Once colorectal cancer has been diagnosed, a multidisciplinary team evaluates each case individually so they can provide the treatment that offers the best chance of curing the patient or illness control. The committee consists of: Radiologists (medical imaging specialists). Nuclear medicine doctors (for specialised studies such as PET-CT). Pathologists (experts studying tumour characteristics). Medical oncologists (specialists in chemotherapy and targeted therapies). Radiation

For colorectal cancer with metastasis (stage IV): Treatments targeting the EGFR receptor (cetuximab and panitumumab) are administered intravenously; they are used as monotherapy or in combination with chemotherapy; and are effective only in patients without mutations in the RAS gene (KRAS and NRAS), also referred to as native RAS or RAS wild type. Anti-angiogenic treatment (bevacizumab or aflibercept) is indicated for patients with metastases, in combination with chemotherapy and i

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Treatment of colorectal cancer

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Choice of treatment
Systemic treatment of colorectal cancer (Chemotherapy and Targeted Theraphy)
Targeted therapy

Choice of treatment

Once colorectal cancer has been diagnosed, a multidisciplinary team evaluates each case individually so they can provide the treatment that offers the best chance of curing the patient or illness control.

The committee consists of:

Radiologists (medical imaging specialists).
Nuclear medicine doctors (for specialised studies such as PET-CT).
Pathologists (experts studying tumour characteristics).
Medical oncologists (specialists in chemotherapy and targeted therapies).
Radiation oncologists (radiotherapy specialists).
Surgeons (specialising in the colon, rectum, liver and peritoneum).
Advanced practice nurses, specialising in colorectal cancer.

Once the committee has reached consensus after reviewing the additional test results, it establishes a treatment plan, which the responsible physician then explains to the patient.

The professional’s explanation of the plan to the patient includes:

Available treatment options.
The benefits and possible side effects.
Additional tests required.

The treatment is then established based on:

Tumour type. To complete the tumour diagnosis, molecular testing is performed to guide the prognosis and treatment of the patient. The following is determined:
- DNA repair protein status:
  - Stable tumours (MSS): expression of all proteins.
  - Unstable tumours (MSI): loss of one or more DNA repair proteins.
- RAS gene status (KRAS, NRAS)
- BRAF gene status.
Phase or stage of the disease (TNM).
- Localised stages (I and II): the cancer is limited to the colon or rectum.
- Locally advanced stages (III): cancer is limited but has greater local extension; for example with lymph node involvement.
- Metastatic stages: cancer has spread to other parts of the body.

Type of treatment

There are various types of individual and combination therapies that can be used to treat cancer:

Local treatment:

Minimally invasive options, including endoscopic, surgical and local ablative techniques.

Systemic treatment:

Targeted therapies: Anti-VEGF (bevacizumab) and Anti-EGFR (panitumumab, cetuximab).
New therapies such as immunotherapy with BRAF inhibitors.

Surgical treatment of colorectal cancer

Surgery is the most effective treatment for many cases of colorectal cancer. The most common treatment for colorectal cancer is removal of the tumour and surrounding fat tissue, where the lymph nodes are found.

Once resected, the surgical specimen is sent for analysis by the anatomical pathology service and the results help clarify whether further treatment is required (chemotherapy or radiotherapy).

Currently, the vast majority of these interventions are minimally invasive surgical techniques.

Laparoscopic and transanal surgery

While the patient is under general anaesthesia, the abdominal cavity is filled with carbon dioxide so that the surgeon can operate inside with long, thin instruments inserted through small incisions of 5-12 mm in the abdominal wall. An optical device is inserted through one of these incisions, allowing the surgeon to visualise the entire abdominal cavity and the area to be operated on. This technique causes less pain after surgery because only small cuts are made and the tissues are handled gently. It also gives better cosmetic results and helps patients recover faster, so they can get back sooner to their normal lives.

Because of its location, rectal surgery has a degree of technical difficulty greater than colon surgery. The rectum lies within a limited space inside the pelvis surrounded by structures that have to be preserved: the iliac vessels, ureters, bladder, prostate, seminal vesicles and the vagina. Despite the advantages of laparoscopic surgery in providing easier access to this space and better visualisation, it remains challenging and requires surgeons experienced in these techniques.

In some hospitals, rectal resection is performed by combining abdominal laparoscopic surgery with a transanal approach, such that two surgical teams are working simultaneously. This provides oncologically sound resections, with negative margins, while avoiding the technical difficulties of conventional open and laparoscopic surgery of the rectum. Patients who have the greatest difficulty are overweight males with a narrow pelvis, where the tumour is located in the middle or lower rectum.

