Colorectal cancer is the third most common cancer in the United Kingdom.1 Colorectal cancer includes cancerous growths in the colon, rectum and appendix. Colorectal cancer is more prevalent among older people. The incidence in people between the ages of 45 and 49 years is 20 per 100,000 as compared to 300 per 100,000 for men and 200 per 100,000 for women amongst those over 75 years of age.1
The cancer can spread to the lymph nodes and other distant sites. This is known as metastasic colorectal cancer. When the cancer spreads beyond extent of lymph nodes, the patient is diagnosed of Stage IV metastatic colorectal cancer. Metastatic colorectal cancer may be present as a new disease or develop even after patient undergoes surgery for colorectal cancer. A study shows that 50% of patients who have undergone surgery for colorectal cancer will develop distant metastases. The 5 year survival rate for metastatic colorectal cancer without treatment is 12%1.
The most common site where the metastatic colorectal cancer spread to is the liver. 50% of patients with metastatic colorectal disease show up with liver as the only site of metastasis1. 10% of patients with metastatic colorectal cancer have pulmonary metastates4. Patients who have liver metastases may suffer from jaundice and abdominal swelling. Patients with metastatic colorectal cancer will also experience pain in the organ that the cancer has spread to. As an example, patients who have metastatic colorectal cancer in the bone may experience continuous, severe and localized pain in the rib or the back.
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Metastates in the brain may lead to problems with memory, concentration, balance or movement. Lung metastates will result in cough and shortness of breath.
As metastatic colorectal cancer is an advanced disease, it requires a combination of treatment including chemotherapy, palliative surgery, radiation, physiological support and symptom control to improve the duration and quality of the patient's remaining life. The treatment of metastatic colorectal cancer depends upon the site and extent of metastates. Normally, surgery will be the first choice for patients who have resectable metastates because the as surgery is the only option for long term survival. For others, chemotherapy is the first option. Chemotherapy cannot cure the disease but it can improve symptoms and may render unresectable tumour resectable.
Only approximately 10% of patients with metastatic colorectal cancer have potentially resectable liver metastates while another 14% may be able to undergo surgery after receiving chemotherapy1. Surgical resection increases the life expectancy of patients. Several recent large series on resection for colorectal liver metastases (CRLM) have reported five year survival ranging from 25% to 44%. However, there is also a risk with surgical resection with operative mortality between 0- 6.6%2. Poor prognostic factors for patients with liver metastases are multiple metastases, metastates larger than 5 cm in diameter, synchronous presentation of metastates and high tumour marker levels14. Liver resection might also lead to hepatic failure depending on the extent of resection and presence of liver disease. Complications such as haemorrhage, bile leak, intra-abdominal sepsis, and cardiopulmonary dysfunction can also lead to post-operative liver failure2. There is also a risk of recurrence after undergoing liver metastates resection. 60% of patients experienced tumour recurrence after liver surgery for colorectal metastates3. Besides liver metastates, surgical resection is also normally the first choice for treatment of pulmonary metastates4. In a research conducted among 58 patients who have undergone pulmonary resection, there was no operative morbidity. The 5 and 10 year survival was 29% and 20% respectively. In addition, all the 10 year survivors who are still alive now did not experience any recurrences4. However, this study is relatively small and cannot represent the whole population.
The type of treatment given to the patient also depends on the general health of the patient. Patients who are sufficiently fit with a WHO performance status 2 or better are treated with first or second line active chemotherapy1. The common first line chemotherapies include FOLFOX, FOLFIRI and XELOX regimen. FOLFIRI, FOLFOX and XELOX are known as conventional chemotherapy as they attack rapidly dividing cells which not only includes cancer cells but also lining of gastrointestinal tract, bone marrow and hair.
