BACKGROUND + Incidence/prevalence: The third most common diagnosed cancer and third leading cause of death among men and women in the United States. Approximately 39 220 cases are diagnosed annually in the United States Outcomes: 5-Year survival across all stages estimated at 67% (SEER data) Demographics: Lifetime risk 1 in 20 (5%). Highest incidence in Western countries Risk factors: Increasing age, familial syndromes (FAP, HNPCC, Peutz-Jeghers syndrome, juvenile polyposis), personal or family history of polyps, obesity, sedentary lifestyle, EtOH consumption, tobacco use, inflammatory bowel disease, low-fiber diet, and Western diet . .TUMOR BIOLOGY AND CHARACTERISTICS + Genetics: TCGA genomic profiling identified ~16% of colorectal cancers hypermutated. Frequent mutations in APC, TP53, SMAD4, PIK3CA, and KRAS (Cancer Genome Atlas Network Nature 2012). Four consensus molecular subtypes proposed include CMS1 (hypermutated microsatellite unstable, 14%), CMS2 (epithelial with marked WNT and MYC signaling, 37%), CMS3 (epithelial and metabolically dysregulated, 13%), and CMS4 (mesenchymal, 23%) (Guinney et al. Nature Med 2015). Pathology: Majority adenocarcinomas (90%). _- Minority neuroendocrine, mesenchymal tumors or lymphomas. IHC testing for mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) commonly conducted and predictive of response to immunotherapy (Le et al. Science 2017). Consider testing for BRAF and KRAS mutations. Imaging: MRI accurate tool for local staging and for assessment of pelvic lymphadenopathy. Tumors typically visualized on high- resolution T2-weighted sequences, with increased signal on DWI sequence. Endorectal US can help distinguish between T1 and T2 tumors. .ANATOMY * Rectum: Begins at the rectosigmoid junction at the level of S3.Total length of the rectum estimated to be between 12 and 15 cm. Squamous mucosa ends at the dentate line (~2 cm from anal verge). Internal anal sphincter ends 2 cm superior to dentate line (~4 cm from anal verge). Colon: Cecum is the junction between the small and large intestines (intraperitoneal) —+ ascending colon (retroperitoneal) — transverse colon (intraperitoneal) —+ descending colon (retroperitoneal) — sigmoid colon (intraperitoneal). Lymph node drainage: © Upper half rectum: Superior hemorrhoidal > IMA —> para-aortic © Lower half rectum: Inferior + middle hemorrhoidal — internal iliac, obturator presacral nodes © Involvement of anal canal: Superficial inguinal nodes © Invading anterior structures (prostate, bladder, vagina) — external iliac .. Workup History and physical: DRE for all patients and pelvic exam in women Labs: CBC, CMP, CEA Procedures/biopsy: Colonoscopy with biopsy of primary(ies) Imaging: Contrast-enhanced CTs of the chest/abdomen/pelvis (important to image the liver) for all patients. MRI of the pelvis w/ contrast typically done as well (if available). Contrast-enhanced PETICT is not routinely indicated.COLON AND RECTAL CANCER STAGING (AJCC 8TH EDITION) T Stage Tis Carcinoma in situ (intramucosal) 'N Stage Na regional LN involved TI Invades the submucosa NIb 2-3 regional LNs involved T2_ Invades the muscularis propria Nic Tumor deposie feasa acne Hoe N2a__ 4-6 regional LNs involved Invades through the muscularis propria Ta pee the pericolorecal dasus N2b >7 regional LNs involved M Stage Mla Metastasis to | distal organ Téa Invades through visceral pertoneum 41) esasasis to >I distal organ T4b Tumor directly invades or adheres to Mic Metastasis to peritoneal surface adjacent organs or structures ‘distal organ involvement ‘Summative Stage NO Niac | N2a_N2b 0 N2c Mia Mib Mic To nm B ive Ta Tab ‘Note: TisNOMO is Stage 0TREATMENT ALGORITHM FOR RECTAL CANCER Surgical resection — chemoRT or observation (observation considered if pTI-2NOMO with RO resection) ChemoRT — surgical resection — chemotherapy Chemotherapy — +/— chemoRT or short-course radiation = surgical resection of primary and definitive local treatment of metastatic disease (in either order) > chemotherapy Chemotherapy or best supportive care Treatment for colon cancer is surgical + adjuvant chemo without routine use of adjuvant RT. Local control benefit of adjuvant RT was seen in T4 tumors invading adjoining structures, associated with perforation or fistula, or in the setting of residual disease (Willett et al. Cancer J Sci Am 1999). However, this was not confirmed when tested in the phase Ill Int 0130 trial comparing adjuvant chemo to chemo+RT (Martenson et al. JCO 2004) in T4 or T3N+ patients. Consider RT to metastatic sites if oligometastatic with good PS.RADIATION TREATMENT TECHNIQUE FOR RECTAL CANCER + SIM: Prone on a bellyboard, Vac-Lok device, comfortably full bladder, and marker on anal verge (wire perineal scars if post-op). Scan from mid lumbar spine to middle femur, isocenter midline at top of femoral heads. Dose: 45 Gy in 25 fractions at 1.8 Gy/fx — cone-down boost to 50.4 Gy in 1.8 Gy/tx Recurrent after prior RT: 39 Gy in 1.5 Gy/fx bidShort course: 25 Gy at 5 Gy/fx Target: Pre-op: GTV, mesorectum, internal iliac, obturator, presacral nodes Post-op: Tumor bed, anastomosis, mesorectum, internal iliac, obturator, presacral nodes Considerations: If T4 disease (invasion into anterior