Pierluigi Pilati Chirurgia Generale Padova - Aimav · I TUMORI DI INTERESSE ASSICURATIVO ......

I TUMORI DI INTERESSE ASSICURATIVO

I TUMORI DEL COLON RETTO

Pierluigi PilatiChirurgia Generale

ULSS 16Padova

Siegal, CA Cancer J Clin 2014

Colorectal cancer

EPIDEMIOLOGY

→ 1,2 million new cancer cases per year (413.000 cases/year in Europe)

→ Median incidence in Italy: 88/100.000 (males); 70/100.000 (females); that value increases consensually with age, particularly in 50-60 years old patients

Colorectal cancer

EPIDEMIOLOGY

Colorectal cancer

EPIDEMIOLOGY

• > in Industrialized countries, but rapidly in less-developed nations that adopt features of a Western lifestyle

• Immigrants in Industrialized countries have an higher incidence compared to residents remaining in their native countries

DeVita, Cancer 2011

Colorectal cancer

EPIDEMIOLOGY

Colorectal cancer

BIOLOGY

The genetic basis of CRC is best appreciated in light of the adenoma-carcinoma sequence and the premise that CRCs arise from benign precursor polyps

The progression is slow (5-10 yrs)

Most frequent molecular alterations in multiple genes that cause colorectal cancer

POLYP

Macroscopic protrusion of the colonic mucosa into the bowel lumen

NEOPLASTIC POLYPS

BENIGN MALIGNANT

Adenomatous polyp Carcinoma in situ

-tubular Invasive carcinoma

-tubular-villous Polypoid carcinoma

-villous

NON NEOPLASTIC POLYPS

Hyperplastic polyps

Juvenile polyps

Peutz-Jeghers

Infiammatory polyps

RISK OF MALIGNANT DEGENERATION

HISTOLOGICAL PATTERN DIMENSION

Adenomatous polyp <1 CM 1%

-tubular 5% 1-2 CM 10%

-tubular-villous 20% >2 CM 20%

-villous 40%

Colorectal cancer

BIOLOGY

Pedunculated (with stalk) polyps can be resected with application of cautery through a snare localized around the polyp stalk.

Endoscopic polypectomy

Colorectal cancer

Some sessile polyps require special techniques. Saline is injected into the submucosa area in order to elevate the polyp and facilitate removal by snare.

Colorectal cancer

Endoscopic polypectomy

Colorectal cancer

ENDOSCOPIC TREATEMENT

• Polypectomy is radical if

• pTIS

• T1

• Free margin

• No lymphovascular invasion

• G1

• Endoscopic follow-up is necessary

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

INCREASED RISK DECREASED RISK

Inflammatory bowel disease Antioxidant vitaminconsumption

Diabetes Consumption of fresh fruit and vegetables

Obesity Use of nonsteroidal antiinflammatory drugs

High red meat consumption High calcium diet

Overcooked red meat consumption

High fiber diet

High saturated fat consumption

Excess alchol consumption

Sedentary lifestyle

Cigarette smoking

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

Colorectal cancer

COLO RECTAL CANCER RISK: FAMILIAL HISTORY

DeVita, Cancer 2011

5%

Colorectal cancer

COLO RECTAL CANCER RISK

DeVita, Cancer 2011

5%5%

INFLAMMATORY BOWEL DISEASEPersonal history

Colorectal cancer

the risk of CRC begins to increase 8 or 10 years after the establishment of diagnosis

screening starting 8-10 yr after onset of symptoms of pancolitis

Colonscopy every 1-2 yrs If low grade or high grade dysplasia: surgical consultation for

resection

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

Colorectal cancer

COLO RECTAL CANCER RISK: FAMILIAL HISTORY

DeVita, Cancer 2011

5%

Is the most common of the recognized inherited colorectal cancer syndromes

Autosomal dominant disorder, involved mutation of DNA mismatch repair genes (MMR): MSH2, MLH1, MSH6, PMS1 e PMS2

The lifetime risk of cancer in HNPCC is 80% for colorectal cancer (usually in the third and fourth decades of life)

Familial Colorectal cancer

Hereditary Non-Polyposys Colorectal Cancer (HNPCC)



