# Radiation Oncology/Colon

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
    See also: Colon randomized evidence
    See also: NSABP Colon trials
    See also: Rectum Official Guidelines (for now, contains colorectal guidelines)

## Staging
### Current Staging

AJCC 7th edition (2009)
Primary Tumor:
* T1 - invades submucosa
* T2 - invades muscularis propria
* T3 - invades through muscularis propria into pericolorectal tissues
* T4
** T4a - penetrates to the surface of the visceral peritoneum
** T4b - directly invades or is adherent to other organs or structures
Layers: are the epithelium, basement membrane (defines intraepithelial), lamina propria (defines intramucosal) - contains capillaries and lymphatics (but little chance for mets), muscularis mucosae, submucosa (loose connective tissue), muscularis propria (circular and longitudinal layers), subserosa (single layer of cells).
Difference between rectum and colon is that most of the rectum lacks serosa. Thus for the rectum, a T3 is invasion into perirectal fat; for colon, T3 is invasion of subserosa. Also for the rectum, T4 is only invasion of other organs, whereas for the colon T4 can also be perforation through serosa.
Regional Lymph Nodes:
* N1 - 1 to 3 lymph nodes
** N1a - 1 lymph node
** N1b - 2-3 lymph nodes
** N1c - tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
* N2 - 4 or more
** N2a - 4-6 lymph nodes
** N2b - 7 or more lymph nodes
Distant Metastasis:
* M0 - none
* M1 - yes
** M1a - metastasis confined to one organ or site
** M1b - metastasis in more than one organ/site or the peritoneum
Stage Grouping:
* I - T1-2 N0 M0
* IIA - T3 N0 M0
* IIB - T4a N0 M0
* IIC - T4b N0 M0
* IIIA - T1-2 N1 M0, T1 N2a M0
* IIIB - T3-T4a N1 M0, T2-T3 N2a, T1-T2 N2b
* IIIC - T4a N2a, T3-T4a N2b, T4b N1-N2
* IVA - M1a
* IVB - M1b
Changes from 6th edition:
* T4 subdivided into T4a/b
* N1 subdivided into N1a/b/c, N2 into N2a/b
* Added satellite tumor deposits (N1c)
* Stage II subdivided into IIA/B/C
* Stage III: T4bN1 was reclassified from IIIB to IIIC; T1N2a reclassified from IIIC to IIIA; T1N2b, T2N2, and T3N2a reclassified from IIIC to IIIB.
* M1 subdivided into M1a/b. Stage IV subdivided into IVA and IVB.
Dukes stage (1932):
* A - Growth limited to wall of rectum - T1-2 N0 (Stage I)
* B - Extra rectal tissues. No lymph node involvement - T3-4 N0 (IIA - IIB)
* C - Regional lymph nodes - N+ (IIIA-C)
** modified 1935: C1 - regional lymph nodes, C2 - mesenteric nodes
** named for Cuthbert E. Dukes
    No PMID - "The classification of cancer of the rectum." Dukes CE. J Pathol Bacteriol. 1932;35:323.
    No PMID - "Lymphatic spread in cancer of the rectum." Gabriel WB, Dukes C, et al. Br J Surg. 1935;23:395.
Modified Astler-Coller (1954):
* A - Limited to mucosa - T1 N0
* B1 - Involves muscularis propria but not through it - T2 N0
* B2 - Through muscularis propria - T3 N0
* B3 - T4 N0
* C1 - T1-2 N+
* C2 - T3 N+
* C3 - T4 N+
* D - M1
** PMID 13159135 [Full text on PMC] — "The prognostic significance of direct extension of carcinoma of the colon and rectum." Astler VB and Coller FA. Ann Surg. 1954 Jun;139(6):846-52.

### Older staging editions

AJCC 6th Edition (2002)
* T1 - invades submucosa
* T2 - invades muscularis propria
* T3 - invades into subserosa or into non-peritonealized pericoloic or perirectal tissues
* T4 - invades other organs or structures or perforates visceral peritoneum
* N1 - 1 to 3 lymph nodes
* N2 - 4 or more
Stage grouping:
* I - T1-2 N0 M0
* IIA - T3 N0 M0
* IIB - T4 N0 M0
* IIIA - T1-2 N1 M0
* IIIB - T3-4 N1 M0
* IIIC - N2
* IV - M1
Changes in AJCC staging:
* 6th ed: divided into IIA and IIB and into IIIA, B, C

