Colorectal Cancer Symptoms, Prognosis and Treatment
Colorectal cancer is a malignant neoplasm involving the colon, rectum, and anal canal.
Pathophysiology of Colorectal Cancer :
- Development of a colorectal neoplasm is a multistep process of genetic and phenotypic alterations of normal bowel epithelium structure and function leading to unregulated cell growth, proliferation, and tumor development.
- Sequential mutations within colonic epithelium result in cellular replication or enhanced invasiveness. Genetic changes include mutational activation of oncogenes and inactivation of tumor suppressor genes.
- Adenocarcinomas account for more than 90% of tumors of the large intestine.
Clinical Manifestation :
- Signs and symptoms of colorectal cancer can be extremely varied, subtle, and nonspecific. Patients with early-stage colorectal cancer are often asymptomatic, and lesions are usually detected by screening procedures.
- Blood in the stool is the most common sign; however, any change in bowel habits, vague abdominal discomfort, or abdominal distention may be a warning sign.
- Less common signs and symptoms include nausea, vomiting, and, if anemia is severe, fatigue.
- Approximately 20% of patients with colorectal cancer present with metastatic disease. The most common site of metastasis is the liver, followed by the lungs and then bones.
Prevention and Screening of Colorectal Cancer ;
- Primary prevention is aimed at preventing colorectal cancer in an at-risk population. To date, the only strategy shown to reduce the risk is chemoprevention with celecoxib in people with familial adenomatous polyposis (FAP).
- Secondary prevention is aimed at preventing malignancy in a population that has already manifested an initial disease process. Secondary prevention includes procedures ranging from colonoscopic removal of precancerous polyps to total colectomy for high-risk individuals (e.g., FAP).
- American Cancer Society guidelines for average-risk individuals include annual occult fecal blood testing starting at age 50 years and examination of the colon every 5 or 10 years depending on the procedure. Digital rectal examination is not effective alone and should be performed with other screening examinations.
Colorectal Cancer Diagnosis :
- When colorectal carcinoma is suspected, a careful history and physical examination should be performed to identify risk factors and clinical manifestations.
- The entire large bowel should be evaluated by colonoscopy or proctosigmoidoscopy with double-contrast barium enema.
- Baseline laboratory tests should include complete blood cell count, prothrombin time (PT), activated partial thromboplastin time (aPTT), liver and renal function tests, and serum carcinoembryonic antigen (CEA). Serum CEA can serve as a marker for colorectal cancer and for monitoring response to treatment, but it is too insensitive and nonspecific to be used as a screening test for early-stage colorectal cancer.
- Radiographic imaging studies include chest x-ray, bone scan, abdominal computed tomography (CT) scan or ultrasound, positron emission tomography (PET), ultrasonography, and magnetic resonance imaging (MRI).
- Immunodetection of tumors using tumor-directed antibodies is an imaging technique for early detection of colorectal cancers. These tests might also be useful for identifying metastatic or recurrent disease in patients with rising CEA levels.
- Stage of colorectal cancer should be determined at diagnosis to predict prognosis and to develop treatment options. Stage is based on the size of the primary tumor (T1-4, presence and extent of lymph node involvement (N1-2, and presence or absence of distant metastases (M).
Desired Outcome :
- The goal of treatment depends on the stage of disease. Stages I, II, and III are potentially curable; the goals are to eradicate micrometastatic disease and to prevent recurrence. Stage IV is incurable; the goals are to alleviate symptoms, avoid disease-related complications, and prolong survival. In all stages, treatment decisions require careful assessment of relative risks and benefits.
Colorectar Cancer Treatments :
- Treatment modalities are surgery, radiation therapy (XRT), and chemotherapy and biomodulators. This section on treatment begins with an overview of each modality and associated toxicities. Next, this section addresses separately adjuvant therapy and treatment of metastatic disease.
- Adjuvant therapy is administered after complete tumor resection to eliminate residual local or metastatic microscopic disease.
- Adjuvant therapy differs for colon and rectal cancer because their natural history and recurrence patterns differ. Rectal cancer is more difficult to resect with wide margins, so local recurrences are more frequent than with colon cancer. Adjuvant XRT plus chemotherapy is considered standard for stage II or III rectal cancer. Adjuvant chemotherapy is standard for stage III colon cancer and can be considered for high-risk stage II colon cancer. Adjuvant therapy is not indicated for stage I colorectal cancer because most patients are cured by surgical resection alone.
- Neoadjuvant therapy is administered before surgery to shrink the tumor, there- by making it resectable. Neoadjuvant XRT may also prevent local recurrence.
- Chemotherapy is the primary treatment modality for metastatic colorectal cancer. Treatment options are generally similar for metastatic cancer of the colon and rectum.
- Surgical removal of the primary tumor is the treatment of choice for most patients with operable disease.
- Surgery for colon cancer generally involves complete tumor resection with an appropriate margin of tumor-free bowel and a regional lymphadenectomy.
- Surgery for rectal cancer depends on the area involved. Although less than 33% of these patients require permanent colostomy, frequent complications include urinary retention, incontinence, impotence, and local-regional recurrence.
