Multimodal Treatment of Rectal Cancer

Abstract

Background

Colorectal cancer is one of the three most common types of cancer in Germany. Approximately 30% of these cancers are located in the rectum, corresponding to about 18 000 new cases per year.

Methods

This review is based on publications retrieved by a selective search in the PubMed database, including current guidelines and recommendations.

Results

Specialized imaging, particularly magnetic resonance imaging, is essential for treatment planning. In very early stages of this disease, tumors without risk factors can be excised locally. Otherwise, radical surgical resection with lymphadenectomy remains the standard treatment, and can be performed either minimally invasive or open. At present, neoadjuvant treatment plans are evolving in the direction of total neoadjuvant therapy. In addition, recent studies investigate whether the improved efficacy of neoadjuvant therapy might now enable patients with a complete clinical remission to be spared from surgical resection (organ-preserving watch-and-wait strategy).

Conclusion

The treatment of rectal cancer is a prime example of an interdisciplinary, multimodal approach. In the past, the focus was mainly on improving oncologic outcomes; at present, increasing attention is being devoted to the patients‘ quality of life as well and the functional aspects of the various modes of treatment.

Colorectal carcinoma is one of the three most common types of cancer in the Western world (e1, e2). Approximately 30% of colorectal carcinomas are located in the rectum (e1, e2). In Germany, there are some 18,000 new cases of rectal carcinoma per year (e3). Men are more commonly affected than women; the median age of onset is 73 years in women and 69 years in men (e3). The incidence among persons under age 50 is now rising (e3, e4).

Incidence.

Approximately 30% of cases of colorectal cancer are located in the rectum, corresponding to about 18 000 new cases in Germany per year.

The diagnosis and treatment of rectal cancer have changed fundamentally in recent decades. Major developments have included the implementation of total mesorectal excision (TME), minimally invasive surgery, neoadjuvant (preoperative) therapy, magnetic resonance imaging (MRI), and standardized histopathological evaluation. In this review, we present and explain the current principles of treatment. The broad scope of the topic does not permit a detailed discussion of all relevant aspects; we refer the reader to pertinent reviews and guidelines for further information (1– 6).

Learning objectives

This article is intended to give readers knowledge of:

• the principles of pre-treatment diagnostic evaluation,

• the main treatment strategies and, in particular, how they vary depending on the site of the lesion in the upper versus the middle or lower third of the rectum, and

• the principles of surgical and perioperative treatment.

Pre-treatment diagnostic evaluation

Interdisciplinarity.

Because of the complexity of the disease, the treatment of rectal cancer is a prime example of an interdisciplinary, multimodal approach.

The following examinations should be standard components of the pre-treatment diagnostic evaluation (3):

Digital rectal examination

A digital rectal examination should be performed to assess sphincter function. If the tumor is located in the lower (possibly middle) third of the rectum, digital rectal examination enables the evaluation of sphincteric or vaginal involvement.

Rigid rectoscopy

Rigid rectoscopy should be performed for precise localization of the height of the lesion, as flexible endoscopy is not precise enough for this purpose. The distance from the anocutaneous line (linea anocutanea) to the inferior edge of the tumor is measured so that the tumor can be assigned to the lower (< 6 cm), middle (6 cm = 12 cm), or upper third of the rectum (12 cm-16 cm) (3) (figure 1). As shown in Figure 1, the height of the lesion largely determines the available treatment options. Moreover, the distance from the tumor to the superior edge of the sphincter is very important for surgical planning. Rectoscopy can be supplemented with endorectal ultrasonography (endosonography), if the necessary expertise is available.

Figure 1.

The male rectum. Its conventional division into upper, middle, and lower third is shown; the mesorectum, mesorectal fascia, and presacal fascia are marked as well. The plane of surgical dissection should generally be between these two fascial layers. Tumors of the lower and middle third of the rectum are usually removed with total mesorectal excision (TME), while those of the upper third of the rectum are usually removed with partial mesorectal excision (PME).

Total colonoscopy

A total colonoscopy should be performed to rule out simultaneous second malignancies, which may be present in 3–4% of cases (3, e5, e6).

