# Radiation Oncology/Rectum/Overview

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## Epidemiology

* 40,000 cases annually in US
* Equal distribution among males and females
* Median age 7th decade
* Dietary risk: high fat, low residue, low antioxidants
* Presentation: BRBPR or change in BM, also narrowing of stools, pain
* Histology: adenocarcinoma

## Anatomy

* Squamous mucosa ends at dentate line, approximately 2 cm above anal verge
* Internal anal sphincter muscles end another 3 cm cephalad, approximately 5 cm above anal verge
Relations to peritoneum: (see also at Colon)
* 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
Margins and gross anatomy:
* Margins to assess:
** For tumor above the anterior peritoneal reflection: serosal margin and radial margin
** For tumor below the anterior reflection: circumferential radial margin
* see Cancer Care Ontario: Rectal Cancer Grossing Guideline
** Images of mesorectal excision, showing:
*** 1) Anterior surface and posterior surface of rectal specimen, denoting peritoneal reflection and mesorectum. The peritoneal reflection is low anteriorly, high posteriorly. The resection margin of the mesorectum is non-circumferential above the reflection and is circumferential (the CRM) below the reflection.
*** 2) Cancers that are located below the posterior peritoneal reflection but above the anterior reflection have a serosal margin anteriorly as well as a non-circumferential radial margin posteriorly. Cancers below the anterior reflection have a circumferential resection margin (CRM).
Nodal drainage:
* At risk - internal iliac, presacral
** Include external iliac if tumor invades bladder, vagina, prostate, or cervix
** Include inguinal nodes if tumor extends to or is caudal to the dentate line

## Recurrence patterns

* 1 - Presacral space
* 2 - Anastomosis, or perineum if APR
* 3 - Pelvis, including posterior wall of bladder
* <10% involve common illiac or paraaortic LNs
* Metastatic - liver and lung. Inguinal LNs uncommon
Locoregional and Total Failures :
| Stage N0 | LR | TR | Stage N+ | LR | TR |
| T1-2N0 | 10% | 15% | T1-2N+ | 50% | 70% |
| T3N0 | 25% | 40% | T3N+ | 40% | 70% |
| T4N0 | 50% | 70% | T4N+ | N/A | N/A |
TME excision may result in significantly lower LR (<10%)
Prevention of local recurrence is a major goal of radiotherapy

## Prognostic factors

Adjuvant treatment:
* Gunderson pooled analyses
** PMID 12243812, 2002 — "Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: a pooled analysis." Gunderson LL et al. Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):386-96.
** PMID 15067027, 2004 — "Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis." Gunderson LL et al. J Clin Oncol. 2004 May 15;22(10):1785-96.
** Data pooled from several trials. Found 3 risk groups: intermediate (T1-2/N1, T3/N0), moderately high (T1-2/N2, T3/N1, T4/N0), high (T3/N2, T4/N1, T4/N2). For int risk, results of surgery+CT similar to surgery+RT/CT.

## Patterns of failure

* Memorial Hospital (NY), 1984 (1968–76) - PMID 6692324 — "Patterns of pelvic recurrence following definitive resections of rectal cancer." Pilipshen SJ et al. Cancer. 1984 Mar 15;53(6):1354-62.
** 412 pts s/p APR or LAR. Evaluated first site of recurrence.
** 182 recurrences (44.2%), of which 105/182 were pelvic (57.6%), with 55/103(?) pelvic as the only recurrence or 50/79 with pelvic recurrence as the predominant component with extra-pelvic failure also present.
** Pelvic recurrence rate 29.7% for B2 (T4N0) and 22.1% for C1 (T1-2N1), higher still for C2(T3-4N1).
Local failure after surgery:
* PMID 6192900 (1983, Rich T et al., Mass.General)
** 8% Dukes' A, 31% Dukes' B, 50% Dukes' C. For stage II, 17% for microscopic extension beyond the wall (MAC-B2m) vs 54% invading other organs (MAC-B3). For Stage III, 36% if confined to wall or with microscopic extension (MAC-C1/C2m) vs 67% MAC-C3.
* PMID 6863077, 1983 (U.Florida) — "Patterns of recurrence in adenocarcinoma of the rectum and rectosigmoid treated with surgery alone: implications in treatment planning with adjuvant radiation therapy." Mendenhall WM et al. Int J Radiat Oncol Biol Phys. 1983 Jul;9(7):977-85.