## Anatomy

Relations to peritoneum:
* cecum: intraperitoneal
* ascending colon: retroperitoneal
** posterior surface lacks serosa, is in direct contact with the retroperitoneum. anterior and lateral surfaces have serosa.
* transverse colon: intraperitoneal
* descending colon: retroperitoneal
** posterior surface lacks serosa, is in direct contact with the retroperitoneum. anterior and lateral surfaces have serosa.
* sigmoid colon: intraperitoneal
* rectum:
** upper third: covered by peritoneum on the anterior wall and both sides
** middle third: covered by peritoneum only on the anterior wall
** lower third: infraperitoneal

## Epidemiology

* #2 cause of cancer deaths in US after lung cancer with 185,000 new cases and 55,000 deaths/year. Affects males/females equally. Lifetime risk is 5%.
* 5% due to mutations in mismatch repair genes; 1% due to FAP gene.
* Patients with familial risk (two or more first or second degree relatives) make up about 20% of patients; those with autosomal dominant mutations make up 5-10%.
* Average age (for sporadic cases) is 63
* Increased risk with moderate/heavy alcohol use, animal fat, and red meat.
* Folate intake associated with a decreased risk.

## Survival

* Stage I: 85-100%
* Stage IIA: 70%
* Stage IIB: 30%
* Stage IIIA-B: 60%
* Stage IIIC: 30%
* Stage IV: 3%

## Treatment Overview

Treatment is surgical. >12 lymph nodes required for adequate surgical staging.
NCCN Guidelines :
| Stage | Adjuvant Chemo | Adjuvant RT |
| Tis, T1-2 N0 | None |
| T3-4 N0 | Capecitabine 5-FU/Leucovorin 5-FU/Leucovorin/Oxaliplatin Clinical trial Observation | Consider in T4 with penetration to fixed structure |
| T1-4 N1-2 | 5-FU/Leucovorin/Oxaliplatin Capecitabine 5-FU/Leucovorin | Consider in T4 with penetration to fixed structure |

## Primary Surgery

Surgical technique:
* RTOG 94-15 / INT 0146 / NCCTG 93-46-53 (closed 2001) - Laparoscopic colectomy vs open colectomy.
Patterns of failure:
* MGH
** 1985 (1970-1977) PMID 3973649 -- "Obstructive and perforative colonic carcinoma: patterns of failure." (Willett C, J Clin Oncol. 1985 Mar;3(3):379-84.)
*** Retrospective. 77 patients with obstruction and 34 with perforation; compared with control 400 patients. Minimum F/U 5 years
*** 5-year OS: obstruction/perforation 31% vs. 59%; DFS 44% vs. 75%
*** Obstruction: 42% local failure (28% local only, 72% local and distant)
*** Perforation: 44% local failure
*** Control group: 14% local failure
** 1984 PMID 6735753 -- "Local failure following curative resection of colonic adenocarcinoma." (Willett C, Int J Radiat Oncol Biol Phys. 1984 May;10(5):645-51.)
*** Retrospective. 533 patients.
*** LR: overall 19%, 30% local only / 70% concurrent local and distant failure
*** LR: 82% in tumor bed and adjacent soft tissues, 18% in LNs
*** By stage: B3/C2-C3 LR >30%, A/B1-B2/C1 <4%
*** By LN: LN1 27%, LN5+ 50%
* 1981 PMID 7209752 -- "Analysis of recurrence patterns following curative resection for carcinoma of the colon and rectum." (Malcolm AW, Surg Gynecol Obstet. 1981 Feb;152(2):131-6.)
** Retrospective. 285 patients.
** Recurrence by location: overall 27%; right 24%, transverse 10%, left 11%, sigmoid/rectum 35%
** Recurrence by stage: A 13%, B1 11%, C1 32%, B2-3 37%, C2-3 56%
** Recurrence by location/stage: right (0%, 9%, 33%, 28%, 43%), transverse/left (too few), sigmoid (11%, 15%, 40%, 52%, 62%), rectum (29%, 14%, 40%, 46%, 60%)

