Updated 6 May 2008

Management Guidelines for Bevacizumab-Related Side Effects in Patients with Colorectal Cancer

Background

Chemotherapy is helpful in the palliation of selected patients with metastatic disease. While the Nordic Group study suggested some benefit from early treatment of metastatic disease (ie, in asymptomatic patients), the confirmatory cooperative group trial [Ackland 2001] was closed early due to lack of accrual. Currently, it is considered reasonable to delay treatment in asymptomatic individuals, who are not deemed to be at risk of relatively rapid development of significant symptoms or organ compromise related to their metastases. This approach is most appropriate for patients whose risk of chemotherapy toxicity is high (eg: those with poor performance status or multiple co-morbidities.) For younger patients, or for patients with bulky disease, initiation of chemotherapy prior to development of symptoms or greater tumor burden may be preferable.

Options for therapy of metastatic colorectal cancer have expanded greatly in the past decade . In addition to the familiar 5-Fluorouracil (with or without Folinic acid [Leucovorin]), the armamentarium includes other fluoropyrimidine analogues (eg, the oral agent Capecitabine (Xeloda®)), the thymidylate synthase inhibitor Raltitrexed (Tomudex® ), and other agents targeting non-folate pathways, especially Irinotecan (Camptosar®, CPT-11) and Oxaliplatin (Eloxatin®).

In addition to conventional cytotoxic chemotherapy, there has been exciting progress in the quest to develop therapies which more specifically target malignant cells, and which are accordingly less toxic to normal cells. Several agents which directly or indirectly target angiogenesis (the means whereby cells stimulate the creation of blood vessels, a normal process often exploited by cancer cells to expand their blood supply) have recently shown activity in advanced colorectal cancer. Bevacizumab (Avastin®), a monoclonal antibody directed against Vascular Endothelial Growth Factor (VEGF), was shown in early studies to improve survival when used in combination with 5FU/Leucovorin or with multiagent chemotherapy regimens [Kabbinivar 2003, Hurwitz 2004]. While confirmatory clinical trails are ongoing or recently completed, this agent is currently approved (in combination with multi-agent chemotherapy) for first line therapy of metastatic colorectal cancer. Prior approval from the Compassionate Access Program (CAP) is required. Cetuximab (Erbitux®) is a monoclonal antibody directed against the Epidermal Growth Factor Receptor. Studies have demonstrated improved response rates but only a very modest improvement in survival in patients previously treated with multiagent chemotherapy [Jonker 2007]. Further research and studies involving other cytotoxic agents and “biologic” therapies (including tyrosine kinase inhibitors, other monoclonal antibodies, vaccines, etc) continue. This is an area in which our recommendations are expected to undergo considerable revision over the next decade.

The number of combinations of the available agents speaks to the current dearth of unequivocal evidence to support one regimen over another as the gold standard in patients with good performance status. What is clear is that the previous "standard" regimens of bolus or infusional 5FU, with or without Folinic Acid have been surpassed by newer combinations involving 5FU, Folinic Acid and either Irinotecan or Oxaliplatin. These combination chemotherapy regimens are increasingly paired with the monoclonal antibody, Bevacizumab. Additionally, in these multi-drug combinations, administering the 5-FU by the infusional route (over 24-48 hours) seems to reduce certain toxicities and improve tolerance. Previous regimens employing bolus 5FU (eg the former BCCA protocol UGIIRFUFA (also known as the “IFL” or “Saltz” regimen)) are no longer favored, due to concerns about increased toxicity and mortality.

The choice of treatment in an individual patient depends on patient factors (preference, performance status, organ function) and logistics (geography, availability, etc.) In selected patients with good performance status, initial (first-line) therapy with combination therapy is the preferred option. For more debilitated or frail patients, or those who wish somewhat less aggressive therapy, single agents may be employed (see discussion below.)

Physicians unfamiliar with the treatment of metastatic colorectal cancer are encouraged to seek advice from a member of the BCCA GI Systemic Therapy Group.

