Rectal cancer





Approximately 43,000 new cases and an estimated 12,000 deaths each year from rectal carcinoma.

Accounts for approximately 1/3 of patients newly diagnosed with colorectal cancer in the US.

The incidence of rectal cancer peaks at age 75 years.

Approximately 704,000 cases and 311,000 deaths occur annually across the world based on 2018 data.

It is estimated that 5-15% of all sporadic colorectal cancers are mismatch repair-deficient or microsatellite instability high.

Mismatch repair deficient tumors respond poorly to standard chemotherapy regimen‘ss.

Rectal disease patterns vary throughout the world due to diverse diet, lifestyle and quality of screening programs along with treatment options.

The rectum anatomically begins above the dentate line: Which marks the cephalic extent of the anal canal, and extends above the peritoneal reflection to the sigmoid colon.

Rectal tumors are classified lower rectal, mid rectal, and upper rectal lesions, but the most valuable information about localization refers of a rectal tumor is whether or not is surrounded by peritoneum.

Peritonealized tumors are managed as colon tumors.

Rectal tumors lacking the peritoneal covering for a higher risk of local recurrence and requires different medical approaches including more radical surgery.

Surgical technical difficulties in obtaining a wide surgical margin, proximity of the rectum to pelvic structures, absence of serosa surrounding the rectum makes rectal cancer a high-risk disease for a local recurrence.

The depth of infiltration of the primary tumor, the T classification, and nodal status are important prognostic factors for local and distant metastases after surgery.

Local advanced rectal cancers present significant problems due to the complex anatomy, close proximity to genitourinary structures, and lymphatic drainage and blood supply beyond the portal circulation.

Rectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression.

Mesorectal extension depth in patients with T3 rectal cancers after neoadjuvant chemoradiotherapy is significant for recurrence, especially when it is >5mm-associated with a poor prognosis.

Neoadjuvant chemoradiotherapy followed by total mesotevtal excision is highly effective in providing local tumor control of local advanced rectal cancer: but over a quarter of patients treated with chemoradiotherapy and total mesorectal excision develop distant metastasis which means the leading cause of death in these patients.

Neoadjuvant therapy in locally advanced rectal cancer with induction chemotherapy with a fluoropyrimidine in combination with oxaliplatin followed by chemoradiotherapy and then surgery results in pathological complete response rates in up to a quarter of patients: associated with Mark complication in toxic effects including bowel, urinary, and sexual dysfunction, infertility and altered quality of life.

MRI is currently the best available noninvasive modality, and T2 weighted images is the key sequence for local staging of rectal cancer.

Compared with endoscopic rectal ultrasound, MRI can better determine the proximity of the primary tumor to the mesorectal fascia, the presence of extramural vascular invasion, involvement of the extra mesorectal pelvic lymph nodes and anterior peritoneal reflection, all important factors that can upstage tumors.

Preoperative MRI staging by high-quality MRI indicates that it can predict pathological findings, including involvement of the circumferential resection margin, extramural vascular invasion and extranodal tumor deposits, all of which affect cancer outcomes: by contrast preoperative lymph node staging is less prognostically accurate.

When rectal tumors lack peritonealization total Meso-rectal excision and neoadjuvant chemo radiation are effective procedures.

The majority of patients with localized, including locally advanced rectal cancer, will become long-term survivors.

With  the use of MRI and improvements in rectal cancer surgery, neoadjuvant radiotherapy may be safely omitted in most cases of localized rectal cancer.

Neoadjuvant chemoradiation followed by surgery with or without adjuvant chemo therapy has been the main stage of treatment of local advanced rectal cancer and has helped reduce rates of local recurrence to less than 5%, but rates of systemic failure are still high at 20-30%, leading to a five-year overall survival of 75% at best.

Even in patients with stage IV disease and few resectable distant metastases have an approximately 20% probability to survive for more than 5 years after diagnosis.

Treatment with neoadjuvant therapy followed by surgery with TME is standard of care for patients with deperitonealized T3 or N1 distal rectal tumors.

For stage II in III rectal cancer neoadjuvant chemoradiotherapy is a better approach than adjuvant chemo radiotherapy, providing improved local control with reduced toxicity: the five-year cumulative incidence of local relapse was 6% for the neoadjuvant treatment group compare with 13% for an adjuvant treatment group (Sauer).

