Therefore, while these studies justify the use of laparoscopy in rectal cancer, it is prudent to wait for the

final results of the larger COLOR II and ACOSOG Z6051 trials before endorsing laparoscopy as the

preferred surgical approach to LARC.

Table 68-9 Open versus Laparoscopic Rectal Resections: Results of the Most

Representative Series

Many surgeons currently perform a hybrid approach consisting of the laparoscopic lymphovascular

control and colon mobilization, and the open mesorectal dissection and anastomosis through a lower

abdominal transverse incision. The hybrid approach is aimed at facilitating the most technically

challenging portion of the operation: the dissection of the distal rectum and the creation of the

anastomosis. With this approach the size of the abdominal wall incision is smaller compared with a

totally open procedure, but larger than with a totally laparoscopic procedure. Although there is some

evidence of short-term advantages to this approach compared to open surgery,237 long-term benefits

compared to the totally open or laparoscopic approaches are unknown.

The robotic platform (da Vinci®) was introduced to the surgical armamentarium to facilitate the

minimally invasive approach to procedures such as prostatectomy, hysterectomy, and TME, which

require optimal visualization and dexterity in the narrow pelvic space. The experience accumulated thus

far – based on retrospective institutional case series – suggests that robotic TME is equivalent to

laparoscopic TME in terms of completeness of the mesorectal excision, CRM positivity, and short-term

oncologic outcomes. Conversion rates appear to be lower compared to laparoscopic TME, but hospital

charges are higher.238 A prospective, randomized study comparing laparoscopic and robotic TME – the

Robotic Versus Laparoscopic Resection for Rectal Cancer (ROLARR) trial – has completed accrual, but

the results are not available yet.239 However, as laparoscopy has not become standard in LARC, it is

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likely that the controversy regarding the benefit of robotic TME will continue for years.

The transanal–transabdominal proctectomy, or down-to-up TME, is a transanal, minimally invasive

approach for the dissection of the distal rectum in patients with a narrow pelvis.240,241 With this

approach, lymphovascular control, the entire colonic mobilization, and dissection of the upper rectum

are performed using conventional transabdominal laparoscopy. The dissection of the distal rectum is

performed through the anus, using either conventional transanal equipment for very distal tumors, or

endoscopic equipment (TEMS, TEO, TAMIS) for higher tumors. The rectal wall is incised

circumferentially, distal to the tumor, and the MRF is identified. The lumen of the colon is closed with a

purse-string suture to avoid contamination. The dissection is carried cephalad in the proper plane until

the abdominal field is reached. The specimen is then removed, and the anastomosis performed through

the anus. This approach is particularly useful for patients with very distal rectal cancers treated with

chemoradiation therapy, in which the surgeon has no anatomical cues about where to transect the

rectum in order to achieve a negative distal margin. The transanal approach allows the surgeon to

choose precisely the point for transecting the rectum while visualizing the distal edge of the tumor. The

benefit of the down-to-up approach for higher rectal cancers that could be treated with a conventional

transabdominal dissection and a double-stapled anastomosis are uncertain.

Adjuvant Chemoradiation for Locally Advanced Rectal Cancer

Several randomized, controlled trials conducted in the pre-TME era demonstrated that radiation therapy

(RT) given before or after surgery reduced the rate of LR, compared to surgery alone.242–244 However,

the relevance of these trials was later questioned, because surgery was not standardized and the LR

rates reported in the control arms – approximately 25% – were considered too high compared to that of

patients treated in later years with surgery alone according to TME principles.129 The efficacy of RT in

the setting of quality TME surgical resection was investigated in the Dutch Colorectal Cancer Group

trial, which randomized 1,861 patients with resectable disease to TME alone or short-course RT (SCRT)

(5Gy a day × 5 days, for a total dose of 25Gy), followed by TME within 2 to 7 days. The study showed

that SCRT reduced the rate of LR in resectable rectal cancer treated by TME, compared to TME alone;

however, SCRT did not provide a significant survival benefit.245 This trial proved that preoperative RT

decreases the rate of LR in LARC patients treated with TME surgery.

The benefit of combining chemotherapy with RT was proven by several randomized trials that

compared postoperative RT combined with 5-FU, administered as a bolus or as continuous venous

infusion (CVI), to postoperative RT alone, in patients with pathologic stage II and III rectal

cancer.246,247 The results proved that combined 5-FU and radiation was more effective than radiation

alone in reducing the risk of LR, and that CVI 5-FU was associated with lower toxicity compared to

bolus 5-FU.

The European Organization for Research and Treatment of Cancer (EORTC) protocol 22921 was

developed to assess the effect of adding CT to preoperative RT, and the subsequent value of

postoperative CT in rectal cancer patients.248 At the 5-year mark, LR was significantly lower in all three

arms receiving any CT (pre- or postoperative) compared to preoperative RT alone, indicating a benefit

of CT in reducing the risk of LR, regardless of when it was administered. The addition of CT to RT did

not impact survival. Additional work by the Federation Francophone de la Cancerologie Digestive

corroborated these findings.249 These studies showed that, similar to what was found using

postoperative radiation, adding CT to preoperative RT also reduced the rate of LR, compared to

preoperative RT alone.

