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2.9 Lower Digestive System - RECTAL CANCER Cheat Sheet (DRAFT) by

This is a draft cheat sheet. It is a work in progress and is not finished yet.

Anatomy

The large intestine, which is about 1.5m long and 6.5cm in diameter, extends from the ileum to the anus.
Struct­urally, the four major regions of the large intestine are the cecum, colon, rectum and anal canal.
The rectum, the last 20cm of the gastro­-in­tes­tinal tract, lies anteriorly to the sacrum and coccyx. The terminal 2-3cm of the rectum is called the anal canal. The rectum is totally sheathed in longit­udinal muscle fibres, and is continuous with the anal canal.
The colore­ctum is lined with columnar epithelium as far as the dentate line in the middle of the anal canal, where sensitive squamous epithelium in continuity with that of the perineum takes over.
Mass perist­altic movements push faecal material from the sigmoid colon into the rectum. The resulting distention of the rectal wall stimulates stretch receptors, which initiates a defecation reflex that empties the rectum.
The defecation reflex occurs in response to distention of the rectal wall, receptors send sensory nerve impulses to the descending colon, sigmoid colon, rectum and anus. The resulting contra­ction of the longit­udinal rectal muscles shortens the rectum, thereby increasing the pressure within it.
This pressure, plus parasy­mpa­thetic stimul­ation, opens the internal anal sphincter.
The amount of bowel movements that a person has over a given period of time depends on various factors such as diet, health and stress. The normal range of bowel activity varies from two or three bowel movements per day to three or four bowel movements per week.

Epidem­iology and Aetiology

Colorectal cancer is the second most common cancer in both men and women in Australia (Cancer Council Australia 2009). Eighty per cent of cases are sporadic with no known hereditary genetic associ­ations.
In Australia, there are more than 12,500 new cases diagnosed each year. The risk of being diagnosed by age 85 is 1 in 10 for men and 1 in 15 for women. More than 4372 people die of colorectal cancer each year.
Indivi­duals with certain known single­-gene disorders are at an increased risk of developing rectal cancer. Single gene disorders related to known symptoms account for about 10-15% of colorectal cancers.
Hereditary non-po­lyposis colorectal cancer (HNPCC) results from defects in MMR genes and represents the most common form of hereditary colorectal cancer. Less than 5% of all colorectal cancer cases are HNPCC.
People with HNPCC often develop large bowel cancer before the age of 50. They commonly have one or more adenomas in the bowel. The majority of geneti­cally defined cases involve hMSH2 on chromosome 2p, and hMLH1 on chromosome 3p.In affected families, 15-60% of family members are found to have mutations in hMSH2 or hMLH1; the mutation prevalence depends on features of the family history.
Other risk factors include: personal history of colorectal adenomas, first degree family history of colorectal cancer or colorectal adenomas, inflam­matory bowel disease, obesity and smoking.

Histology and Pathology

The wall of the large intestine contains the typical four layers found in the rest of the GI tract: mucosa, sub-mu­cosa, muscularis and serosa.
The epithelium of the mucosa is simple columnnar epithelium that contains mostly absorptive and goblet cells.
The absorptive cells function primarily in water absorp­tion; the goblet cells secrete mucus that lubricates the passage of the colonic contents.
Solitary lymphatic nodules are also found in the lamina propria of the mucosa and may extend through the muscularis mucosae.
The management of localised rectal cancer is increa­singly multid­isc­ipl­inary and patient focused, involving the patient and family, the surgeon, medical and radiation oncolo­gists, radiol­ogist, pathol­ogist, and others.
Decision making is strongly influenced by patient preference and co-mor­bid­ities, as well as tumour staging and other prognostic factors. Many of the latter are determined primarily by the pathol­ogist. The amount and complexity of inform­ation required from the pathol­ogist has increased apace with the develo­pment of increa­singly sophis­ticated surgical and adjuvant or neo-ad­juvant treatm­ents.
Accurate, detailed and compre­hensive pathology reporting has become essential, and the role of the pathol­ogist in the multid­isc­ipl­inary team is being apprec­iated increa­singly.
Pathol­ogical reporting of rectal cancer provides important prognostic inform­ation about the risk of both systemic relapse and local pelvic recurr­ence. Ideally, the report should provide the clinician with all the known pathol­ogical variables that have been shown to influence prognosis. These include:
-Tumour type
-Maximum depth of penetr­ation of rectal wall
-Tumour diameter
-Tumour differ­ent­iation
-Distance to nearest margin
-Number of nodes examined
-Vascular invasion
-Stage
-Circumferential margin involv­ement
-Macroscopic descri­ption of tumour situ
-Position of positive nodes
-Peri-neural invasion
For the surgeon, the pathology report of a rectal cancer specimen has added signif­icance. If circum­fer­ential margins are carefully examined and reported they provide useful feedback on the quality of surgery and an indication of the risk of local recurrence in a given patient.
Accurate pathology reporting allows approp­riate pathol­ogical staging, and provides an assessment of the effect of neo-ad­juvant therapy and a guide to the need for post-o­per­ative adjuvant therapy if pre-op­erative treatment has not been admini­stered.
Uniformity of staging allows direct comparison of patient outcomes between centres.

