31 Pharmacologic Treatment of GI Malignancies

Question 1

Review and Preview of Chemotherapy for the Treatment of Cancer

• Chemotherapeutic agents
  
  • can either be used/
  • for either/
• In adjuvant therapy/
• For neoadjuvant therapy/
• In some cases, both neoadjuvant and adjuvant therapy/

Answer 1

• Chemotherapeutic agents
  
  • can either be used singly or in combination chemotherapy or radiotherapy (CRT)
  • for either curative intent or to provide palliative care.
• In adjuvant therapy, chemotherapeutic agents are given following surgical removal of the primary tumor.
• For neoadjuvant therapy, a chemotherapeutic agent is given (often in combination with radiotherapy) prior to surgical intervention to decrease the size of the tumor (downstaging).
• In some cases, both neoadjuvant and adjuvant therapy may be considered.

Question 2

Characteristics of Chemotherapeutic Drugs

• Most anticancer drugs
• IMPORTANT CONCEPT 1: Chemotherapeutic agents that damage DNA or inhibit DNA synthesis/

Answer 2

• Most anticancer drugs are cytotoxic agents that inhibit DNA synthesis or cause irreparable damage to DNA itself.
• IMPORTANT CONCEPT 1: Chemotherapeutic agents that damage DNA or inhibit DNA synthesis are much more effective at killing rapidly dividing cells than dormant cells that are in the G0 phase of the cell cycle.

Question 3

Anti-metabolites (p.7)

• These agents are analogues of/
• For example, some of these agents lead to/
• Alternatively, as a result of their incorporation into a growing DNA or RNA molecule, some anti-metabolites interfere with/

Answer 3

• These agents are analogues of normal metabolites that typically target enzymes involved in nucleotide and nucleic acid biosynthesis.
• For example, some of these agents lead to depletion of essential precursors required for DNA or RNA synthesis.
• Alternatively, as a result of their incorporation into a growing DNA or RNA molecule, some anti-metabolites interfere with the further synthesis, processing and/or function of DNA or RNA.

Question 4

Anti-metabolites:
5-fluorouracil (5-FU) (p.8+10)

• A pyrimidine analogue that is converted to/
  
  • 5-FU can also be ultimately converted to /
  • In addition, FdUMP is an effective inhibitor of/
  • In this manner, 5-FU also depletes/
• IMPORTANT CONCEPT 2: Cytotoxic effects of 5-FU are mediated mainly by/
• 5-FU
  
  • rarely used as/
  • administered/
• Capecitabine (Xeloda®)

Answer 4

• A pyrimidine analogue that is converted to FdUMP by thymidylate synthase, the enzyme responsible for converting dUMP to dTMP.
  
  • 5-FU can also be ultimately converted to FdTTP and FUTP and thereby be incorporated into DNA and RNA, respectively.
  • In addition, FdUMP is an effective inhibitor of the thymidylate synthase enzyme, which results in reduced accumulation of dTMP (product of thymidylate synthase).
  • In this manner, 5-FU also depletes an essential precursor for de novo or repair-mediated DNA synthesis.
• IMPORTANT CONCEPT 2: Cytotoxic effects of 5-FU are mediated mainly by its effects on both DNA and RNA synthesis and function.
• 5-FU
  
  • rarely used as a single agent
  • administered parenterally since its absorption following oral administration is unpredictable and incomplete.
• Capecitabine (Xeloda®) is an orally administered prodrug that is enzymatically converted to 5-FU in tumors.

Question 5

Anti-metabolites:
Gemcitabine (Gemzar®) (p.13)

• a fluorinated pyrimidine analogue that is converted to/
• F-dCTP causes/
• DNA containing incorporated F-dCTP is resistant to/
• Gemcitabine may increase/

Answer 5

• a fluorinated pyrimidine analogue that is converted to F-dCTP and ultimately incorporated into DNA.
• F-dCTP causes termination once incorporated into a growing DNA chain.
• DNA containing incorporated F-dCTP is resistant to repair.
• Gemcitabine may increase the cytotoxicity of other agents such as platinum compounds and radiation therapy due to its inhibitory effects on DNA repair systems.

Question 6

Platinum coordination complexes (p.14-15)

• react with/
  
  • As a result, DNA replication and transcription/
• cisplatin is used to treat/
• oxaliplatin (Eloxatin®)
  
  • more effective for/
  • Oxaliplatin-DNA adducts
  • oxaliplatin cytotoxicity is less dependent on/
• Cisplatin-induced apoptosis requires/

Answer 6

• react with susceptible sites on DNA leading to the formation predominantly of intrastrand crosslinks.
  