Trials have demonstrated adjuvant chemotherapy likely improves survival, whereas adjucant radiation decreases local recurrence in locally advanced rectal carcinoma.

T1 and T2 tumors that do not penetrate the muscularis propria have a low risk of regional lymph node metastases of less than 10%.

Endoscopy is done to detect the tumor and obtain tissue for histologic diagnosis, and to assess tumor dimensions, distance from the anal sphincter, and relation to landmarks such as the prostate or vagina with a view toward future surgery.

The entire large intestine is examined by colonoscopy, proctosigmoidoscopy combined with contrast enema, or computed tomography (CT) colonography to exclude synchronous lesions.

Risk of lymph node metastases in varying studies: T1 10-18%, T2 17-47%, T3 66%, and T4 79%.

Owing to abundant lymphatic drainage rectal cancers harbors a higher risk of local recurrence, metastases, and treatment failure than do other colon cancers.

Division into three main groups: easily resectable, borderline resectable lesions and patients with fixed unresectable cancers for whom surgery leaves tumor within the pelvis.

Very low lying rectal tumors usually require abdominal perineal resection that completely removes the distal colon, rectum, and anal sphincter complex with a resulting permanent colostomy.

Abdominal peritoneal resection is the standard of care for patients with early-stage T2 N0 distal rectal tumors and may not require multimodality treatment.

Resectable lesions may have residual microscopic disease at surgical margins or within lymph nodes, or in distant metastatic sites.

Colon cancer studies suggest an inadequate number of nodes being assessed may result in under staging with prognostic and possible therapeutic impact, and studies show that increased nodal harvest is associated with improved survival: however in rectal cancer in the era of neoadjuvant therapy a lowered lymph node count after such treatment is not associated with under staging or inferior survival (Govindarajan A et al).

In patients with locally advanced cancer, lymph node involvement and positive margins are common findings.

Differs from colon cancer primarily in the risk of local recurrence, which is higher as a result of narrow anatomical confines of the pelvis, making clear margins it difficult to achieve.

Risk of local recurrence higher with local excision and increases proportionally with progressive tumor stage.

The management of localized RC is presently is a combination of radiation and chemotherapy which is associated with a 15-20% pathologic complete response, sphincter spring surgery rate of 39-44% and surgical downstaging of 40-80%

Chemoradiation with celoecoxib for localized rectal cancer demonstrated high rates of complete pathologic remission, sphincter sparing surgery, and surgical downstaging and lowered rate of skin toxicity (Arauio-Mino E).

Increased risk for pelvic recurrences following proctectomy suspected to be due incomplete resection of the mesorectum.

The mesorectal fascia acts as a natural barrier to the radial spread of rectal cancer.

Patients with T! and T2 node negative rectal cancer can be candidates for local excision, while T3 and T4 or node positive rectal tumors are managed with total mesorectal ecxision decreasing the local recurrence rate from 38% to below 10%.

Endorectal ultrasound the most accurate technique for preoperative staging.

2.5 fold increased risk for local recurrence in patients treated by noncolorectal surgeons.

Preoperative radiation as an adjunct to surgery still has an associated recurrence rate as high as 16-43%.

The total dose of radiation is limited in rectal cancer to maintaining anal sphincter function and avoiding small bowel or bladder injury.

Improvement in local regional control of disease resulting from preoperative chemotherapy/radiotherapy and standardized surgical technique of total mesorectal excision in locally advanced resectable rectal cancer has not been associated with improved survival.

In randomized controlled studies of preoperative chemoradiation and standardized surgical resection for locally advanced resectable has been associated with distant metastases of a 24-28%, although local recurrence rates are only 7-10%.

Preoperative chemotherapy and radiation offer little benefit and may induce significant morbidity for those with T1 and T2 tumors, therefore an adequate assessment of tumor staging is crucial to determine appropriate therapy.

Preoperative mFOLFOX6 chemotherapy alone can downstage rectal cancer 35% compared with fluorouracil radiotherapy in patients with rectal cancer.

In patients with locally advanced rectal cancer, who are eligible for sphincter sparing surgery, pre-operative FOLFOX was non-inferior to preoperative chemoradiotherapy with respect to disease free survival (Schrag D).

Excision of an intact mesorectum with uninvolved margins the local recurrence rates are as low as 5%.

