Epidemiology

Colorectal cancer is the third leading cause worldwide. Colon cancer is more common than rectal cancer, the report colon / rectum in industrialized countries is 2/1. In Europe there are diagnosed 250,000 new cases justifying 9% of all malignancies.

In Romania the estimated incidence for 2000 was 26.43 to 100,000 inhabitants and the mortality of 15.27 to 100,000 inhabitants.

Risk factors:

Colorectal cancer most commonly occurs sporadically and is inherited in only 5% of cases. Studies indicate that when immigrant population moves from a low risk area (Japan) to a high risk area (USA), colorectal cancer incidence rises rapidly in the first generation of Japanese immigrants.

1. Diet is the most important exogenous factor identified so far.

The risk increases with increasing consumption of meat (red meat, processed meat) and decreases fat and increasing fiber, fruit and vegetables. Studies have shown an increased risk of colon cancer in patients with low physical activity.

Alcohol consumption (more than 30 grams / day), seems to increase the risk of rectal cancer. This term has a broken rectal tissue (eg by creating permanent colostomy diverting ileostomy) is an independent risk factor for the occurrence of rectal cancer (rectum remaining in) or stoma cancer, many years after the initial surgery. Other risk factors include obesity corporeal fat, abdominal fat and a small number of tasks. Nonsteroidal anti-inflammatory drugs reduce this risk.

Foods that contain dietary fiber and garlic, milk and calcium protect against this cancer. There is limited evidence that non-starch vegetables (salads and fresh herbs, seeds, sprouts, herbs, spices, spices, olive oil, nuts and coconut, seaweed) fruits, folate foods, vitamin D, selenium, fish protects against colorectal cancer and such as cheese foods containing animal fat and sugar are causes of colorectal cancer.

2. Non- food factors

Non-food risk factors of colon cancer include smoking, use of nonsteroidal anti-inflammatory drug chronic aspirin. Smoking has been positively associated with colorectal adenomas which are precursor lesions for colorectal cancer. Thus exposure to tobacco can be an initiator of carcinogenesis colorectal factor. IN US 1 in 5 cases of colorectal cancer can be attributed to tobacco use. Aspirin significantly reduces relapse sporadic adenomatous polyps.

Crohn’s disease and ulcerative colitis increases risk of colon cancer. Patients who had a previous malignant tumor are also at an increased pace of developing colorectal cancer. The use of estrogen and progestin decreased incidence of colorectal cancer.

3. Genetic Factors

– Familial adenomatous polyposis

– Peutz- Jeghers syndrome

– Juvenile adenomatous polyposis

– Nonpolipoid hereditary colon cancer

– Family history of colorectal polyps or cancer

Histologic classification of malignant tumors of colorectal

I. Malignant epithelial tumors

1. Adenocarcinoma 80-85%

2. mucinous adenocarcinoma 10-15%

3. signet ring cell carcinoma 1-2%

4. Squamous cell carcinoma 2-3%

5. adenoscuamos carcinoma 2-3%

6. undifferentiated carcinoma1%

7. small cell carcinoma (neuroendocrine) 1%

8. unclassified carcinoma

II. Carcinoid tumors

III. Nonepithelial tumors:

a leiomyosarcoma

a hemangiosarcoma

IV. Lymphomas

V. metastatic tumors

Location:

– Check the upward plus 24%

– Transverse 12%

– The downward 6%,

– Rectosigmoidian 34%

– Rectum 19%.

A “malignant polyp” is a polyp with cancer invading the muscularis mucosae in the submucosa (pT1). pTis not considered malignant polyp.

Favorable histologic features are: histological grading 1 or 2, there angiolimphatic invasion and resection margin is negative.

There is no consensus regarding the positive resection margin. Positive resection margin was defined:

1). Tumor to <1 mm of the edge of resection

2). Tumor at <2 mm from the resection

3). Tumor cells present in the resection margin

Adverse histologic features are: histological grading 3-4 angiolymphatic invasion, positive resection margin.