Natural History, Diagnosis and Staging

Signs and symptoms of colorectal cancer include diarrhea, consti­pation, cramping, abdominal pain, and rectal bleeding, either visible or occult.
The colonic and rectal mucosa are only one cell thick and have a glandular archit­ecture of epithelial cell inter-­spread with goblet cells that synthesize mucus.
The pathologic stage of rectal cancer relates to the degree the tumour extends through the mucosa and colon wall, which in turn relates to prognosis and treatment selection.
Over the past decades several classi­fic­ation systems have been in use intern­ati­onally to stage rectal tumours.
The TNM staging system is now recognised as the standard for colorectal cancer staging intern­ati­onally in all discip­lines.
The TNM system has three main advantages over the other systems.
Firstly, it is data­-dr­iven and has a process in place for cont­inuous improv­ement based on ongoing expert review of existing data.
Secondly, it has a comp­reh­ensive set of defini­tions and rules of applic­ation that ensure uniform use.
Third, it is mult­idi­sci­pli­nary in design and is pertinent to all modern techniques of stage evalua­tion.
As newer anatomic and molecular markers are uncovered and their value in rectal cancer staging, predic­tab­ility to treatment response and treatment selection is defined, the role of such markers in the TNM system may need consid­era­tion.
Accurate staging of rectal cancer provides crucial inform­ation about the location and size of the primary tumour in the rectum and if present the size, number and location of any metast­ases.
Accurate initial staging can influence therapy by determ­ining the type of surgical interv­ention and the choice of neo-ad­juvant therapy to maximise the likelihood of clear margins.
In primary rectal cancer, pelvic imaging (CT, MRI, PET) helps to determine the depth of tumour invasion, the distance from the anal sphincter, the potential for negative surgical margins and the involv­ement of loco-r­egional lymph nodes or adjacent organs.
Additi­onally clinical evaluation and staging procedure may include:
1. Digital rectal examin­ation and/or recto-­vaginal examin­ation and rigid procto­scopy to determine if sphincter saving surgery is possible.
2. Complete colono­scopy to eliminate cancers elsewhere in the bowel.
3. Endo­-rectal ultrasound (EUS) to assess the depth of tumour growth in the rectal wall. EUS is reported to have accuracies for T staging varying between 69% and 97%, and remains the most accurate imaging modality for assessing tumour in-growth into the rectal wall.
The natural history of rectal cancer demons­trates major lymphatic spread in a cephalad direction contained within the peri-r­ectal fascia and along the mesore­ctum, that is commonly dissected by standard TME (total mesorectal excision) surgery.
Outside the mesorectum is a space containing vessels, nerves and lympha­tics; that is usually not dissected. The external iliac nodes may only become at risk with anterior tumour extension and adjacent organ involv­ement. Lesions that extend to the anal canal or lower third of the vagina can spread to the inguinal nodes.
Rectal cancer is an ideal model for cancer screening due to its relatively well defined natural history and when diagnosed in the early stages effective treatment can be offered.

Management Strategies

Surgery is the primary treatment for rectal cancer.
Early stage tumours are also candidates for removal of the tumour through a flexible endoscope or other minimally invasive surgery approa­ches.
Combined radiation therapy and chemot­herapy improve local control for patients with tumour extending beyond the rectal wall or lymph node involv­ement. These combined treatments may also be indicated for patients whose cancers relapse at the primary site or in nearby lymph nodes after initial treatment.
Pre-op­erative staging is used to determine the indication for neoadj­uvant therapy as well as the indication for local excision versus radical cancer resection. Local excision is likely to be curative for patients with a primary tumour that is limited to the sub-mucosa (T1N0M0), without high-risk features and in the absence of metastatic disease.
In approp­riate patients, minimally invasive proced­ures, such as local excision or laparo­scopic resection allow for improved patient comfort, shorter hospital stays and earlier return to pre-op­erative activity levels.
Once the tumour invades the muscularis propria (T2), radical rectal resection in acceptable operative patients is recomm­ended. In patients with transmural or node positive disease (T3, T4 and/ or N1) with no distant metast­ases, preope­rative chemor­adi­ation followed by radical resection according to the principles of total mesorectal excision has become widely accept­able.
During the planning and conduct of a radical operation for a locally advanced rectal cancer, a number of signif­icant issues are consid­ered. These include:
-total mesorectal excision (TME)
-autonomic nerve preser­vation (ANP)
-circumferential resection margin (CRM)
-distal resection margin
-sphincter preser­vation
-options for restor­ation of bowel continuity
-laparoscopic approaches
-postoperative quality of life
Although preope­rative short-term radiot­herapy for rectal cancer results in increased local control, there is more long-term bowel dysfun­ction in irradiated patients than in patients who undergo total mesorectal excision (TME) alone. Rectal cancer patients should be informed on late morbidity of both radiot­herapy and TME. Future strategies should be aimed at selecting patients for radiot­herapy who are at high risk for local failure.