## Post-operative radiotherapy

Randomized
* Intergroup 0130 (1992-96) - chemo vs chemo + RT
** 187 pts. Randomized Phase III. Resected pts with: 1) T4 (any site), or 2) T3N+ (of ascending or descending colon only). Trial closed due to poor accrual (goal of 700 pts).
** PMID 15249584, 2004 — "Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130." Martenson JA Jr et al. J Clin Oncol. 2004 Aug 15;22(16):3277-83.
*** 5-yr OS 62% (chemo) vs 58% (chemo/RT), NS. No difference in 5-yr DFS 51% vs 51%.
** Comments: Lots of issues - End point survival without looking at local control, RT fields included para-aortic LNs, not sufficient power (accrued 25% patients), high number of ineligible patients (15%), broad eligibility criteria (including low risk T3N1), chemotherapy now outdated, inability in many patients to determine tumor location (no preop imaging, no surgical clips), radial margins often not examined on pathology
Retrospective
* MGH
** 1999 PMID 10439171 -- "Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer?" (Willett CG, Cancer J Sci Am. 1999 Jul-Aug;5(4):242-7.)
*** Retrospective. 152 patients with T4, treated with post-op RT +/- 5FU. 110 had R0, 42 had residual tumor
*** T4N1: 10-year LC 88%, DFS 58%; if more than 1 LN worse outcome
*** T4 and perforation/fistula: LC 81%, DFS 53%
*** R+: DFS 19%
*** Conclusion: compared to historical controls, RT should be considered for 1) invasion of adjoining structures, 2) associated perforation or fistula, or 3) residual disease
** 1993 (1976-1989) PMID 8501497 -- "Postoperative radiation therapy for high-risk colon carcinoma." (Willett CG, J Clin Oncol. 1993 Jun;11(6):1112-7.)
*** Retrospective. 203 post-op RT +/- 5-FU after resection of B2-3 or C2-3 colon. 15% residual disease. Compared to 395 historical control undergoing surgery only
*** Improvement after RT in: 1) B3 and C3, 2) associated abscess or fistula, 3) residual local disease after subtotal resection
* Mayo, 1997 (1974-1994) PMID 9054876 -- "The treatment of locally advanced colon cancer." (Schild SE, Int J Radiat Oncol Biol Phys. 1997 Jan 1;37(1):51-8.)
** Retrospective. 103 patients with locally advanced colon CA, 40 R0, 18 R1, 35 R2. Median F/U 5.8 years
** EBRT given 1-4 after resection to tumor bed + LNs 16-60 Gy; IORT to 11 patients. Chemo 77 patients
** 5-year LR: 10% R0, 54% R1, 79% R2 (SS); 5-year OS: 66% R0, 47% R1, 23% R2 (SS)
** IORT: LR IORT 11% vs. EBRT only 82% (SS); 5-year OS: IORT 76% vs. EBRT only 26%
** Conclusion: In locally advanced colon, high probability of local control with EBRT +/- 5-FU. IORT improves control with residual disease
* West Florida, 1996 PMID 8876884 -- "Postoperative radiotherapy for locally advanced colon cancer." (Amos EH, Ann Surg Oncol. 1996 Sep;3(5):431-6.)
** Retrospective. 78 patients with complete resection of B2-C colon CA. 28 patients RT <=45 Gy, 50 patients RT 50-55 Gy. 27 patients 5-FU. Minimum F/U 3 years
** LR: 12%; RT <45 Gy 24% vs. RT 50-55 4% (SS)
** Side effects: bowel obstruction 3 patients, sarcoma 1 patient
** Conclusion: PORT improves risk of LR in locally advanced colon CA
** Editorial: PMID 8876882 -- "Postoperative radiotherapy for locally advanced colon cancer." (Janjan NA, Ann Surg Oncol. 1996 Sep;3(5):421-2.)
IORT
* Mayo, 1997 (1981-1995) PMID 9112459 -- "Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU." (Gunderson LL, Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):601-14.)
** Retrospective. 61 patients treated with surgery, IORT 10-20 Gy, usually with EBRT 45-55 Gy +/- 5-FU. Residual disease at IORT unresected 1, gross 16, microscopic/negative 39
** Failure: in-field 25% in gross vs. 5% in microscopic/negative
** Conclusion: OS and disease control improved with IORT
Adjuvant liver chemo-RT
* GITSG, 1991 PMID 1938512 -- "Adjuvant therapy with hepatic irradiation plus fluorouracil in colon carcinoma. The Gastrointestinal Tumor Study Group." (No Authors, Int J Radiat Oncol Biol Phys. 1991 Oct;21(5):1151-6.)
** Randomized. 300 patients. Curative resection of transmural or N+ colon cancer, treated with 1) observation or 2) 5-FU + 21Gy to liver
** No benefit; liver recurrence rate same

