Case
A 42-year-old man presents to his primary care physician with a chief complaint of rectal bleeding. He is generally healthy and takes no medications. Review of his family history is significant for uterine cancer, diagnosed in his mother at the age of 32 years, and colon cancer, diagnosed in his maternal uncle at the age of 54 years.
Therapeutics
Case continued
The patient underwent a colon cancer staging evaluation, including computed tomography scan of the abdomen and pelvis that showed no signs of distant metastases. Based on the patient’s age, family history, and cancer histology, Hereditary non-polyposis colorectal cancer was strongly suspected. Further testing of the tumor specimen revealed that the ascending colon cancer exhibited the microsatellite instability-high phenotype. The patient was referred for genetic counseling and a germline mutation was detected in MLH1.
Colorectal cancer treatment is determined largely by TMN stage and may include surgical intervention, chemotherapy, and/or radiation therapy. Surgical resection is generally the mainstay of colorectal cancer therapy, unless contraindicated by tumor stage, patient co-morbidities, or other factors. At least 12 regional lymph nodes should be removed along with the primary tumor for definitive pathologic staging. Anastamotic site recurrence rates for all colorectal cancer are 2-4% but may be as much as 10 times higher for rectal cancers, due to differences in surgical technique and/or tumor biology. Resection of isolated liver and lung metastases appears to improve the survival rate for some patients.
Postoperative (also known as “adjuvant”) chemotherapy is routinely recommended for stage III CRCs and may be considered for select stage II CRCs , using one of several combination regimens including 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (collectively referred to as FOLFOX). In a large, randomized, controlled trial of subjects with stage II or III colorectal cancer, adjuvant FOLFOX therapy improved the 3-year disease free survival rate from 72.9 to 78.2%. On average, treating 19 patients with FOLFOX instead of 5-FU and leucovorin would prevent one additional colorectal cancer recurrence at 3 years. However, the added benefit of oxaliplatin is counter-balanced by possible drug-induced toxicities, such as peripheral neuropathy.
An array of chemotherapy options exists for patients with metastatic colorectal cancer. First-line combination therapy with either FOLFOX or FOLFIRI (substituting irinotectan for oxaliplatin) appears to provide a response rate (denned as a composite of either complete disappearance of all detectable disease or as a decrease in tumor size by RECIST criteria) of 31-56%, with a median progression-free survival of 7-8 months. Further benefits might be achieved by adding a biologic agent such as bevacizumab.
Table Colorectal cancer chemotherapeutic agents
| Agent | Mechanism of action | Indications | Common toxicities |
| 5- Fluorouraci (5-FU) | Blocks the enzyme thymidylate synthase, which is essential for DNA synthesis | Multiple uses in combination with other agents in the adjuvant (postoperative) and palliative settings | Nausea, diarrhea Myelosuppression Fatigue |
| Capecitabine | Blocks thymidylate synthase (orally administered prodrug converted to 5-FU) | Multiple uses in combination with other agents in the adjuvant (postoperative) and metastatic setting | Nausea, diarrhea Myelosuppression FatiguePalmar-plantar syndrome (hand-foot syndrome) |
| Oxaliplatin | Inhibits DNA replication and transcription by forming inter- and intra-strand DNA adducts/ cross-links | Used in combination with 5-FU, LV (FOLFOX) in the adjuvant (postoperative) and metastatic setting | Peripheral neuropathy Nausea, diarrhea FatigueMyelosuppression Hypersensitivity |
| Irinotecan | Inhibits topoisomerase 1, an enzyme that facilitates the uncoiling and recoiling of DNA during replication | Used alone or in combination with 5FU, LV (FOLFIRI) in the metastatic setting | Cholinergic (acute diarrhea) Nausea, late diarrhea FatigueMyelosuppression Alopecia |
| Bevacizumab | Monoclonal antibody that binds to VEGF ligand | Used in combination with either FOLFOX or FOLFIRI in the metastatic setting | HypertensionArterial thrombotic events Impaired wound healing Gastrointestinal perforation |
| Cetuximab | Monoclonal antibody to EGFR (chimeric) that blocks the ligand-binding site | Used with irinotecan or as a single agent in the metastatic setting | Acneform rash Hypersensitivity Hypomagnesemia Fatigue |
| Panitumumab | Monoclonal antibody to EGFR (fully humanized) that blocks the ligand-binding site | Used as a single agent in the metastatic setting | Acneform rashHypomagnesemia
Fatigue |
External beam radiation therapy combined with systemic chemotherapy is used to treat locally advanced (T3, T4, and/or node-positive) rectal cancers. In a landmark study from 1985, the Gastrointestinal Tumor Study Group found a 33% recurrence rate among patients with locally advanced, surgically treated rectal cancer who received postoperative combination chemotherapy and radiation therapy, compared to a 55% recurrence rate for patients treated with surgery alone, after 80 months of follow-up.
The number needed treat with adjuvant combination therapy to prevent one additional recurrence was five in this cohort. Subsequent, large trials have further denned the benefits of radiation therapy for treating locally advanced rectal cancer, with pre-operative (also known as “neoadjuvant”) chemoradio-therapy to down-size the tumor, now considered standard of care. Most patients who receive neoadjuvant chemoradiation therapy are also candidates for adjuvant chemotherapy. For recurrent rectal cancers, long-term survival can be achieved for some patients using surgical resection, intraoperative radiation therapy, and adjuvant chemoradiation therapy.
Patients who develop bowel obstruction or other complications of locally advanced or metastatic disease may benefit from palliative chemotherapy or radiation therapy. Palliation through mechanical stenting and decompression techniques is also feasible.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.