Over the past ten to fifteen years, there has been significant improvement in the median overall survival of patients with this disease. As the chart below indicates, with the addition of various chemotherapy agents to create new combination regimens, there has been an improvement in both response rates and overall survival, such that, in 2008, the outlook for a reasonably fit patient with metastatic colorectal cancer approaches and may even exceed 24 months.

Figure 1: Response rates (%) and median overall survival (months) with various treatment strategies in metastatic colorectal cancer. Data modified from Dr. R. Burkes

Initial therapy in Patients with Good Performance Status

The BC Cancer Agency recommends combination chemotherapy in the first line therapy of fit patients with metastatic colon cancer. Either FOLFIRI (GIFOLFIRI, bolus and infusional 5FU/FA/Irinotecan) or FOLFOX (UGIFOLFOX, bolus and infusional 5FU/FA/Oxaliplatin) may be employed [Tournigand 2004]. The choice is often dependent on toxicity implications (patient characteristics, physician preference), but may also be influenced by the availability of funding for Bevacizumab (Avastin®) (see more, below). Combinations of the oral 5FU drug Capecitabine with Irinotecan (UGICAPIRI) or oxaliplatin (UGICAPOX) for patients ineligible for the corresponding infusional 5FU protocols may be available through the Compassionate Access Program (CAP, formerly the Undesignated program.)

Bevacizumab has been made available (with CAP approval) for the first six months of therapy when used in combination with FOLFIRI (UGIFFIRB). Its use with FOLFOX may be considered in exceptional cases (via CAP.) Potential toxicities of Bevacizumab include proteinuria, hypertension, thrombosis (venous and arterial), bleeding, perforation and central nervous system effects. Accordingly, careful monitoring is required, as stipulated in the protocol and in the document linked below.

Management Guidelines for Bevacizumab-Related Side Effects in Patients with Colorectal Cancer

Therapy in Patients not Eligible for Combination Chemotherapy

In patients who are not fit or not willing to receive initial triple combination regimens, single agent therapy may be employed. Infusional 5FU (GIFUINF, GIAVFL) or oral fluoropyrimidine analogues (eg, Capecitabine, GIAVCAP) are well tolerated. Raltitrexed (GIRALT), with a convenient intravenous schedule (every three weeks) may also be employed, but is generally reserved for patients unable to tolerate 5-FU. As Capecitabine and Raltitrexed are renally excreted, dose reductions are essential for patients with diminished renal function. Single agent Irinotecan (GIIR) may also be employed.

Oxaliplatin is not active as a single agent in colorectal cancer.

Subsequent Therapy in all Patients

For patients whose disease progresses after first line chemotherapy, a trial of therapy with an agent not previously employed (from the list above) can be contemplated, if their general condition permits. Some patients treated first line with a triple combination may be well enough to receive the alternate triple regimen upon progression. Retreatment with some or all of the same drugs may be an option if the progression free interval since treatment has been long (generally greater than 6 months.)

There is no standard approach to third line (or later) therapy, although activity is reported with the monoclonal antibody, Cetuximab (Erbitux®) [Jonker 2007]. This agent is not currently funded by the BC Cancer Agency. Consideration may be given to employing further infusional 5FU (GIFUINF, GIAVFL) in fit patients whose disease did not progress during prior 5FU-based therapy. Eligible patients should be encouraged to participate in clinical trials, where available.

Local Palliative Therapies

Palliative radiotherapy may be helpful for localized pain or bleeding. Transanal laser therapy may be helpful for control of bleeding or obstruction from malignancies situated low in the rectal/anal area. Transanal stenting may also be of value for obstruction. Non-resectable liver lesions are sometimes appropriate for non-drug therapies, such as radiofrequency ablation (RFA) or palliative external beam radiotherapy.

References

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2. Colorectal Cancer Collaborative Group. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000; 321:531-5
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