PANCREATIC CANCREATIC CANCER ADJUVANT THERAPY

Colorectal Cancer
Robert F. Marschke, Jr., M.D.
December 4, 2009

Risk factors

• Cigarette smoking
• Increased body mass index
• Chemical exposures
• Beta-naphthylamine and benzidine
• Genetic predisposition in up to 5%
• P16 germline mutation (associated with  malignant melanoma)
• Also increased with brca-2 mutation

 General information

• More than 40,000 cases each year in the united states
• 15-20% resectable (r0 or r1)
• 5-year survival 30% node negative, 10% node positive

Surgery

• Surgery is possible if tumor does not involve the celiac artery or the superior mesenteric artery
• Staging before definitive pancreatic cancer surgery may include:
  upper gastroiontestinal endoscopy with ultrasonography
  and
  exploratory laparoscopic surgery

Adjuvant therapy

• What is adjuvant therapy? Adjuvant therapy means cancer treatments in addition to surgery
• Pancreatic cancer adjuvant therapy results are controversial
• Study limitations include:
• Underpowered
• Poor methodology
• Inconsistent reporting of staging
• Incomplete (terminated due to lack of accrual)
• Conflicting results are reported

Uncontrolled adjuvant therapy studies

• Postoperative retrospective with historical controls
• Johns Hopkins
• 616 patients, 5-fu chemoradiotherapy sometimes followed by 5-fu for 2 – 6 months
• Better median survival for treated patients (25 vs. 19 months)
• Postoperative
• Mayo Clinic
• 472 patients adjuvant radiotherapy with or without 5-fu
• Better median survival for chemoradiotherapy patients 25 months vs. 19 months

Controlled postoperative adjuvant therapy studies

• Espac-1   2004
• 541 patients randomised
• Significant median survival benefit for adjuvant leucovorin modulated 5-fu chemotherapy
• 19.7 months vs. 14 months
• 541 patients randomised
• Inferior median survival for chemoradiotherapy vs. Observation (13.9 months vs. 16 months)
• There are many criticisms of both methodologyand performance for this study 

• Rtog 9704 2008
• 442 patients
• Gemcitabine, then 5-fu chemoradiation, then gemcitabine vs. 5-fu, then 5-fu chemoradiation, then 5-fu
• Preliminary:  trend toward better median and 3-year survival with gemcitabine  --- subset analysis showsbenefit limited to cancer of the head of the pancreas

• Conko-001    
• Gemcitabine vs. Observation
• Longer disease free survival for gemcitabine: 13.4 months vs. 6.9 months
• A trend for improve overall survival with gemcitabine 22.8 months vs. 20 months
• Neoadjuvant therapy for pancreatic adenocarcinoma
• What is neoadjuvant therapy?  Neoadjuvant therapy is cancer treatment given before cancer surgery
• What is neoadjuvant therapy?
• Neoadjuvant therapy is cancer treatment given before cancer surgery
• Neoadjuvant external beam rt + chemotherapy + intraoperative radiotherapy (iort):
• Appears to be promising
• Randomised studies not yet done
• Conventional wisdom: one-third of patients require hospitalization for side effects and complications

Preoperative chemoradiation and ioert for unresectable or borderline resectable pancreas cancer 

Leonard L. Gunderson, Adyr A. Moss, Matthew G. Callister, K. Sudahkar Reddy, David C. Mulligan, Kristin L. Mekeel, Robert Marschke, and Mitesh Borad

SUBMITTED FOR PUBLICATION

26 patients with locally unresectable or borderline resectable pancreas cancer
Median and overall survival improved with resesection (r0/r1/r2; n=12) vs no resection (n=14)

Median 23 vs 10 mo
2-year, 40 vs 17%
3-year, 40 vs 0%
P = 0.011, log-rank

 Neoadjuvant therapy for pancreatic adenocarcinoma

• Ecog 1200 
• Prospective randomised phase ii neoadjuvant trial
• Preop gemcitabine chemoradiotherapy with postop gemcitabine vs. Preop gemcitabine + 5-fu + cisplatin followed by preop 5-fu chemoradiotherapy with postop gemcitabine

New concepts in adjuvant therapy for pancreatic adenocarcinoma

• A phase I tolerability and pharmacokinetic study of adjuvant erlotinib and capecitabine with concurrent radiation in resected pancreatic cancer patients
• 2008 gastrointestinal cancers symposium abstract 217
• W. Ma, J. M. Herman, D. Laheru, W. A. Messersmith, A. Jimeno, M. Rudek, Y. Khan, A. Howard, R. Schulick, R. Donehower, M. Hidalgo
  
