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The hallmark side effects of irinotecan are watery diarrhea and a small increase in the risk of thrombotic complications (Cunningham et al, 1998; Rougier et al, 1998; Douillard et al, 2000; Saltz et al, 2000).

Oxaliplatin

Oxaliplatin is a water-soluble platinum derivative and is an inactive prodrug that requires in vivo biotransformation. There is no evidence of cytochrome P450 metabolism of the DACH ring in vitro. The route of elimination is predominantly (54%) urinary; fecal excretion accounts for 2% of elimination.

Oxaliplatin has synergistic antitumor activity with 5-FU against a broad spectrum of different cisplatin-resistant cell lines. Oxaliplatin's major mechanism of action is DNA adduct formation through platinum interstrand and intrastrand DNA cross-links, leading to inhibition of DNA replication, interference with transcriptional activation, and induction of tumor cell apoptosis.

Three pivotal phase III trials of oxaliplatin in the frontline treatment of metastatic colorectal cancer are summarized in Table 9-2. In 2 trials (de Gramont et al, 2000; Giacchetti et al, 2000), the combination of oxali-platin with infusional 5-FU and leucovorin was compared with infusional 5-FU and leucovorin. The 3-drug combinations were associated with improved tumor response rates and improved time to progression but had no impact on overall survival (Table 9-2). The lack of survival benefit was thought to be due in large part to crossover or sample size.

The North Central Cancer Treatment Group (Pitot et al, 2003) then compared the IFL regimen, the regimen of irinotecan and oxaliplatin (IROX), and FOLFOX4 in patients with metastatic colorectal cancer. Compared with IFL, FOLFOX4 demonstrated a superior response rate (45% vs 31%), time to progression (8.7 months vs 6.9 months), and median overall survival (19.5 months vs 14.8 months) and an improved side effect profile. IROX also appeared to be superior to IFL. Three caveats need to be emphasized: (1) Sixty percent of patients in the FOLFOX4 arm received irinotecan for salvage therapy, while only 25% of patients in the IFL arm received oxaliplatin as second-line therapy; (2) FOLFOX4 employed infu-sional 5-FU, which is superior to the bolus 5-FU used in the IFL arm; and (3) exposure to all 3 active agents is associated with longer median survival.

FOLFOX4 was also studied as second-line therapy in patients in whom IFL failed. Compared with 5-FU and leucovorin, FOLFOX4 was associated with an improved response rate (9.8% vs 0.7%) and time to tumor progression (5.6 months vs 2.6 months). There was also a trend toward a survival benefit (9.8 months vs 8.7 months; P = .07) (Rothenberg et al, 2001).

The side effects of oxaliplatin include acute dysthesia during oxaliplatin infusion, cumulative sensory neuropathy, and thrombocytopenia.

Capecitabine

If 5-FU is administered orally, 90% of the 5-FU is metabolized by di-pyrimidine dehydrogenase in the gut or peripheral blood monocytes. Administration of oral fluoropyrimidines combined with either a reversible dipyrimidine dehydrogenase inhibitor (e.g., tegafur) or an irreversible dipyrimidine dehydrogenase inhibitor (e.g., eniluracil) did not result in significant therapeutic advantages over intravenous infusion of 5-FU and leucovorin.

Capecitabine, a 5-FU prodrug, is more active than bolus 5-FU and leu-covorin and has a side effect profile similar to that of infusional 5-FU. Capecitabine is converted to 5-FU by a 3-step enzymatic reaction—by car-boxylesterase in the gut, cytidine deaminase in the liver and tumor, and finally, thymidine phosphorylase, the level of which is 3- to 15-fold higher in tumor tissue than in adjacent normal tissue. Because of the enzymatic conversion and preferential conversion to 5-FU by high levels of thymi-dine phosphorylase in tumor tissue, the mean concentration of 5-FU ratios was more than 3 times as high in primary tumor tissue as in adjacent healthy tissue and more than 21 times as high in primary tumor tissue as in plasma. In contrast, administration ratios of tumor to healthy tissue or plasma were all close to 1, indicating no tumor selectivity.