Magnetic resonance imaging (MRI)

In recent years, high-resolution MRI has become the gold standard for the evaluation of local tumor spread, mainly because it enables improved visualization of the (lesser) pelvic structures (7– 11). The features of particular importance for treatment planning are the depth of infiltration into the perirectal fat, the relation of the tumor to the mesorectal fascia, and extramural vascular infiltration (EMVI) (figure 2).

Figure 2.

Magnetic resonance images before treatment

a) A man with a locally limited carcinoma (cT3a N- CRM- EMVI-) in the middle third of the rectum: T2-weighted MRI in the axial plane shows limited infiltration into the mesorectal fat (arrow), with EMVI negativity and without lymph node involvement. MRF, mesorectal fascia (dashed line).

b) A woman with a locally advanced carcinoma (cT3d N2 CRM+ EMVI+) in the middle and lower third of the rectum: T2-weighted MRI in the axial plane shows tumor infitration into the mesorectal fat extending to the mesorecdtal fascia (dashed arrow), along wth EMVI positivity (*) and lymph node involvement (arrow). MRF, mesorectal fascia (dashed line).

Evaluation for distant metastases

According to the German clinical practice guideline, abdominal ultrasonography and a chest x-ray suffice (3). If these studies yield abnormal or unclear findings, they should be supplemented by computerized tomography (CT) and/or MRI. This recommendation, however, is often not followed, and a CT is commonly obtained as a primary study.

Tumor markers

Local pretreatment diagnostic evaluation.

The standard local pretreatment diagnostic evaluation includes a digital rectal examination, rigid rectoscopy, total colonoscopy, and an MRI of the pelvis.

Tumor markers are often nonspecific and are therefore used primarily for follow-up. For rectal carcinoma, the serum CEA level should be measured before treatment (3).

Principles of treatment

The main principles of treatment are shown in Figure 3; above all, the height of the lesion above the anocutaneous line is of critical importance. Therapeutic decision-making in rectal cancer is complex and must necessarily be presented here in a simplified and less than comprehensive manner. For example, we will not discuss the proper procedure for patients who already have distant metastases. Moreover, the patient’s age and concomitant illnesses, if any, obviously play a role in therapeutic decision-making. All treatments should be agreed upon beforehand after consideration by a specialized interdisciplinary tumor board.

Figure 3A.

Principles of treatment of carcinoma of the middle and lower third of the rectum without distant metastasis (cM0)

*¹= low-risk constellation (see text)

*²= high-risk constellation (see text)

*³= according to the German clinical practice guidleline, either short-term radiotherapy for 5 days (5 × 5 Gy) or long-term radiochemotherapy (25–28 fractions of 1.8–2.0 Gy each)

*⁴= for details, see eTable 3.

*⁵= according to the German clinical practice guideline, there is no clear recommendation for or against adjuvant chemotherapy after neoadjuvant therapy and oncologic resection; escalation: for example, in cT4, involvement of the mesorectal fascia, or extensive lymph node involvement; de-escalation: for example, in cT3a/b cN- CRM- EMVI- (middle third) or in cT1/2 CRM- EMVI- and uncertain cN+ (lower and middle third).

*⁶= details on follow-up recommendations in a watch-and-wait setting are given in eTable 4.

The dashed lines stand for treatment options that are already a part of clinical practice, even if individual aspects have not yet been thoroughly documented in the current guideline or are still being tested in clinical trials.

cCR, clinical complete response; TME, total mesorectal excision; TNT, total neoadjuvant therapy

Principles of surgical treatment

Local excision

The probability of lymph node metastases arising in T1 carcinoma of the rectum is 10–20%. A distinction is drawn between low- and high-risk situations. The following constitutes a low-risk constellation (3):

• T1 carcinoma

• G1/G2

• L0

• diameter < 3 cm

When these criteria are met, the likelihood of lymph node metastases is much lower, so that local excision can be performed (level 1b evidence, agreement >95%) (Figure 3). An R0 resection is a prerequisite for local excision. An oncologic resection is generally advised for patients with an R1 resection or if there are additional risk factors (3).