Robotic surgery

Among the minimally invasive surgical techniques is robotic surgery, introduced at the Hospital Clínic in 2014. To perform this surgery, the surgeon is away from the patient and operates by sitting at a console and controlling 4 robotic arms. An assistant surgeon stays next to the patient and exchanges the robotic instruments. With robotic surgery, the surgeon has an immersive vision in three dimensions, with an extension of 20 times the vision of the human eye. This provides very careful dissection and minimises blood loss and injuries to neighbouring structures that need to be preserved.

Complications associated with colorectal surgery

Colorectal surgery may lead to postoperative complications, such as haemorrhage, anastomotic dehiscence (opening of the suture that joins the two ends of the colon) and surgical wound infection. Some of these complications can be managed conservatively, for example with antibiotics or local wound care.

In certain cases, when complications are more severe, a new surgical intervention is required along with the creation of a stoma. A stoma is a surgical opening made in the abdomen to bring out part of the small intestine or colon, so that waste products can leave the body for collection in a bag. A colostomy is when the large intestine (colon) is brought out through the stoma, and an ileostomy when the lower part of the small intestine (ileum) is brought through it. These stomata can be temporary or permanent. Temporary stomata require a new surgical intervention to rebuild intestinal transit.

Removal of the rectum means some patients may experience problems such as urinary dysfunction (urinary incontinence or retention), sexual dysfunction and anorectal dysfunction (faecal incontinence, multiple bowel movements per day, faecal urgency, etc.). In most patients these problems improve as the months go by until they disappear approximately one year after surgery. Other cases require specific therapies to address these functional problems, which are due to the manipulation of small nerve roots in the pelvis that supply all of the organs involved.

Radiotherapy. Radiation therapy, or radiotherapy, uses high-energy X-rays to destroy cancer cells. It has different applications in colorectal cancer and can be given alone or in combination with chemotherapy to reduce the size of the tumor before surgery (in rectal cancer), or to treat colorectal cancer that has spread outside the colon or rectum, such as to the bones or brain, to relieve symptoms in advanced cases (palliative radiotherapy).

Systemic treatment of colorectal cancer (Chemotherapy and Targeted Theraphy)

Chemotherapy. Chemotherapy is the most used treatment for colorectal cancer. It is generally administered intravenously, but in some cases it may be taken orally.

Chemotherapy inhibits the growth of cells in the process of division. It affects both tumour and healthy cells, which is what causes the symptoms associated with the treatment, known as adverse effects or side effects.

Chemotherapy can be administered as a single drug (monotherapy) or a two-drug combination (polychemotherapy). Some of the most used drugs include the fluoropyrimidines (5-fluorouracil [5-FU], capecitabine), irinotecan, oxaliplatin and TAS-102 (trifluridine/tipiracil).

The number of cycles depends on each tumour’s characteristics and stage, but patients generally receive 6–12 treatment cycles, that is about 3–6 months of treatment. Different tests are conducted throughout the treatment to evaluate its effectiveness.

Treatment depends on the stage of the disease

Stage I or II colorectal cancer

It is yet to be established whether or not patients with node-negative colorectal cancer benefit from adjuvant (postoperative) chemotherapy and radiotherapy.

Stage III colorectal cancer

Adjuvant (postoperative) chemotherapy comprising the intravenous administration of two drugs (typically fluorouracil and/or capecitabine with oxaliplatin) is recommended for patients with colon cancer under the age of 70. Chemotherapy is usually administered every 2 or 3 weeks, depending on the dose, and over a period of 3–6 months. Oral fluorouracil (capecitabine) monotherapy is recommended for patients aged over 70.

Treatment for patients with localised rectal cancer includes neoadjuvant (preoperative) radio-chemotherapy. Chemotherapy can be administered via continuous intravenous infusion (5-FU) or as tablets (capecitabine) and at the same time as radiotherapy. Surgery must be performed between 6 and 8 weeks after completing the course of radio-chemotherapy. The role of adjuvant chemotherapy has not been established.

Stage IV colorectal cancer

Around 20–25% of patients with initially localised cancer will eventually present metastasis during monitoring. Furthermore, in a significant number of patients the cancer has already spread when they are first diagnosed.

The primary objectives of treatment are:

Control disease-related symptoms.
Prolong survival.
Improve the quality of life

Evaluation before treatment

Before starting systemic treatment, it is essential to carry out a comprehensive evaluation of the patient, taking into account:

General condition and functional status.
The tumour’s genetic profile, such as the presence or absence of genetic mutations (e.g., in the RAS, BRAF, or MSI genes).
Therapies available and their possible effectiveness.

Metastatic disease treatment is organised along therapeutic lines. Each line is selected according to the tumour response, tolerance to previous treatment and the specific characteristics of the patient:

First line treatment:
- In patients with stable tumours (MSS), chemotherapy treatment is given, using a combination of two drugs: FOLFOX (fluorouracil and oxaliplatin) or FOLFIRI (fluorouracil and irinotecan).
- Immunotherapy is considered in patients with unstable tumours. There are currently two approved treatments: pembrolizumab and nivolumab/ipilimumab.
- Monotherapy is considered appropriate for patients over 70 years.