- Common complications of surgery for both colon and rectal caner include infection, anastomotic leakage, obstruction, adhesions, and malabsorption syndromes.
- Surgery is rarely indicated for metastatic colorectal cancer, except for discrete hepatic and possibly other metastases that can be resected.
- XRT can be administered with curative surgical resection to prevent local recurrence of rectal cancer, before surgery to shrink a rectal tumor and make it operable, or in advanced or metastatic disease to alleviate symptoms. Adjuvant XRT, however, does not have a definitive role in colon cancer because recurrences are usually extrapelvic.
- Acute adverse effects associated with XRT include hematologic depression, dysuria, diarrhea, abdominal cramping, and proctitis. Chronic symptoms may persist for months after XRT and may involve diarrhea, proctitis, enteritis, small-bowel obstruction, perineal tenderness, and impaired wound healing.
CHEMOTHERAPY AND BIOMODULATORS
- Fluorouracil (5-FU) is the most widely used chemotherapeutic agent for colorectal cancer. Biomodulators are usually added to 5-FU to modify its activity and improve response rates, unless it is administered by continuous intravenous (IV) infusion.
- Administration method affects clinical activity and toxicity. 5-FU is administered by IV bolus once weekly or daily for 5 days each month, or by continuous IV infusion over 5 days. Continuous infusion appears to have better clinical activity, but bolus administration is more popular in the United States because of ease of administration and lower cost.
- Continuous IV infusion of 5-FU is generally well tolerated but is associated with palmar-plantar erythrodysesthesia or hand-foot syndrome. This distinct skin toxicity can be acutely disabling, but it is reversible and not life-threat- ening. IV bolus administration is associated with leukopenia, which is dose limiting and can be life-threatening. Both methods are associated with a similar incidence of mucositis, diarrhea, nausea and vomiting, and alopecia.
- Oral cryotherapy reduces the incidence and severity of stomatitis. Patients should chew and hold ice chips in the mouth for 5 minutes before, during, and for 30 minutes after bolus administration of 5-FU.
- Capecitabine is an oral fluoropyrimidine, which has efficacy and safety profiles similar to those of IV infusion of 5-FU.
- Combined 5-FU and XRT results in severe hematologic toxicity, enteritis, and diarrhea compared with either chemotherapy or XRT alone.
- Leucovorin improves 5-FU cytotoxicity. Toxicity depends on the regimen. High-dose leucovorin is associated with dose-limiting diarrhea, whereas low-dose leucovorin is associated with neutropenia and stomatitis.
- Levamisole is a synthetic, oral anthelmintic drug with immunomodulatory properties. Toxicities are generally minimal and reversible. Toxicities include metallic taste, arthralgias, central nervous system (CNS) toxicities (e.g., mood changes, sleep disorders, or cerebellar ataxia), and hepatic toxicity.
- Irinotecan is a topoisomerase I inhibitor. Irinotecan is associated with two distinct patterns of diarrhea that require appropriate intervention.
- Early-onset diarrhea occurs 2 to 6 hours after administration and is characterized by lacrimation, diaphoresis, abdominal cramping, flushing, and/or diarrhea. These cholinergic symptoms respond to atropine 0.25 to 1.0 mg IV or SC.
- Late-onset diarrhea occurs 1 to 12 days after administration, lasts 3 to 5 days, and can be fatal. Late-onset diarrhea requires aggressive, high-dose loperamide beginning with 4 mg after the first soft or watery stool, followed by 2 mg every 2 hours until symptom free for 12 hours.
- Oxaliplatin has a mechanism similar to that of cisplatin and might have better activity against colorectal cancer.
- Unlike other platinums, oxaliplatin is associated with minimal renal toxicity, hematologic toxicity, and nausea and vomiting.
- Oxaliplatin is associated with neuropathies. Acute neuropathy is reversible within 2 weeks, usually occurs peripherally, and is precipitated by exposure to cold. Persistent neuropathy is cumulative and is characterized by paresthesias, dysesthesias, and hypoesthesias.
- Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF).
- Bevacizumab does not increase the frequency of typical adverse events when added to chemotherapy.
- Bevacizumab is associated with hypertension, which is easily managed with oral antihypertensive agents.
- Bevacizumab is also associated with gastrointestinal perforation. This rare, but potentially fatal, complication necessitates prompt evaluation of abdominal pain associated with vomiting or constipation.
- Cetuximab is a chimeric monoclonal antibody directed against epidermal growth factor receptor (EGFR).
- Cetuximab is generally well tolerated. The most common adverse events are acne-like skin rash, asthenia, lethargy, malaise, and fatigue.
ADJUVANT THERAPY FOR COLON CANCER
- 5-FU combined with leucovorin or levamisole significantly reduces the risk of relapse and death in patients with stage III colon cancer. 5-FU and leucovorin has become the standard , because a 6-month course is as effective as 12 months of 5-FU and levamisole.
- The value of adjuvant therapy for stage II colon cancer is less clear, but high-risk individuals will probably benefit and should be offered adjuvant therapy in a clinical trial.