Oncologic rectal resection

Magnetic resonance imaging.

MRI is of central importance for treatment planning because it enables good visualization of pelvic anatomic structures, above all the mesorectal fat and the relation of the tumor to the mesorectal fascia.

An oncologic rectal resection includes removal of the primary malignancy as well as the potentially involved lymph nodes, with adequate safety margins in the oral, aboral, and circumferential directions. The following are important considerations:

• Removal of the potentially involved lymph nodes involves excision of the mesorectum (figure 1). For tumors located in the lower and middle third of the rectum, the mesorectum is usually removed completely down to the level of the pelvic floor; this is called a total mesorectal excision (TME) (Figures 1 and 3a). For tumors in the upper third of the rectum, a partial mesorectal excision (PME) can be performed (3), in which the rectum is removed down to 5 cm below the tumor (Figures 1 and 3b).

• The dissection should be performed within the TME layer, i.e., between the mesorectal and presacral fasciae (figure 1). The mesorectal fascia envelops the mesorectum, while the presacral fascia covers the neural and venous plexuses. Sparing the autonomic pelvic nerves is important to minimize the risk of postoperative dysfunction. The quality of the TME is later documented in the pathology report; the integrity of the surgical specimen is a major prognostic factor (e7 - e9).

• Oncologic resection can be performed via open surgery, or else in a minimally invasive (laparoscopic) procedure if the requisite expertise is available (3) (grade A recommendation, level 1a evidence, agreement >95%), as the two types of operation yield similar functional and oncologic outcomes (Table 1; see eMethods). The same seems to be true of robot-assisted surgery, although there has been only one large-scale randomized trial of this method to date, and the long-term oncologic results have not yet been published (Table 1; see eMethods). For advanced T3 and T4 carcinomas, however, no data are yet available from controlled studies that might document the benefit of a minimally invasive approach.

• If the sphincter is involved, a rectal resection including removal of the sphincter must be performed, i.e., an abdominoperineal resection (3, 12).

• If the adjacent organs (e.g., the vagina or the prostate gland) are affected, en bloc resection is necessary.

• When a TME is performed, a diverting stoma is usually created to allow healing (with conservative management) in case of postoperative insufficiency of the anastomosis. When a PME is performed, stool deviation can usually be omitted. The intended site of the stoma should be marked preoperatively.

Figure 3B.

Principles of treatment of carcinoma of the middle and upper third of the rectum without distant metastasis (cM0)

*¹= low-risk constellation (see text)

*²= high-risk constellation (see text)

*³= for details, see eTable 3

PME, partial mesorectal excision

Table 1. Overview of selected randomized trials in rectal carcinoma: techniques of surgical resection.

	COREAN		COLOR II		ACOSOG Z6051		ALaCaRT		ROLARR
	Open	Lap.	Open	Lap.	Open	Lap.	Open	Lap.	Lap.	Robot
Patients [number]	170	170	345	699	222	240	235	238	230	236
Tumor height [cm]	0–9		0–15		0–12		0–15		0–15
Tumor stage	cT3 cN0–2 cM0		cT1–3 cN0–2 cM0		cUICC II, IIIA/B		cT1–3		cT1–3 cN0–2 cM0
Conversion rate [%]	1.2		17		11,3		9		12.2	8.1
p value	–		–		–		–		0.16
Duration of surgery [minutes]	197.0	244.9	188	240	220.6	266.2	190	210	261.0	298.5
p value	< 0.0001		< 0.0001		< 0.001		0.007		–
CRM+ [%]	4.1	2.9	10*1	10*1	7.7	12.1	3	7	6.3	5.1
p value	0.770		0.850		0.11		0.06		0.56
TME mesorectal [%]	74.7	72.4	88	84	81.6	72.9	92	87	77.6	76.4
p value	0.414		–		–		0.06		0.14
Length of hosptal stay [days]	9*2	8*2	9*2	8 *2	7.0	7.3	8	8	8.2	8.0
p value	0.056		0.036		0.10		0.21		–
Complications [%]	23.5*3	21.2*3	40	37	58.1	57.1	–	–	31.7	33.1
p value	0.603		0.424		0.93		–		0.84
Anastomotic insufficiency [%]	0	1.2	10	13	2.3	2.1	3	3	9.9	12.2
p value	0.499		0.462		–		0.98		–
DFS [%]	72.5*4	79.2*4	70.8*4	74.8*4	83.2*4	79.5*4	82*4	80*4	–	–
p value	< 0.0001		–		n.s.		–		–
OS [%]	90.4*4	91.7*4	83.6 *4	86.7 *4	–	–	93*4	94*4	–	–
p value	n. s.		–		–		–		–
Local recurrence [%]	4.9*4	2.6*4	5*4	5*4	4.5 *5	4.6 *5	3.1*5	5.4*5	–	–
p value	n. s.		n. s.		n. s.		0.21		–
Mortality [%]	0	0	2	1	0.9	0.8	0.85	0.4	0.9	0.8
p value	–		0.409		0.95		–		–

