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Illustrative Case Series
Beginning with this month's issue, we will spotlight a new case series that involves a guest oncologist reviewing a pertinent case study in the field. In upcoming issues, we will be adding a new round-up section featuring an expert in a particular specialty of oncology, as well as a fresh new look for the publication.
Colon Cancer in a Piano Instructor
Guest Discussant, Robert Fenton, MD, PhD, Associate, Institute for Advanced Studies in Aging, Washington, DC. Dr. Fenton reports no financial relationship relevant to this field of study.
A 68-year-old white female presented to her internist complaining of fatigue for the past month. The patient is a piano teacher who traveled to her students' houses for their lessons, which had become a significant effort for her. She complained of no other symptoms, specifically no abdominal pain or change in appetite, weight, or bowel habits, as well as no chest pain, dyspnea, orthopnea, or edema. She denied noticing blood in her urine or stool, and had no vaginal bleeding. Her past medical history was notable for hypertension, osteoarthritis of both knees, and osteoporosis. She has two grown, healthy children, never smoked, and occasionally drank a glass of wine with dinner. She received yearly mammograms, Pap smears, and had her last colonoscopy seven years earlier (no abnormalities were found). Her chronic medications were hydrochlorothiazide, lisinopril, calcium, vitamin D, and Fosamax. In addition, she took Motrin 400 mg whenever her arthritis was bothering her, as often as 3-4 times per day. Her blood pressure was 125/74, heart rate 85, and room air oxygen saturation 94%. There were no orthostatic changes. Her physical exam was unremarkable other than mild pain on range-of-motion testing of both knees. Laboratory studies revealed a microcytic anemia (MCV 79) with a hemoglobin of 10.4 g/dL and a hematocrit of 32%. WBC was 6,300, with a normal differential, and there were 235,000 platelets. SGOT, SGPT, bilirubin, LDH, electrolytes, and renal function were all within normal limits. Routine blood tests performed four years earlier revealed a hemoglobin of 13.9 g/dL and a hematocrit of 42%.
The patient has a microcytic anemia with fairly acute onset of exertional dyspnea, especially for someone with no history of smoking, pulmonary, or cardiac disease. Therefore, her exertional dyspnea is probably related to the anemia. Iron deficiency is almost certainly the cause of the anemia, but what is the cause of the iron deficiency? Given the history of significant NSAID use, gastric ulcer with chronic bleeding must be ruled out. Other possibilities would include other sources of bleeding, none of which are apparent from the history. This does not, however, eliminate the possibility of a bleeding source anywhere in the GI tract, and the possibility of colorectal cancer cannot be ignored.
Blood tests confirmed the diagnosis of iron deficiency: serum iron, 60 mcg/dL; serum ferritin, 14 ng/mL; TIBC, 380 mcg/dL; transferrin saturation, 11%. Ferrous sulfate 325 mg po/tid to be taken with ascorbic acid tablets (250 mg) was prescribed. An EKG was normal.
Standard of Care
The patient was referred to a gastroenterologist, who performed an upper endoscopy that demonstrated some mild gastritis, but no ulcers or obvious source of bleeding. Prilosec was prescribed, and a colonoscopy was scheduled for the following week. This demonstrated a large, fungating lesion in the cecum, measuring approximately 6 cm in diameter. Biopsy of the mass showed moderately differentiated adenocarcinoma. CT scan of the abdomen and pelvis performed with contrast showed mild thickening of the wall of the bowel in the region of the cecum, but no evidence of perforation, hepatic metastases, or enlarged LN. CXR was normal, and CEA was 8.5 ng/mL. The patient was taken to surgery, where the cecal mass was identified and a right hemicolectomy with anastomosis was performed; no perforation or tumor penetration of the bowel wall was noted. Pathology revealed a 5.5 cm, moderately well-differentiated adenocarcinoma with penetration into the muscularis mucosa (T2). The surgical specimen contained 23 LN, five of which were positive for adenocarcinoma. Surgical margins were adequate (> 5 cm) and free of tumor. The patient made an unremarkable recovery and was referred to a medical oncologist for adjuvant chemotherapy for stage III colon cancer.