In the era total mesorectal excision the long-term committed incidence of local recurrence is about 11% with surgery alone.


Total meso rectal excision defined as complete resection of the visceral meso rectum with pelvic nerve preservation is considered the primary reason for decreasing the local recurrence rate from 25% to less than 5-10%,  in patients  with medically operable locally advanced rectal cancer.

Optimized multimodal treatment with chemoradiation plus total mesorectal excision has significantly lowered local recurrence rate, but approximately 40% develop distal metastases.

In neoadjuvant rectal cancer treatment the primary target is not clinically apparent mass,but the microscopic extensions of tumor that may be missed by subsequent surgery: It is the microscopic disease tht is the root of local failure and result in pain and morbidity.

After conventional surgery there is a high incidence of local recurrence-25-40%.

Review of pathological specimens revealed local recurrence due to foci of malignant cells in the ectum several centimeters distal to the lower edge of the rectal tumor.

Involvement of the lateral or circumferential resection margin is the most important factor for the risk of local recurrence after rectal cancer surgery and more relevant than distal or proximal resection margins.

Positive circumferential margins is relevant for local and systemic failure.

Abdominal perineal resection (APR) performed in 20-30% of patients.

Low anterior resection for similar tumors as those resected with APR shows no significant differences in overall survival rates or local recurrence rates.

The excision of the intact mesorectum with uninvolved margins is associated with a local recurrence rate is low as 5%.

Total mesorectal excision (TME), dissection under direct vision between parietal and visceral planes of the pelvic fascia allowing complete resection of an intact rectum along with its surrounding mesorectum within the pelvic fascia and well defined margin is the present surgical approach.

With the use of total mesorectal excision 5 year survival rates have risen from 45-50% to 75% and local recurrence rates have decreased from 30% to 5-8% and sphincter preservation has increased by at least 20% for middle and lower rectal cancers, the rates of impotence and bladder dysfunction declined from 50-85% to 15% or less.

Removing all of the mesorectum containing lymph nodes and tumor is paramount to achieve a good outcome and a minimal recurrence rate.

Involvement of the circumferential resection margin or distal resection margin and the quality of surgical total mesorectal excision is related to the local recurrence and long-term survival rate.

Among patients with T1-T3 rectal tumors laparoscopic surgery was not found to be noninferior to open surgery for successful resection (Stevenson ARL et al).

In a randomized trial of low rectal cancer laparoscopic surgery provided pathological comes comparable to open surgery with a higher sphincter preservation rate and favorable postoperative recovery (LASRE clinical trial).

A prospective randomized comparison total mesorectal excision has demonstrated preoperative chemoradiation improves local control, with superior sphincter preservation, and reduce treatment-related toxicity compared to postoperative chemoradiation (Sauer R).

In a cohort study of 32,467 patients found that the use of postoperative chemotherapy/radiation therapy has decreased significantly in recent years, while preoperative chemotherapy/radiation therapy and multiagent chemotherapy increased significantly: The greater use of perioperative therapy for stage 2/3 rectal cancer has been associated with significant survival improvement in the clinical setting(Kennecke HF).

Laparoscopic surgery acceptance in rectal cancer surgery has not been universal because of isolated reports documenting higher but none significant rates of circumferential positive margins and a trend toward worsening of sexual function following a laparoscopic anterior resection.

Three and five-year followup rates for standard open rectal cancer surgery and laparoscopic surgery for rectal cancer have not demonstrated differences in local or distant recurrence rates, nor in overall disease-free survival rates.

Extirpation of locally advanced lesions T3/4 or N1/2 is difficult because of the close confines of the bony pelvis limit access to deep tumors to allow clear circumferential margins while avoiding injury to autonomic nerves that can affect bladder and sexual function.

The Working Group Of Surgical Oncology/Working Group Of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO) Trial compared preoperative and postoperative therapy and indicating that the former had a lowered incidence of local recurrence 6% vs. 15%, less acute toxicity 27% vs. 40%, and chronic toxicities 14% vs. 24%, a higher incidence of sphincter preservation 39% vs. 20% and no difference in five-year survival 74% vs. 76% (Sauer R).

In an updated analysis of the above study there was an absolute 3% decrease in 10 year local relapse, it will be important discussion with similar long-term survival and proportion of distant metastasis at 30%.