Management Strate­gies: Radiation Therapy

During the past decades a range of radiation therapy treatment modalities have been utilised for rectal cancer patients. These options include:
1. post-o­per­ative chemo-­rad­iation with different 5-fluo­rou­racil (5-FU) based schedules
2. pre-op­erative radiot­herapy short course (5 fractions of 5Gy in 5 days)
3. long course radiation therapy with or without chemot­herapy
4. intra-­ope­rative radiation therapy (IORT)
Local control and acute and late effects on normal tissue are dependent on the volume, total dose, dose per fraction and overall treatment time. To achieve a high probab­ility of steril­isation of micros­copic disease, a dose of the order of 50Gy in 25 fractions given over 5 weeks is required.
In trials of short course pre-op­erative radiot­herapy 5 fractions of 5Gy corres­ponds approx­imately to a dose of 42Gy in 21 fractions of 2Gy over 29 days.
n increasing body of data suggests the superi­ority of pre-op­erative radiot­herapy combined with chemot­herapy in terms of local control, diseas­e-free survival and reduction of bowel toxici­ties. As mentioned above there are two types of pre-op­erative radiot­herapy:
frac­tio­nated radiot­her­apy and short course.
Shor­t-c­ourse pre-op­erative radiot­her­apy is delivered one week before surgery in 5 daily fractions of 5 Gy without any chemot­herapy.
Preo­per­ative fractioned radiot­her­apy is delivered in a period longer than 5 weeks (daily doses of 1.8–2 Gy for total doses of 45–50 Gy), usually with a 5-FU schedule, and is followed by surgery which is performed 4–6 weeks after in order to restore the acute damage and as well as to reduce tumour volume.
Probably the most important argument in favour of pre-op­erative radiation therapy is tumour regres­sion, which may improve the likelihood of a successful resection with free margins. The possib­ilities of preserving the sphincter are increased for regressing tumours arising in the distal rectum.
From this point of view, short-­course radiation offers low tumour reduction probab­ilities due to the surgery timing. The choice of treatment is fracti­onated radiot­herapy because it offers a high probab­ility of sphincter preser­vation.
After pre-op­erative chemo- and radiot­herapy, a pathologic complete response rate of 10–25% has been reported as well as a tumour down staging rate of 40–80% with both improved local control and survival.
Radi­ation Therapy PLANNING
The advantage of preope­rative radiation therapy planning relies on the presence of tumour tissue, which can be easily located and radiol­ogi­cally defined for target­-volume defini­tion. The GTV and CTV can be delineated as soft tissue anatomy on CT images, often accomp­anied by other imaging modalities (Positron Emission Tomography (PET), and MRI). Unfort­una­tely, the standard CT-based GTV deline­ation remains associated with consid­erable inaccuracy and extension of rectal carcinoma into the rectal wall or peri-r­ectal tissue structures usually is not visible.
Therefore, target­-volume definition is frequently achieved by bypassing the location inaccuracy of target struct­ures, and the small pelvis is outlined directly and generously to include all target struct­ures.
The planning target volume (PTV) used in many clinical centres for rectal radiation therapy is therefore large and concave, due to the inclusion of the primary tumour or its surgical bed, the local lympha­tics, and the pre-sacral area.
The upper limit of the field can be just above the top of the sacrum, and the inferior margin may extend 4-5cm below the inferior limit of the tumour. Laterally, the pelvic side walls and internal iliac nodes may also be included.
Small bowel toxicity due to the close proximity and large PTV is common.
At simulation or CT the patient is positioned prone. Depending upon the centre protocol and the radiation oncolo­gist’s prefer­ence, the patient may be placed on the “ belly board”. The theory behind the belly board is that the patient’s “belly” falls into the hole, as does the small bowel. This is using gravity to move the small bowel away from the radiation fields, so reducing dose to that critical structure, and ultimately minimising toxicity. If the patient has a full bladder this can also help push small bowel out of the treatment fields.
The planning of rectal cancer involves taking the inform­ation acquired at simula­tion/CT and optimising the dose distri­bution for the CT for that patient.
Many depart­ments will treat rectal cancer patients with a threefield technique, consisting of a posterior and two opposed lateral fields. Since the rectum is a posterior structure, for early stage disease (that is, the disease is not adhered to nearby structures such as bladder, prostate or vagina) and anterior field would only increase the toxicity of the treatment.
For long course pre-op­erative radiation therapy the prescribed doses is usually 45 Gy in 25 fractions to the tumour bed and regional lymph nodes, treating all fields once a day, five times a week. A reduced field size may then be delivered up to 50.4 Gy, and sometimes 54 Gy, for those patients with gross or micros­copic residual disease and is treated on consec­utive treatment days.
A reduced field size to the tumour bed coming off the lymph nodes is used to reduce small bowel toxicity.
The prescribed doses equate to 1.8 Gy per fraction. (This is lower than the 2 Gy per day used for many other treatment sites.) The smaller fraction size is essential due to the large size of the fields, and the inclusion of some bowel in the fields should reduce some of the toxicity.
If the patient is also having chemot­herapy, the bowel may be even more sensitive. Remember that the belly board and full bladder also help reduce small bowel volume within the fields. If treatment is planned with a full bladder, the patient should be treated with a full bladder daily.