## Adjuvant chemotherapy
### Regimens

(Note: This section is intended to highlight some of the common chemotherapy regimens used today, but an in-depth discussion of chemotherapy should be reserved for a Medical Oncology textbook)
Chemotherapy is recommended for all Stage III (i.e. node-positive) patients. Some stage II (T3-4 N0) patients may also benefit, but the treatment is made on a case-by-case basis.
* Mayo Regimen (5-FU/LV)
** 5-FU, 425 mg/m2/d IV days 1-5. LV 20 mg/m2/d IV days 1-5. Repeat q28d x 6 cycles.
* Roswell Park (5-FU/LV)
** 5-FU, 500 mg/m2/d IV weekly x 6. LV 500 mg/m2/d IV weekly x 6. Repeat q8w x 4 cycles.
* FOLFOX 4 (5-FU/LV/Oxaliplatin)
** Oxaliplatin, 85 mg/m2 IV day 1. LV, 200 mg/m2/day IV days 1-2. 5-FU, 400 mg/m2/day IV days 1-2. 5-FU, 600 mg/m2/day CI over 22 h, days 1-2. Repeat q14d x 12 cycles.
* IFL (bolus 5-FU/LV/Irinotecan) - not used, excess mortality from increased toxicity
* FOLFIRI (infusional 5-FU/LV/Irinotecan)
* Xeloda (capecitabine)
** 1250 mg/m2 BID x 14 days. Repeat q21d x 8 cycles.

### Trials

See: NSABP Colon trials
* CALGB 89803
** Randomized. 1264 patients with completely resected Stage III colon CA. Treated with weekly bolus 5-FU/Leukovorin +/- irinotecan
** 2007 PMID 17687149 -- "Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803." (Saltz LB, J Clin Oncol. 2007 Aug 10;25(23):3456-61.)
*** Outcome: No difference in DFS or OS
*** Toxicity: Significantly higher in 5-FU/LV/Irinotecan arm
*** Conclusion: Addition of irinotecan not beneficial in completely resected Stage III
* NSABP C-01 (1977-83)
** 1166 pts. Dukes B and C. Randomized after curative resection to 1) chemotherapy with 5-FU, semustine, and vincristine, 2) BCG, or 3) no further treatment.
** First report: PMID 3276901 (1988)
*** Showed increase in DFS and survival for chemotherapy. Increased survival but not DFS for BCG (due to decrease in non-cancer related deaths)
** 10-year results: PMID 15292384 (2004)
*** No difference in DFS or survival for chemotherapy group. Decrease in non-cancer related deaths for BCG.
** Conclusion: DFS benefit for chemotherapy disappears by 10 years.

## Pelvic Recurrence

* Mayo, 2001 (1981-1994) PMID 11286833 -- "Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients." (Haddock MG, Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1267-74.)
** Retrospective. 51 patients. Salvage surgery + IORT after prior EBRT. IORT 20 Gy (10-30) + in 37 patients EBRT median 25 Gy + 20 patients 5-FU
** Median OS: 23 months; 2-year OS 48%
** 2-year LR: 40%; trend to improvement if IORT + EBRT >30 Gy (LR 19%). 2-year DM: 56%
** Side effects: peripheral neuropathy related to IORT (32% patients); ureteral narrowing/obstruction
** Conclusion: local control can be obtained, but survival poor due to distant mets
* MD Anderson, 1996 PMID 8597512 -- "Preoperative infusional chemoradiation, selective intraoperative radiation, and resection for locally advanced pelvic recurrence of colorectal adenocarcinoma." (Lowy AM, Ann Surg. 1996 Feb;223(2):177-85.)
** Prospective. 43 patients with locally advanced pelvic recurrence of CRC. Treated with RT 45 Gy + C.I. 5-FU and/or cisplatin, followed by surgery + IORT 10-20 Gy or BT. Median F/U 26 months
** 40 patients underwent surgery, 77% with curative intent. 88% SM-, 48% sphincter-preserving
** Side effects: 51%
** LR rate: 36%, 5-year OS: 58%
** Conclusion: Preop CRT can increase resectability and enable sphincter preservation

