Management ofLocally Advanced Rectal Cancer-An

evidence based approach

Prepared ByRanjita Pallavi, MDPGY-3, Department of Internal Medicine

TNM Staging-Rectal Cancer

Neoadjuvant RT in Rectal Cancer

• To lower local failure rates and improve survival in resectable cancers

• “Sterilization” of the mesorectal lymphatic channels, preventing dissemination of viable tumor cells during mesorectal dissection

• Exclusion of the small bowel from the radiation field by the native rectum (after resection, the small bowel can become tethered in the pelvis by adhesions where it is then subject to repeat radiation exposure).

• Reducing tumor volume may facilitate resection and increase likelihood of a sphincter-sparing procedure.

• Irradiating tissue that is surgery-naïve and thus better oxygenated may result in increased sensitivity to RT.

• Preoperative radiation that includes structures that will be resected increases the likelihood that an anastomosis with healthy colon can be performed (Superior function of the nonirradiated neorectum).

Neoadjuvant Chemotherapy in Rectal Cancer

Is pre-op ChemoRT preferred over post-op?

Neoadjuvant Therapy Trials

German Rectal Cancer Study Group

Results:• 421 patients were assigned to receive preoperative

chemoradiotherapy.• 402 patients received postoperative

chemoradiotherapy.• Median follow up 46 months.• Primary end-point: Overall survival.• Overall five-year survival rates were 76% and 74%

respectively (P=0.80).• Five-year cumulative incidence of local relapse was

6% for patients assigned to preoperative chemoradiotherapy and 13% in the postoperative-treatment group (P=0.006).

• Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group, as compared with 40% of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P=0.01).

N Engl J Med. 2004 Oct 21;351(17):1731-40.

German Rectal Cancer Study Group

N Engl J Med. 2004 Oct 21;351(17):1731-40.

German Rectal Cancer Study Group

German Rectal Cancer Study Group

Other favorable findings include:• Evidence of tumor downstaging after preoperative chemoradiotherapy, in terms

of the rate of complete pathological response (8 percent, vs. 0 percent in the postoperative-chemoradiotherapy group)

• Similar rates of sphincter preservation, despite the preponderance of distal tumors in the preoperative-chemoradiotherapy group.

• Similar perioperative morbidity and mortality rates.• Improved treatment compliance and decreased rates of severe acute and long-

term toxic effects in the preoperative-chemoradiotherapy group.

One disadvantage of preoperative chemoradiotherapy is the possibility of overtreating early-stage tumors.

Sauer et al. found that in 18 percent of the patients randomly assigned to postoperative chemoradiotherapy, the tumor had been overstaged during the initial evaluation, despite the use of endorectal ultrasonography.

German Rectal Cancer Study Group

• Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT.

• Median follow up of 134 months.• According to intention-to-treat analysis,

overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P .048).

• No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P .9) and disease-free survival.

German Rectal Cancer Study Group – Follow up Data

German Rectal Cancer Study Group – Follow up Data

RT Regimens

• Two preoperative external beam RT (EBRT) regimens: short course and long course.

• Short-course RT, also known as the 5 × 5 gray (Gy) regimen: offers 5 daily doses of 5 Gy (total of 25 Gy)

• It is usually followed by radical resection within one week of completing RT.• Long-course regimens deliver daily doses of RT in significantly smaller fractions

(about 1.8 Gy-2 Gy) over a longer period of 25 days to 28 days. • The total RT dose delivered by this regimen is 45 Gy to 54 Gy and seems to be

biologically equivalent to the 25 Gy short-course regimen.• After long-course RT, radical surgery is delayed for 6 weeks to 8 weeks. • The 2 regimens also differ with respect to concurrent CTx, which is typically offered

with long-course but not short-course regimens.

Types of RT

• External Beam RT• High dose endorectal brachytherapy• Contact RT• Intraoperative RT• Stereotactic body RT

NCCN Guidelines

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

• 139 uT3/T4 N0/N+ rectal cancers were included.

• Dworak classification for regression was used.

• Tumor downstaging occurred in 46.7 percent.

• CONCLUSION: After preoperative therapy, the sterilized disease shows an excellent prognosis.

• The minimal residual disease has a much better prognosis in comparison with the gross residual disease.

Dis Colon Rectum, October 2005

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

CA: A Cancer Journal for CliniciansVolume 62, Issue 3, pages 173-202, 9 APR 2012

Posttreatment Response Assessment

NCCN guidelines recommend grading tumor response after neoadjuvant therapy.

0-Complete response: No remaining viable cancer cells.1-Moderate response: Only small clusters or single cancer cells remaining.2-Minimal response: Residual cancer remaining, but with predominant fibrosis.3-Poor response: Minimal or no tumor kill; extensive residual cancer.