Controversy exists regarding the removal of malignant polyps on sessile endoscopic appearance. The literature seems to indicate that endoscopic removal of sessile polyp is accompanied by a significantly higher incidence of adverse consequences (residual disease, local recurrence, mortality, marrow metastases but not associated with lymph node metastasis) than malignant polyps. However configuration in itself not a bad prognostic factor and removing polyps with grading 1-2, without angiolymphatic invasion and negative resection margins can be performed successfully by endoscopic polypectomy.

For pathological staging following should be reported:

– Histological grading

– Penetration depth (pT)

– The number of invaded lymph nodes assessed and number (pN)

– Status edges proximal and distal radial.

Evaluation of lymph nodes

AJCC and College of American Pathologists recommends examining least 12 lymph nodes to accurately identify stage II colorectal cancer. The number of lymph nodes obtained varies according to age, sex, tumor grading and tumor headquarters. For stage II colon cancer are required to obtain 12 lymph nodes. If you do not get this number of lymph pathologist should seek more material with potential lymph node tissue. It showed that the number of lymph is a negative independent prognostic factor for patients with stage IIIB and IIIC colon cancer.

Sentinel lymph node micrometastases by immunohistochemistry and detection

Sentinel lymph node examination of histologic HE admits an intense investigation and / or immunohistochemistry to detect the presence of metastatic carcinoma. The studies reported in the literature have used multiple sections of HE and immunohistochemical study to detect positive cells cito- keratine. There is unanimity in terms of defining real metastatic carcinoma. Confusion took birth when isolated tumor cells (ITC) were considered as micrometastatic disease in contradiction with real micrometastatic disease that involves the tumor aggregates> 0.2 mm but <2 mm. Some investigators believe that size should not affect diagnosis of metastatic cancer. Currently the use of sentinel lymph node and detection of tumor cells by immunohistochemistry should only consider as investigational and results used with care in therapeutic decision.

KRAS mutation testing

Mutations in codons 12 and 13 of exon 2 of the KRAS gene coding region predict lack of response to target the antibodies against the epidermal growth factor receptor. Testing for mutations in codons 12 and 13 should be performed only in certified laboratories. Testing can be performed on tissue fixed in formalin and embedded in paraffin. Testing can be performed on primary tumor tissue or metastatic tissue.

BRAF mutation testing

Small studies suggest that patients with mutations in the BRAF gene do not respond to therapy with antibodies against target the epidermal growth factor receptor. BRAF V600E testing may be performed on tissue fixed in formalin and embedded in paraffin. This can be done by PCR amplification and direct analysis of the DNA sequence.

Tumor markers

Carcino-embryonic antigen (CEA). Healthy individuals who do not smoke have lower values ​​of 5ng / ml in 99% of cases.

ACE is increased to 60-94% of patients with advanced colorectal cancer, metastatic. False negative values ​​were found in 24% of patients. There correlation between preoperative serum concentration of ACE and tumor mass, and after curative resection of the ACE returns to normal six weeks. ACE is useful in monitoring patients and detecting recurrence and metastasis. The low level of ACE is indicative of effective therapy and ACE increasing levels indicate the presence of disease.

Screening

It uses the following tests: digital rectal examination, occult blood test (THO), flexible sigmoidoscopy, colonoscopy and barium enema.

I. In low-risk patients are recommended:

1. The digital rectal exam annually starting at 40 years (or 50 years)

2. Occult blood test annually

3. Flexible sigmoidoscopy 5 years

4. Double-contrast barium enema 5-10 years

5. Colonoscopy to 10 years

II. At-risk patients are recommended:

1. Familial adenomatous polyposis (FAP). Sigmoidoscopy is done annually from the age of 10-12 years to 24 years from 24 years to 34 years, sigmoidoscopy is 2 years and after 34 years sigmoidoscopy is done every 5 years.

2. Non-polipoid hereditary colon cancer (HNPCC). History of HNPCC:  families are subjected annually to colonoscopy every 2 years starting from 24 years to 35 years and after 35 years it annually.

3. Family history of colorectal cancer or adenomatous polyps. Screening starts from 35-40 years with annual THO and complete colonoscopy or double-contrast barium enema 5 years.