## Chemotherapy for metastatic disease

Randomized trials for first-line therapy
* BICC-C -- Irinotecan-based regimens
** Randomized. 430 patients. Arm 1) FOLFIRI (infusional 5-FU, leucovorin, irinotecan) vs. Arm 2) mIFL (bolus 5-FU, leucovorin, irinotecan) vs. Arm 3) CapeIRI (capecitabine, irinotecan). Concurrently +/- celecoxib. After amendment, dropped Arm 3. Then additional 117 patients randomized to bevacizumab: FOLFIRI-Bev or mILF-Bev. Primary endpoint PFS
** 2007 PMID 17947725 -- "Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study." (Fuchs CS, J Clin Oncol. 2007 Oct 20;25(30):4779-86.)
*** Outcome: PFS FOLFIRI 7.6 month vs. mIFL 5.9 months (SS) vs. CapeIRI (SS).
*** Secondary: FOLFIRI-Bev no median reached yet vs. mIFL-Bev 19.2 (SS)
*** Conclusion: FOLFIRI and FOLFIRI-Bev better than their comparators
* SGO -- XELOX vs. FUOX
** Randomized. 348 patients. Arm 1) XELOX (oral capecitabine 1,000 mg/m2 bid for 14 days plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks) vs. Arm 2) FUOX (continuous-infusion FU 2,250 mg/m2 during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks)
** 2007 PMID 17548839 -- "Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. (Diaz-Rubio E, J Clin Oncol. 2007 Sep 20;25(27):4224-30.)
*** Outcome: median TTP 9 months (NS), median OS 18 vs. 21 months (NS)
*** Toxicity: comparable
*** Conclusion: XELOX is an alternative to FUOX
* AIO -- CAPOX vs. FUFOX
** Randomized. 474 patients, first line therapy. Arm 1) CAPOX (capecitabine 1,000 mg/m2 bid, days 1 to 14 plus oxaliplatin 70 mg/m2 days 1 and 8, repeated every 22 days) vs. Arm 2) FUFOX (oxaliplatin 50 mg/m2 followed by leucovorin 500 mg/m2 plus FU 2,000 mg/m2 as a 22-hour infusion days 1, 8, 15, and 22, repeated every 36 days). Primary end point: PFS
** 2007 PMID 17548840 -- "Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group." (Porschen R, J Clin Oncol. 2007 Sep 20;25(27):4217-23.) ***Outcome: median PFS CAPOX 7 months vs. FUFOX 8 months (NS); median OS 17 months vs. 19 months (NS)
*** Toxicity: CAPOX higher Grade 2-3 hand-foot syndrome
*** Conclusion: CAPOX slightly worse efficacy and toxicity than FUFOX
* GONO Trial -- FOLFOXIRI vs. FOLFIRI"
** Randomized. 244 patients, unresectable metastatic CRC, no prior chemo for advanced disease. Treated with 1) FOLFOXIRI (irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks) vs. FOLFIRI (infusional fluorouracil, leucovorin, and irinotecan). Primary end-point response rate (RR)
** 2007 PMID 17470860 -- "Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest." (Falcone A, J Clin Oncol. 2007 May 1;25(13):1670-6.)
*** Toxicity: Grade 2-3 neurotoxicity 19% vs. 0% (SS), Grade 3-4 neutropenia (50% vs. 28%, SS)
*** Response rate: 66% vs. 41% (SS); better R0 secondary resection rate of mets
*** Outcome: median PFS 9.8 months vs. 6.9 months (SS); median OS 22.6 months vs. 16.7 months (SS)
** Conclusion: FOLFOXIRI improves RR, PFS, and OS with manageable toxicity

## Familial syndromes

* Familial adenomatous polyposis (FAP)
** Adenomatous polyposis coli (APC) gene (5q21) - gatekeeper (controls other downstream genes).
** 100% progress to carcinoma, most by age 30, often in teens. 100s-1000s of polyps. Other malignancies: thyroid, GB, adrenal. image
* Cowden's syndrome
** Autosomal dominant with facial tricholemmomas, acral keratoses, oral mucosal papillomas, colorectal polyps. Patients have increased risk of malignancy (breast and thyroid cancer), but not in polyps.
* Gardner syndrome
** Colonic adenomatous polyps plus multiple osteomas (skull, mandible, long bones), epidermal cysts, fibromatosis (usually intraabdominal after surgery), fibromas, lipomas, impacted and supernumerary teeth, dental cysts, lymphoid polyps in small intestine and fundic gland polyps in stomach. 100% develop colon cancer. Other malignancies: periampullary, thyroid, adrenal.
** Mutation in APC gene but has variable penetrance so not all extracolonic features are present.
* Lynch syndrome (HNPCC)
** Most common hereditary colon syndrome (but less than 5% of carcinomas). Dominant. Type 1 - 50% risk of colon ca in relatives. Type 2 - also with endometrial ca, cholangiocarcinoma. Favorable clinical course (increased survival, respond better to chemo).
** Criteria: 3 colon cancers in which 2 people are first-degree relatives of the third. Cancer in 2 generations. One diagnosis before age 50. No evidence of FAP.
** Average age of developing cancer: 45 years (vs 63)
** Screening: full colonoscopy q3y beginning age 20-25; annual endometrial screening age 25-35;