Treatment/Prognosis

Question 1

What is the Tx paradigm for nonmet rectal cancer?

Answer 1

Nonmet rectal cancer Tx paradigm: in general, T1–2N0 rectal cancer pts get upfront Sg +/– adj CRT, whereas T3–4 or N+ pts may rcv neoadj CRT → Sg and adj 5-FU/leucovorin or FOLFOX. Total neoadjuvant therapy (TNT), which involves delivering all chemo & CRT before Sg, is gaining in prevalence.

Question 2

What are the surgical options for rectal cancer pts?

Answer 2

The surgical options for rectal cancer include transanal excision (local excision), or transabdominal resection (APR for low-lying lesions, or low anterior resection (LAR) for mid/upper-lying lesions).

Question 3

What are the criteria for transanal excision alone in rectal cancer? On what 2 studies is this based?

Answer 3

The criteria for transanal excision alone in rectal cancer include T1 lesion, <3-cm tumor that is superficial (<3 mm submucosal depth), lesion involving ≤1/3 of rectal circumference, N0 by EUS or MRI, low-grade tumor/no LVI, –margins, and reliable pt.

CALGB 89-84 (Steele GD et al., Ann Surg Oncol 1999; update Greenberg J et al., Dis Col Rectum 2008): phases I–II intergroup trial that treated all T1 or T2 Dz with local excision. Eligibility: tumor ≤4 cm, ≤10 cm from dentate line, ≤40% bowel circumference, and ≥2-mm-deep margin. T1 Dz had Sg alone, and T2 Dz all rcvd adj CRT to 54 Gy. 10-yr OS was 78% (T1) and 75% (T2), and 10-yr LF was 8% (T1) and 18% (T2). Therefore, even with adj CRT T2 lesions treated via local excision are associated with high recurrence rates.

RTOG 82-02 (Russell AH et al., IJROBP 2000): similar eligibility criteria as CALGB 89-84, phase II, all transanal excision. T1 lesions ≤3 cm, ≥3-mm margins, well to moderately differentiated tumors, no LVI; normal CEA levels were observed after Sg. Pts with T1 with poor-risk features and all T2–3N0 pts rcvd adj CRT (5-FU). 5-yr OS was 78%, with LF rates of 4% (T1), 16% (T2), and 23% (T3).

Question 4

For pts who cannot have a definitive transabdominal resection, what are the indications for adj CRT after transanal excision of rectal cancer?

Answer 4

For pts who cannot have a definitive transabdominal resection, adj CRT alone should be administered to pts with a high-risk T1 lesion after local excision (poorly differentiated, with bad histologies, margins <3 mm, >3-cm size, and +LVSI); all T2 cancers after local excision; and for all T3–4 or N+ cancers after LAR or APR. Low-risk T1 tumors after local excision do not need adj therapy.

Question 5

What definitive transabdominal surgical approach for rectal cancer permits sphincter preservation?

Answer 5

LAR spares the sphincter and is therefore a preferred surgical option (if feasible) for rectal cancer pts; in contrast, APR requires a colostomy.

Question 6

What is the approximate LR rate for T3–4 or N1 rectal cancer after Sg alone?

Answer 6

The historic LR rate for T3–4 or N1 rectal cancer is ~25%. This is improved with better Sg (i.e., total mesorectal excision [TME], 10-yr LR 11% [van Gijn W et al., Lancet Oncol 2011]).

Question 7

What is the significance of a positive circumferential margin at the time of Sg for rectal cancer?

Answer 7

A positive circumferential margin predicts for inf LC, DM, and OS rates after Sg for rectal cancer based on meta-analysis. (Nagtegaal ID et al., JCO 2008)

Question 8

What kind of surgical technique is currently standard in the surgical management of rectal cancer? Why is this important?

Answer 8

TME is a standard surgical technique in the operative management of rectal cancer and is carried out with LAR or APR. It helps reduce the rate of positive radial margins and improves LC.

Question 9

What are the indications for adj CRT after definitive transabdominal resection for rectal cancer?

Answer 9

After a definitive transabdominal resection (LAR or APR—TME or non-TME based) for rectal cancer, adj CRT is indicated if the pathology is N+ or ≥T3.

Question 10

What are some options for rectal cancer pts with solitary or oligometastatic Dz to the liver that is resectable?