4. Personal history of colorectal cancer or adenomatous polyps.

Screening is done by colonoscopy at 1 year after resection and if it is normal, further examinations are to 3 years.

5. Inflammatory bowel disease

Surveillance colonoscopy should begin after 8 years of diagnosis in patients with pancolitis and after 15 years in those with left colitis involving the colon. It makes colonoscopy every 1-2 years.

Signs and symptoms: rectal, fecal occult blood, abdominal pain, abnormal transit, diarrhea, constipation, alternating diarrhea-constipation, partial or complete intestinal obstruction, perforation, abdominal tumor. In advanced stages occur: anorexia, fever, anemia, weight loss, liver metastases, lymph node metastases.

For diagnosis and staging is recommended:

– History, clinical examination,

– Full blood count, biochemical tests,

– Rectal examination,

– Flexible sigmoidoscopy,

– Barium enema, colonoscopy with biopsy,

– Ultrasound,

– CXR,

– CT. abdominal MRI

– Laparotomy with surgical exploration,

– Pathologic evaluation of resected specimen.

It is necessary to analyze at least 12 lymph nodes, and for the N0 must all be negative.

The diagnosis is confirmed on histology.

– Table no. TNM staging of colorectal carcinoma 17

Primary Tumor (T)

Tx – primary tumor cannot be evaluated

T0 – there is no evidence of primary tumor

Tis – Carcinoma in situ: intraepithelial and lamina propria invasion

T1 – Tumor invading the submucosa

T2 – Tumor invades muscle

T3 – Tumor exceeded muscle tissue reaching subseries or pericolic tissue or perirectal

T4 – Tumor directly invades organs or structures and / or perforates visceral peritoneum.

Regional lymph nodes (N)

Nx – regional lymph nodes cannot be assessed

N0 – no regional lymph node metastases

N1 – regional lymph node metastases 1-3

N2- metastases in four or more regional lymph nodes

Distant metastasis (M)

Mx – distant metastasis cannot be assessed

M0 – no distant metastases

M1 – distant metastases

Stages: Dukes

 (Turnbul 1967)

Stg.0Tis N0 M0 A

Stg.I T1 N0 M0 B1

                         T2 N0 M0 B1

Stg.II T3 N0 M0 B2

                          T4 N0 M0 B3

Stg.III T N1 M0 any C1 (T1-2 N1-2)

                          T N2 M0 any C2 (T3 N1-2)

                                                                                                            C3 (T4 N1-2)

Stg IV any T any N M1 D

TREATMENT

Therapeutic indication

Surgery is the mainstay of treatment for colorectal cancer.

Colon cancer

Tis, T1, No, Mo

       T2, No, Mo

For these TNM not strongly recommend adjuvant treatment

T3, No, MO

For this category consider 3 options:

– Capecitabine or 5 FUR / Leucovorin

– Clinical trial

– Observation

T3, No, Mo with increased risk of systemic relapse

Increased risk of relapse include histological grading 3-4, lymphatic invasion / vascular, intestinal obstruction, <12 lymph nodes examined, positive margins, or undetermined area, localized perforation)

T4, No, MO

For these TNM there are 3 options:

– May FUR / leucovorin / oxaliplatin, or capecitabine or 5 FUR / Leucovorin,

– Clinical trial

– Observation

T1-4, N1-2, Mo

Track the category is recommended for:

– May FUR / Leucovorin / Oxaliplatin or

– May FUR / Leucovorin or

– Capecitabine

Any T Any N M1 colonic adenocarcinoma with suspected or proven synchronous metastasis

A) . Isolated pulmonary metastases or isolated resectable hepatic metastases.

a) It is recommended colectomy with synchronous resection or metastasis stage. After surgery, chemotherapy is recommended or observation or short course of chemotherapy whether the patient received neoadjuvant chemotherapy previously.

b) neoadjuvant chemotherapy for 2-3 months followed by colectomy with synchronous resection or metastasis stage.

c) colectomy followed by chemotherapy after resection of stage 2-3 months and metastasis.