Considerations for Adjuvant Therapy in Colon Cancer
The benefit of adjuvant chemotherapy for stage III colon cancer was established by the NSABP C-03 and NCCTG phase-III, randomized studies. In both trials, 5-FU plus leucovorin was administered according to the Mayo Clinic bolus schedule (5-FU, 425 mg/m2 d1-5 every 4-5 weeks) for six cycles.1,2 These data were confirmed by the IMPACT study of pooled data from three randomized studies of Dukes B or C patients who received 5-FU/LV or observation; a three-year OS benefit of 83% vs. 78% was noted (22% reduction in death).3
A subsequent study showed that infusion of 5-FU-LV by the de Gramont regimen (LV 200 mg/m2 over 2h followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 continuous IV infusion over 22 hours, repeated on day two and every two weeks) was at least as effective as bolus 5-FU/LV, but caused less diarrhea, mucositis, and neutropenia.4 Note that a statistically significant benefit of adjuvant therapy for DFS and OS has only been observed in patients with positive LN (stage III, Dukes C). The role of adjuvant therapy for LN-negative disease (stage II, Dukes B) is generally not recommended, except in patients with high-risk features (e.g., T4 primary, perforation or obstruction, fewer than 13 LN identified in surgical specimen, lymphovascular, or neuronal microscopic invasion in primary tumor).
More recently, capecitabine, an oral fluoropyrimidine, was shown to be at least as effective as 5-FU/LV, and was FDA approved for the adjuvant therapy of stage III colon cancer.5 It is well tolerated when administered at 1 g/m2 BID for 14 of 21 days, with hand-foot syndrome being increased compared with 5-FU/LV regimens. Capecitabine is costly and not covered by all insurance companies for adjuvant treatment of colorectal cancer.
The MOSAIC trial demonstrated a significant improvement when oxaliplatin was added to 5-FU/LV in the adjuvant setting. In this randomized study of 2,246 patients with resected stage-II or -III colon cancer, patients received either the standard de Gramont infusional 5-FU/LV course of therapy, with or without the addition of oxaliplatin (85 mg/m2), in a regimen designated FOLFOX4.6 With a median follow-up of over 6.5 years, FOLFOX resulted in a significant improvement in DFS (73 vs. 67%, HR 0.80) and OS (79 vs. 76%, p = 0.046).7 The benefits were noted in stage III, but not stage II patients. Grade 3 peripheral neuropathy was noted in 13% of FOLFOX patients, but < 1% had persistent grade 3 neuropathy after four years. NSABP C-07 randomized patients to weekly 5-FU/LV (Roswell Park regimen), with or without oxaliplatin, every other week (treatment on a six- out of eight-week cycle).8 Addition of oxaliplatin significantly improved DFS, with a trend toward improved OS, again only in stage-III patients. This regimen, using bolus 5-FU, appeared to be significantly more toxic than FOLFOX4 (e.g., diarrhea and dehydration). In another phase-III study, the addition of oxaliplatin (130 mg/m2 dL, every 21 days) to capecitabine (1 g/m2 BID for 14 of 21 days) (referred to as the Xelox regimen) was shown to have a reasonable toxicity profile when compared to either the Mayo clinic or Roswell Park bolus 5-FU/LV adjuvant regimens, with more peripheral neuropathy and hand-foot syndrome.9 Efficacy data have not been published yet. On the basis of these and other studies, the addition of oxaliplatin to fluoropyrimidines is now the established standard of care for the adjuvant therapy of stage-III colorectal cancer.
Amazingly, a number of phase-III studies have demonstrated that irinotecan, a topoisomerase I inhibitor that is an important component of the treatment of metastatic colon cancer, provides no additional benefit to bolus or infusional 5-FU/LV in the adjuvant setting;10,11 the reason for this is not apparent. Similarly, although the addition of bevacizumab (Avastin) to FOLFOX and other regimens significantly enhances anti-tumor activity against metastatic disease, a recent phase-III study demonstrated the bevacizumab + FOLFOX6 was not better than FOLFOX6 alone in the adjuvant setting.12
Considerations for Adjuvant Therapy in Elderly Patients
Adjuvant chemotherapy for stage-III colorectal cancer provides an approximate 30% decreased risk of recurrence and a 22%-32% reduction in mortality. The relative benefit of adjuvant 5-FU/LV and capecitabine is just as great in older patients as in younger patients.13 Furthermore, the toxicity profiles are similar, with a trend toward more diarrhea in elderly patients receiving the Mayo bolus regimen.14 The data for FOLFOX treatment in patients > 70 years are ambiguous, with one pooled analysis demonstrating an equal benefit to younger patients and one indicating that the benefits did not extend to patients older than age 70.15,16 These data suggest that it is important to consider the overall condition of elderly patients before recommending oxaliplatin-based regimens that have greater treatment-related toxicities than 5-FU/LV alone. Fit elderly patients may receive mFOLFOX6, but careful consideration must be given to less fit or frail elderly patients. For patients who cannot receive oxaliplatin (pre-existing neuropathy or medical co-morbidities), 5-FU/LV (de Gramont regimen preferable due to reduced toxicity) or capecitabine for six months is a reasonable choice.