Answer 10

Surgical resection of the metastatic site is the only modality with proven survival benefit, although SBRT may be considered if surgery is declined. How these cases should be managed needs to be determined on a case-by-case basis in a multidisciplinary setting. Some options for oligometastatic (resectable) rectal cancer include:

Question 11

What are the most commonly used sensitizing chemo regimens given with RT for rectal cancer?

Answer 11

Continuous infusion (CI) 5-FU (225–250 mg/m2/day) or capecitabine (Xeloda) 825 mg/m2 bid 5–7 days/wk are commonly used sensitizing chemo regimens.

Question 12

What did NSABP-04 show regarding the addition of oxaliplatin to preop CRT?

Answer 12

NSABP-04 randomly assigned clinical stage II or III rectal cancer undergoing preop RT (45 Gy in 25 fx over 5 wks + boost of 5.4 Gy–10.8 Gy in 3–6 daily fx) to 1 of 4 chemo regimens in a 2 × 2 design: CI 5-FU (225 mg/m2 5 days/wk), with or without intravenous oxaliplatin (50 mg/m2/wk × 5) or oral Cape (825 mg/m2 bid 5 days/wk), with or without oxaliplatin (50 mg/m2/wk × 5). There was no difference in LRF, pCR, DFS, or OS. However, oxaliplatin added significant grade 3–4 GI toxicity, and is therefore not indicated in combination with RT in the preop setting (p < 0.0001). Additionally, this trial establishes capecitabine as another standard of care option along with CI 5-FU in the preop setting. (Allegra CJ et al., JNCI 2015)

Question 13

What are the data addressing adj RT alone in rectal cancer, and what do they show?

Answer 13

There are many RCTs (e.g., MRC 3, NSABP R-01) that investigated adj RT alone, showing improvement in LC only but no improvement in OS, DFS, or MFS); this was confirmed by a meta-analysis. (CCCG, Lancet 2001)

Question 14

What major studies established a role for adj CRT in rectal cancer?

Answer 14

Gastro-Intestinal Study Group (GITSG) 7175 (GITSG collaborators, NEJM 1985; Thomas PR et al., Radiother Oncol 1988) randomized pts after Sg to observation, chemo alone, RT alone, or CRT and found that adj CRT in rectal cancer significantly improved OS (45% vs. 27% at 10 yrs) and LF rates (10% vs. 25%) when c/w Sg alone.

Intergroup/NCCTG 79-47-51 (Krook JE et al., NEJM 1991) randomized stages II–III rectal cancer pts to RT alone or CRT (5-FU × 2 → 5-FU + RT → 5-FU × 2) after Sg (50% APR). 5-yr LR, DM, and OS were better for CRT (LR: 14% vs. 25%; DM: 29% vs. 46%; OS: 55% vs. 45%). There was worse acute grade 3–4 diarrhea (20% vs. 5%) but no late complications for the CRT arm.

Question 15

Which study compared Sg alone with preop RT in rectal cancer? What did it find, and what were its limitations?

Answer 15

The Swedish Rectal Cancer trial (NEJM 1997) compared neoadj RT (25 Gy in 5 fx) to Sg alone in rectal cancer and found a significant improvement in OS (38% vs. 30%) and LR (9% vs. 26%) at 13 yrs with neoadj RT. The trial is often criticized b/c TME was not used and there was a high-recurrence rate for the Sg alone arm (26%).

Question 16

Does the use of TME eliminate the benefit from neoadj RT for rectal cancer?

Answer 16

No. TME does not offset the benefit of neoadj RT based on the Dutch TME study (Peeters KC et al., Ann Surg 2007). The study compared TME alone to neoadj RT and TME and found no OS benefit, but there was an improved LR rate (6% vs. 11%) with the addition of neoadj RT. The NCCTG (N1048) PROSPECT study is investigating whether RT may be omitted for T3N0-1M0 or T2N1M0 patients.

Question 17

What was the RT dose/fx scheme in the Dutch and Swedish rectal cancer studies? How long after the completion of RT do pts go to Sg?

Answer 17

Both the Dutch and Swedish rectal cancer studies used neoadj RT in 25 Gy in 5 fx (5 Gy × 5). Pts typically underwent surgical resection within 1 wk of RT completion.