• Development of a neoadjuvant candidate score in pancreatic cancer patients who underwent a palliative bypass procedure at the time of attempted curative resection
• 5 factors were found to predict early mortality (death within 6 months):
• Serum ca19-9 >100 (rr 1.4, p=0.041)
• Poor tumor differentiation (rr 1.38, p=0.023)
• Discovery of metastatic disease (rr 2.0, p<0.0001)
• Tumor in the body/tail of the pancreas (rr 1.4, p=0.049)
• Significant nausea and vomiting at presentation (rr 1.3, p=0.012)

Conclusions

• Postoperative adjuvant pancreatic cancer therapy studies show a significant improvement in disease free survival.  Measurable benefit in overall survival
• Standard clinical practice:  postoperative gemcitabine followed by 5-fu based chemoradiotherapy. Followed by gemcitabine
• Neoadjuvant therapy is appropriate for locally advanced unresectable pancreatic adenocarcinoma

COLORECTAL POLYPS AND THE RISK OF COLORECTAL CANCER
December 4, 2009
Robert F. Marschke, Jr., M.D.

 Hyperplastic polyps

• The most common nonneoplastic polyp
• Small nodules of normal cellular components
• May be indistinguishable grossly from adenomatous polyps
• Do not exhibit dysplasia
• Characteristic serrated ("saw tooth") pattern
• Proliferation is mainly in the basal portion of the crypt

Hyperplastic polyposis syndrome 

• Increases the risk of colorectal cancer
• Five or more hyperplastic polyps proximal to the sigmoid colon, two greater than 1 cm
  or
• Hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first degree relative with
  hyperplastic polyposis
  or
• More than 30 hyperplastic polyps distributed throughout the colon

• High levels of uncommon gene methylation of polyps and colonic mucosa
• No identified germline mutation
• Screening colonoscopies are recommended for first-degree relatives of affected individuals
• High levels of uncommon gene methylation of polyps and colonic mucosa
• No identified germline mutation
• Screening colonoscopies are recommended for first-degree relatives of affected individuals

Depressed adenomatous polyps

• Particularly likely to harbor high-grade dysplasia or to be malignant
• Flat and depressed adenomas were initially described in asia
•  recently recognized more frequently in western populations

Colonoscopy

• Optimal for the detection of adenomatous polyps
•  provides therapeutic polypectomy in addition to a diagnosis
• Colonoscopic miss rates:
• 27 percent for adenomas <5 mm
• 13 percent for those 6 to 9 mm
• 6 percent for adenomas >1 cm
• The amount of time taken by colonoscopists during withdrawal of the colonoscope is a powerful predictor of adenoma detection rate

Surveillance Recommendations

• Patients with only 1 or 2 small (<1 cm) tubular adenomas may have their next follow-up colonoscopy in 5-10 years, based upon prior findings, family history, etc.
• Patients with 3 to 10 adenomas, adenoma > 1 cm, villous adenoma, or high-grade dysplasia should have follow-up colonoscopy in 3 years
• Patients who have more than 10 synchronous adenomas should:
• Repeat colonoscopy in less than three years   
• Be evaluated for inherited colorectal cancer
• Patients with sessile adenomas that are removed piecemeal should have colonoscopy in 2-6 months to verify complete removal
• More intensive surveillance is indicated:
• When the family history is suspicious for inherited colorectal cancer
• Or if genetic testing has confirmed hereditary colorectal cancer

Cetuximab

• A chimeric monoclonal antibody
• An epidermal growth factor receptor (egfr) inhibitor
•  for the treatment of metastatic colorectal
• Binds the extracellular domain of the egfr of all cells that express egfr preventing ligand binding and activation of the receptor
• This blocks the downstream signaling of egfr resulting in impaired cell
  growth and proliferation
• Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity

What is KRAS?

• Kras is a gene that codes for a protein that plays an important role in the epidermal growth factor receptor (egfr) pathway
• Kras regulates downstream egfr signaling proteins associated with tumor survival, angiogenesis, proliferation & metastasis
• In tumors with wild-type kras the protein is only temporarily activated in response to certain stimuli such as egfr signaling
• Tumors with the mutated kras gene have the kras protein permanently turned on even without activation by upstream egfr mediated signaling
• As a result the downstream effects that lead to tumor growth and spread continue unregulated
• In colorectal cancer 65% of patients have wild-type kras
• 35% have the mutant version
• Hypothesis: because the kras protein is permanently turned in patients with mutant kras cetuximab inhibition of downstream egfr signaling is less efficient and tumor continues to grow, proliferate and spread

Cetuximab benefits patients with metastatic colorectal cancer

• Multiple studies confirm a benefit for cetuximab treated metastatic colorectal cancer patients with a wild type kras mutation
• Objective tumor response in 27 of 66 kras tumor wild-type patients
  versus 0 of 42 in kras tumor mutation patients
• Median overall survival was significantly better in kras wild type versus mutation (43.0 versus 27 weeks; p = 0.020)