Ryan et al. Histopathology 2005;47:141-146

Does neoadjuvant therapy increase chances of sphincter preserving surgery?

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

• Since 1976, the rate of sphincter saving surgery has increased from 20% to 75%.

• In none of the 17 trials it was possible to demonstrate a significant benefit of the neo-adjuvant regimens on the rate of sphincter saving surgery.

• The improvement in conservative surgery appears to be the result of new technologies and changes in surgical concepts, such as incorporation of total mesorectal excision (TME) and the techniques for very low anastomosis.

• There was a reduction in the risk of 5-year local recurrence partly due to these neo-adjuvant treatments.

• These neo-adjuvant regimens had no significant impact on the overall 5-year survival.

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

Can Capecitabine replace 5-Fluorouracil in peri-operative ChemoRT?

• Between March, 2002, and December, 2007, 401 patients were randomly allocated.

• 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41–72).

• 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67–82] vs 67% [58–74]; p=0·0004; post-hoc test for superiority p=0·05).

• 3-year disease-free survival was 75% (95% CI 68–81) in the capecitabine group and 67% (59–73) in the fluorouracil group (p=0·07).

• Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04).

• Diarrhoea was the most common adverse event in both groups.

• Patients in the capecitabine group had more hand-foot skin reactions than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine.

• Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

How much time should elapse between pre-operative ChemoRT and definite surgery?

• The patients were divided into two groups according to the neoadjuvant–surgery interval: ≤7 weeks (group A, n = 48), and >7 weeks (group B, n = 84).

• The median interval between chemoradiation and surgery was 56 days (range 13–173 days).

• There was no in-hospital mortality. • The pCR and near pCR rates were higher with longer

interval: 17% in group A, 35% in group B (P = 0.03). • Patients operated at an interval >7 weeks had

significantly better disease–free survival (P = 0.05).• Surgery type, operative time, number of intraoperative

blood transfusions, postoperative complications, and length of hospitalization were not influenced by the interval length.

• A neoadjuvant–surgery interval >7 weeks was associated with higher rates of pCR and near pCR, decreased recurrence and improved disease–free survival.

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

NCCN guidelines recommend an interval of 5-12 weeks following completion of full-dose 5 ½-week chemoRT prior to surgical resection in order to allow for patient recuperation from chemoRT-associated toxicities.

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

Can neoadjuvant treatment response be an early response indicator?

• 725 patients were classified by tumor response: complete (ypT0N0) (131; 18.1%), intermediate (ypT1-2N0) (210; 29.0%), and poor (ypT3-4 or N+) (384; 53.0%).

• Age, sex, cN stage, and tumor location were not related to tumor response.

• Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v1.4% v 4.4%; P = .002).

• Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes.

Neoadjuvant Therapy – Locally Advanced Rectal Cancer

• A total of 21 eligible RCTs were identified and used for meta-analysis purposes.

• Overall, 16,215 patients with colorectal cancer were enrolled, 9,785 being affected with rectal carcinoma.

• Considering patients with rectal cancer only, 4,854 cases were randomized to receive potentially curative surgery of the primary tumour plus adjuvant chemotherapy and 4,367 to receive surgery plus observation.

• 11 RCTs had been performed in Western countries and 10 in Japan.

• All trials used fluoropyrimidine-based chemotherapy (no modern drugs - such as oxaliplatin, irinotecan or biological agents - were tested).

• The meta-analysis of these RCTs showed a significant reduction in the risk of death (17%) among patients undergoing postoperative chemotherapy as compared to those undergoing observation (HR=0.83, CI: 0.76-0.91).

• There was a reduction in the risk of disease recurrence (25%) among patients undergoing adjuvant chemotherapy as compared to those undergoing observation (HR=0.75, CI: 0.68-0.83).

Adjuvant Therapy – Locally Advanced Rectal Cancer

NCCN Guidelines

NCCN Guidelines

A 4-Tiered Process

The development and execution of a treatment plan is really a 4-step process that is conducted at 2 time points if nCRT is provided: before and after treatment. The 4 tiers of assessment are: 1) Conventional therapy: identification of stage-directed, standard therapy for the tumor;2) Qualified therapy: modification of the conventional therapy plan based on evaluation of tumor features that define higher or lower oncologic risk within the stage grouping or present particular surgical challenges;3) Tailored therapy: recommendations based on assessment of patient factors that influence the feasibility or suitability of the qualified therapy plan;4) Actual therapy: the treatment that is actually provided

NCCN Guidelines

NCCN Guidelines

Thank You