Despite these pharmacologic advantages of capecitabine, 2 large randomized phase III trials conducted in the United States and Europe (Hoff et al, 2001; Van Cutsem et al, 2001) showed that although capecitabine produced a higher tumor response rate (25% vs 14%) than bolus 5-FU and leucovorin, capecitabine was not associated with benefits in terms of time to tumor progression or overall survival. However, the toxicity profile of capecitabine was better than that of 5-FU and leucovorin and similar to that of continuous-infusion 5-FU.

Capecitabine may be administered alone or in combination with either irinotecan (regimen known as XELIRI) or oxaliplatin (regimen known as XELOX) in the frontline treatment of metastatic colorectal cancer. The phase II data showed that XELIRI or XELOX may replace the inconvenient infusional 5-FU without compromising the response rate and safety profiles. In a phase II study conduced at M. D. Anderson (Patt et al, 2003), XELIRI was associated with a response rate of 42%, an overall tumor control rate of 74%, and median time to progression of 7.1 months. Randomized phase III trials comparing capecitabine-based combination regimens to the standard FOLFIRI or FOLFOX regimens are ongoing.

Two common side effects of capecitabine are hand-foot syndrome and diarrhea (Patt et al, 2003; Van Cutsem et al, 2003).

Targeted Therapy

In recent years, there has been exponential growth in our knowledge of cancer cell growth and survival. Cancer cells have 6 essential hallmarks:

self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and evasion of apoptosis. In turn, understanding of the mechanisms underlying cancer growth, invasion, and survival advantage has led to the identification of molecular targets and the development of molecular therapies for all malignancies, including colon cancer.

Bevacizumab

Vascular endothelial growth factor (VEGF) is a very potent angiogenic factor. It is overexpressed in 70% to 80% of colorectal cancers and is associated with poor prognosis. Bevacizumab (Avastin) is a recombinant humanized (93%) chimeric immunoglobulin-G monoclonal antibody with a serum half-life in humans of 17 to 21 days. Bevacizumab blocks all VEGF isoforms with high affinity and high specificity and prevents VEGF binding to all VEGF receptors. Bevacizumab also blocks angiogenesis, preventing activation through VEGF and activation of downstream signaling pathways and endothelial cell proliferation and migration. A phase II study showed that addition of bevacizumab (5 mg/kg intravenously every 2 weeks) to 5-FU and leucovorin improved tumor response rate, enhanced median time to tumor progression to 9 months, and enhanced median overall survival to 21.5 months (Kabbinavar et al, 2003). In a randomized phase III study comparing bevacizumab (5 mg/kg intravenously every 2 weeks) plus the IFL regimen versus IFL alone in front-line treatment of stage IV colorectal cancer, the regimen with bevacizumab was associated with an enhanced response rate (44.9% vs 34.7%) and improved median time to tumor progression (10.4 months vs 7.1 months, P = .0014) and median overall survival (20.3 months vs 15.6 months; P = .00003). The unique side effects of bevacizumab included manageable hypertension (10% of patients), proteinuria, and rare abdominal perforations (Hurwitz et al, 2003). It is interesting that a randomized phase III study failed to show that adding the tyrosine kinase inhibitor SU5416 (a VEGF inhibitor) to the IFL regimen failed to produce a survival advantage over IFL alone. It is important to note that bevacizumab plus 5-FU and leucovorin without irinotecan produced median survival close to 20 months. Bevacizumab is now approved for firstline treatment of metastatic colorectal cancer. Other VEGF tyrosine kinase inhibitors—for example, PTK-787—are currently in phase III clinical development.

Cetuximab

In colorectal cancer, epidermal growth factor receptor (EGFR) has been associated with all 6 of the hallmarks of cancer mentioned at the beginning of the Targeted Therapy section. Overexpression of EGFR is noted in 70% to 80% of colorectal cancers. In vitro and in vivo models support EGFR as a valid molecular target for many solid tumors, including colo-rectal cancer.