Management Strate­gies: Chemot­herapy

Recurrence for rectal cancer tends to occur in the liver, lung and bone.
For this reason adjuvant chemot­herapy has a good rationale.
The aim of adjuvant chemot­herapy is to eradicate micro-­met­astases
Regardless of whether chemot­herapy is delivered pre-op­era­tively or post-o­per­atively it has been shown to have no effect on overall survival, however is seen to increased local control.
It is recognised that rectal cancer needs a multid­isc­ipl­inary approach, radiot­herapy and chemot­herapy being necessary comple­ments of surgery to obtain the best chance of cure in stage II and III disease. The problems encoun­tered in everyday practice in admini­stering combin­ation adjuvant therapy in the operated colon and the success in treating locally advanced rectal lesions with neo-ad­juvant radio-­che­mot­herapy has favoured attempts in treating operable tumours with a pre-op­erative multid­isc­ipl­inary approach.
Chemot­herapy schedules for rectal cancer usually have a 5- florou­racil (5-FU) base, combined with leucov­orin, capeci­tabine, oxalip­latin or irinot­ecan. The pre-op­erative toxicity of these drug combin­ations has been found to relatively low. In the post-o­per­ative setting, the toxicity of chemot­herapy depends on the individual patient and the local situation after surgery.
5-FU is an inhibitor of thymid­ylate synthase and its anti-p­rol­ife­rative effect is primarily the inhibition of DNA synthesis. The mode of action of 5-FU together with its ability to render cells more sensitive to radiation, demons­trated both in vitro and in vivo, make this drug highly approp­riate for combined chemo-­rad­iot­herapy.
The challenge of the future will be the selection of patients on the basis of biological prognostic factors and the choice of the best chemot­herapy regimen according to predictive molecular markers.
The other direction taken in research in the neo-ad­juvant setting is to assess new biological therapies able to select­ively target pathways that are critical for tumour growth and develo­pment, like angiog­ene­sis (the develo­pment of new blood vessels)

Side Effect Management

The use of chemo-­irr­adi­ation has been shown to diminish the risk of local recurr­ence.
There is strong evidence though that both pre-op­erative and post operative radiation therapy for rectal patients results in adverse effects to bowel function.
During combined modality treatm­ents, acute side effects such as diarrhea and increased bowel frequency, acute proctitis, and dysuria are common.
These conditions are usually transient and resolve within a few weeks following the completion of radiation. Management involves the use of antisp­asmodic and/or anti-c­hol­inergic medica­tions.
The symptoms appear to be a function of the dose volume and fraction size, rather than the total dose.
Late onset compli­cations from chemo-­rad­iation for rectal patients include:
-small bowel enteritis
-small bowel obstru­ction
-fibrosis resulting in urogenital dysfun­ction
-vascular toxicity
-bladder and urethral sphincter dysfun­ction
-urinary dysfun­ction
-sexual dysfun­ction
-psychological issues
Late onset compli­cations occur less frequently than acute side effects but are more serious. The initial symptoms commonly occur 6–18 months following completion of radiation therapy.
Some surgical techniques may also contribute to many of these late onset compli­cat­ions.
The primary goals of post therapy follow up for rectal cancer patients are: improve survival, manage treatment toxicities and adverse effects, assess the efficacy of the initial therapy, detect new malign­ancies, detect potential curable recurr­ence, provide supportive care to the patient and carers, and assist in the mainte­nance or improv­ement of quality of life.
  

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