  • As a result, DNA replication and transcription are disrupted along with the generation of single- and double-stranded breaks.
• cisplatin is used to treat many cancers,
• oxaliplatin (Eloxatin®)
  
  • more effective for colorectal cancer.
  • Oxaliplatin-DNA adducts are bulkier than those formed with cisplatin and therefore less susceptible to DNA repair enzymes.
  • oxaliplatin cytotoxicity is less dependent on specific cellular proteins (i.e. high mobility group (HMG) proteins and components of the DNA mismatch repair (MMR) system) than cisplatin.
• Cisplatin-induced apoptosis requires the recognition of cisplatin-DNA adducts by the MMR system.

Question 7

Anti-mitotics (p.16)

• interfere with/
• Paclitaxel (Taxol®)
  
  • a natural compound that binds to/
  • results in the formation of/
  • aqueous solubility
• docetaxel (Taxotere®)
  
  • solubility
• vehicles used for both paclitaxel and docetaxel cause/
• IMPORTANT CONCEPT 3: Pretreatment with anti-histamines or glucocorticoids is required to/

Answer 7

• interfere with microtubule synthesis or degradation, leading to inhibition of cell division.
• Paclitaxel (Taxol®)
  
  • a natural compound that binds to ß-tubulin and stabilizes microtubules.
  • results in the formation of aberrant microtubule bundles during mitosis, mitotic arrest and ultimately apoptosis.
  • poor aqueous solubility
• docetaxel (Taxotere®)
  
  • improved solubility.
• vehicles used for both paclitaxel and docetaxel cause severe hypersensitive reactions.
• IMPORTANT CONCEPT 3: Pretreatment with anti-histamines or glucocorticoids is required to reduce the adverse hypersensitive reactions caused by vehicles used for relatively insoluble anti-mitotics.

Question 8

Topoisomerase Inhibitors (p.18-19)

• Irinotecan (Camptosar®)
  
  • an analogue of/
  • stabilizes/
  • If not repaired, this complex leads to the formation of/
  • sometimes preferred over other topoisomerase I inhibitors due to its /
• Epirubicin (Ellence®)
  
  • a synthetic derivative of/
  • forms/
• IMPORTANT CONCEPT 4: The limitation of topoisomerase inhibitors to S phase of the cell cycle requires/

Answer 8

• Irinotecan (Camptosar®)
  
  • an analogue of camptothecin
  • stabilizes the covalent complex formed between a nicked DNA strand and topoisomerase I.
  • If not repaired, this complex leads to the formation of a double-stranded DNA break during DNA synthesis (i.e. S phase) and ultimately cell death.
  • sometimes preferred over other topoisomerase I inhibitors due to its relatively long half-life.
• Epirubicin (Ellence®)
  
  • a synthetic derivative of naturally produced anthracyclines
  • forms a tripartite complex with DNA and topoisomerase II blocking the re-ligation of double stranded DNA breaks generated during DNA replication.
    
    • Accumulation of double-stranded DNA breaks triggers apoptosis.
• IMPORTANT CONCEPT 4: The limitation of topoisomerase inhibitors to S phase of the cell cycle requires prolonged exposure for any therapeutic benefit.

Question 9

Antibiotics:
Mitomycin C

• an antibiotic that/
• often used in combination with/

Answer 9

• an antibiotic that alkylates DNA leading to the
  
  • inhibition of DNA synthesis
  • formation of single and double-stranded DNA breaks.
• often used in combination with 5-FU, cisplatin and other chemotherapeutic agents to treat various GI cancers (i.e. colorectal, pancreatic, esophageal).

Question 10

Targeted Chemotherapy (p.23)

• Monoclonal antibodies against various growth factor receptors and signaling molecules (e.g. epidermal growth factor receptor (EGFR); vascular epithelial cell growth factor (VEGF) receptor) are being evaluated for their use as either/
• These agents typically bind to/
• also being targeted by newly developed chemotherapeutic agents
• IMPORTANT CONCEPT 5: Targeted chemotherapeutic agents are directed towards/

Answer 10

• Monoclonal antibodies against various growth factor receptors and signaling molecules (e.g. epidermal growth factor receptor (EGFR); vascular epithelial cell growth factor (VEGF) receptor) are being evaluated for their use as either
  
  • first line agents in combination with chemotherapeutic agents,
  • monotherapy for patients that have failed combination chemotherapy.
• These agents typically bind to plasma membrane receptors and inhibit their intracellular signaling.
• The enzymatic activity (e.g. tyrosine kinase) of some growth factor receptors is also being targeted by newly developed chemotherapeutic agents.
• IMPORTANT CONCEPT 5: Targeted chemotherapeutic agents are directed towards specific molecules (e.g. growth factor receptors) that are overexpressed or highly active in cancer cells.