Cetuximab (Erbitux) is a human-murine chimeric anti-EGFR immunoglobulin G monoclonal antibody. Cetuximab binds to EGFR with a binding affinity approximately one log higher than that of the natural ligand, transforming growth factor beta, preventing EGFR receptor dimer-ization and blocking EGFR signaling pathways. A phase II study in 121 patients previously treated with the IFL regimen showed that cetuximab plus IFL produced a response in 22.5% of patients and stable disease in 26.7% (Saltz et al, 2002). Cetuximab alone is associated with a response rate of 10% and with a median response duration of 6 months. In a randomized study, cetuximab (loading dose of 400 mg/m2 intravenously, then 250 mg/m2 intravenously weekly) plus irinotecan (100 to 125 mg/m2 intravenously weekly for 4 weeks or 200 to 250 mg/m2 intravenously every 3 weeks) also produced a response rate of 22% with a median response duration of 4 months in heavily pretreated patients previously treated with irinotecan or oxaliplatin. All clinical parameters except the development of an acneiform rash, including EGFR expression, were predictors of response. Anaphylactic reaction occurs in less than 5% and acneiform skin rash occurs in about 50% of patients treated with cetuximab (Saltz et al, 2000; Cunningham et al, 2003).

Other EGFR antagonists, including small-molecule tyrosine kinase inhibitors (e.g., gefitinib [Iressa]) and monoclonal antibodies (e.g., EMD 2000), have also been developed.

Celecoxib

Overexpression of COX-2 is seen in 70% to 80% of colorectal cancers and is also a strong prognostic factor. Celecoxib is a specific COX-2 inhibitor that is already approved for treatment of osteoarthritis and rheumatoid arthritis and prevention of colon polyps in patients with FAP. COX-2 inhibitors avoid the side effects of COX-1 inhibition, which include increased risk of gastritis, peptic ulcers, and gastrointestinal bleeding. The preliminary M. D. Anderson experience suggests that concurrent use of celecoxib and capecitabine with or without radiotherapy reduces the incidence of capecitabine-induced hand-foot syndrome while significantly enhancing the overall tumor response rate, time to tumor progression, and overall survival (Lin et al, 2002). A number of prospective randomized phase III studies involving celecoxib are currently in progress.

Management of Colon Cancer by Stage Carcinoma In Situ

Carcinoma in situ can almost always be cured by polypectomy alone or repeated polypectomy if complete endoscopic removal of the carcinoma in situ cannot be documented. Polypectomy may also be adequate for small T1 tumors that are margin-negative (i.e., no adenocarcinoma within 3 mm of the cauterized margin), well or moderately differentiated, and without lymphovascular or vascular invasion.

Stage I Colon Cancer

Polypectomy with negative margins is usually adequate for treatment of carcinoma in situ or small, well-differentiated T1 tumors with greater-than-3 mm cauterized margins and absence of lymphovascular invasion. Hemicolectomy with local-regional lymph node dissection is required for T1 tumors that are poorly differentiated, were previously treated with piecemeal polypectomy without clearly defined margins, or have evidence of lymphovascular invasion and for T2 or more advanced tumors.

The 10-year survival rate for patients with stage I colon cancer exceeds 90%. The primary goal of management of stage I disease is secondary prevention of new adenomatous polyps. Follow-up clinical examinations (measurement of CEA) should be conducted every 6 months for 2 years, then yearly for 5 years. Surveillance colonoscopy should be done within the first year after diagnosis and every 3 to 5 years thereafter. Low-dose aspirin therapy (81 mg by mouth daily) may be appropriate.

Stage II Colon Cancer

The 5-year survival rate for patients with stage II colon cancer treated with surgery alone is about 80%. The role of adjuvant 5-FU and leucovorin in patients with stage II colon cancer is controversial. Dozens of individual studies failed to demonstrate a statistically significant benefit of 5-FU-based adjuvant treatment over observation alone; however, 3 meta-analyses suggested that adjuvant 5-FU and leucovorin produced an overall survival benefit of 2%, raising the overall survival rate from 81% to 83% (Erlichman, 1997; IMPACT, 1999; Mamounas et al, 1999). Therefore, it is imperative to discuss the pros and cons of 5-FU adjuvant treatment with patients, taking into account factors such as the patient's age, life expectancy, and general health.