Mutation of MMR genes → MSI (mycrosatellite instability)

Approximately 60% of germline mutations in HNPCC are found

Clinical diagnosis

HNPCC is defined classically by the modified Amsterdam Criteria



Clinical diagnosis


Hereditary Non-Polyposys Colon Cancer (HNPCC)

Patients with CRC who should undergo testing for MSI

(Bethesda criteria):

Individuals with CRC Cancer in families that meet Amsterdam criteria

Individuals with two HNPCC-related cancers

Individuals with CRC cancer and a first degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma: one cancer before age 45 and adenoma before age 40

Individuals with CRC cancer or endometrial cancer before age 50

Individuals with Right-sided CRC cancer with an undifferentiated pattern on histopathology before age 45

Individuals with Signet-ring cell type colorectal cancer before age 45

Individuals with Adenomas diagnosed at age < 40 years

• HNPCC pts with CCR: colectomy (ileo-rectal anastomosis )

• HNPCC mutation found: colonscopy every 1-3 yrs (starting 20-25 yrs)

• Female mutation found: pelvic ultrasound annually (starting 25-35 yrs)


Hereditary Non-Polyposys Colon Cancer (HNPCC)

Patient management

• Men and women at risk for HNPCC need examinations of the entire colon (colonscopy).

• Women at risk should also have yearly endometrial and ovarian screening.

Colorectal cancer

COLO RECTAL CANCER RISK

De Vita, Cancer 2011

Familial Adenomatous Polyposis (FAP)

• FAP is an inherited condition that primarily affects the gastrointestinal tract.

• Is caused by a mutation on chromosome 5 gene APC (“Adenomatous Polyposis Coli”)

• This disorder leads to hundreds or thousands of colonic polyps that develop in patients in their teens to 30s

• If the colon is not surgically removed 100% of patients progress to colorectal cancer


• Benign conditions (congenital hypertrophy of the retinal pigment epithelium, mandibular osteomas, supernumerary teeth, epidermal cysts, adrenal cortical adenomas, desmoid tumors)

• Malignant conditions (thyroid tumors, gastric-small intestinal polyps with a 5% to 10% risk of duodenal and/or ampullary adenocarcinoma, and brain tumors)

EXTRACOLONIC MANIFESTATIONS


Familial Adenomatous Polyposis (FAP)

Genetic counseling is available and recommended for individuals with suspected

FAP and for their family members.


Familial Adenomatous Polyposis (FAP)PATIENT MANAGEMENT

ASCO guidelines 2012

APC GENE TEST AT 10-12 YEARS

How identificate a persons at high genetic risk of CRC who should undergo genetic testing??

1- history who satisfied Bethesda Criteria (HNPCC ?)

2- patient with suspected or diagnosed intestinal polyposis (FAP?)

Clinical criteria


Right colon

Growing and ulcerated neoplasia

Anemia

Palpable mass

Left colon

Infiltrating neoplasia

Bowel habit alteration

Blood in the stool

Obstruction

Colorectal cancer

LOCATION AND SYMPTOMS

Occult bleeding 75%

Rectal bleeding 55%

Anemia 55%

Abdominal pain 50%

Weight loss 40%

Constipation and anorexia 25%

Diarrhea 20%

Nausea and vomiting 20%

Tenesmus 10%

Colorectal cancer

SYMPTOMS AT DIAGNOSIS

• Massive bleeding rare

• Obstruction left colon

• Perforation

– neoplasia

– caecum diastatic perforation

• Invasion or compression of adjacent structures

Colorectal cancer

COMPLICATIONS

Colorectal cancer

DIAGNOSIS

Personal history

Colorectal cancer

DIAGNOSIS

Personal history

Colorectal cancer

DIAGNOSISPersonal history

Colonoscopy

Ca in situ

Ca ulcerato

Carcinoma vegetante

Colorectal cancer

DIAGNOSIS

Growing neoplasia

Stenotic neoplasia

Double contrast barium enema

Colorectal cancer

DIAGNOSIS

→ 15 - 50% of patients will develop metastatic disease by these

pathways:

Loco-regional

Blood circulation

Colorectal cancer

DISSEMINATION

CONTIGUITY LIMPHATIC BLOOD

Eco

Thorax-abdominal CT scan

Pelvi MRI

CEA (Prognostic value )

Colorectal cancer

STAGING

INTRAOPERATIVE ULTRASOUND

Colorectal cancer

STAGING

10-20%:identify liver undiagnosed liver mts change the surgical strategy

1. to remove en block the neoplastic mass and the involved structure, with at least 5 cm of “neoplastic-free” colon before and after the tumor

2. to remove locoregional lymph nodes (> 12 lymph nodes)

Principles of Oncologic Surgery

Colorectal cancer

TREATEMENT

Right Hemicolectomy

Right Hemicolectomy Extended Right Hemicolectomy

Resection of transverseLeft Hemicolectomy and sigmoid

colon resection

Colorectal cancer

SURGERY

Rectosigmoid resection combined with hepatic resection (segment III) for metastasis

SURGERYColorectal cancer

LAPAROSCOPIC SURGERY FOR COLORECTAL CANCER

Colorectal cancer

N Engl J Med 2004;350:2050-9

Randomized Trial on 872 patients

N Engl J Med 2004;350,2050-2059

Comparison of laparoscopically assisted and open colectomy for COLON cancer: randomized trial on 872 pts (COST trial).

Colorectal cancer

TREATEMENT

N Engl J Med. 2004;350;2050-2059

Outcomes: morbility and mortality

Colorectal cancer

TREATEMENT

Outcomes pain and hospital stay

N Engl J Med. 2004;350,2050-2059

Colorectal cancer

TREATEMENT

Colorectal cancer

TNM STAGE

The TNM system is one of the most widely used cancer staging systems. This system has been accepted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC).

The TNM system is based on the size and/or extent (reach) of the primary tumor (T), the amount of spread to nearby lymph nodes (N), and the presence of metastasis (M)

Extended primary tumor (T3/4)

Regional lymph nodes involved (N+)

Presence of metastases (M+)

Colorectal cancer

TNM STAGE

WORSE PROGNOSISINCREASED RECURRENCE

DeVita, Cancer 2011

Colorectal cancer

Survival and Recurrence rate

DUKES TNM 5 - years Survival (%) Recurrence(%)Local Distant

A I 90% 5 10

B II 70-90% 10-20 20-25

C III 70-90% per T1-T2, N1 60-80% per T1-T2, N230-50% per T3-T4, N1-2

10-20 20-2530 25

35-50 40-60

D IV 10%-

DeVita, Cancer 2011

Stage

5-y

ear

Su

rviv

al

10

20

30

40

5060

70

80

90

100Localized(stage I-II)

Regional(stage III)

Distant metastases(stage IV)

Manfredi Ann Surg 2008

LIVER FAILURE DUE TO LIVER METASTASES IS THE MAJOR DETERMINANT OF SURVIVAL

Colorectal cancer

DISSEMINATION

PROGNOSTIC FACTORS

Age More advanced stage if age >40 yrs

Sympthoms More advanced stage if sympthoms

Complications Worse prognosis

Tumor morphology Advanced stage: growing > ulcerated

Vascular invasion Worse prognosis if present

Lymphatic invasion Worse prognosis if present

Perineural invasion Worse prognosis if present

Lymphocyte infiltration

Better prognosis if present

CEA Poor prognosis if preoperative > 5ng/ml

Aneuploidy Worse prognosis if present

Site Sigmoid and rectal cancer

Colorectal cancer

PROGNOSTIC FACTORS

Colorectal cancer

Dukes C: survival related number lymphonodes involved

T3…

Colorectal cancer

EPIDEMIOLOGY

Colorectal cancer

TREATEMENT

Primary prevention: preventing the developments of cancer

Secondary prevention (SCREENING):early detection of cancer

Tertiary prevention: preventing the cancer recurrence

Colorectal cancer

PREVENTION

Primary prevention:

Colorectal cancer

PREVENTION

Three categories:

1. Avoidance of noxious substances

2. Chemoprevention: ingestion of natural o synthetic substances

3. Prophylactic colectomy (genetic syndromes)

Colorectal cancer

PRIMARY PREVENTIONAvoidance of noxious substances

Red meat: eating beaf, pork o lamb > 5 times/week--> 3-fold increase RR colon cancer

