Cancer Chemotherapy

Cancer Chemotherapy

Cancer continues to be the second leading cause of mortality from disease in the USA, accounting for nearly 500,000 deaths in 2008. Cancer is a disease characterized by a loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation. Cells that have undergone neoplastic transformation usu-ally express cell surface antigens that may be of normal fetal type, may display other signs of apparent immaturity, and may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. It is now well established that a small subpopulation of cells, referred to as tumor stem cells, reside within a tumor mass. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic (colony-forming) capability, and they are characterized by chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. This genetic instability also allows them to become resistant to chemotherapy and radiotherapy. The invasive and metastatic processes as well as a series of metabolic abnormalities associated with the cancer result in tumor-related symptoms and eventual death of the patient unless the neoplasm can be eradicated with treatment.

CASE STUDY

A 55-year-old man presents with increasing fatigue, 15-pound weight loss, and a microcytic anemia. Colonoscopy identifies a mass in the ascending colon, and biopsy specimens reveal well-differentiated colorectal cancer (CRC). He undergoes surgical resection and is found to have high-risk stage III CRC with five positive lymph nodes. After surgery, he feels entirely well with no symptoms. Of note, he has no other comorbid illnesses. What is this patient’s prognosis? Shouldhe receive adjuvant chemotherapy? The patient receives a combination of 5-fluorouracil (5-FU), leucovorin, and oxali-platin as adjuvant therapy. One week after receiving the first cycle of therapy, he experiences significant toxicity in the form of myelosuppression, diarrhea, and altered mental sta-tus. What is the most likely explanation for this increased toxicity? Is there any role for genetic testing to determine the etiology of this level of toxicity?

CASE STUDY ANSWER

The 5-year survival rate for patients with high-risk stage CRC is on the order of 25–30%. Because the patient has no symptoms after surgery and has no comorbid illnesses, he would be an appropriate candidate to receive aggressive adjuvant chemotherapy. The usual recommendation would be to administer 6 months of oxaliplatin-based chemo-therapy using either infusional 5-FU or oral capecitabine as the fluoropyrimidine base in combination with oxalipla-tin. Adjuvant chemotherapy is usually begun 4–6 weeks after surgery to allow sufficient time for surgical wound to heal.Patients with partial or complete deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) experience an increased incidence of severe toxicity to fluoropyrimidines in the form of myelosuppression, gastrointestinal toxicity, and neurotoxicity. Although mutations in DPD can be identified in peripheral blood mononuclear cells, nearly 50% of patients who exhibit severe 5-FU toxicity do not have a defined muta-tion in the DPD gene. In addition, such mutations may not result in reduced expression of the DPD protein or in altered enzymatic activity. For this reason, genetic testing is not rec-ommended at this time as part of routine clinical practice.