The subset of patients with perforated T4 tumors have a much higher risk of locoregional recurrence—up to 50%—after treatment with surgery alone. Therefore, these patients should be offered not only systemic adjuvant chemotherapy but also chemoradiation with an optimal fluoropy-rimidine plus radiotherapy at 45 Gy for 5 weeks (Willett et al, 1993, 1999). In patients with stage II colon cancer in the MOSAIC study (discussed in detail in the next section), the FOLFOX4 regimen achieved a relative risk reduction of 18%, or a gain in disease-free survival from 83.9% to 86.6% (de Gramont et al, 2003).

Other poor prognostic markers (high tumor grade and perineural, lymphatic, or vascular invasion) are useful in estimating the risk of recurrence but have not been prospectively validated as a guide for adjuvant treatment (Erlichman, 1997).

Stage III Colon Cancer

The 5-year survival rate for patients with stage III colon cancer treated with surgery alone is 40% to 60%. Lymph node metastasis is the strongest predictor of survival. Results of the many pivotal studies of adjuvant therapy for patients with stage III disease are as follows: (1) Adjuvant 5-FU and levamisole for 1 year improved the disease-free survival and overall survival rates by 30% and 20%, respectively, over observation. (2) Adjuvant 5-FU and leucovorin for 6 months produced survival rates equivalent to those seen with 5-FU and levamisole for 1 year, and the addition of levamisole to 5-FU and leucovorin did not increase the effect of 5-FU and leucovorin alone but did increase toxicity.

The Mayo Clinic and Roswell Park regimens (Table 9-3) are the 2 most commonly used regimens for adjuvant treatment of colon cancer. It is important to bear in mind that the Mayo Clinic regimen was associated with a far higher incidence of neutropenia than was the Roswell Park regimen, and that the Roswell Park regimen was associated with a higher incidence of diarrhea (Moertel et al, 1995; O'Connell et al, 1998; O'Dwyer et al, 2001). It is also important to point out that elderly patients (those older than 70 years) benefit from adjuvant 5-FU and leucovorin to the same degree as do younger patients (Sargent et al, 2001). A large randomized phase III study that compared capecitabine versus the Mayo Clinic regimen demonstrated improved safety in favor of capecitabine (Twelves et al, 2003).

In a large randomized phase III study (the MOSAIC study) in patients with stage II and III colon cancer, the FOLFOX4 regimen resulted in superior 3-year disease-free survival (78% vs 73%; P < .01) compared with 5-

Table 9-3. Commonly Used Adjuvant Chemotherapy Regimens for Patients with Stage III Colon Cancer*

Mayo Clinic Regimen

5-FU 425 mg/m2 IV bolus daily x 5 Leucovorin 20 mg/m2 IV daily x 5 Repeat every 4-5 weeks for 6 cycles

Roswell Park Regimen Leucovorin 500 mg/m2 over 2 hours 5-FU 500 mg/m2 bolus mid of leucovorin Weekly x 6 followed by a 2-week rest for 4 cycles

* The pros and cons of adding oxaliplatin to 5-FU in the adjuvant treatment of colon cancer should be discussed with patients prior to initiation of treatment.

More likely to cause myelosuppression

More likely to cause diarrhea

FU and leucovorin, achieving a relative risk reduction of 23% in both stage II and stage III patients. In subset analyses, FOLFOX4 improved disease-free survival from 65% to 71% in patients with stage III disease, with a relative risk reduction of 24% (hazard ratio, 0.76). FOLFOX4 was very safe—it was associated with an all-cause mortality rate of 0.5% in both arms, and the incidence of febrile neutropenia was less than 2%. Of concern was the development of grade 2 and grade 3 sensory neuropathy in 31.5% and 12.4%, respectively, of patients. Fortunately, the grade 3 sensory neuropathy was reversible: the percentage of patients with this side effect after 1 year of follow-up had declined to 1%. Although the median follow-up time is short at 3 years, this is the first clinical trial to show that addition of a new class of cytotoxic agent, oxaliplatin, to 5-FU and leucovorin produced improved disease-free survival at 3 years (de Gramont et al, 2003). In contrast, the Cancer and Leukemia Group B 89803 trial, which compared the IFL regimen versus 5-FU and leucovorin (Roswell Park regimen) in patients with stage III colon cancer, reported unexpected 60-day mortality rates of 2.2% in the experimental IFL arm. The final analysis demonstrated neither a disease-free nor an overall survival difference between the 2 regimens.

