Treatment/Prognosis Flashcards
What is the Tx paradigm for nonmet rectal cancer?
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.
What are the surgical options for rectal cancer pts?
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).
What are the criteria for transanal excision alone in rectal cancer? On what 2 studies is this based?
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).
For pts who cannot have a definitive transabdominal resection, what are the indications for adj CRT after transanal excision of rectal cancer?
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.
What definitive transabdominal surgical approach for rectal cancer permits sphincter preservation?
LAR spares the sphincter and is therefore a preferred surgical option (if feasible) for rectal cancer pts; in contrast, APR requires a colostomy.
What is the approximate LR rate for T3–4 or N1 rectal cancer after Sg alone?
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]).
What is the significance of a positive circumferential margin at the time of Sg for rectal cancer?
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)
What kind of surgical technique is currently standard in the surgical management of rectal cancer? Why is this important?
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.
What are the indications for adj CRT after definitive transabdominal resection for rectal cancer?
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.
What are some options for rectal cancer pts with solitary or oligometastatic Dz to the liver that is resectable?
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:
What are the most commonly used sensitizing chemo regimens given with RT for rectal cancer?
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.
What did NSABP-04 show regarding the addition of oxaliplatin to preop CRT?
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)
What are the data addressing adj RT alone in rectal cancer, and what do they show?
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)
What major studies established a role for adj CRT in rectal cancer?
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.
Which study compared Sg alone with preop RT in rectal cancer? What did it find, and what were its limitations?
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%).
Does the use of TME eliminate the benefit from neoadj RT for rectal cancer?
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.
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?
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.
What were the arms in the MRC CR07/NCIC C016 rectal cancer study, and what were its main findings?
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.
Is neoadj short-course RT an acceptable alternative to standard CRT for locally advanced rectal cancer?
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)
What is the optimal timing for Sg after short course preop RT?
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)
Which major European rectal cancer study compared neoadj CRT to adj CRT and what were its findings?
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)
What is the pathologic CR rate for preop CRT for rectal cancer?
According to the German Rectal Cancer trial, the pCR rate is 8%.
What is the pathologic CR rate following TNT for rectal cancer?
The pathologic CR rate with TNT ranges from 14–36%. (Cercek A et al. JAMA Oncology 2018)
Does the extent of pathologic response correlate with outcome?
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.
