Treatment of Metastatic Colorectal Cancer

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INCIDENCE IN IRELAND

• Colorectal cancer (CRC) is the second most common invasive cancer diagnosed in women (after breast cancer) and in men (after prostate cancer). Approximately 1,031 women and 1,405 men were diagnosed with CRC annually during 2009-2011.
• 11.5% (in women) and 13.7% (in men) of all invasive cancers (excluding non-melanoma skin cancer) were CRC in 2009-2011. Between 2005 and 2011, 93.1% of patients diagnosed with CRC were aged 50 years or older.
• CRC was the third leading cause of cancer death in women, after lung cancer and breast cancer, and the second leading cause of cancer death in men after lung cancer in 2009-2011. It accounted for 10.3% and 13% of cancer deaths in females and males respectively in 2011.¹

DIAGNOSIS AND STAGING

Clinical or biochemical suspicion of metastatic CRC (mCRC) should always be confirmed by radiological imaging.

Laboratory tests should include:

• Complete blood count
• Blood chemistries and liver/renal function tests
• Serum carcinoembryonic antigen

Imaging studies may include:

• Chest radiography
• Chest/abdominal/pelvic computed tomography (CT)
• Abdominal barium study
• Contrast ultrasonography of the abdomen and liver
• Abdominal/pelvic magnetic resonance imaging
• Positron emission tomography (PET), including fusion PET-CT scan

Other procedures may be warranted:

• Colonoscopy
• Sigmoidoscopy
• Biopsy of suspicious lesions
• Double-contrast barium enema.²

THERAPEUTIC STRATEGIES

Factors influencing choice of first-line treatment

Selecting the best treatment strategy for patients with mCRC should be undertaken by a multidisciplinary expert team. Relevant factors which should be considered are:

Tumour biology-related factors

• Localization
  – Liver- or lung-only metastases vs multiple sites
  – Potentially R0-resectable lesions after induction chemotherapy and sufficient downsizing vs massive disease extension
• Growth dynamics
  – Aggressive vs indolent growth
• Asymptomatic vs symptomatic disease
• Imminent relevant tumour symptoms if low active or inactive treatment
• Second-line treatment after ineffective first-line single-agent treatment may not be possible anymore
• Chemosensitivity
• Prognostic molecular or biochemical markers (e.g. BRAF mutation)

Patient-related factors

• Age
• Co-morbidities
• Physical capacity to tolerate more intensive treatment
• Eligibility for potential secondary resection of liver/lung
• Psychological capacity/willingness to undergo more intensive treatment

Efficacy/safety profile of therapy

• Potential to induce maximal regression of metastases size/number
• Potential to prolong progression-free survival (PFS) or overall survival (OS)
• Safety profile
• Drug sensitivity/predictive biomarkers.³

Currently available treatments

Cytotoxic agents used to treat mCRC include:

• Fluoropyrimidines
  – 5-fluorouracil (5-FU), given intravenously with a second drug called leucovorin (5-FU/LV), or alternatively,
  – capecitabine, given orally (e.g. Capecitabine Sandoz, Xeloda)
• Oxaliplatin (e.g. Hospira Oxaliplatin)
• Irinotecan (e.g. Actavis Irinotecan, Campto)

Several combination regimens may be considered:

• 5-FU/LV/oxaliplatin (FOLFOX)
• 5-FU/LV/irinotecan (FOLFIRI)
• Capecitabine/oxaliplatin (CAPOX)
• 5-FU/LV/oxaliplatin/irinotecan (FOLFOXIRI)

Targeted biological agents include:

Anti-vascular endothelial growth factor (VEGF) agents

• Bevacizumab (Avastin)
• Aflibercept (Zaltrap)

Anti-epidermal growth factor receptor (EGFR) antibodies

• Cetuximab (Erbitux)
• Panitumumab (Vectibix)

Multikinase inhibitor

• Regorafenib (Stivarga)⁴

Stratification of patients for first-line treatment

Patients can be subdivided into four clinical groups:

Group 0: Clearly R0-resectable liver and/or lung metastases
Patients in whom metastases are limited to liver and/or lung metastases, which are clearly R0 resectable.

Group 1: Potentially resectable liver and/or lung metastases
Achievement of a disease-free status after downsizing by induction chemotherapy, enabling secondary surgery, is the only means of giving the potential of long-term survival or cure in an otherwise incurable/palliative situation. The most active induction chemotherapy should be selected upfront.

Group 2: Unlikely resectable disseminated disease
The treatment aim here is palliative rather than curative (with individual exception, e.g. in case of high chemosensitivity and extensive response). In patients with symptoms, more aggressive biology or extensive disease, very active first-line treatment with a high likelihood to induce metastases regression in short time, is appropriate.

Group 3: Never-resectable metastatic disease
Maximal shrinkage of metastases is not the primary treatment aim; without present or imminent symptoms and limited risk for rapid deterioration, the aim is rather prevention of tumour progression and prolongation of life with minimal treatment burden. Non-intensive/sequential treatment may be appropriate for these patients.^3,4

Selection of treatment strategy

The definition of a treatment aim is important for the choice of a first-line treatment.

Surgical resection provides the only potentially curative option for patients with limited metastatic disease in the liver and/or lung. Perioperative chemotherapy or postoperative adjuvant chemotherapy with FOLFOX may be considered.