Question 18

What were the arms in the MRC CR07/NCIC C016 rectal cancer study, and what were its main findings?

Answer 18

The MRC CR07/NCIC C016 rectal cancer study (Sebag-Montefiore D et al., Lancet 2009) randomized pts to preop RT (25 Gy in 5 fx) vs. selective postop CRT (45 Gy in 25 fx) and found better outcomes with preop RT for LR (4% vs. 11%, SS) and DFS (77% vs. 71%, SS). OS was similar at 4-yr f/u. A short neoadj RT course is an acceptable option.

Question 19

Is neoadj short-course RT an acceptable alternative to standard CRT for locally advanced rectal cancer?

Answer 19

Yes. Trans-Tasman Radiation Oncology Group 01.04 randomized locally advanced rectal cancer pts to neoadj short course RT (5 Gy × 5) and early Sg vs. standard CRT (50.4 Gy + 5-FU 225 mg/m2/day) and Sg in 4–6 wks. 3-yr LRR were 7.5% vs. 4.4% (p = 0.24) and 5-yr OS was 74% vs. 70%, respectively. Late toxicity rates were not different. In addition, a recent phase III randomized trial from the Polish Colorectal Study Group found a benefit when pts with fixed T3 or T4 tumors were treated with 5 × 5 Gy and 3 cycles of FOLFOX4 (group A) as opposed to 50.4 Gy in 28 fx combined with bolus 5-FU 325 and leucovorin (oxaliplatin was initially included and then removed in 2012). There was no difference in LR or pathologic CR, but the short course CRT was associated with lower toxicity and improved OS (73% vs. 65%, p = 0.046). (Bujko K et al., Ann Oncol 2016)

Question 20

What is the optimal timing for Sg after short course preop RT?

Answer 20

Although Sg is typically done 1 wk after completion of short course radiotherapy, new randomized data suggests fewer postsurgical complications if Sg is delayed 4–8 wks. The Stockholm III was a phase III randomized, nonblinded, noninferiority trial which compared pts planned for an APR who rcvd either 5 × 5 Gy RT dose with Sg within 1 wk (short-course radiotherapy) or after 4–8 wks (short-course radiotherapy with delay) or 25 × 2 Gy RT dose with Sg after 4–8 wks (long-course radiotherapy with delay). Oncologic results were similar in all 3 groups. Although RT-induced toxicity was seen after short-course radiotherapy with delay, postop complications were significantly reduced c/w short-course radiotherapy (41% vs. 53%, p = 0.001). (Erlandsson J et al., Lancet Oncol 2017)

Question 21

Which major European rectal cancer study compared neoadj CRT to adj CRT and what were its findings?

Answer 21

The German Rectal Cancer trial (Sauer R et al., NEJM 2004) compared preop to postop CRT in T3–4 or N+ rectal cancer (RT was 50.4 Gy for neoadj arm and 55.8 Gy for postop arm with 5-FU chemo [CI 5-FU days 1–5 at 1,000 mg/day, wks 1 and 5]). All pts rcvd 4 additional cycles of bolus 5-FU (500 mg/m2/day, days 1–5, q4wks) at 4 wks after completion of initial therapy. The study found a similar 5-yr OS and DFS b/t the 2 arms but better LR rates (6% vs. 13%), fewer acute (27% vs. 40%) and late toxicities (14% vs. 24%), and better sphincter-preservation rates (39% vs. 19%) in the preop CRT arm. Most of the acute and late toxicities were b/c of acute/chronic diarrhea and anastomotic stricture. A recent update confirmed persistent benefit in LRR (7.1% vs. 10.1%, p = 0.05) with no significant differences in DM rates and DFS. (Sauer R et al., JCO 2012)

Question 22

What is the pathologic CR rate for preop CRT for rectal cancer?

Answer 22

According to the German Rectal Cancer trial, the pCR rate is 8%.

Question 23

What is the pathologic CR rate following TNT for rectal cancer?

Answer 23

The pathologic CR rate with TNT ranges from 14–36%. (Cercek A et al. JAMA Oncology 2018)

Question 24

Does the extent of pathologic response correlate with outcome?