Isolated lung metastases and / or unresectable isolated liver metastases

a) systemic chemotherapy plus / minus bevacizumab or cetuximab or panitumab

b) colonic resection is considered only in case of imminent bleeding or imminent intestinal obstruction

Where is reassessing every two months and if restored Covert colectomy is performed with synchronous resection or metastasis stage. Chemotherapy is given adequate for metastases whether it is resectable or not.

B). Abdominal metastases / Synchronous peritoneal colon cancer

– If colon cancer is recommended obstructive adequate adjuvant chemotherapy for advanced stages of the disease.

– If colon cancer is associated with intestinal obstruction recommend:

– Colonic resection

– Diverting colostomy

– Intestinal bypass or stent

Subsequently adequate chemotherapy is recommended for metastatic colon cancer.

Colon cancer relapse

a) Increase CEA Series. In this case we recommend:

– clinical exam

– CT Thorax / abdomen / pelvis

– consider PET -CT

If data obtained negative repeat clinical examination and CT chest / abdomen / pelvis to 3 months.

If you discover relapse recommend surgical resection if possible adjuvant systemic therapy. If not resected systemic treatment is recommended. Where is reassessing every two months and if returns to metastasis resection is performed Covert. Chemotherapy for metastatic adequate subsequently administered.

b). Metachronous metastasis detected by CT, MRI and / or biopsy.

Surgical resection is recommended if possible adjuvant systemic therapy. If not resected systemic treatment is recommended. Where is reassessing every two months and if returns to metastasis resection is performed Covert. Chemotherapy for metastatic adequate subsequently administered.

A. Stage I (T1, T2), stage II (T3N0)

We recommend surgical excision of the primary tumor associated with regional lymph node dissection.

Not recommended adjuvant chemotherapy or radiotherapy.

B. stage II colon cancer (T4N0M0) and stage III

We recommend surgical resection associated with extended lymph node dissection. Postoperative adjuvant chemotherapy is recommended for stage III and T4 complicated with obstruction or perforation. The most used chemotherapy regimen is FOL FU (5 fluorouracil associated with Leucovorin) which begins 3-5 weeks after surgery.

Postoperative radiotherapy is recommended for T4 N0-2 M0 colonic tumors regardless of tumor headquarters, T3 N1-2 M0 transverse colon and sigmoid environmental excluding tumors with close resection margins. The total dose is of 45 Gy to the primary tumor bed and lymph nodes.

C. rectal cancer stage II (T4N0M0) and stage III

Combination therapy is recommended. If the lesion can easily remove it performs initial surgical treatment with radiotherapy and then chemotherapy. If considered inoperable lesion initiating treatment with chemoradiotherapy. At 8 weeks after the end of radiotherapy surgical resection is performed. 4 weeks after surgery begins chemotherapy for at least six months.

D. Colorectal cancer stage IV

Stg.IV recommended chemotherapy patients. For patients with metastatic colorectal cancer who were treated with chemotherapy is recommended Irinotecan 5 FUR association and Leucovorin.

 In patients with isolated liver metastases resection is recommended metastasis.

 Palliative surgical treatment is recommended in case of intestinal obstruction.

 Palliative radiotherapy is indicated for bone and brain metastases.

Therapeutic Methods

Surgical treatment. Radical resection with curative intent is suitable for 80-90% of patients with colorectal cancer. Surgical treatment should include assessment of liver metastases. Liver metastases may occur in 13-21% of patients negative for intraoperative ultrasonography. The free edges of the tumor are usually obtained by resection of at least 5 cm distal and proximal normal bowel tumor. It is associated regional lymph node dissection is necessary to highlight at least 12 nodes. Invaded adjacent organs and colon must be resected together with the primary tumor.

It is recommended prior mobilization tumor vascular ligation to prevent further development of distant metastases due to sowing. If the presence of ovarian metastases, they should be removed by oophorectomy.

In women in post menopause prophylactic oophorectomy is recommended because of the risk of metastasis 1-7% thereafter. In patients who underwent curative resection for overall survival rate varies between 55-75%.

In patients with colon cancer and liver resection both metastatic disease should be treated with curative intent headquarters. They can be resected in a single operation or depending on the specific stage of complexity, hepatectomy or colectomy, comorbid diseases, surgical exposure and urging surgeon.