Second line treatment:
- In patients with stable tumours (MSS), chemotherapy is given with drugs not previously used.
- In patients with unstable tumours (MSI), immunotherapy is used if they have not previously received it.
- Monotherapy is considered appropriate for patients over 70 years.
Third line treatment:
- TAS-102 ± bevacizumab
- Regorafenib (not approved by CatSalut)
- Bevacizumab is considered appropriate for patients over 70 years.
Fourth line treatment: Fruquintinib and TAS-102.

Complications associated with systemic treatment

Depending on the specific type of chemotherapy administered, each treatment will cause different side effects.

Some of the symptoms that could appear include: tiredness (asthenia), changes in dietary preferences, nausea, vomiting, hair loss, inflammation of the mouth’s mucous membrane, fever, constipation/diarrhoea, muscular pain, neurotoxicity (pain, tingling or a loss of feeling in fingers and toes), redness, pain and lesions on hands and feet, acne-like eruption and nail lesions.

The chemotherapy used to treat colorectal cancer does not usually cause alopecia (hair loss) or vomiting.

Capecitabine can cause oedema and redness on the soles of the feet and palms of the hands. It can also cause diarrhoea and, on rare occasions, mouth ulcers (mucositis). If these side effects occur, then it is important to inform your usual doctor and, if in doubt, stop taking the drug.

The combination of fluorouracil and oxaliplatin via continuous infusion (FOLFOX) can also produce of mucositis, diarrhoea and fever due to low defences. This combination also tends to cause moderate tiredness, especially in the first few days after treatment. Oxaliplatin can provoke neurotoxicity (numbness in the hands and feet), particularly after 8–12 treatment cycles. This side effect may persist even after the end of treatment.

The other chemotherapy combination (FOLFIRI) can produce diarrhoea, abdominal pain and a greater degree of alopecia than FOLFOX, but it does not cause neurotoxicity.

TAS-102 is fairly well tolerated and the only side effects worth mentioning are anaemia, low defences and reduced platelet counts.

Targeted therapy

For colorectal cancer with metastasis (stage IV):

Treatments targeting the EGFR receptor (cetuximab and panitumumab) are administered intravenously; they are used as monotherapy or in combination with chemotherapy; and are effective only in patients without mutations in the RAS gene (KRAS and NRAS), also referred to as native RAS or RAS wild type.
Anti-angiogenic treatment (bevacizumab or aflibercept) is indicated for patients with metastases, in combination with chemotherapy and is also administered intravenously.
BRAF inhibitors, in patients with BRAF V600E gene mutations, administered orally in combination with anti-EGFR therapy. Not for clinical use; not approved by CatSalut.

Targeted therapy complications

Cetuximab and panitumumab: toxicity mainly dermatological, in the form of acneiform eruptions (small bumps) and/or scaly patches.

Bevacizumab and aflibercept: thrombosis, hypertension, proteinuria and spontaneous haemorrhaging.
TAS-102: asthenia, anaemia, neutropenia (low red blood cell count) and low platelet count.

Immunotherapy: can cause side effects related to the immune system, different from chemotherapy. Side effects are usually mild and reversible if detected and treated on time. They may appear weeks, months or even a year after the treatment.

Main side effects according to the organs affected:

Skin. Rash (redness, eruption, inflammation), pruritus (itching) and loss of pigmentation (vitiligo).

Gastrointestinal system. Diarrhoea, colitis (colon inflammation), sometimes with blood present or severe abdominal pain.

Endocrine organs:
- Thyroid disorders (hyperthyroidism or hypothyroidism).
- Inflammation of the pituitary gland (hypophysitis).
- Symptoms: fatigue, weight loss, nausea/vomiting, excessive thirst.
Lungs. Pneumonitis (pulmonary inflammation), which can cause respiratory distress or cough.

Liver. Autoimmune hepatitis (liver inflammation).

General symptoms. Fatigue, unexplained fever, muscle weakness, joint pain, headache and confusion.

Personalised treatment with anti-EGFR antibodies

Cetuximab and panitumumab are monoclonal antibodies that target receptors located on the surface of epidermal growth factor cells (EGFR). These receptors are involved in tumour cell survival and growth. Anti-EGFR antibody therapy is only indicated in patients with wild-type RAS colorectal cancer (with no mutations in their RAS genes) because it is only beneficial in these cases. Contrastingly, anti-EGFR therapy is not indicated for patients with RAS mutated colorectal cancer as it does not offer any benefit and could even be harmful. Anti-EGFR therapy in patients with wild-type RAS colorectal cancer provides a significant clinical benefit as it increases the likelihood of a response, improves control over the disease and increases patient survival.