Case Study (2/2)
Case Study: Metastatic Colorectal Cancer
M.A. is a 47-year-old woman who works as a software engineer and is newly married. Approximately 2 months after her honeymoon, she visited her primary care doctor because of a change in her bowel habits. Her stools were found to be guaiac positive. After further evaluation with colonoscopy and computed tomography (CT), colorectal cancer (CRC) metastatic to her liver was diagnosed. Her CT scans showed 2 lesions in the liver, the largest measuring approximately 3.5 cm. Because M.A. showed some mild obstructive symptoms, her colon lesion was resected; it measured 3 cm, with 5 of 12 lymph nodes being positive. Pathology revealed a moderately differentiated adenocarcinoma. At the time of surgery, her carcinoembryonic antigen (CEA) level was 385.5. This elevation of the CEA level at diagnosis makes it a useful marker for clinicians, as a guide to therapy and patient response; routine serial measurements are appropriate.
Clinical Observation: If M.A.'s CEA test result had been negative, serial measurements would have been less useful for gauging her response to treatment. Not all CRC tumors present with elevated CEA levels; approximately 60% of CRC tumors express CEA, and false-negative results are more common in poorly differentiated tumors (Klassen et al BC Med J. 2000;183-186. Available at: http://www.bcma.org/public/bc_medical_journal/BCMJ/2000/may_2000/FollowUp.asp).
At this time, M.A. is not considered to be a candidate for liver resection, but because of her age and otherwise relatively healthy status, she is started on chemotherapy with bevacizumab in the hope that she will become a resection candidate in the future.
Choices for therapy are discussed with M.A. and her husband. The offered therapy options are fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI) with the addition of bevacizumab. Side effects are discussed, and M.A. ultimately chooses to start FOLFOX4 with bevacizumab once her surgery site has healed sufficiently. She decides to proceed with this oxaliplatin-based regimen rather than the irinotecan-containing FOLFIRI, because she has had some problems with mild diarrhea since her colon resection, although she is concerned about neurotoxicity from the oxaliplatin as well.
Clinical Observation: It is recommended that a patient wait 28 days after surgery and allow the surgical wound to heal completely before beginning treatment with bevacizumab, an angiogenesis-inhibitor monoclonal antibody that targets vascular endothelial growth factor (VEGF), as the agent could potentially interfere with wound healing (Avastin [package insert]. Genentech Inc; 2004).
The regimen for M.A. includes oxaliplatin 85 mg/m2 intravenously (IV) over 2 hours on day 1, with leucovorin 200 mg/m2 IV over 2 hours on days 1 and 2 plus fluorouracil 400 mg/m2 IV bolus, then 600 mg/m2 IV over 22 hours as a continuous infusion on days 1 and 2. This regimen is repeated every 2 weeks. The bevacizumab is given as a 5-mg/kg IV infusion every 2 weeks. M.A.'s blood pressure is 135/80. She tolerates the regimen for 6 weeks but begins to note significant nausea and mild vomiting with her treatments. Her antiemetic regimen has consisted of dexamethasone 10 mg IV before chemotherapy, with prochlorperazine 10 mg orally (PO) and ondansetron 16 mg. Her home antiemetics are ondansetron 8-mg tablets twice a day with prochlorperazine. Significantly, her nausea seems to be worse on days 4 and 5, when her chemotherapy is almost finished.
Clinical Observation: Although oxaliplatin is considered a moderately emetogenic chemotherapy agent (30%-60% frequency of emesis), this patient seems to be suffering from delayed emesis. Fluorouracil is considered to be a low-risk emetogenic agent and probably is not the cause of this patient's nausea. Because her antiemetics on day 1 are not effective, a change in the antiemetics is appropriate (The NCCN Clinical Practice Guidelines in Oncology. 2006. Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf).
M.A.'s antiemetics are changed to aprepitant 125 mg on day 1, with 80 mg on days 2 and 3. Her steroid is changed to 12 mg on day 1, with 8 mg on days 2 and 3. Her ondansetron dose is increased to 24 mg PO on day 1. She is requested to stop her ondansetron after day 1 and, instead, to take prochlorperazine for the delayed period if needed for breakthrough nausea and vomiting.,. At the next visit, M.A. announces that her nausea and vomiting are much better, and the regimen is kept the same for her future therapies.
Clinical Observation: Aprepitant, a neurokinin-1 agent receptor inhibitor, blocks substance P, a mediator of chemotherapy-induced nausea and vomiting. It is given over 3 days and, to be effective, needs to be given as a 3-drug regimen, with a steroid such as dexamethasone and a 5-HT3 antagonist such as ondansetron (The NCCN Clinical Practice Guidelines in Oncology. 2006. Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf). If the patient had still suffered some nausea on day 4 or 5, a switch from the 5-HT3 to palonosetron would have been considered. However, the increased dose of ondansetron along with the addition of aprepitant was effective. Drug-drug interactions can occur with aprepitant, as it is a substrate, moderate inducer, and moderate inhibitor of CYP 3A4. Therefore, the dose of dexamethasone is lowered approximately 50% when given with aprepitant. Patients on warfarin should have their prothrombin time (reported as international normalized ratio [INR]) monitored about 7 to 10 days after aprepitant administration (Emend [package insert]. Merck & Co Inc; 2005).
M.A. does well until cycle 5. Although she experiences mild neuropathy symptoms with her oxaliplatin infusions, at cycle 5 she notes a tingling and burning of the hands, which does not resolve between infusions. She still describes her symptoms as mild, although they do not go away as before. This bothers her, as she has more difficulty using her computer. Her toxicity is characterized as grade 2, and M.A. is started on magnesium and calcium gluconate infusions of 1 g each, before and after each infusion of oxaliplatin. Although this adds to her infusion time in the chair, she states that it relieves her neuropathy symptoms somewhat and she wishes to continue the therapy.
Clinical Observation: A retrospective cohort of 161 patients receiving oxaliplatin showed improvement in a group that received calcium gluconate and magnesium sulfate (Ca/Mg) infusions. At the end of the treatment, 20% of the patients in the Ca/Mg group had neuropathy, compared with 45% in the nontreated group, and distal and lingual paresthesias were also lower in the Ca/Mg group during treatment (Gamelin et al. Clin Cancer Res. 2004;4055-4061).
M.A. is able to complete 9 treatments, at which point her restaging CT shows that 1 of her 2 liver lesions cannot be visualized, and the other measures 1 cm. Her CEA level is now 38.6. Resection of her liver lesion is completed successfully, and she finishes her chemotherapy treatments, for a total of 6 months of therapy. She is placed on surveillance, with CEAs every 3 months and periodic CT scans. The plan is to repeat her colonoscopy in 1 year.
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