Hepatic resection is the treatment of choice for resectable colon cancer with liver metastases. Re-resection should be used in selected patients. Intra-arterial embolization and external radiation should be used in selected cases comply.

In patients with lung metastases resection of pulmonary metastases is recommended provided that the primary tumor was resected with curative intent. Metastable synchronous pulmonary disease patients can be operated synchronously or using one way stage.

Reassessment for resection should be performed 2 months after preoperative chemotherapy and every 2 months thereafter.

Radiotherapy

It utilizes modern irradiation techniques with megavoltage linear accelerator (> 6 MV) 3 or 4 fields treated daily. Irradiation is daily 5 days / week with a daily fractionation of 1.8 Gy / day up to a total dose of 45 Gy.

Adjuvant Radiotherapy

We recommend:

– Stg.II locally advanced rectal cancer (T4) and stg.III

– T4 N0-2 M0 colon cancer

                           T3 N1-2 M0

– Colorectal cancer with positive margins

Preoperative Radiotherapy is used to treat locally advanced rectal cancer. It is given between 2500 – 4500 cGy administered 5 days and 4 weeks to not delay the surgical act.

Primary radiotherapy for unresectable tumors

It is recommended to tumors with little or no mobility. The total dose is 4500 – 6000 cGy in split doses of 1.8 Gy / day in 5-7 weeks.

Preoperative radiotherapy and postoperative can be used alone or in combination with chemotherapy.

Adjuvant Chemotherapy

Capecitabine appears to be equivalent to 5 Fur / Leucovorin in stg III colon cancer patients. This is an extrapolation based on available data.

FOLFOX is superior fluoropyrimidine therapy alone in patients with stage III colon cancer. FOLFOX therapy is reasonable for std II colon cancer patients at intermediate risk or high risk and is not indicated in patients with medium risk or good. Flox is an alternative to FOLFOX.

5FUR / Leucovorin / Irinotecan (FOLFIRI) in bolus should not be used as adjunctive therapy and 5 FUR / Leucovorin / Irinotecan (FOLFIRI) was superior to infusional 5 not FUR / Leucovorin. No data are available on capecitabine containing regimens.

Bevacizumab, cetuximab or irinotecan panitumab situation should not be used in patients with colon cancer adjuvant for std II or III except situatiilo5r a clinical trial.

In the end adjuvant colon cancer may be used:

1. leucovorin 500 mg / m2, IVP 2 h, repeated weekly x 6 weeks

5 FUR 500mg / m2 bolus 1 hour after starting treatment with leucovorin, repeated weekly x 6 weeks.

Rest 2 weeks x 4 cycles

2. leucovorin 400 mg / m2, IVP 2 hours, day 1

5 FUR 400mg / m2 bolus 1 hour after starting treatment with leucovorin and then 1200mg / m2 x 2 days (total 2400mg / m2)

Repeat 2 weeks x 24 weeks

3. Capecitabine 1250 mg / m2 x2 / day days 1-14, one week break

Repeat in 21 days x 24 weeks

4. flox (category 2B)

Leucovorin 500 mg / m2, IVP 2 h, repeated weekly x 6 weeks

5 FUR 500mg / m2 bolus 1 hour after starting treatment with leucovorin, repeated weekly x 6 weeks.

Oxaliplatin 85mg / m2 in the 1,3,5 weeks of each cycle

Rest 2 weeks x 3 cycles

5 m FOLFOX6

Oxaliplatin 85mg / m2 IVP in 2 hours Day1

Leucovorin 400 mg / m2, IVP 2 hours, day 1

5 FUR 400mg / m2 bolus 1 hour after starting treatment with leucovorin and then 1200mg / m2 x 2 days (total 2400mg / m2)

Repeat 2 weeks x 24 weeks

Chemotherapy in advanced or metastatic colorectal cancer

A. Patient suitable for intensive chemotherapy

1. Initial Therapy

a). Cape ± bevacizumab or FOLFOX / ox ± Bevacizumab

b). Cetuximab or panitumumab ± FOLFOX (gene mutation in patients with KRAS)

Therapy after first progression

a). FOLFIRI or Irinotecan

b). FOLFIRI + cetuximab or panitumumab (in patients with WT KRAS mutation)

c). Cetuximab (KRAS mutation in patients with WT) + irinotecan (category 2b).