Modified from (12, e60).

COREAN (e47, e48); COLOR II (e50, e51); ACOSOG Z6051 (e55, e56); ALaCaRT (e57, e58); ROLARR (e59)

*1 CRM cut-off: 2 mm (otherwise 1 mm); * 2 postoperative hospital stay; * 3 only surgical complications; * 4 at 3 years; * 5 at 2 years.

CRM, circumferential resection margin; DFS, disease-free survival; Lap., laparoscopy; n.s., not significant;; OS, overall survival; TME, total mesorectal excision

Perioperative treatment

Tumor site and treatment planning.

An important determinant of the proper treatment is whether the tumor is located in the lower (< 6 cm), middle (6 cm ≤ 12 cm), or upper third of the rectum (12 cm-16 cm)

Local excision.

In a low-risk situation, a T1 carcinoma can be excised locally.

Rectal carcinomas in the upper third are usually resected primarily (figure 3b), unless there is an increased risk of local recurrence (3) (grade A recommendation, level 1b evidence, agreement >95%). Preoperative (neoadjuvant) therapy is given only in exceptional cases or in the setting of a clinical trial. Postoperative (adjuvant) chemotherapy is given as recommended for colon carcinoma (3).

In contrast, for locally advanced carcinomas (cT3/4 and/or cN+) in the middle and lower third of the rectum, neoadjuvant radiotherapy is a key element of multimodal treatment (3) (grade A recommendation, level 1b evidence, agreement >75–95%). In this situation, radiotherapy significantly lowers the locoregional recurrence rate compared to surgery alone (etable 1) (13– 16, e10 - e13). It can be delivered either as short-term irradiation or as long-term radiochemotherapy (3) (grade 0 recommendation, level 1b evidence, agreement >95%). Two randomized trials revealed no significant differences between these two preoperative radiotherapy regimens with respect to recurrence and survival rates in the overall population (e12, e13) (etable 1). Nonetheless, radiochemotherapy is preferred in some situations in order to shrink (“downsize”) tumors more effectively before surgery, particularly with advanced T4 tumors, mesorectal fascial involvement documented by preoperative imaging, and low-lying tumors where the sphincter is to be preserved. Radiochemotherapy can be performed either with infusional 5-fluorouracil (5-FU) or more easily with capecitabine, an oral prodrug of 5-FU (e14). In the classic setting, surgery is usually performed 6–8 weeks after radiochemotherapy (3); after short-term radiotherapy, surgery is performed either very soon (within 10 days of the start of radiotherapy) or at an interval of 4–8 weeks (3, e15). Total neoadjuvant therapy (TNT) (17– 21) involves a postponement of restaging by up to 22–24 weeks (19) or 35 weeks (21) after the start of therapy.

eTable 1. Overview of selected randomized trials for rectal carcinoma: neoadjuvant radio- and radiochemotherapy.