Stage IV Colon Cancer

About half of all patients with colon cancer die of metastatic or recurrent disease, and one quarter of patients present with synchronous stage IV disease. Sites of metastasis often include lymph nodes in the primary tumor drainage basin or in the para-aortic retroperitoneal chain. The liver is the most common visceral-organ site of colon cancer metastasis, followed by the lungs, peritoneum, and bone. Rare metastases to the adrenal gland, brain, and thyroid gland have also been reported. Mucinous tumors, especially of signet-ring-cell type, have a predilection for causing abdominal carcinomatosis, similar to presentations of ovarian cancer. The differential diagnosis is often straightforward; however, immunohisto-chemical studies with cytokeratin markers may be required. Second colon cancer primary tumors are more commonly encountered in younger patients and patients with an underlying genetic predisposition, such as patients with hereditary nonpolyposis colorectal cancer.

Even though an increasing number of therapeutic regimens are available for the first-line and second-line treatment of metastatic colorectal cancer, all eligible patients should be strongly encouraged to participate in well-designed clinical trials. Moreover, treatment of patients should be individualized on the basis of many clinical variables that affect the clinical outcome. Some of these variables are performance status, synchronous or metachronous metastasis, pattern and sites of metastasis, disease-free interval from primary tumor diagnosis or treatment, surgical resectability, feasibility of palliative or definitive chemoradiation, comorbid conditions, patient age, and patient preference and lifestyle.

Patients with synchronous resectable or borderline resectable metastases should undergo surgical removal of the primary tumor first and then combination chemotherapy before metastasectomy is explored. Patients with high-volume systemic metastases, unless there are emergent surgical indications (e.g., bleeding, perforation, or obstruction), should preferably proceed to chemotherapy before surgery for the primary tumor. Hemi-colectomy with or without colostomy is indicated if there is evidence of bowel perforation, obstruction, or bleeding. Occasionally, bowel obstruction can be successfully managed with the deployment of colonic stents or argon laser ablation.

For patients with high-volume unresectable metastases involving multiple visceral sites, the goal of therapy is to prolong survival and maintain or improve the patient's overall quality of life. The median survival for patients with metastatic colorectal cancer has increased from 9 months with best supportive care to 12 months with 5-FU and leucovorin to 14 to 17 months with combination chemotherapy to 20 months with an optimal fluoropyrimidine plus either irinotecan or oxaliplatin or combination treatment with bevacizumab and IFL.

The pros and cons of irinotecan versus oxaliplatin are as follows: (1) Infusional 5-FU is the optimal way of administering 5-FU. The de Gramont and AIO infusional-5-FU-plus-leucovorin regimens are the most commonly used in combination with irinotecan (e.g., FOLFIRI) and oxaliplatin (e.g., FOLFOX4). (2) FOLFOX4 is superior to IFL in terms of clinical outcomes but is equivalent to FOLFIRI. Furthermore, the optimal sequential monotherapy has not been carefully studied. Exposure to all active agents is associated with optimal survival benefits (3). The combination of 5-FU and leucovorin is synergistic with oxaliplatin but likely additive with irinotecan. Single-agent oxaliplatin produces weak antitumor activity, whereas irinotecan is an effective antitumor agent, producing a response rate of 25% when given as monotherapy in the first-line and second-line settings. (4) Cumulative sensory neuropathy secondary to oxaliplatin does not occur after 4 to 6 cycles of treatment, and efficacy is evident within the first 2 cycles of treatment. However, the tradeoff is cumulative neuropathy, hypersensitivity reactions, and thrombocytopenia. In contrast, with irinotecan, diarrhea is not a cumulative toxicity, but fatigue occurs in some patients (Kohne et al, 2003; Pitot et al, 2003).