structures including the bladder, vagina, prostate), cover external iliac nodes. If locally advanced or recurrent, consider intraoperative radiation therapy (10-15 Gy, electrons, or HDR brachytherapy) + Technique: 3DCRT: 3-field PA and opposed laterals, use IMRT for short-course radiation (Fig. 38.1).Figure 38.1 Standard PA and lateral fields. Initial Fields: 45 Gy in 25 Fractions Superior LS/SI border Inferior Bottom of obturator foramen or 3 cm below tumor Anterior 3 cm anterior to sacral promontory Posterior __| em behind sacrum Lateral. em beyond pelvic inlet Cone-Down Boost: 5.4 Gy in 25 Fractions 2-cm expansion on GTV expanding posteriorly to include the sacrum using opposed laterals+ IGRT: Weekly kV imaging * Planning directive (for conventional fractionation): Ensure coverage of GTV by 50.4 Gy isodose line Spinal cord D max < 45 Gy Femoral heads V45 < 20% Bowel “bag” V45 < 195 co Bladder V50 < 30%SURGERY * Transanal excision (TAE): Sphincter-preserving, full-thickness local excision with adequate margin. Consider for low-lying (<10 cm) T1NO lesions <30% circumferential involvement, <3 cm in size, clear margins, low-intermediate grade, and no LVI. Consider post-op chemoRT or radical surgery if path shows high-risk features, staging is upgraded, or there are inadequate margins. Low anterior resection (LAR): Sphincter-preserving total mesorectal excision (TME). Dissection and anastomosis below peritoneal reflection with ligation of superior and middle hemorrhoidal arteries. Adequate LN dissection removes 212 LNs. Abdominoperineal resection (APR): Total mesorectal excision (TME) with complete removal of the rectum and anal canal and permanent colostomy. Adequate LN dissection removes 212 LNs. .CHEMOTHERAPY = Concurrent: Capecitabine (825 mgim? bid, 5 days a week) or continuous infusion 5-FU (225 mgim2/d) * Adjuvant/neoadjuvant: FOLFOX (folinic acid, oxaliplatin, 5-FU), or capecitabine, or CAPOX (capecitabine + oxaliplatin). . . . Sipe EFFECT MANAGEMENT Nausea: First-line Zofran (8 mg q8h PRN) — second-line Compazine (10 mg 6h pm) — ABH (lorazepam 0.34 mg, diphenhydramine 25 mg, and haloperidol 1.5 mg) 1 capsule q6h Diarrhea: First-4ine Imodium titrating to a max of 8 pills/day + second- line alternating Lomotil 2 pills and Imodium 2 pills every 3 hours Cystitis: Urgency/frequency and dysuria. UA to ro UTI. Treat if positive. Skin care: First-line sitz baths, Aquaphor, and Domeboro powder — Silvadene cream and hydrogel dressings (Cool Magic) Diarrhea/abdominal pain. first-line alternating Lomotil and Imodium (as above) — second-line steroid enemas. Hand and foot syndrome: Redness, swelling, and pain in the hand and foot. Consult with medical oncology about reducing concurrent capecitabine dose.FoLLow-up History/physical and CEA: Every 3-4 months for 3 years + every 6 months for 2 years CT of the chest/abdomen/pelvis: Every year Colonoscopy: At years 1 and 3 and every 5 years thereafter Vaginal dilators for womenNOTABLE TRIALS Neoadjuvant chemoradiation + German rectal trial (Sauer et al. NEJM 2004; Sauer et al. JCO 2012): Two-arm prospective randomized phase II trial comparing patients undergoing neoadjuvant chemoRT followed by surgery vs surgery followed by adjuvant chemoradiation. Both groups received adjuvant chemotherapy with bolus 5-FU. No OS survival difference but 10-year local recurrence is 7.1% vs 10.1% (P = .048, HR 0.60) favoring neoadjuvant approach. Grade 3-4 acute toxicities reduced (27% vs 40%, P = .001) along with grade 3-4 long-term toxicities (14% vs 24%, P = .01) in neoadjuvant-treated patients. Increased sphincter preservation among unfavorable patients in neoadjuvant group NSABP R-04 trial (O'Connell et al. JCO 2014; Allegra et al. INCI 2015): Four-arm prospective randomized phase III trial comparing concurrent infusional 5-FU vs capecitabine, vs 5-FU + oxaliplatin, vs capecitabine + oxaliplatin. No significant difference in pathologic complete response, locoregional control, and overall survival. Increased diarrhea with oxaliplatin Short-course (SC) radiation * Dutch Trial (Kapitejin et al. NEJM 2001; van Gijn et al. Lancet Oncol 2011): Two-arm prospective randomized phase III trial comparing SC + surgery (TME required) vs surgery alone. SC consisted of 25 Gy in 5 fractions given over 1 week. Surgery could include APR, LAR, or Hartmann procedure. 10-Year local recurrence improved with neoadjuvant SC (5% vs 11%, P< .0001). Polish Trial (Byjko et al. Ann Oncol 2016): cT3-T4 patients randomized prospective phase III trial comparing neoadjuvant SC RT followed by 3 cycles of FOLFOX4 to neoadjuvant long-course chemoRT to 50.4 Gy/28 fx combined with concurrent bolus 5-FU and leucovorin. Primary endpoint was RO resection rate (77% SC vs 71% long course, P = .07). 3-Year OS favoring SC (73% vs 65%, P = .0046) TROG 01.04 (Ngan et al, JCO 2012): Two-arm randomized phase II! trial comparing SC followed by surgery and adjuvant chemotherapy to long course chemoRT followed by surgery and adjuvant chemotherapy. Trial was powered to detect a 3-year local recurrence rate of 15% for SC and 5% for long course. At 3 years, local recurrence was not significantly different between the arms (7.5% SC vs 4.4% long course, P = .24).