The Intergroup postoperative rectal adjuvant trial INT 0114 in patients with T3-4 and N+ disease showed rates of local control and survival I continue to decrease beyond 5 years: At 7 years, the local recurrence rate was 17% and survival 56% versus 14% and 64%, respectively at 5 years (Tepper JE et al).

In contrast to the above patients who received preoperative chemoradiotherapy in the German CAO/ARO/AIO-94 trial there was a decrease in survival at 10 years versus 5 years (74% versus 60%) but no change in 86% local recurrence rate (Rob MS et al).

Common treatments include preoperative chemo radiation with Capecitabine for 5 to 6 weeks followed by surgical resection.

The degree to which the primary rectal cancer regresses in response to chemoradiation is associated with outcome: 15-20% of patients whose tumors respond completely to 5FU and 50.4 Gy have less than 10% recurrence at five years.

The majority of patients treated with chemo radiation have a less than complete response, but with tumor down staging and downsizing, it is the final pathologic stage, rather than the previous treatment clinical stage which most closely predicts recurrence.

In patients treated with chemoradiation and have a minimal or no response, without downsizing are likely to have incomplete resections, require permanent colostomy and experienced recurrence

Postoperative chemoradiation associated with the QTC pathological T. and N. staging compared with preoperative clinical staging in approximately 60% of patients and is associated with a complete pathological response in 8-31% of patients (KIMjs, Bouzouerne H).

In a randomized study of preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus fluoracil alone in locally advanced rectal cancer: The inclusion of oxaliplatinum into fluorouracil based combined modality therapy led to more patients achieving a pathological complete response than did standard treatment (German CAO/ARO/AIO-04).

NSABP R-03 trial compared pre-and postoperative therapy and found a significant improvement in five-year disease free survival for preoperative therapy of 64% vs. 53% and an non-significant improvement in five-year overall survival of 75% vs. 66%, with no difference in five year local recurrence rates of 11%(Roh MS).

Pathologic lymph node status following preoperative radiotherapy is a significant predictor of outcome, such that persistence of metastases is associated with an increased risk of long-term cancer related mortality and may serve as a marker for a tumors biologic behavior.

NSABP R-03 study indicated that there were no recurrences in the 15% of patients who achieved pathological complete remission.

Preoperative chemo-radiation still associated with about a 22% incidence of lymph node positive disease at the time of surgery, compared to about 40% of patients who undergo surgery alone (Guillem JG).

The addition oxaliplatin to 5-FU preoperative chemoradiation therapy increased toxicity without affecting the primary tumor response: The rate of pathological complete remission was 16% for both arms of the study with similar nodal involvement found at the time of surgery (Achele C et al).

Stage I (T1 ot T2, N),M0) often cured with surgical resection alone.

NCC and guidelines recommend trimodality treatment with neoadjuvant chemo radiotherapy, surgical resection with total mesorectal excision, plus additional chemotherapy most commonly in the adjuvant setting for stage II or stage III rectal cancer.

Trimodal therapy is associated with the best survival outcomes for patients diagnosed with locally advanced rectal cancer.

Patients with stage II and III rectal cancer, defined as invading beyond the submucosa or involving regional lymph nodes, should be treated with a combination of surgical resection, chemotherapy and radiation.

For stage II and III  locally advanced rectal cancer treated with preoperative chemotherapy and radiation followed by surgery, four months of adjuvant chemo therapy improves overall survivall.

Treatment for clinical stage II or III locally advanced rectal cancer (T3/4, 0),  or node positive) consists of preoperative chemoradiotherapy followed by TME and postoperative adjuvant chemotherapy with fluorouracil and  o so platinum.

Patients with rectal cancer, who have enlarged the lateral lymph nodes, have an increased risk of lateral local recurrence

Adjuvant chemo therapy in rectal cancer shows a significant increase in disease free survival in subgroup analysis of patients with proximal tumors of 10-15 cm above the anal verge with fewer distal recurrences.

Local recurrence rates have fallen to less than 5-10% in the contemporary literature.

There is an estimated 35% distal relapse rate with rectal cancer.

For lesions infiltrating the muscular layer and the perirectal adipose tissue and located in the lower third of the rectum (T3tumors within 6 cm of the anal verge) are traditionally treated by abdominal perineal resection.

Postoperative chemoradiation have serious hematologic side effects of 30%, long-tern enteritis of 5% and poor sphincter function.