Resectable recurrences include anastomotic recurrence, isolated liver or lung metastasis, recurrence in regional draining lymph nodes, and isolated peritoneal metastasis on a case-by-case basis. The liver is the most common site of visceral metastases, and isolated liver metastases can be treated with segmentectomy or extended left or right trisegmentectomy with or without radiofrequency ablation (Goldberg et al, 1998). Similarly, pulmonary metastases can be resected through lobectomy, partial lobec-tomy, or wedge resection depending on the size and number of lesions. The role of adjuvant chemotherapy after metastasectomy is controversial.

Because the risk of recurrence after metastasectomy is approximately 70% to 80%, it would be prudent to recommend adjuvant treatment with infu-sional 5-FU with either oxaliplatin or irinotecan in certain patients; other patients could be offered observation. The selection of patients for adjuvant treatment should be largely based on whether patients previously received 5-FU and leucovorin or duration of response to neoadjuvant chemotherapy and, importantly, the disease-free interval prior to tumor resection.

Treatment with adjuvant 5-FU and leucovorin plus hepatic arterial infusion of FUdR improves the hepatic disease-free survival rate at 2 years but not the median overall survival over treatment with 5-FU and leucovorin alone. Even though hepatic arterial infusion with FUdR for liver metastasis from colorectal cancer improved the tumor response rates (range, 35% to 80%), the improved response rates did not translate into meaningful survival benefits (Kemeny et al, 1999). With the advent of newer targeted and cytotoxic chemotherapy for colorectal cancer, use of hepatic arterial infusion has largely fallen out of favor at M. D. Anderson because of the lack of systemic effect and the serious short-term and long-term complications.

For symptomatic or life-threatening metastases that can be encompassed by the radiation portal, chemoradiation is a highly effective but underutilized therapeutic tool. With 3-dimensional conformal planning techniques, metastases that can be safely irradiated include regional nodal metastases, unilateral liver or lung metastases, limited bone metastases, and metastases associated with impending cord compression. Either infu-sional 5-FU (250 to 300mg/m2/day continuous infusion) or capecitabine is used as the radiation sensitizer. Radiation activates already upregulated thymidine phosphorylase in the tumor tissue, and thymidine phosphory-lase converts capecitabine to 5-FU preferentially in the tumor tissue. The dose of capecitabine is either 900 to 1,000 mg/m2 twice daily Monday through Friday or 825 mg/m2 twice daily Monday through Sunday during radiotherapy. Long-term survival has been observed in patients who received radiotherapy with or without surgery.

Management of Side Effects

Diarrhea

Diarrhea is a common side effect of all colorectal cancer chemotherapy regimens, especially those that include irinotecan administered weekly rather than on an every-3-week schedule. Irinotecan produces both acute and delayed diarrhea. The acute phase occurs with 12 hours of irinotecan infusion and manifests as acute salivation, nausea, abdominal cramping, and diarrhea due to an exaggerated vagal response. Acute diarrhea responds well to atropine. The delayed phase occurs within 4 to 6 weeks of irinotecan exposure and manifests as onset of acute abdominal cramping, followed by progressive cholera-like watery diarrhea that can lead to vascular collapse in the absence of prompt intervention. Patients should receive loperamide or diphenoxylate at the first sign of loose stool or abdominal cramping and then every 2 to 4 hours until the diarrhea resolves. Laxatives, stool softeners, and bowel motility agents, as well as dairy products, fruit juice, alcohol, and coffee, need to be discontinued. For patients who cannot maintain adequate oral hydration, parenteral fluid may be needed. The so-called BRAT diet (bananas, rice, applesauce, and toast) or a low-fiber diet (crackers, soft noodles, and chicken) is recommended. Fever greater than 101°F (38.3°C), diarrhea persisting more than 24 hours, and bloody stools are indications for hospitalization. Patients should receive parenteral fluid or nutrition, antibiotics, antidiar-rheal medications, opium tincture, and octreotide. The dose and schedule of octreotide (subcutaneous, intravenous, and depot) should be based on the severity of diarrhea.