- None of the administration methods for 5-FU and leucovorin is considered standard. The regimens have similar efficacy but different toxicity profiles, treatment costs, and compliance issues. Many practitioners prefer the weekly, high-dose regimen (i.e., Roswell Park regimen) because of less toxicity, except for diarrhea.
- New adjuvant regimens are being evaluated such as the addition of a newer agent to 5-FU and leucovorin.
ADJUVANT AND NEOADJUVANT THERAPY FOR RECTAL CANCER
- The goal of adjuvant XRT for rectal cancer is to decrease local tumor recurrence after surgery, preserve the sphincter, and, with preoperative radiotherapy, improve resectability.
- 5-FU enhances the cytotoxic effects of XRT. Compared with XRT alone, the combination reduces local tumor recurrence and improves survival in high-risk patients.
- Continuous infusions of 5-FU, which may provide more effective radiosensitization, significantly improve disease-free and overall survival compared with IV bolus injections. Unlike adjuvant therapy for colon cancer, leucovorin and other biomodulators have not yet been shown to improve the efficacy of adjuvant 5-FU in rectal cancer.
- More research is needed to determine the best way to combine surgery, XRT, and chemotherapy. Available findings indicate that the extent of tumor involvement is important. For resectable T2 or larger lesions, postoperative 5-FU-based chemotherapy and XRT is appropriate. For unresectable tumors, neoadjuvant chemoradiation followed by surgery followed by postoperative 5-FU, with or without postoperative XRT, should be considered.
TREATMENT OF METASTATIC COLORECTAL CANCER
- 5-FU is incorporated into first-line regimens for metastatic colorectal cancer, usually in combination with leucovorin.
The optimal combination of 5-FU with leucovorin regimen is controversial. Historically, 5-FU plus low-dose leucovorin (i.e., Mayo Clinic regimen) was the most popular regimen for metastatic colorectal cancer based on response rates, toxicity, and drug costs. A weekly schedule of 5-FU (bolus or continuous IV) combined with leucovorin is more convenient for the patient.
- Adding a newer agent (i.e., triple-drug therapy) prolongs survival and is the standard first-line approach for patients who can tolerate the additional toxicity, which can be substantial. The optimal triple-drug regimen is unknown.
- Adding irinotecan to 5-FU and leucovorin prolonged survival by 2 to 3 months in previously untreated patients (p <.05 in two studies).
- Adding oxaliplatin to 5-FU and leucovorin improved response rates (p <.05 in two studies) and survival (p <.05 in one study) in previously untreated patients.
- Adding bevacizumab to 5-FU and leucovorin improved response rates and survival (p <.05 in two studies) in previously untreated patients. Bevacizumab is being evaluated in combination with other agents as first-line or salvage therapy.
Capecitabine monotherapy is suitable for first-line therapy in patients not likely to tolerate triple-drug therapy. Capecitabine produced superior response rates and comparable survival compared with 5-FU and leucovorin in a pooled analysis. Capecitabine is being evaluated in combination with irinotecan or oxaliplatin.
Second-line or salvage therapy is based on type of and response to previous treatment, site and extent of disease, and patient factors and treatment preferences. The optimal sequence of regimens has not been established.
A different regimen is generally used as salvage therapy, unless first-line therapy induced disease stabilization or a better response. Preliminary evidence supports reinstitution of previously active first-line therapy. Therefore, 5-FU can be included in salvage regimens, either in combination with an agent not previously used or by a different route (e.g., continuous IV infusion or capecitabine).
After failure of first-line therapy, patients should be encouraged to participate in clinical trials, which are being conducted to evaluate sequencing and many new treatments.
- After failure of 5-FU, irinotecan monotherapy prolonged survival by 2 to 3 months compared with best supportive care (p <.05) and with 5-FU by continuous infusion (p not significant).
The combination of oxaliplatin, 5-FU, and leucovorin is effective as salvage therapy. Unlike irinotecan, oxaliplatin does not have substantial activity as monotherapy.
- Cetuximab produced encouraging response rates in patients with irinotecan-refractory disease, especially when it was combined with irinotecan. Cetuximab is also suitable as salvage therapy for patients with oxaliplatin-refractory disease, and ongoing studies are evaluating cetuximab combined with oxaliplatin.
EVALUATION OF THERAPEUTIC OUTCOMES
- The goals of monitoring are to evaluate the benefit of treatment and to detect recurrence.
- Patients who undergo curative surgical resection, with or without adjuvant therapy, require routine follow-up.
- Patients should be evaluated for anticipated side effects such as loose stools or diarrhea, nausea or vomiting, mouth sores, fatigue, and fever.Patients should be closely monitored for side effects that require aggressive intervention such as irinotecan-indu
- ced diarrhea and bevacizumab-induced gastrointestinal perforation. Patients should be evaluated for other treatment-specific side effects such as oxaliplatin-induced neuropathy, cetuximab-induced skin rash, and bevacizumab-induced hypertension.
- Less than half of patients develop symptoms of recurrence such as pain syndromes, changes in bowel habits, rectal or vaginal bleeding, pelvic masses, anorexia, and weight loss. CEA levels may help detect recurrences in asymptomatic patients.
- Quality of life indices should be monitored, especially in patients with metastatic disease.