Red meat

stimulates secretion of endogenous insulin

is a > source of saturated fats

Heavily browned surface or prolonged frying or grilling --> mutagenic heterocyclic amine formed from creatinine

Colorectal cancer


Alcohol: men who drink > 2 drinks (30g) per day 2-fold increase RR colon cancer

Alcohol:

Reduce folate levels

Antagonize metabolism of metyl groups, contributing to abnormal DNA repair

Suppress tumor immune surveillance

Alter composition of bile acids

Induce cit P450 to activate hepatic carcinogenesis

Colorectal cancer


Tobacco:

+ 38% RR for > 40 cigarettes/day

+ 20% RR for > 40 yrs duration

+ 51% RR for increment > 60 pack-yrs

- 4% RR for delay of 10 yrs in smoking initiation

- Association stronger for rectal than colon cancer

Mechanism → Release carcinogenic compounds: aromatic amines, nitrosamines, heterocyclic amines, polynuclear aromatic hydrocarbons

Colorectal cancer


Obesity:

BMI <23 Kg/m2 RR1

BMI 23-24.9 RR +14%

BMI 25-27.4 RR +19%

BMI 27.5-29.9 RR +24%

BMI 30 RR +41%

Ning, Obes Rev 2009

Increase in insulin resistance → stimulation of insulin secretion → mitogenic properties of hyperinsulinemia

Central adiposity appears to more affect the risk of colorectal cancer

Fiber:

European population (EPIC study): -40%

relative risck (RR) for individuals

USA population: no significant

Since 1998 mandatory in USA fortification

with folate of flour and breakfast cereals Bingham, Lancet 2003

Park, JAMA 2005

Colorectal cancer

PRIMARY PREVENTIONChemoprevention

Colorectal cancer


Fish and poultry:

reduced risk of colon cancer and adenoma

good sources of methionine, that improve the regulation of DNA methylation

High in n-3 fatty acids (specially fish), that reduce inflammation, disrupt acitivity of nf-kB and COX-2

Calcium:

22% risk reduction of CRC

Most of risk reduction with intakes of 700 to 800 mg/day

Mechanism:

Binding to toxic secondary bile acids and ionized fatty acids → form insoluble soaps in colon lumen

Directly reducing proliferation and inducing apoptosis in the colonic mucosa

Colorectal cancer


Folate:

Folate deficiency induce p53 mutations

Low dietary folate associated with RR CRC

RCT: folic acid supplementation not significative, because 10 yrs required for any preventative effects

Colorectal cancer


Aspirin and NSAID:

Short term use of aspirine reduce risk af adenoma recurrence

Cole, JNCI 2009

Colorectal cancer


Age-specific incidence of CRC per 100.000/yrs according to modificable risk factors

Chan, Gastroenterology 2010Brenner, Lancet 2014

Colorectal cancer

PRIMARY PREVENTION


Secondary prevention: early detection of cancer

Tertiary prevention: preventing the cancer recurrence

Colorectal cancer

PREVENTION

Colorectal cancer

SECONDARY PREVENTION SCREENING

National Comprehensive Cancer Network (NCCN) FOBT or colonoscopy or sigmoidoscopy +/-FOBT

starting at 50 yrs

European Society of Medical Oncology (ESMO) Faecal occult blood test (FOBT) annual for people aged 50-74 yrs

Associazione italiana di Oncologia Medica (AIOM) Faecal occult blood test (FOBT) annual or sigmoidoscopy every 5

yrs or colonoscopy every 10yrs for people starting at 50 yrs

Colorectal cancer

SECONDARY PREVENTIONGUIDELINES

FOBT (Fecal Occult BloodTest)

meta-analysis of RCTs demonstrated a reduction in mortality of the intervention group of 16% (RR 0.84)

Sensibility for adenomas 1 cm 16-33%

Specificity for adenomas 1 cm 94-98%

Sensibility for CRC 6-46%

Specificity for CRC 80-89%

Mandek, NEJM 2000

Burch, J Med Scren 2007

Whitlock, Ann Int Med 2008

Colorectal cancer

SECONDARY PREVENTION

It also may not detect precancerouslesions or early stage adenomas as bleeding may not bereadily detectable in the presence of these conditions

- RCT: reduction in CRC incidence and mortality of the intervention group of 31% and 38%

- Sensibility for CRC 58-86%--> These variations are likely accounted for by the differences in examiners’experience and skills, and by the risk of proximal lesions in the unexplored colon.