FOLFOX involves the usage of oxaliplatin, infusional 5-fluorouracil and leucovarin. Leucovarin which is a calcium folinate may be substituted by folinic acid. The use of folinic acid together with 5-fluorouracil will increase plasma concentration of 5-fluorouracil. The
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use of infusional 5-fluorouracil and leucovarin alone can increase survival to approximately 10âˆ’12 month. Oxaliplatin, a platinum based alkylating agent is normally given by intravenous infusion8. Oxaliplatin is known for its neurotoxic side effects such as sensory peripheral neuropathy but its neurotoxicity is dose limiting. A clinical study has proven the efficacy and safety of FOLFOX regimen in patients with severe hepatic dysfunction secondary to liver metastates. The drugs were well tolerated and the patients's liver function tests show an improvement7. However, the sample size studied is small as they only involved 3 patients. Instead of using infusional 5-fluorouracil, there are oral analogues of fluorouracil which are available such as tegafur. Tegafur with uracil have been proven to possess similar efficacy as fluorouracil and folinic acid for metastatic colorectal cancer8.
FOLFIRI comprises of Irinotecan, infusional 5-Fluorouracil and leucovarin6.Â Irinotecan inhibits topoimerase I, an enzyme involved in DNA replication. Irinotecan is given by infusion. Besides being incorporated into the FOLFIRI regimen, Irinotecan can also be used as a monotherapy when treatment containing fluorouracil has failed8. However, patients with abnormal glucuronidation of bilirubin such as those with Gilbert's syndrome may be at higher risk of myelosuppression when taking irinotecan11. The most common side effect associated with FOLFIRI is diarrhoea.
XELOX regimen utilises oxaliplatin and capecitabine. Capecitabine is metabolised to fluorouracil8. Both XELOX and FOLFOX have similar efficacy but XELOX offers benefits in terms of clinical safety and convenience over FOLFOX10. There is a lower incidence of anaemia, neutropenia, all grade neuropathy, alopecia among those taking XELOX although the patients taking XELOX might be more prone to hand-to-foot syndrome and diarrhoea10.
Besides the conventional chemotherapy, there is a different type of treatment available to treat metastatic colorectal cancer which is known as targeted therapy. Targeted therapy utilizes antibodies to bind to specific protein that are essential for growth of cancer cells6. The three types of drugs used in targeted therapy are cetuximab, bevacizumab and panitumumab. According to the NCCN guidelines, patients who are subjected to targeted therapy should have their biopsy sample from the tumour tested to determine the status for KRAS tumour marker5. Patients who have mutated KRAS gene should not be given a EGRF inhibitor.
Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor ,which is responsible of stimulating new blood vessel formation in the tumour8. Benvacizumab is not effective by itself6. However, the NICE guidance also do not recommend the use of bevacizumab with fluorouracil plus folinic acid with or without irinotecan as the first line treatment of metastatic colorectal cancer. The addition of bevacizumab to conventional chemotherapy improved the patient's condition in terms of increased overall survival, increased progression free period and reduction of tumour size1. However, bevacizumab is responsible for higher incidences of grade 3 or 4 hypertension among patients taking the combination therapy compared to those taking chemotherapy only. Bevacizumab also increases risk of arterial thromboembolism especially in those with prior arterial thromboembolic event or 65 years old or older1.
Cetuximab is a recombinant monoclonal antibody that inhibits the proliferation of cells by blocking the human epidermal growth factor receptor (EGFR). However, it is only active against EGFR-expressing tumour. Cetuximab can be used in combination with Irinotecan for treatment of EGFR-expressing metastatic colorectal cancer but this combination is not recommended as a second line or subsequent treatment after failure of chemotherapy that has included irinotecan8. Patients must be given an antihistamine before receiving the first infusion of cetuximab. According to manufacturer's submission, the response to cetuximab is linked to an acne-like rash. A randomized controlled trial observed increased life expectancy among patients with grade3 rash compared to those with grade 2 or 1 rash.
Panitumumab is a monoclonal antibody that binds to the EGRF. Panitumumab is indicated as a monotherapy for treatment of EGFR-expressing metastatic colorectal cancer with non-mutated KRAS gene that do not respond to fluoropyrimidine, oxaliplatin and irrotecan containing chemotherapy regimens. A study compared panitumumab with best supportive care in the treatment of metastatic colorectal cancer in patients who have failed standard chemotherapy. Best supportive care excludes usage of active chemotherapy. Panitumumab was found to decrease tumour progression rate by 46% and significantly improve disease control compared to best supportive care12.