The German Rectal Cancer Group (CAO/ARO/AIO 94) compared preoperative versus postoperative

CRT in 823 patients with clinical T3–4/N+ rectal cancer.250 RT in this trial consisted of 50.4 Gy in 25

fractions with bolus 5-FU as a radiosensitizer. In the preoperative treatment group, surgery was

performed 6 weeks after completion of CRT. Both groups had surgery according to TME principles, and

received postoperative adjuvant CT. The preoperative CRT group had less toxicity and lower 5-year LR

rates compared to the postoperative CRT group (6% vs. 13%). This study found no differences in the

rates of DR, DSS, or OS. The NSABP R-03 study also compared the use of preoperative versus

postoperative 5-FU/LV, using 45 Gy in 25 fractions in T3/4, N+ patients, to evaluate differences in

DFS, LR, or OS.251 Despite stopping the study early due to limited accrual, the R-03 study reported

better DFS in the preoperative CRT group, compared to the postoperative group, with a near-significant

difference (p = 0.065) in OS and no difference in LR. The results of these two trials established

preoperative CRT as the preferred treatment for LARC in both Europe and the United States.

More recently, it has been shown that capecitabine is noninferior to infusional 5-FU as a

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radiosensitizer for LARC, in both the NSABP R-04 trial and the German Cancer Research Center multicenter trial.252,253 Several large, prospective trials have failed to prove that the addition of oxaliplatin to

a fluoropyrimidine (5-FU or capecitabine) is superior to fluoropyrimidine alone as a radiosensitizer in

patients with LARC.252,254–256 In fact, patients receiving the oxaliplatin plus a fluoropyrimidine had a

greater rate of adverse events, with similar or lower tumor response rates. Therefore, based on the

current evidence, oxaliplatin is not recommended as a radiosensitizer to a fluoropyrimidine in patients

with LARC.

In addition to the standard hypofractionation (180 to 200 cGy a fraction) commonly delivered during

the standard CRT, radiation therapy is also frequently delivered as short course (SCRT) using fewer,

larger fractions (5 Gy daily fractions for 5 consecutive days and a total dose of 25 Gy). In these patients,

surgery is performed within 7 days of completion of the radiation. Both schemes are biologically

equivalent in eradicating cancer cells, but SCRT has the potential benefits of shorter duration of

treatment, more efficient utilization of resources, and reduced cost compared to CRT. However, higher

dose per fraction increases the risk of delayed toxicity, and tumor regression is lower with SCRT. Two

prospective, randomized trials comparing SCRT with CRT have reported equivalent local tumor control

with both regimens, and the selection between CRT and SCRT is based on doctor and patient

preferences.257,258 In general, CRT is preferred in the setting of large tumors that may benefit from

maximal tumor regression before surgery.

Current guidelines recommend CRT with the aim of reducing the risk of LR for all patients with stage

II and III rectal cancer. However, the risk of LR is variable depending on the distance of the tumor from

the anal verge, the risk being lower for tumors located in the upper rectum compared to those in the

lower rectum. It is possible that some patients with high rectal cancers, specifically those with T3N0

tumors and a clear CRM, may not actually benefit from preoperative radiation but may simply be

exposed to radiation-associated toxicity. A current trial in the United States seeks to address this

question by comparing the outcomes of rectal cancer patients treated with neoadjuvant chemotherapy,

with or without radiation, before TME.259

Adjuvant Chemotherapy for Locally Advanced Rectal Cancer

In the past, LR was the dominant problem in patients with LARC, but in the modern era more patients

develop distant metastasis than LR. Consequently, patients with LARC treated with neoadjuvant CRT

and TME are recommended for postoperative adjuvant chemotherapy, with the aim of reducing distant

metastasis and improving survival. However, the data supporting this recommendation are limited, and

based heavily on experience using adjuvant therapy for resected colon cancers. The QUASAR study

discussed above showed that adjuvant chemotherapy has a modest effect in lowering recurrence and

improving survival in stage II/III CRCs following curative-intent surgery.153 However, the cohort was

not powered to demonstrate differences in the 29% of rectal cancer patients who were accrued, and the

association with better outcomes stems from subset analysis. In contrast, the 10-year update of the

EORTC 22921 trial showed no difference in OS or DFS with the addition of 5-FU–based postoperative

chemotherapy in rectal cancer patients treated with preoperative RT or CRT and TME.260 However,

these results have been criticized because the proportion of patients receiving the full dose of

postoperative adjuvant chemotherapy was only 43%, thus underestimating the therapeutic effect. A

meta-analysis of 21 controlled trials in patients receiving potentially curative surgery, including a total

of 4,854 patients randomized to surgery plus fluoropyrimidine-based postoperative chemotherapy, and

4,367 patients to surgery and observation, has shown a significant reduction in the risk of death (17%)

(HR = 0.83, CI: 0.76–0.91) and a reduction in the risk of DR (25%) (HR = 0.75, CI: 0.68–0.83) among

patients undergoing adjuvant chemotherapy, compared to those undergoing observation.261 Available

data were insufficient to investigate the effect of adjuvant chemotherapy separately in different TNM

stages. These data support the use of postoperative chemotherapy after curative-intent surgery in

patients with rectal cancer. Similar to colon cancer patients, patients with LARC treated with CRT and

TME are recommended to receive 5-FU or capecitabine plus oxaliplatin-based adjuvant chemotherapy.

The length of adjuvant treatment in rectal cancer is shorter compared to colon cancer (4 months vs. 6

months), given the use of sensitizing 5-FU or capecitabine during CRT.

A common criticism about the use of postoperative adjuvant chemotherapy after curative surgery in

patients with rectal cancer is low treatment compliance. In some series, up to 27% of eligible patients

never start treatment, and more than 50% require dose reductions or treatment interruptions or

delays.248,256 This is particularly relevant, as a systematic review of 10 studies – including more than

15,000 patients – evaluated the effect of timing on the efficacy of postoperative adjuvant therapy,

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