	Swedish Rectal Cancer Trial			Dutch CKVO 95–04 Dutch TME Trial			German Rectal Cancer TrialCAO/ARO/AIO-94			Polish Trial			Trans-Tasman Radiation Oncology Group Trial 01.04
	RT	OP	p value	RT	OP	p value	preop	postop	p value	RT	CRT	p value	RT	CRT	p value
Treatment	neoadjuvant 5 × 5 Gy versus primary surgery			neoadjuvant 5 × 5 Gy versus primary surgery			neoadjuvant CRT versus adjuvant CRT			neoadjuvant 5 × 5 Gy versus neoadjuvant CRT			neoadjuvant 5 × 5 Gy versus neoadjuvant CRT
Number of patients	553	557	–	924	937	–	405	394	–	155	157	–	162	161	–
Tumor stage	Dukes A, B, C			AJCC I–IV			cT3/4 cN−/+ or cT1/2 cN+			cT3/4, no sphicter involvement			cT3 cN−/+ cM0
Years of follow-up	5			2			5			4			3
local recurrences [%]	11	27	< 0.001	2.4	8.2	< 0.001	6	13	0.006	10.6	15.6	0.21	7.5	4.4	0.24
disease-free survival [%]	–	–	–	–	–	–	68	65	0.32	58.4	55.6	0.82	–	–	–
overall survival [%]	58	48	0.004	82	81.8	0.84	76	74	0.8	67.2	66.2	0.96	–	–	–
Years of long-term follow-up	13			10			10			–			5
local recurrences [%]	9	26	0.001	5	11	< 0.0001	7.1	10.1	0.048	–	–	–	7.5	5.7	0.51
disease-free survival [%]	72	62	0.03	–	–	–	68.1	67.8	0.65	–	–	–	–	–	–
overall survival [%]	38	30	0.008	48	49	0.86	59.6	59.9	0.85	–	–	–	74	70	0.62
Remarks	not disease-free survival, but rather “cancer-specific” survial			–			less grade 3/4 toxicity in neoadjuvant group (27% vs. 40%, p = 0.001)			more acute toxicity after radiochemotherapy (18.2% vs. 3.2%, p < 0.001); no difference in long-term toxicity			middle and lower thirdof the rectum

Swedish Rectal Cancer Trial (13, e10); Dutch CKVO 95–04/Dutch TME Trial (14, e11); German Rectal Cancer Trial/CAO/ARO/AIO-94 (15, 16); Polish Trial (e12); Trans-Tasman Radiation Oncology Group Trial 01.04 (e13)

CRT: radiochemotherapy (50.4 Gy + 5-FU); OP, operation; RT, Radiotherapie

The longstanding practice in Germany has been to give adjuvant chemotherapy in the wake of neoadjuvant therapy and surgical resection regardless of the response to treatment. This approach is controversial internationally (e16 - e19). Randomized trials in which adjuvant chemotherapy after neoadjuvant therapy and resection of the primary lesion was compared with follow-up care alone have not revealed any improvement in disease-free survival (e16). From today‘s perspective, however, the bolus 5-FU regimen used in these trials is no longer appropriate in view of its poor tolerability and low efficacy. In contrast, a large-scale, randomized phase II trial revealed that a combination of infusional 5-FU and oxaliplatin prolonged disease-free survival compared to a bolus regimen for patients at high risk (e20). The current German clinical practice guideline contains no clear recommendation for or against adjuvant therapy after neoadjuvant therapy and surgical resection (3). The indication for adjuvant chemotherapy should thus be considered by the tumor board in the light of the center‘s experience and the patient‘s risk profile and personal preference.

Treatment escalation

Intensificationof neoadjuvant therapy

Principles of oncologic resection.

An oncologic rectal resection includes removal of the primary malignancy as well as the potentially involved lymph nodes, with adequate safety margins.