Question 11

Basic Features of GI Malignancies

• Colorectal cancers
• stomach cancer
• Many GI cancers have

Answer 11

• Colorectal cancers are the second-most common cause of cancer death in the US
• stomach cancer is the second-most common cause of cancer death in the world.
• Many GI cancers have a gender bias in the US and also have poor cure rates.

Question 12

Esophageal Cancer (p.25)

• Prevalence
• The most important risk factor
• Major risk factors
• more likely to develop this cancer
• Non-surgical treatment

Answer 12

• Prevalence
  
  • rare cancer in the US,
  • its prevalence has been increasing in Asia and parts of Africa.
• The most important risk factor
  
  • (GERD) leading to Barrett’s esophagus.
• Major risk factors
  
  • Tobacco use and alcohol abuse, but more so for squamous cell esophageal cancer.
• Males and African Americans are more likely to develop this cancer.
• Non-surgical treatment
  
  • depends upon the tumor staging and location
  • could include neoadjuvant or adjuvant radiotherapy and/or CRT with 5-FU.
  • Esophageal cancer has a very high case to fatality ratio (83%) so chemotherapy is mainly palliative.

Question 13

Liver Cancer (p.27)

• The major risk factor
• Other important risk factors
• gender
• Treatment of hepatocellular cancer

Answer 13

• The major risk factor
  
  • Hepatitis C virus infection
• Other important risk factors
  
  • alcohol abuse, obesity, diabetes and smoking
• Men are twice as likely as women to get hepatocellular cancer.
• Treatment of hepatocellular cancer
  
  • based upon stage of the disease and presence of cirrhosis.
  • Partial surgical resection or liver transplantation is the mainstay treatment
  • targeted chemotherapy with the multi-kinase inhibitor sorafenib (Nexavar®) is also being considered

Question 14

Biliary Track and Gallbladder Cancer

• Prevalence
• The most common risk factor
• Non-surgical treatment for gallbladder cancer and cancer of the bile duct (cholangiocarcinoma) includes/

Answer 14

• Prevalence
  
  • not a common cancer in the US,
  • twice as common in women as in men
  • higher prevalence in Hispanic and Native American women.
• The most common risk factor
  
  • the presence of gallstones
• Non-surgical treatment for gallbladder cancer and cancer of the bile duct (cholangiocarcinoma) includes combination chemotherapy with cisplatin and the nucleoside analogue gemcitabine.

Question 15

Small Bowel Cancer

• frequency
• mainly treated/
• The major risk factor

Answer 15

• Adenocarcinomas of the duodenum are the most common form of small bowel cancer
• mainly treated surgically.
  
  • Chemotherapy plays a limited role in treatment of these cancers.
• The major risk factor
  
  • Crohn’s disease

Question 16

Anal Cancer

• frequency
• associated with/
• treatment

Answer 16

• rare very treatable form of GI cancer
• associated with infections of the high-risk form of human papilloma virus (HPV), HPV-16.
• treatment
  
  • Surgery is not a recommended primary treatment of anal cancer
  • combination chemotherapy with mitomycin/5-FU or CRT as primary therapies.

Question 17

Pancreatic Cancer

• Pancreatic cancer
  
  • curability
  • Over 90% of pancreatic tumors are/
  • surgery
  • chemotherapy or CRT
• IMPORTANT CONCEPT 6: Current chemotherapeutic agents to treat pancreatic cancer mainly provide/
• Current strategies to enhance the early diagnosis and development of novel, targeted chemotherapeutic agents have focused on the three established precursor lesions of pancreatic cancer,
  
  • precursor lesions
  • usually curable by/
• IMPORTANT CONCEPT 7: Since surgical resection of pancreatic tissue is associated with/

Answer 17

• Pancreatic cancer
  
  • one of the least curable of all cancers
  • Over 90% of pancreatic tumors are exocrine carcinomas (ductal adenocarcinoma).
  • surgery must be included in any treatment with the goal of curing pancreatic cancer,
    
    • patients are typically not diagnosed until the disease has advanced.
    • ~80% of pancreatic cancer patients are not candidates for curative resection.
  • Single agent, combined chemotherapy or CRT are considered depending on disease stage and whether surgical candidate.
    