Five-year survival rates of 20%–45% have been reported with surgical resection of R0-resectable liver metastases. Resection of resectable lung metastases also offers 25%–35% five-year survival rates in carefully selected patients.

Most patients have metastatic disease that initially is not suitable for potentially curative resection. However, some of these patients can have metastases that become suitable for resection after a major response has been achieved with combination chemotherapy.

It is recommended that patients are re-evaluated during treatment by a multidisciplinary team including interventional radiologists and radiation oncologists, since ablative techniques (e.g. radiofrequency ablations, stereotactic body radiation therapy and infusional ablative methods) may be helpful in controlling disease.⁴

Treatment of patients with clearly unresectable mCRC should be seen as a continuum of care in which the determination of the goals of the treatment is important; prolongation of survival, cure, improving tumour-related symptoms, stopping tumour progression and/or maintaining quality of life.

Survival is longer when a patient is exposed to all of the available cytotoxics at some point during the course of treatment, and this could also be applied to the targeted biological agents. The ESMO have therefore proposed different strategic scenarios (see algorithm below). The choice of scenario depends on molecular characterisation of the tumour, the goal of treatment, the toxicity of agents and activity of anti-EGFR antibodies in later lines.

Combination chemotherapy FOLFOX or FOLFIRI provides higher response rates (RRs), longer PFS and better survival than 5-FU/LV alone. FOLFOX and FOLFIRI result in similar outcomes when used as first-line therapy; the choice between them is often based upon expected side effects. They also have potentially different interactions with biologicals.

CAPOX is an alternative to FOLFOX based on similar activity and safety profiles; however, some side-effects (including diarrhea and hand-foot syndrome) may be more pronounced with CAPOX.⁴

Bevacizumab is a monoclonal antibody that binds VEGF, the key driver of vasculogenesis and angiogenesis. It is indicated for the treatment of mCRC in combination with fluoropyrimidine-based chemotherapy. It enhances the anti-tumour effect of other chemotherapy regimens, but is not effective when given by itself.

Bevacizumab has been shown to increase the survival, PFS and RR in first-line treatment in combination with FOLFIRI and in combination with 5-FU/LV or capecitabine alone. It has also been shown to improve the PFS in combination with a fluoropyrimidine plus oxaliplatin in first-line treatment of mCRC. The combination of FOLFOXIRI plus bevacizumab has shown better PFS and RR than FOLFIRI plus bevacizumab in a trial with also one of the longest survivals reported to date.

However, the benefits of adding bevacizumab to these chemotherapy regimens must be balanced against the potentially serious side-effects that can occur with this drug (e.g. bleeding, blood clots). Bevacizumab is usually continued in combination with a cytotoxic agent/combination until progression or toxicity.⁴

Aflibercept is a recombinant fusion protein that binds to VEGF  and prevents it from activating its receptors on tumour cells. It is indicated in combination with FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.

Cetuximab is a monoclonal antibody directed against EGFR, which is found in about 80 percent of colorectal cancers. It is indicated for the treatment of EGFR-expressing, wild-type RAS mCRC in combination with irinotecan-based chemotherapy, in first-line in combination with FOLFOX, or as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.

Panitumumab is a monoclonal antibody which also targets EGFR. It is indicated for wild-type RAS mCRC in first-line in combination with FOLFOX or FOLFIRI, in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan), or as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The benefit of anti-EGFR antibodies in all treatment lines and either as a single agent or in combination with any chemotherapy regimen is limited to patients with wild-type RAS mCRC. The availability of an expanded RAS status is a prerequisite for any use of anti-EGFR antibodies and must not be used otherwise. Anti-EGFR antibodies are not recommended in combination with capecitabine-based regimens, and should not be combined with bevacizumab or aflibercept.⁴

Regorafenib is a protein kinase inhibitor which blocks multiple kinases including those involved in tumour angiogenesis and the tumour microenvironment. It is indicated for the treatment of mCRC in patients who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.

Regorafenib has shown significant improvement of survival and PFS in patients refractory to all available cytotoxics and to bevacizumab and to the anti-EGFR antibodies; it can be proposed as a standard treatment in last line in fit and motivated patients with mCRC.

In patients who started with bevacizumab (in combination with a cytotoxic doublet) in first-line, the targeted biological options for second-line treatment are bevacizumab, aflibercept and, in wild-type RAS patients, anti-EGFR antibodies such as cetuximab or panitumumab. Considerations include the choice of treatment in first-line, the biology of the disease, the molecular characterisation of the tumour, the time on first-line treatment (very short treatment on bevacizumab does not favour the continuation of bevacizumab), the toxicity of the agents, and the activity of the anti-EGFR antibodies in later lines. Continuation of bevacizumab with changed cytotoxic backbone in second-line increases the outcome after progression in first-line. Therefore, 5-FU/LV and bevacizumab could be continued throughout first- and second-line treatment, and solely irinotecan and oxaliplatin will be exchanged by each other.⁴

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References:
1. Cancer in Ireland 1994-2011: Annual report of the National Cancer Registry Ireland. Published May 2014.

2. http://emedicine.medscape.com/article/277496-overview. Accessed 20th April 2015.

3. Schmoll H. J. et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012, 23: 2479–2516.

4. Van Cutsem E. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014, 25 (Suppl. 3): iii1–iii9.

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Caroline McDermott