- When sigmoidoscopy detects a carcinoma or an adenoma of >10 mm, conducting a complete study of the colon is mandatory given the major incidence of synchronic lesions proximal to the tract explored. It has been estimated that 5–16% of colonoscopies are performed after sigmoidoscopy

Segnan, JNCI 2011Weissfiled, JNCI 2005

Colorectal cancer

SECONDARY PREVENTIONSigmoidoscopy: examination of the mucous surface with a flexible endoscope uP to 60 cm from the anal verge

Colonoscopy:

this test not only favors CRC detection in early stages but also reduces the incidence of CRC as it identifies and resects polyps

For each 1% in colonoscopies → 3% reduction in mortality rates

A colonoscopy in the previous 10 yrs is associated with a 59% reduction CRC incidence

Several cohort studies demonstrate that polyp removal lower incidence of CRC by 76-90%

Rex. Gastr Endoscop 2013

Tarraga Lopez, Clin Med Ins Gastro 2014

Colorectal cancer


Colonoscopy 0.01-0.05 % hemorrhages

0.01-0.05% perforations

0.03% deaths

low-residue diet on the days before the test

lassative

Examination takes 20-40 min, most people fully recovered afterone hour

Baxter, Ann Int Med 2009

Tarraga Lopez, Clin Med Ins Gastro 2014

Colorectal cancer


Other screnning tools:

FOBT + sigmoidoscopy: 2 RCTs concluded that not better than sigmoidoscopy Colongraphy CT:

No RCT to assess the efficacy Similar rate in detecting polyps 10 mm and advanced CRC than colonoscopy If positive, colonoscopy mandatory 0.05% symptomatic colon perforations

Fecal DNA detection: Higher sensitivity than FOBT to detect CRC and adenomas High cost and cost-effective ratio No RCT to evaluate the efficacy in terms of incidence and mortality

Sosna, Am J Roentgenol 2008

Colorectal cancer


All these screening tolls have been demostrated not equivalent to colonoscopy

COST/EFFECTIVENESS

All studies consistently found that CRC screening is cost-effective compared with no screening, for each of the screening strategies

The incremental CE ratios for the different strategies ranged from $1200 per life-year saved (SIG once at 55 years of age) to $92,900 per life-year saved

(RFOBT plus SIG every 5 years).

Frazier, JAMA 2000

Lansdorp-Vogelaar, Epid Reviews 2011

Cruzado, Best Pract Res Clin Gastr 2013

Colorectal cancer


Lansdorp-Vogelaar, Epid Reviews 2011

Colorectal cancer


Colorectal cancer


Among the 1-time screening alternatives,

COLONOSCOPY was the most effective

option with a lifetime reduction in CRC

mortality of 31% and an incremental CE

ratio of $22,400 per life-year saved-

Frazier, JAMA 2000

Colorectal cancer


Colorectal cancer


→ As of 2008, the basic screening modalities remain remarkably similar to those used in 1980 when the original guideline was issued, even when taking into account the development of newer technology in subsequent years

→ In an ideal world, the first line screening should be performed to identify a high risk segment of the population and then use a more extensive test (colonoscopy) on this sub group to reduce incidence of advanced diseases

Colorectal cancer



Secondary prevention: halting the progression from polyp to cancer

Tertiary prevention: preventing the cancer

recurrence

Colorectal cancer

PREVENTION

NCCN 2014

PE, CEA every 3-6 mo for 2yrs, than 6 mo for 5 yrs

CT total body annually for 5 yrs

Colonoscopy: after 1 yr, if no preop for obstrucing lesions in 3-6 mo

If no polyp > 1 cm, no HG dysplasia : repeat in 3yrs, than every 5 yrs

If advanced adenoma: repeat in 1 yr

Colorectal cancer

TERTIARY PREVENTION

MULTIDISCIPLINARY TEAM MEETING (MDT)