    • Gemcitabine, 5-FU, oxaliplatin and cisplatin are common agents used to treat pancreatic cancer.
• IMPORTANT CONCEPT 6: Current chemotherapeutic agents to treat pancreatic cancer mainly provide palliative support given the advanced stage at which most of these cancers are detected and their inoperability.
• Current strategies to enhance the early diagnosis and development of novel, targeted chemotherapeutic agents have focused on the three established precursor lesions of pancreatic cancer,
  
  • pancreatic intraepithelial neoplasia (PanINs), intraductal papillary mucinous neoplasms (IMPNs) and mucinous cystic neoplasms (MCN).
  • usually curable by surgical resection if not present with cancerous lesions.
• IMPORTANT CONCEPT 7: Since surgical resection of pancreatic tissue is associated with significant morbidity and risk of mortality, better diagnostic markers and methods are need to distinguish true precursor pre-neoplastic from benign lesions.

Question 18

Pancreatic Cancer (p.34+36-37)

• Recent approaches to detect curable pancreatic neoplastic lesions
  
  • endoscopic ultrasound (EUS)
  • whole exome sequencing (WES).
• IMPORTANT CONCEPT 8: Early screening to detect curable pre-neoplastic pancreatic lesions is limited by/
• serum biomarkers
  
  • may distinguish/
  • many genetic alterations have been detected in pancreatic cancers and precursor lesions leading to ongoing clinical trials that are examining agents targeted to molecules such as/

Answer 18

• Recent approaches to detect curable pancreatic neoplastic lesions
  
  • endoscopic ultrasound (EUS)
    
    • has a relatively low accuracy rate (70%) for distinguishing between pancreatic cancer and localized prostatitis even though it can detect masses as small as 1 cm.
    • more sensitive (93% accuracy rate) for detecting pancreatic cancers less then 3 cm in size than MRI (67%) and CT (53%).
  • whole exome sequencing (WES).
    
    • can detect mutant alleles in mixed tissue even if present in 1/1000th the amount of the wild type allele.
    • The best tissue source to detect shed tumor DNA is pancreatic secretions collected by endoscopy following secretin-stimulation.
• IMPORTANT CONCEPT 8: Early screening to detect curable pre-neoplastic pancreatic lesions is limited by their small size and relative short length of time (i.e. typically ~5 years) before their progression to cancer.
• serum biomarkers
  
  • may distinguish non-malignant conditions (e.g. pancreatitis) from pancreatic cancer.
    
    • Although little pancreatic tumor DNA can be detected in blood
  • many genetic alterations have been detected in pancreatic cancers and precursor lesions leading to ongoing clinical trials that are examining agents targeted to molecules such as VEGF, EGFR and Raf-1.

Question 19

Colorectal Cancer

• Colorectal cancer
• Surgery
• adjuvant chemotherapy
• the combination of leucovorin (reduced folic acid)/5-FU/Oxaliplatin (FOLFOX)
  
  • leucovorin
  • Oxaliplatin
  • 5-FU/leucovorin/irinotecan (FOLFIRI)

Answer 19

• Colorectal cancer is the second leading cause of cancer death in the US in both men and women.
• Surgery represents the only curative treatment in 75-80% of cases
• adjuvant chemotherapy
  
  • used to kill microscopic metastases that may be present and reduce the risk of recurrence.
  • improves progression-free and overall survival
• the combination of leucovorin (reduced folic acid)/5-FU/Oxaliplatin (FOLFOX) is an FDA approved first line combined chemotherapy for advanced stage colon cancer.
  
  • leucovorin is used to enhance the inhibitory effects of 5-FU on thymidylate synthase by increasing the pool of enzyme available to interact with 5-FU (i.e. in a complex with tetrahydrofolate).
  • Oxaliplatin reduces the expression of thymidylate synthase, which may account for its enhancement of 5-FU cytotoxic action.
  • Another common combination chemotherapy for colorectal cancer is a similar formulation of 5-FU/leucovorin/irinotecan (FOLFIRI).