Over the past 15 years, there have been several randomized phase 3 trials of preoperative radiochemotherapy intensified by the addition of oxaliplatin, in the hope that this can prolong survival. The data from all of these randomized trials were recently pooled in a meta-analysis (22). The addition of oxaliplatin did, in fact, prolong disease-free survival (DFS) to a statistically significant extent (p = 0.03), but the clinical benefit was small, with a hazard ratio of only 0.9 [95% confidence interval: 0.81; 0.99]. The addition of oxaliplatin also significantly increased side effects. Retrospective analyses suggest that disease-free survival was particularly prolonged in younger patients: for example, another meta-analysis with pooling of individual patient data from three trials revealed significant prolongation of disease-free survival for patients under age 60 (HR 0.77; 95% CI: [0.62; 0.96]; p = 0.02) (23). In summary, neoadjuvant radiochemotherapy with the addition of oxaliplatin is not standard treatment, but can be considered, in our opinion, especially for younger patients.

Total neoadjuvant therapy

The fact that no meaningful improvement of clinical outcomes has been documented either after neoadjuvant radiochemotherapy intensified with oxaliplatin or after adjuvant chemotherapy per se implies the need for new approaches in perioperative treatment. Total neoadjuvant therapy (TNT) is one such promising approach: it consists of oxaliplatin-containing chemotherapy given in addition to neoadjuvant radio(chemo)therapy. It can be administered either before the radio(chemo)therapy (induction therapy), or after it (consolidation therapy) (17– 21). TNT makes it possible for optimized chemotherapy to be delivered in full because it is tolerated better, without any increase in surgical morbidity; it also enables the early systemic treatment of micrometastases, which might improve (disease-free) survival. Moreover, the rate of pathological complete response (pCR) after TNT is in the range of 25–30% (etable 2). pCR means that processing of the operative specimen reveals no tumor cells in the area of the former tumor bed or lymph nodes. Thus, for a certain number patients, TNT thereby makes a non-operative watch-and-wait strategy a feasible option.

eTable 2. Overview of randomized trials in rectal carcinoma: total neoadjuvant therapy.

	CAO/ARO/AIO-12		RAPIDO		UNICANCER-PRODIGE 23		OPRA
	TNT A	TNT B	TNT	CRT	TNT	CRT	TNT A	TNT B
Therapy	A: induction chemotherapy + CRT B: CRT + consolidation chemotherapy		RT + consolidation chemotherapy vs. CRT (possibly with adjuvant chemotherapy)		FOLFIRINOX + CRT vs. CRT		A: induction chemotherapy + CRT B: CRT + consolidation chemotherapy
Number of patients	156	150	462	450	231	230	158	146
Tumor stage	cT3 (lower third), >cT3b (middle third), cT4 or cN+, cM0		cT4 or cN2 or CRM+ or EMVI+, cM0		cT3/4 cN−/+ cM0		cT3/4 cN− or cN+, cM0
pCR [%]	17	25	28	14	28	12	–	–
p value	–		< 0.0001		< 00001		–
Local recurrence* [%]	6	5	–	–	4	6	–	–
p value	0.67		–		0.56		–
Locoregional failure* [%]	–	–	8.3	6.0	–	–	–	–
p value	–		0.12		–		–
Disease-free survival* [%]	73	73	–	–	76	69	76	76
p value	0.82		–		0.034		0.98
Disease-related treatment failure* [%]	–	–	23.7	30.4	–	–	–	–
p value	–		0.019		–		–
Overall survival* [%]	92	92	89.1	88.8	91	88	–	–
p value	0.81		0.59		0.0773		–
Non-operative management [n]	–	–	–	–	–	–	105	120
p value	–		–		–		–
Local regrowth after NOM* [n]	–	–	–	–	–	–	42	33
p value	–		–		–		0.03
TME-free survival* [%]	–	–	–	–	–	–	41	53
p value	–		–		–		0.01
Remarks	–		incl. upper third of rectum locoregional failure: local tumor progression with resulting unresectability, R2 resection, or local recurrence disease-related treatment failure: first appearance of locoregional failure (see above),distant metastases, new colorectal second carcinoma, or treatment-related death		incl. upper third of rectum		after completion of TNT: TME in case of incomplete clinical response, or NOM (= watch and wait), in case of cCR or near-cCR

CAO/ARO/AIO-12 (17, 18); RAPIDO (19); UNICANCER-PRODIGE 23 (20); OPRA (21)

CRT, radiochemotherapy; NOM, non-operative management (=watch and wait); pCR, pathological complete response; TME, total mesorectal excision; TNT, total neoadjuvant therapy;

vs., versus; at 3 years

TME versus PME.