## Treatment overview

Guidelines:
* Pre-op T1-2N0: treat with primary surgery.
** If N+ or pT3 on pathology then adjuvant chemo-RT
* Pre-op T3 or N+: treat with pre-op chemo-RT followed by surgery, then adjuvant 5-FU/LV or FOLFOX
* Metastatic (resectable): chemo-RT or chemo alone, followed by resection of rectal tumor and mets
* Metastatic (unresectable): enroll on protocol
Historical Overview:
* Initially, rectal cancer was treated with surgery alone, but high cure rates were observed only in early (T1-T2N0) stages. Local recurrence rates in advanced T3-4N0 or N+ were on average 30%.
* Addition of post-op RT improved 5-year local recurrence by 35% (15% vs. 23%) in an 8 trial meta-analysis, but did not impact disease-free survival, distant mets, or overall survival
* In the post-op setting, combined RT with concurrent 5-FU improved local control, distant mets, and overall survival. Continuous infusion 5-FU is superior in overall survival over bolus 5-FU
* However, many patients who need radiation and chemotherapy cannot receive it postoperatively, therefore interest grew in preoperative chemoradiation therapy.
* There is no significant survival difference between preoperative and postoperative RT with chemotherapy. Sauer and the German Rectal Cancer Study Group demonstrated a greater chance of sparing the anal sphinter and fewer side effects with preoperative chemoradiation.
* Therefore, many centers consider preoperative chemoradiation the standard of care in the treatment of T3-4, N1-2, rectal cancer.
* The debate continues, however... to be continued

## Surgical principles

* 85-90% of patients with newly diagnosed rectal CA are technically resectable with:
** Transanal excision for select small T1 tumors (see below).
** APR (abdominoperineal resection)
** LAR (low anterior resection)
** TME (total mesorectal excision) reduces rate of positive radial margins
* In the West, extended lymph node dissection not necessary if clinically negative nodes. Should have at least 14 LN to be considered N0.
* In Japan, lateral lymph node dissection with pelvic autonomic nerve preservation (LLND + PANP) is becoming more popular. Complete PANP is defined as complete preservation of the superior hypogastric plexus, the hypogastric nerves, the sacral nerves, and the pelvic plexuses
Local recurrence rates:
* "Standard" surgery - >20% failure rate (average of randomized prospective trials with surgery only as control arm was 29%)
* Lower figures can be achieved with dedicated well-trained surgeons, and more extensive resection (which of course carries greater surgical mortality)