The continuum of care concept is applied to treatment of metastatic colorectal cancer. Each treatment is individualized. Specific chemotherapy drugs may be given, stopped and restarted according to the need of the patient. There may also be a "maintenance period" which gives the patients a break from the active chemotherapy to have a better quality of life. The patient's response to chemotherapy is monitored with periodic x-ray studies (such as CT scans) every six to eight weeks during therapy. In addition, blood levels of a tumor marker called carcinoembryonic antigen (CEA) are generally measured every one to three months during therapy. If the CEA levels are rising constantly, the disease might be progressing and there is a need for a change in therapy.
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In this clinical scenario, the patient is 67 years old and may be classified as an elderly. The issues that are often linked to cancer treatment in elderly patients are physiological changes associated with aging, burden of coexisting illnesses, altered drug pharmacokinetics and functional impairment. Therefore, the elderly are often not given the optimum treatment due to fear of toxicity. For that reason, a comprehensive geriatric assessment that incorporates various aspects of functionality and health, including mental status, emotional status/depression, activities of daily living (ADLs), instrumental ADLs, home environment, social support, comorbidity, nutrition, and polypharmacy should be conducted before making any treatment decision20.
In my opinion, this patient should be given sequential therapy of FOLFIRI regimen followed by FOLFOX regimen . In this case, planned sequential therapy is more suitable than aggressive combination therapy as tolerability and quality of life is the key issue. The FOLFIRI and FOLFOX regime are less affected by the age of the patient. One pharmacokinetics study found no difference in plasma values of irinotecan or its primary metabolite between patients aged 65 years and younger subjects. This shows that renal or hepatic impairment does not generally require any modification to irinotecan dosage, with the exception of a bilirubin level >2 mg/dl, in which it is recommended not to be used20. Dose intensity also did not differ between patients aged <70 and 70 for either oxaliplatin or 5-Fluorouracil /Leucovarin, suggesting that advancing age did not affect drug delivery for oxaliplatin ,5-fluorouracil and leucovarin.
A Phase II clinical trial supported the use of FOLFIRI as first line treatment in elderly patients as it is an active regimen with manageable toxicity 15. FOLFIRI was also found to improve quality of life among the elderly as shown by a phase III study. A pooled safety and efficacy analysis of FOLFOX in elderly has also maintained same efficacy/toxicity ratio as in younger patients.9 Irinotecan which is included in FOLFIRI was shown to improve survival independent of patient's age13.
The FOLFIRI/ FOLFOX therapy is more advantageous over FOLFOX/FOLFIRI. Patients who receive FOLFIRI regimen first followed by FOLFOX have higher median survival of 21.5 months compared to 20.6 months in patients allocated to the latter(P = .99). As a first-line therapy, FOLFIRI achieved higher response rate compared to FOLFOX (56% vs 54% ) (P = .26). Second-line FOLFIRI achieved 4% RR while FOLFOX achieved 15% RR. In first-line therapy, FOLFOX also result in more severe side effects compared to FOLFIRI. Grade 3/4 mucositis, nausea and vomiting, and grade 2 alopecia were more frequent with FOLFIRI while grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX. The findings of this study was not statistically significant as (P>0.05) in most cases16. However, this study showed that elderly patients (those older than 65 years) did not experience increased toxicity in first-line and second line therapy as compared with younger subjects.
Another study on 5-fluoropyrimidine based chemotherapy found that patients aged older than 65 years might be more prone to diarrhoea,stomatis and infection. This is shown by the higher rates of diarrhea (21% vs. 16%), stomatitis (17% vs. 13%), and infection (4% vs. 2%) in those older than6518.
The guidelines recommend Atropine 0.25-1mg to be given to patients under FOLFIRI regime to minimize cholinergic adverse effects unless contraindicated. Loperamide can be given at the onset of diarrheoa which is often associated with irinotecan17.
The sequential regime of FOLFIRI followed by FOLFOX has the lowest cost-effectiveness ratio compared to FOLFOX or other sequential regimes which include cetuximab or bevacizumab. The cost was calculated in dollars while the effectiveness is assessed in life expectancy in terms of weeks for a 70 year old male19.