• Surgeon

• Medical oncologist

• Radiation oncologist

• Radiologist

• Pathologist

• Internal medicine

AIM

improve patient outcome and guidelines adherence

Meagher, ANZ J Surg 2013

MacDermid, Col Dis 2009

MDT status is an indipendent predictor of SV (P=0.044)

PRIMARY PREVENTION

SECONDARYPREVENTION

MULTIDISCIPLINARY TEAM

i

INCIDENCE

MORTALITYIMPROVE SURGICAL

TECHNIQUE

Pilli’s group

THE WAR IS NOT WIN YETBUT THE WAY IS RIGHT

Virtual colonoscopy

Colorectal cancer

DIAGNOSIS

Chan, Gastroenterology 2010

Colorectal cancer


Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

Colorectal cancer

TNM STAGE

DUKES TNM 5-YEAR SURVIVAL RECURRENCEL D

A I 90% 5 10

B II 70-90% 10-20 20-25

C III 70-90% se T1/2 N160-80% se T1/2 N230-50% se T3/4 N1

10-20 20-25• 2535-50 40-60

D IV 10%

Which surgeon?

Nathan, Ann Surg Oncol 2012

Which center?

Goyer, Clinics and Research in Hepatology and Gastroenterology 2013

Colorectal cancer

TREATMENT

51 PATIENTS CURED!!!

Personal history of IBD

Colorectal cancerPersonal history of IBD

(Crohn's disease, ulcerative colitis)

SCRRENING• Can prevent many deaths• More treatable stage• Can detect and remove nonmalignant

precuros lesion

Colorectal cancer

SECONDARY PREVENTIONGUIDELINES

Tumor residual (R)

Colorectal cancer

TREATEMENT

TUMORAL RESIDUAL

R0 Absence of tumor

R1 Microscopic residual

Sigmoidoscopy

0.03 % hemorrhages

0.015% perforations

0.0025% deaths

Case-control studies estimate a protector effect over a period of 9-10 yrs

Screening every 5yrs because sensitivity < colonscopy, less preparation and variability in examiners’experience

The results of an RCT indicate that 14% of individuals complain of pain (which is strong in 1%) after having been submitted to sigmoidoscopy. If we compare it to colonoscopy, lack of sedation is associated with more discomfort and less adhesion to future sigmoidoscopies

Senore, Dis Colon Rectum 2004Tarraga Lopez, Clin Med Ins Gastro 2014

Colorectal cancer


MULTIDISCIPLINARY TEAM MEETING

Meagher, ANZ J Surg 2013

MacDermid, Col Dis 2009

• Second review radiology investigation: incorrect reports and new findings in 2-20%

• 105 papers in literature that confirm MDT decrease the rate of Circumferential Resection Margins in rectal cancer (1% vs 25%)

• MDT status is an indipendent predictor of SV (P=0.044)

• More patients were given CT in the MDT group (p=0.0023)

Colorectal cancer

Survival e recurrence rate

DUKES TNM 5 Years survival(%) Recurrence (%)L D

A I 90% 5 10

B II 70-90% 10-20 20-25

C III 70-90% per T1-T2, N1 60-80% per T1-T2, N230-50% per T3-T4, N1-2

10-20 20-2530 25

35-50 40-60

PRIMARY PREVENTION

SECONDARYPREVENTION

MULTIDISCIPLINARY TEAM

i

INCIDENCE

MORTALITY

→ 15 - 50% of patients will develop metastatic disease by these

pathways:

Loco-regional

Blood circulation

Colorectal cancer

DISSEMINATION

CONTIGUITY LIMPHATIC BLOOD

Colorectal cancer

ETIOLOGY

DeVita, Cancer 2011

INCREASED RISK DECREASED RISK

Inflammatory bowel disease Antioxidant vitamin consumption

Diabetes Consumption of fresh fruit and vegetables

Obesity Use of nonsteroidal antiinflammatory drugs

High red meat consumption High calcium diet

Overcooked red meat consumption High fiber diet

High saturated fat consumption

Excess alchol consumption

Sedentary lifestyle

Cigarette smoking

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