### Transanal Excision

* Per NCCN v1.2010
** T1 only
** <30% circumference
** <3 cm size
** SM- (>3 mm)
** Mobile (nonfixed)
** Within 8 cm of anal verge
** No LVI+ or PNI+
** No Grade 3
* If found to have high risk features (e.g. T2, SM+, LVI+, Grade 3), need to do full transabdominal resection. If further high risk features (e.g. T3, N+) then adjuvant chemo-RT
* RTOG 89-02 (1989–1992) PMID 10661337 -- "Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02." (Russell AH, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):313-22.)
** Phase II. 65 patients with distal rectal CA, felt to be unsuitable for sphincter-preservation with LAR and requiring APR, <=4 cm diameter, <=40% of rectal circumference, below peritoneal reflection. Local excision using trans-anal or trans-sacral approach, with anal sphincter conservation. Based on T-size, grade and SM, assigned to observation vs 5-FU with RT 50-56 Gy vs. 5-FU with RT 59.4-65 Gy. Median F/U 6.1 years
** Outcome: Local failure (after surgery + adapted chemo-RT) by T-stage: T1 0%, T2 20%, T3 23%. Loco-regional failure 12%. By T-stage: T1 4%, T2 16%, T3 23%. By circumference: <20% 6%, 20-40% 18%. Distant mets 12% (T1 4%, T2 12%, T3 31%). 5-year pelvic control 88%.
** Conclusion: Conservative sphincter-sparing therapy is feasible, but relatively high local failure rate for T2 and T3 lesions
* CALGB 8984 (1990–1995) PMID 18536973 -- "Local excision of distal rectal cancer: an update of cancer and leukemia group B 8984" (Greenberg JH, et al. Dis Colon Rectum. 2008 Aug;51(8):1185-91; discussion 1191–4. Epub 2008 Jun 7.)
** Phase II. 110 patients with rectal lesions < 10 cm from dentate line, < 4 cm diameter, < 40% rectal circumference, and negative margins were included (Note no EUS or MRI). 59 patients found with T1 lesions were treated with local excision alone. 51 Pts found with T2 lesions treated with local excision plus adjuvant radiation (54Gy) + 5-FU (500 mg/m2 intravenously Days 1–3, Days 29–31).
** Outcome: Ten year rates of OS 84% vs 66% (T1 vs T2). DFS 75% vs 64%. LR 8% vs 18%
** Conclusion: Conservative sphincter-sparing therapy is feasible for well selected T1 lesions, but T2 lesions have relatively high LR even with adjuvant ChemoXRT.

### TME

* PMID 7551328, 1995 — "Total mesorectal excision in the operative treatment of carcinoma of the rectum." Enker WE et al. J Am Coll Surg. 1995 Oct;181(4):335-46.
** 246 pts, T3N0 or T(any)N+ treated by TME. At 5 yrs, pelvic recurrence 4% for Dukes' B and 8% for Dukes' C. Risk factors for recurrence were N2 disease and perineural invasion. Adjuvant RT did not prevent LR.
* PMID 9711965, 1998 (1978–97) — "Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997." Heald RJ et al. Arch Surg. 1998 Aug;133(8):894-9.
** DFS 78% at 10 yrs.

### Laparoscopic

* National Taiwan University (1997–1999) -- medial-to-lateral vs lateral-to-medial laparoscopic dissection
** Randomized. 67 patients, rectosigmoid cancer, single surgeon performing laparoscopic dissection. Arm 1) medial-to-lateral dissection vs Arm 2) lateral-to-medial dissection
** 2003 PMID 12616435 -- "Comparison of medial-to-lateral versus traditional lateral-to-medial laparoscopic dissection sequences for resection of rectosigmoid cancers: randomized controlled clinical trial." (Liang JT, World J Surg. 2003 Feb;27(2):190-6.)
*** Outcome: No difference in LN harvest, intraop complications, conversion rate, postop complications, or disability. Improved OR time, C-RP and ESR in medial group
*** Conclusion: Medial-to-lateral dissection may be most appropriate for laparoscopic rectection of rectosigmoid cancers

## Intraoperative RT (IORT)

* Kyorin University; 2008 (2000–2007) PMID 18172677 -- "Intraoperative radiotherapy for oncological and function-preserving surgery in patients with advanced lower rectal cancer." (Masaki T, Langenbecks Arch Surg. 2008 Jan 3 [Epub ahead of print])
** Randomized. 41 patients with advanced lower rectal CA. Arm 1) TME + bilateral lateral LND + limited PANP vs. Arm 2) TME + bilateral lateral LND + complete PANP + IORT to preserved pelvic nerve plexuses
** Outcome: No difference in LR, DFS, OS. Improved time with indwelling catheter and voiding function
** Conclusion: Complete pelvic autonomic nerve preservation with IORT may be useful