Question 20

Colorectal Cancer (p.43-44)

• IMPORTANT CONCEPT 7: Current first-line chemotherapies for colorectal cancer mainly utilize
• cetuximab (Erbitux®)
• bevacizumab (Avastin®)

Answer 20

• IMPORTANT CONCEPT 7: Current first-line chemotherapies for colorectal cancer mainly utilize anti-metabolites combined with agents that increase their effectiveness.
• cetuximab (Erbitux®),
  
  • a monoclonal antibody directed against the EGFR
    
    • being evaluated for treatment Since the EGFR is overexpressed in tumors cells of 60-80% of patients with malignant colorectal cancer,
  • However, activating mutations in downstream EGFR targets (i.e. Ras, B-Raf) are negative predictive biomarkers for anti-EGFR therapy, even in combination with chemotherapeutic agents.
• bevacizumab (Avastin®),
  
  • a monoclonal antibody directed against the VEGF receptor.
  • has shown promising results

Question 21

Molecular Determinants of Drug Sensitivity- Exploiting Biochemical and Molecular Knowledge of Nucleotide Metabolism for Intelligent Design of Chemotherapy to Treat Pancreatic Cancer (p.46)

• Gemcitabine
• pemetrexed [Alimta®]
• IMPORTANT CONCEPT 9: Newly developed combination chemotherapies for the treatment of pancreatic cancer seek to/

Answer 21

• Gemcitabine
  
  • hydrophilic
  • requires a specific transporter (i.e. Equilibrative Nucleoside Transporter-1 [ENT1]) to enter pancreatic cells.
  • overall survival following gemcitabine treatment is increased in pancreatic cancer patients expressing relatively high levels of ENT1.
  • The inhibition of thymidylate synthase (e.g. by 5-FU) can lead to the induction of ENT1 expression and increase the cytotoxic effects of gemcitabine.
• pemetrexed [Alimta®]
  
  • The conversion of gemcitabine to its active cytotoxic agent (i.e. FdCTP) requires the deoxycytidine kinase (dCK) enzyme.
  • The inhibition of thymidylate synthase and other enzymes involved in de novo purine and biosynthesis (e.g. by the anticancer agent pemetrexed [Alimta®]) can trigger the induction of enzymes involved in the salvage nucleoside pathway as a compensatory mechanism (e.g. dCK).
• IMPORTANT CONCEPT 9: Newly developed combination chemotherapies for the treatment of pancreatic cancer seek to enhance tumor cell metabolism of specific drugs that require biochemical conversion to their active cytotoxic species.

Question 22

Chemoprevention of Cancer

• Chemoprevention
• An ideal chemopreventative agent should/

Answer 22

• Chemoprevention refers to the use of pharmacologic or natural agents to inhibit or even reverse of the process of cancer development.
• An ideal chemopreventative agent should intervene early in the process of cancer development before premalignant cells become malignant.

Question 23

Inflammation and Cancer (p.50)

Answer 23

• Inflammation is a well-established cancer risk factor.
  
  • Inflammatory conditions, such as ulcerative colitis and Barrett’s esophagus, predispose to cancer.
• An inflammatory response leads to the recruitment of mast cells and leukocytes to the site of damage and subsequent release of free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can damage lipids and DNA.
• Inflammatory processes can also increase angiogenesis by the induction of VEGF.

Question 24

Non Steroidal Anti-Inflammatory Drugs (NSAIDs) (p.51-52+55)

• NSAIDs
• two types of COX enzymes
• Traditional NSAIDS/
• COX-2 selective inhibitors/
• frequent use of aspirin is associated with/
• NSAIDs have been used in patients with/
• COX-2 selective inhibitors were found to/
• IMPORTANT CONCEPT 10: NSAIDS or other anti-inflammatory agents are potential/

Answer 24

• NSAIDs
  
  • represent a large class of chemically heterogeneous, anti-inflammatory, analgesic, and antipyretic drugs.
  • inhibit cyclooxygenese (COX) enzymes, which catalyze the synthesis of prostaglandins (PGs) from arachidonic acid (AA).
• two types of COX enzymes:
  
  • COX-1: constitutively expressed, involved in GI protection and platelet aggregation
  • COX-2: inducible and involved in inflammation.
• Traditional NSAIDS, such as sulindac, indomethacin, ibuprofen, and aspirin, are nonselective COX inhibitors that inhibit both COX-1 and COX-2.
• COX-2 selective inhibitors, such as celecoxib (Celebrex®) and rofecoxib (Vioxx®), selectively inhibit COX-2.
• frequent use of aspirin is associated with as much as a 50% decrease in the risk of colon cancer.
• NSAIDs have been used in patients with familial adenomatous polyposis (FAP).
• COX-2 selective inhibitors were found to reduce the size and number of colon polyps in FAP patients.
• IMPORTANT CONCEPT 10: NSAIDS or other anti-inflammatory agents are potential chemopreventative agents for colorectal cancer although current drugs are limited by the occurrence of adverse cardiovascular effects.