Serosa 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 and greater curvature, left gastric, common hepatic, splenic, celiac) Distant Mets: Involvement of hepatoduodenal, retropancreatic, para-aortic N1 N2 N3 1-6 regional LNs; 7-15 LNs >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 group 1 R cardiac 2 L cardiac N1 3 Lesser curvature 4 Greater curvature 5 Suprapyloric 6 Infrapyloric 7 L gastric artery 8 Common hepatic artery 9 Celiac artery N2 10 Splenic hilar 11 Splenic artery 12 Hepatic pedicle 13 Retropancreatic 14 Mesenteric root 15 Middle colic artery 16 Paraaortic Distal Tumors 35% -Subtotal gastrectomy Midbody Tumors 15-30% -Total gastrectomy Proximal Tumors 35-50% Siewert Classsification Type 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 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 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 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 Total Cancer Recurrence Surgery alone group was almost double (17 [13.8%] vs. 9 [7.1%]) • 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% D2 36% D1 54% 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