## Radiation technique

Radiation fields: Generally 45 Gy to pelvis using 4-field box followed by boost of 5.4 - 9 Gy, to bring total dose to 50.4-54 Gy.
* AP/PA - Superior border at L5/S1 junction or mid L5 body. Inferior border depends on surgical technique: After APR, include perineum with 1.5 cm margin. After LAR, place border 3–5 cm below anastomosis. For pre-op RT, 4 cm inferior to tumor extent or to anal verge. 2 cm lateral to bony pelvis.
* Laterals - Posterior border 1.5–2 cm behind anterior edge of sacrum (or 1 cm behind sacrum if T4 tumor). Anterior border should cover internal iliac LNs (generally placed 2–3 cm anterior to sacrum promontory, includes 2/3 of femoral heads). At least 3 cm margin on tumor.
CTV delineation
* Leuven; 2006 PMID 16750329 -- "Definition and delineation of the clinical target volume for rectal cancer." (Roels S, Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1129-42. Epub 2006 Jun 5.)
** Guidelines for CTV delineation for pelvic subsites and LN groups at risk
Elective para-aortic irradiation
* EORTC 1983-1992 PMID 11578723 -- "Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group." (Bosset JF, Radiother Oncol. 2001 Oct;61(1):7-13.)
** Randomized. 484 patients with Gunderson-Sosin (modified Aster-Coller) stages B2-B3, C1-C3, age <70. Treated with 1) pelvic RT 50/25 (Lim-RT) vs 2) extended RT to pelvic RT (50/25) plus para-aortic LNs and liver to 25 Gy in 19 fractions (Ext-RT)
** 10-year intrapelvic failure: ~30% in both. 10-year DFS: 31% in both. 10-year OS: 40% vs. 37% (NS)
** Conclusion: Low dose RT to para-aortic nodes and liver doesn't help

## Radiotherapy and inflammatory bowel disease

* Mt. Sinai, 1999 (1960–94) - PMID 10386640 — "Rectal cancer and inflammatory bowel disease: natural history and implications for radiation therapy." Green S et al. Int J Radiat Oncol Biol Phys. 1999 Jul 1;44(4):835-40.
** Retrospective. 47 pts with IBD (35 with ulcerative colitis and 12 with Crohn's) and rectal cancer. Most were treated with RT in an adjuvant fashion.
** Grade 3 or higher acute complications in 20%. 13% developed small bowel obstruction.
** Conclusion: Treatment results are comparable to those with pts treated with non-IBD rectal cancer.