Answer 24

Yes. For example, the neoadjuvant rectal (NAR) score (George TJ et al. Curr Colorectal Cancer Rep 2015), empirically derived and based on the cT, ypT and ypN stages, has been found to predict OS in rectal cancer clinical trials better than ypCR. It is currently being used as the primary endpoint to more quickly assess the efficacy of novel TNT treatment regimens in the ongoing NRG GI-002 trial.

Question 25

Is a wait-and-see non-operative approach a viable option for rectal cancer patients?

Answer 25

Although not yet a standard option, a non-operative wait-and-see approach rather than automatic surgery following a TNT regimen has promising initial results (Habr-Gama et al. Ann Surg 2004). A meta-analysis by Dossa et al. (Lancet Gastroenterol Hepatol 2017) involving 867 pts. in 23 studies found clinical CR rates following CRT ranging from 11–78%, with a pooled 2-year regrowth rate of 15.7%. 95.4% of patients with regrowth had salvage therapies, and following a clinical CR no OS or DFS differences were found between whose with non-operative management (including serial DRE, endoscopy & MRI) and those who had surgery. Benefits of non-operative management may include improved quality of life and avoiding colostomy (Hupkens BJP et al. Dis Colon Rectum 2017). This approach is currently being investigated in the multi-institution MSKCC-based organ preservation for rectal cancer (OPRA) study.

Question 26

What % of pts receiving neoadj CRT will be overtreated b/c of having stage I Dz instead of the presumed more advanced Dz?

Answer 26

~18% of pts will be overtreated with neoadj CRT b/c of an apparent stage I Dz. This is based on the results of the postop arm of the German Rectal Cancer trial, where 18% of the pts did not rcv postop CRT b/c of T1–2N0 Dz found at resection. All of these pts were thought to have T3–4 or N+ Dz based on EUS.

Question 27

What was a major criticism of the German Rectal Cancer trial (Sauer R et al., NEJM 2004)?

Answer 27

A major criticism of the German Rectal Cancer trial (Sauer R et al., NEJM 2004) was that only 54% of adj pts rcvd a full RT dose (vs. 92% in the neoadj arm).

Question 28

Did Sg in the German Rectal Cancer trial involve TME?

Answer 28

Yes. All pts in the German Rectal Cancer trial (Sauer R et al., NEJM 2004) had a TME.

Question 29

What was the sphincter-preservation rate in the neoadj CRT arm in the German Rectal Cancer trial (Sauer R et al., NEJM 2004)?

Answer 29

The sphincter-preservation rate in the neoadj CRT arm in the German Rectal Cancer trial (Sauer R et al., NEJM 2004) was 39% at 5 yrs (vs. 19% in the postop CRT arm).

Question 30

How long after Sg should adj CRT be initiated for rectal cancer?

Answer 30

Adj CRT for rectal cancer should begin 4–6 wks after Sg.

Question 31

What did all pts in the German Rectal Cancer trial (Sauer R et al., NEJM 2004) rcv after either Sg (neoadj CRT arm) or CRT (adj arm)?

Answer 31

All pts in the German Rectal Cancer trial (Sauer R et al., NEJM 2004) rcvd 4–5 cycles of bolus 5-FU (500 mg/m2/day, days 1–5, q4wks) 4 wks after either Sg (neoadj CRT arm) or CRT (adj arm).

Question 32

Which 2 major randomized studies compared neoadj RT to neoadj CRT in rectal cancer, and what did they find? How was CRT delivered in both studies? What was a major limitation of these trials?

Answer 32

The French FFCD 9203 (Gerard JP et al., JCO 2006) and EORTC 22921 (Bosset JF et al., NEJM 2006) compared neoadj RT with neoadj CRT in rectal cancer. The French study found no OS difference but did find improved LR with neoadj CRT at 5 yrs (8% vs. 16%, SS). The EORTC study also found no OS difference and improved LR with neoadj CRT at 5 yrs (9% vs. 17%). Grades 3–4 acute toxicity was higher in the CRT vs. RT arms. Both trials used neoadj CRT with 45 Gy (1.8) and 5-FU (350 mg/m2/day, wks 1 and 5 of RT). A small % of pts actually rcvd adj CT (EORTC: 43%).

Question 33

How should rectal cancer pts be simulated in preparation for RT?