How to Treat this Patient?
This patient may very well benefit from adjuvant therapy. By six weeks postoperatively, her CEA had decreased to 2.2 ng/m and her Hb increased to 13.5 g/dL, coincident with recovery of her exercise tolerance. Given her excellent performance status, she was a candidate for six months mFOLFOX6. However, the patient expressed concerns that oxaliplatin-induced neuropathy could end her piano-playing career. Long-term morbidity from oxaliplatin-based regimens is due to distal sensory neuropathy that can be expected to be grade 3 in 10%-15% of patients receiving 85mg/m2 on an every-other-week schedule for more than four months. In most cases, this neuropathy will resolve, but this occurs over months to years.7 The options available for this patient include: 1) not using oxaliplatin and treating with six months of 5-FU/LV on the de Gramont schedule; 2) treating with six months of mFOLFOX6, with careful monitoring for the development of neuropathy. The problem with this approach is that neuropathy can develop insidiously and progress even after the oxaliplatin is stopped. Although recent data suggest that infusions of 1 g of calcium gluconate and magnesium sulfate, pre- and post-oxaliplatin, can ameliorate neuropathy, the physician cannot guarantee that significant neuropathy will not occur;17,18 3) since neuropathy appears to occur after four months of FOLFOX therapy (using 85 mg/m2 of oxaliplatin), it would be reasonable to treat the patient with 3-4 months of mFOLFOX6 with calcium/magnesium infusions, and then complete the six months with 5-FU/LV alone. Ultimately, the patient will need to weigh the risks/benefits, as presented by her oncologist, and then decide whether to receive oxaliplatin-based adjuvant treatment.
Areas Requiring Further Research
1. Is six months of adjuvant therapy really needed, or would 3-4 months be as efficacious?
2. Are there pharmacogenomic indicators that can identify patients who are most susceptible to toxic effects of drugs (e.g., neuropathy from oxaliplatin; diarrhea and hand-foot syndrome from capecitabine)?19
3. Are there targeted, small-molecule inhibitors that can be added to adjuvant chemotherapy to increase efficacy but not toxicity?
4. Can the group of stage-II patients who might benefit most from adjuvant chemotherapy be more clearly defined?
5. When sequencing the genome of an individual patient's tumor becomes practical, how will the ensuing data on genetic alterations in cancer cells be used to tailor adjuvant therapy in a patient-specific manner?
1. Wolmark N, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from the National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993 11:1879-1887.
2. O'Connell MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 15:246-250.
3. Marsoni S, et al. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet. 1995 345:939-944.
4. Andre T, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: Final results of GERCOR C96.1. J Clin Oncol. 2007 25:3732-3738.
5. Twelves C, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352: 2696-2704.
6. Andre T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 350:2343-2351.
7. Andre T, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II and III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109-3116.
8. Kuebler JP, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol. 2007;25: 2198-2204.
9. Schmoll HJ, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: A planned safety analysis of 1,864 patient. J Clin Oncol. 2007;25:102-109.
10. Saltz LB, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant for stage III colon cancer: Results of CALGB 89803. J Clin Oncol. 2007;25:3456-3461.
11. Van Cutsem E, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009; 27:3117-3125.
12. Wolmark N, et al. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSAABP Protocol C-08 (abstract#4). J Clin Oncol. 2009;27:793s.
13. Sargent DJ, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345:1091-1097.
14. Stein BN, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 1995;75:11-17.
15. Goldberg RM, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006;24:4085-4091.
16. McCleary NA, et al. Impact of older age on the efficacy of newer adjuvant therapies in > 12,500 patients with stage II/III colon cancer: findings from the ACCENT database (abstract #4010). J Clin Oncol. 2009 27:170s.
17. Grothey A, et al. Evaluation of the effect of intravenous calcium and magnesium on chronic and acute neurotoxicity associated with oxaliplatin: Results from a placebo-controlled phase III trial (abstract). J Clin Oncol. 2009 27:174s.
18. Nikcevich DA, et al. Effect of intravenous calcium and magnesium on oxaliplatin-induced sensory neuropathy in adjuvant colon cancer: results of the phase III placebo-controlled double-blind NCCTG trial N04C7 (abstract). J Clin Oncol. 2008 26:180S.
19. Ruzzo A, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007;25: 1247-1254.