2). Initial Therapy

a) + bevacizumab .FOLFIRI

b). FOLFIRI ± cetuximab or panitumumab (in patients with KRAS mutation).

Therapy after first progression

a). FOLFOX or CapeOX

b). Cetuximab (in patients with KRAS mutation) + irinotecan

c). Cetuximab or panitumumab in patients who cannot stand combination

3. Initial Therapy

a). 5FUR / leucovorin + bevacizumab

b). FOLFOXIRI (category 2b)

Therapy after first progression

a). FOLFOX or CapeOx

b). Irinitecan

c). FOLFIRI

B). Patient unsuitable for intensive care

a). Capecitabine ± bevacizumab

b). 5FUR + Leucovorin ± Bevacizumab

c). Cetuximab (in patients with KRAS mutation) -Category 2b

d). Panitumumab (in patients with KRAS mutation) -Category 2b

Chemotherapy regimens for advanced or metastatic colorectal cancer

FOLFOX

FOLFOX6

Oxaliplatin 85 mg / m2 IVP for 2 hours, 1 day,

Leucovorin 400 mg / m2 day 1 IVP in 2 hours,

FUR 5 400 mg / m2 IV bolus on day 1, and then 1200 mg / m2 / day x 2 days IVP

Repeat at 2 weeks

Cape Ox

Oxaliplatin 130 mg / m2 day 1,

Capecitabine 800-1000 mg / m2x2 / day for 14 days

Repeat at 3 weeks

FOLFIRI

Irinotecan 180 mg / m 2 for 30-90 min IVP, day 1,

Leucovorin 400 mg / m2 day 1 IVP in 30-90 min,

FUR 5 400 mg / m2 IV bolus on day 1, and then 1200 mg / m2 / day x 2 days IVP

Repeat 2 weeks

Bevacizumab-based regimens

Bevacizumab 5mg / kg IV (within 10 minutes) every 2 weeks +

5 FUR and Leucovorin or

FOLFOX or

FOLFIRI

Bevacizumab 7.5mg / kg IV (in 10 minutes) every 3 weeks + Cape Ox

Bevacizumab can be administered at a rate of 0.5 mg / kg / min (5 mg / kg 10 min and 7 mg / kg in 15 min)

Prognostic

1. TNM stage of the disease is the most important prognostic factor. Survival at 5 years for std. 0 to 100%, stg.I -90 to 95%; stg.II-75-80%; stg.III (N1 -72% N2-60% N3-40%), 5% stg.IV

2. Location of the tumor. Tumors located in the transverse colon and descending have a worse prognosis as the ascending colon and rectal sigmoid and have a worse prognosis as the colon.

3. Tumors presenting with obstruction and perforation have a worse prognosis tumors without these complications.

4. histological markers.

a) well-differentiated carcinoma (G1, G2) have a better prognosis that the poorly differentiated (G3, G4)

b) mucoid carcinomas have a poor prognosis

c) lymphatic and perineural vascular invasion are unfavorable prognostic factors.

d) lymph node invasion is unfavorable prognostic factors.

5. Molecular markers of prognosis

– Allelic deletion of chromosome 18 q

– Gene mutation p 53

– Aneuploidy

– The overexpression of thymidylate synthase.

Survival at 5 years in patients operated by stage:

            Stg.I 90%

            Stg.II 74%

            Stg.III N1 48%

            Stg.III 34% N2

            Stg.IV 9%

Tracking the operated patients is by historical clinical examination (including rectal examination), THO, blood counts, liver tests, tumor markers (CEA), abdominal ultrasound performed every 3 months for 2 years and 6 months 3 years. Colonoscopy is recommended in the first year after surgery or in the first 6 months unless the surgery was done previously. If normal, repeat at 3 years and then at 5 years. Abdominal and chest CT is recommended annually during the first 5 years and then depending on the symptoms.