Answer 33

Rectal cancer pts should undergo CT simulation in the prone position, on a belly board, and with a full bladder (with optional placement of anal/vaginal markers).

Question 34

What structures should be encompassed within the RT field for rectal cancer?

Answer 34

For rectal cancer, the tumor bed (+ 2 cm margin) and presacral/obturator/internal iliac nodes should be included in the RT fields. (Anorectal contouring atlases: Myerson RJ et al., IJROBP 2009; Ng M et al., IJROBP 2012; Muirhead R et al., Clin Oncol 2014)

Question 35

What additional nodal chain should be included in the RT fields with T4 rectal cancer?

Answer 35

The external iliac nodes should be encompassed for T4 rectal cancers invading ant structures (e.g., bladder, vagina, prostate) but are not necessary for bony sacrum invasion.

Question 36

What RT fields are generally employed for rectal cancer?

Answer 36

Whole pelvis fields (3 fields) with a PA field and 2 opposed lat fields are typically employed for rectal cancer; consider adding a lightly weighted AP field for larger pts.

Question 37

What are the RT doses for rectal cancer?

Answer 37

RT doses for rectal cancer:

Neoadj/postop: initial whole pelvis (3 field) to 45 Gy in 1.8 Gy/fx; CD to tumor bed + 2–3 cm (opposed lats only, or 3D-CRT) to 50.4 Gy (preop) (or 55.8 Gy [postop] if the small bowel is out of the way)

Definitive/unresectable: initial to 45 Gy, CD1 to 50.4 Gy; consider CD2 with conformal RT to 54–59.4 Gy (if dose to the small bowel is limited)

Question 38

When is IORT indicated for rectal cancer, and what is the dose?

Answer 38

IORT should be considered in rectal cancer for close/+margins or as an additional boost, especially with T4 tumors or with recurrent tumors. The typical dose is 10–15 Gy to the 90% IDL.

Question 39

What study showed a benefit with IORT in colorectal cancer?

Answer 39

A retrospective study from Mayo by Gunderson L et al. evaluated IORT in addition to EBRT and found improved OS and LR rates with addition of IORT (10–20 Gy) when c/w historical controls. (IJROBP 1997)

Question 40

When can RT be considered in colon cancer? When is it given in relation to Sg and to what dose?

Answer 40

RT can be considered for fixed T4 colon cancer lesions or with a close/+margin. RT is typically given after resection/debulking to a dose of 45–50.4 Gy.

Question 41

What major study investigated the role of adj RT in colon cancer? What did it find? What was the limitation of this study?

Answer 41

The Intergroup 0130 study (Martenson JA Jr et al., JCO 2004) compared adj chemo to adj CRT in colon cancer and found no difference in OS or LC with addition of RT. Limitations: study was underpowered to show a difference b/t groups, the operative bed was often not marked by surgeon, and it included T3 pts unlikely to benefit from RT.

Question 42

Which randomized study investigated the role of elective P-A RT in rectal cancer? What did it conclude?

Answer 42

The EORTC trial by Bosset et al. evaluated the role of elective P-A RT in rectal cancer (25 Gy to LNs and liver) and found no benefit in terms of OS, DFS, or LC. (Radiother Oncol 2001)

Question 43

What is the Tx paradigm for small bowel cancer, and what is the role of adj chemo and/or RT?

Answer 43

Small bowel cancer Tx paradigm: resection → 5-FU–based chemo. CRT is considered in cases of close/+margins, but retrospective studies have found no convincing benefit. (Kelsey CR et al., IJROBP 2007)

Question 44

Is there a role for IMRT in the Tx for rectal cancer?

Answer 44

RTOG 0822, a single arm phase II study, investigated neoadj XELOX (capecitabine plus oxaliplatin) with IMRT for pts with locally advanced rectal cancer with a primary endpoint of grade ≥2 GI toxicity using RTOG 0247 for historical comparison. Preliminary data reported at ASTRO 2011 showed no statistically significant benefit (51% vs. 58%, p = 0.3). Zhu et al. utilized a similar regimen (XELOX plus IMRT) in a single arm prospective study of 42 pts and noted grade 3 hematologic, GI, and skin toxicities of 4.7%, 14.3%, and 26.2%, respectively. Grade 4 toxicity was not observed.