The extent of pelvic dissection relates directly to the morbidity of postoperative radiation.

Preoperative radiotherapy plus operation significantly improves overall and cancer-specific survival, compared to operation alone.

A recent study (2004) revealed that 5-year incidence of local relapse was 6% for patients treated with preoperative chemoradiation vs. 13% for those patients treated with postoperative chemoradiation.

Preoperative chemoradiation associated with fewer long-term toxic effects than postoperative chemoradiation.

Short course of a radiation with 5 Gy for five days followed by surgery a week later improves local control and improves disease free survival, and possibly improves overall survival, but it does not provide downstaging, as seen with conventional chemoradiation therapy and may have long-term toxic effects (Bi Itrgisson H et al)

Three year local recurrence rates between short course and long course neoadjuvant radiotherapy plus chemotherapy are not significant (Ngan T et al).

The integrity of the surgical specimen and tumor pathologic staging is the most important prognostic factor in the development of recurrent rectal cancer.

Total mesorectal excision completeness is a marker for good surgical technique and predicts the likelihood of local recurrence of rectal cancer.

Pre or postoperative chemoradiation have the same overall survival.

Preoperative radiotherapy provides superior local control and tolerance compared with postoperative radiation.

Postoperative radiotherapy does not increase disease-free survival or overall survival but does reduce locoregional relapse from 13% to 8%.

Larger proportion of patients undergoing preoperative chemoradiation were able to undergo sphincter-saving resections compared to postoperative therapy.

30 day surgical mortality about 3%.

2 year mortality rate 32-34% by low volume surgeons and hospitals and 24-26% for high volume surgeons and hospitals.

A ten year follow-up of patients from EORTC trial 22921 confirmed that 5-FU based chemotherapy after preoperative radiotherapy did not affect survival: 1,011 patients with resectable T3 or T4 rectal adenocarcinomas randomized to preoperative RT alone, preoperative radiotherapy and chemotherapy, preoperative radiotherapy followed by adjuvant chemotherapy and properative radiotherpay and chemotherapy followed by adjuvant chemotherapy.

The optimal time between neoadjuvant chemoradiation therapy and surgery is around 60 days, while much shorter intervals are associated with lower rates of pathologic complete responses, and a longer interval than 60 days is associated with increased rates of positive surgical margins and a 25% increase in mortality (Salo JC).

Local excision and sphincter-saving resection are usually proposed in patients with well-differentiated T1-T2 disease.

Digital rectal exam is inaccurate in staging rectal cancers.

CT scan cannot define layers of rectal wall and therefore is not a accurate assessor of depth of tumor invasion.

CT scanning to assess lymph node involvement is highly variable and should not be used alone in staging rectal cancer.

Local excision and sphincter-saving resection are usually proposed in patients with well-differentiated T1-T2 disease.

For patients with localized rectal cancer short course radiotherapy given is 25Gy in 5 fractions without concurrent chemotherapy and surgery performed within days of completion has compliance benefits, economic benefits, but does not change the preoperative stage of disease unless the surgery is delayed.

The acute toxicity of short course radiation is less than one with long-term chemo radiotherapy.

Long course chemoradio therapy includes 50.4 Gy given overview 5.5 weeks with concurrent 5FU based chemotherapy and surgery performed approximately six weeks later.

Long course chemo radiotherapy can result in pathologic complete responses and tumor down staging, but some reduction in late toxicity compared to short course radiation therapy.

Long course chemo radiotherapy in localized disease may avoid surgery altogether.

ONCORE study of 259 patients diagnosed with rectal adenocarcinoma without distant metastases with preoperative chemoradiation and complete clinical response randomized to watch and wait management or surgical resection: Of 129 patients managed by watch and wait 34% and local regrowth’s and 88% were salvaged-no differences in the 3 year non-regrowth disease-free survival between the watch and wait group and surgical resection group, but no difference in the 3 year overall survival rate between the 2 groups, the watch and wait group had significantly better three-year colostomy free survival.

In a controlled study of patients with stage II or III rectal cancer use of laparoscopic resection compared with open resection failed to meet the criteria for noninferiority for pathological outcomes and the findings do not support the use of laparoscopic resection in such patients (ACOSOG Z6051 trial).

Mismatch repair deficient, locally advanced rectal cancer is highly sensitive to single agent PD-1 blockade (Cercek A).



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