Severe diarrhea secondary to 5-FU is less common and may be due to underlying dipyrimidine dehydrogenase (DPD) deficiency. With only 1 dose of 5-FU, patients with DPD deficiency can develop severe diarrhea, mucositis, neutropenia, cerebellar side effects, and skin rash. Both capecitabine and 5-FU are contraindicated in patients in whom DPD deficiency is suspected.

Hand-Foot Syndrome

The mechanism of hand-foot syndrome is unknown. It appears to be dose related and may be the result of inflammation. The role of high-dose pyri-doxine (vitamin B6) in the treatment of hand-foot syndrome is not clear. The M. D. Anderson experience suggests that concurrent use of celecoxib significantly reduces the overall incidence and severity of capecitabine-induced hand-foot syndrome, by about 30% to 50% (Lin et al, 2002).

Neuropathy

Sensory neuropathy induced by oxaliplatin can be reduced with concurrent infusion of calcium gluconate at 1 gram and MgSO4 at 1 gram. A stop-and-go strategy (termed OPTIMOX) has also been suggested: (1) Stop when there is evidence of grade 2 or greater neuropathy or the cumulative dose level is reached. (2) Go when the sensory neuropathy has regressed to grade 1 or less or when disease progresses with 5-FU and leucovorin alone.

Surveillance after Treatment

The risk of colon cancer recurrence is highest during the first 2 to 3 years after diagnosis; more than 90% of recurrences occur within the first 5 years.

CEA is a nonspecific tumor-associated antigen, the level of which may be elevated 3 to 6 months before radiographic evidence of disease becomes apparent. CEA levels can be quite elevated in other malignancies (e.g., lung cancer, breast cancer, and thyroid cancer) and as a result of smoking, alcohol use, hepatitis, and inflammatory bowel disease (but the level is usually less than 6 ng/ml). CEA level remains normal in approximately 20% of patients with colorectal cancer, so CEA is not a useful marker for screening (Benson et al, 2000; Bast et al, 2001). Either CA19.9 or CA125 is also elevated in some colon cancer cases.

General guidelines for surveillance for patients with stage II or III colon cancer at M. D. Anderson are as follows: (1) Clinical examination and CEA testing every 3 months for the first year, every 4 months for the second year, every 6 months for the next 3 years, and then annually. Complete blood cell count and measurement of liver enzymes are optional. (2) Chest radiography and computed tomography every 6 months for the first 2 years, then annually. These tests are especially important for patients with a higher risk of recurrence (N2 disease) or with negative CEA findings.

Because of the high risk of recurrence, surveillance for patients who have undergone metastasectomy is more intense: (1) Clinical examination, measurement of CEA level, chest radiography (or computed tomography of the chest in patients with lung metastases), and CT scan of the abdomen and pelvis every 3 to 4 months for the first 2 years and every 6 months thereafter.

Surveillance colonoscopy should be performed in all patients with a history of colorectal cancer within 1 year after the initial diagnosis and then every 3 to 5 years.

Future Directions

Molecular and genetic studies of colon cancer have delineated molecular pathways of carcinogenesis and identified a plethora of molecular prognostic markers, including DNA proliferative index, p53, pRb, bcl-2, DCC (18q) deletion, microsatellite instability, transforming growth factor recep-tor-II, and overexpression of DPD, thymidine phosphorylase, thymidylate synthase, COX-2, EGFR, and VEGF. Microsatellite instability and transforming growth factor receptor-II appear to be favorable prognostic factors (Takahashi et al, 1998; Ioachim et al, 1999; van Triest et al, 1999; Watanabe et al, 2001). Integration and validation of these molecular markers in prospective clinical trials would be an important first step toward individualizing therapy in patients with colon cancer. Markers might be useful in identifying high-risk stage II and III patients for adjuvant treatment. Or they might be used to determine sensitivity or resistance to chemother-apy—e.g., low-level expression of DPD, thymidine phosphorylase, and thymidylate synthase predicts 5-FU sensitivity, while high levels of DPD,

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Constipation Prescription

Constipation Prescription

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