## Non-surgical treatment

Primary radiotherapy or chemoradiotherapy for medically inoperable pts or pts who refuse surgery
* Australia, 2007 (1998–2005)- PMID 17896138 — "Long-Term Outcomes of Patients with Localized Rectal Cancer Treated with Chemoradiation or Radiotherapy Alone Because of Medical Inoperability or Patient Refusal." Lim L et al. Dis Colon Rectum. 2007 Sep 26 [Epub ahead of print]
** 48 pts (50% medically inoperable, 50% refused surgery). ChemoRT in 36 pts, RT alone in 12.
** Median f/u 49 mo. 18 pts w/ disease progression. 16 pts dead with disease, 9 dead from other causes.
** Chemo/RT or RT results in good PFS and OS times in pts who do not undergo surgery. Many pts, however, progress.
* Princess Margaret, 1995 (1978–87) - PMID 7836077 -- "Adenocarcinoma of the rectum treated by radical external radiation therapy." (Brierley JD, Int J Radiat Oncol Biol Phys. 1995 Jan 15;31(2):255-9.)
** 229 pts, medically unfit or refused surgery. Various RT regimens; most commonly 52 Gy in 20 fx. No chemo-RT.
** Pt population: Tumor was mobile: 97, partially fixed: 37, fixed: 77, unknown: 18.
** Mean f/u 5.8 yrs. 5 yr OS 27% (OS for pts with mobile tumors: 48%, partially fixed: 27%, fixed: 4%). cCR in 50% / 30% / 9% (mobile / p.fixed / fixed). Time to cCR 3–6 months (from start of RT). Local failure: 69% / 87% / 97%. 50 pts had salvage surgery.
** Conclusion: RT can cure some pts with mobile or partially fixed tumors, although local failure is common
Non-surgical treatment strategy in operable patients
* Netherlands, 2011 - No PMID yet Abstract -- "Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer" (Maas M, J Clin Oncol Published online before print November 7, 2011.)
** Pts with a clinical CR after neoadjuvant chemo-RT were selected for close observation rather than surgery. Compared this patients with a cohort of pts with a pCR after chemo-RT.
** 21 pts had cCR after chemo-RT (11% of pts). Mean f/u 25 months. 20 of 21 pts alive without disease; 1 pt had LR, with surgical salvage.
** Conclusion: a wait-and-see policy for patients achieving a CR is feasible, and early results suggest the outcome is favorable
* Brazil (São Paulo), 2004 (1991–2002) - PMID 15383798 -- "Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results." (Habr-Gama A, Ann Surg. 2004 Oct;240(4):711-7)
** 265 pts with resectable distal rectal ca (within 7 cm of the anal verge) received 50.4 Gy + 5-FU/LV. Those with clinical complete response at 8 weeks (with negative biopsy) were not immediately operated on but had intensive follow-up; while those with incomplete response had surgery. Compared the patients with complete clinical response (non-operative treatment) vs those with initial incomplete response who had complete pathologic response at the time of surgery. Neither group received adjuvant chemotherapy. Preop staging: T3-T4 in 80-95%, N+ in 22-27%.
** Patients must have had a sustained complete response for 12 months to be considered "stage 0" and in the observation group.
** 71 pts had cCR (26.8%) and formed the Observation group, whereas 194 made up the incomplete responders. 22 pts (8.3%) of the incomplete responders had pCR at the time of surgery and made up the Resection group.
** For all 93 pts (35%) with "stage 0" (OB group + R group), 10-yr OS and DFS 97% and 84%; no significant difference between groups; local recurrence in 2 pts
** Conclusion: "Stage 0" rectal cancer (pCR or cCR after chemo-RT) is associated with excellent long-term results irrespective of treatment strategy.

## Squamous cell carcinoma

* MSKCC; 2007 (1983–2005) PMID 17661147 -- "Squamous-cell carcinoma of the rectum: a rare but curable tumor." (Nahas CS, Dis Colon Rectum. 2007 Sep;50(9):1393-400.)
** 12 pts. Treated with chemotherapy only (n=1), chemo/RT (n=2), induction chemo then chemo/RT and surgery (n=2), chemo/RT then surgery (n=5), surgery then chemo/RT (n=2). (Surgery in 9 of 12). RT 50.4 Gy.
** Of those treated with upfront chemo and/or RT (n=10): 2 had CR with chemo/RT and did not receive surgery; 7 partial responders went on to have surgery and 6 of 7 had pCR.
** All pts alive and NED at median f/u 2.6 yr.
** Conclusion: "Our data suggest that most patients treated with upfront chemoradiation therapy followed by surgery did well. Sphincter-preserving surgery is usually feasible. Clinical judgment of tumor response after chemoradiation is not completely reliable. Immunohistochemistry suggests a common cellular origin for rectal squamous-cell carcinoma and rectal adenocarcinoma, which is different from anal squamous-cell carcinoma."

## Follow-up exams

Per NCCN guidelines, physical exam every 3 months for 2 years then every 6m for 5 yrs total; CEA every 3 months (same as physical exam) if T2 or greater; CT scan if at high risk for recurrence (perineural invasion, lymphovascular invasion, poorly differentiated); colonoscopy in 1 year, then repeat at least every 2–3 years.

## Other Resources

* ASTRO/ARRO Journal Club Webinar 2011 - "The Changing Management of Rectal Cancer" with Christopher Willett, MD