For tumors located in the lower and middle thirds of the rectum, a total mesorectal excision (TME) is usually performed; for those in the upper third of the rectum, a partial mesorectal excision (PME) can be performed.

According to a joint position statement of three German oncological associations (in oncology, surgery, and radiooncology, respectively: Arbeitsgemeinschaft Internistische Onkologie [AIO], Assoziation Chirurgische Onkologie [ACO], Arbeitsgemeinschaft Radiologische Onkologie [ARO]), TNT should be considered the preferred new therapeutic option for patients with locally advanced rectal cancer, with radiotherapy either as long-term radiochemotherapy (with capecitabine or infusional 5-FU) or as short-term radiotherapy (24). These two TNT concepts are now being compared in the ongoing ACO/ARO/AIO-18.1 trial (efigure a).

eFigure a.

The randomized ACO/ARO/AIO-18.1 trial of the German Rectal Cancer Study Group

Arm A: 5 × 5 Gy (25 Gy) followed by consolidation chemotherapy (9 cycles of mFOLFOX6 or, alternatively, 6 cycles of CAPOX); Arm B: 5-FU/oxaliplatin-based long-term radiochemotherapy (54 Gy) followed by consolidation chemotherapy (6 cycles of mFOLFOX6 or, alternatively, 4 cycles of CAPOX). In both arms, re-staging is performed 22–24 weeks after the initiation of therapy. If a cCR (clinical complete response) is achieved, there is the option of a watch-and-wait strategy. The primary endpoint is TME-free survival (intact rectum, no radical tumor resection, no stoma). Inclusion criteria: see diagram.

R, randomization; RT, radiotherapy; TME. total mesorectal excision; 5-FU, 5-fluorouracil.

De-escalation of therapy

Primary resection without neoadjuvant therapy

The general recommendation for neoadjuvant therapy of all rectal cancers in UICC stages II and III (cT3/4 and/or cN+) is not without its problems. The status of the lymph nodes plays a key role in the indication, yet both MRI and endosonography have significant weaknesses in the assessment of lymph nodes (7– 11, e21 - e23). Moreover, neoadjuvant therapy followed by surgery can worsen the long-term functional outcome, by causing fibrosis and other sequelae (e24 - e29). Typical side effects and consequences of radiochemotherapy include (painful) proctitis, acute and chronic diarrhea, local skin reactions, bone marrow suppression with resulting systemic infections, and, over the long term, peripheral neuropathy or damage to the pelvic autonomic nerves. A question being studied at present is whether one of the two local therapy modalities can be omitted under certain conditions.

Resection techniques.

Oncologic resection can be performed either via open surgery or in a minimally invasive procedure, with proper patient selection, if the requisite expertise is available.

In the nonrandomized MERCURY study, MRI-based assessment of the depth of extramural infiltration and of the potentially affected circumferential resection margin (CRM) was used for the first time to select patients for primary surgery without radiotherapy (25, 26). MRI criteria associated with a good prognosis were then defined. These included, among others, a carcinoma without extramural venous infiltration or a T3 tumor in the middle and/or upper third of the rectum with less than 5 mm of extramural infiltration (27). It was shown thereafter in the MERCURY-II study that MRI yields a relatively reliable assessment of the potential surgical resection plane (negative CRM) even in deep-seated rectal cancer that has not been treated presurgically (28).

Upper third of the rectum.

Rectal carcinomas in the upper third are usually resected locally. Postoperative (adjuvant) chemotherapy is given as recommended for colon carcinoma.

MRI was also used as a selection criterion for neoadjuvant radiotherapy in the multicenter, observational OCUM study (29, 30, e30 - e32). Patients with adenocarcinoma of the rectum (cT2–4 cN-/+ cM0) at any site were included. Neoadjuvant radiochemotherapy was considered to be indicated for patients with certain risk factors (high-risk group), i.e., cT4 carcinomas, potential involvement of the mesorectal fascia (distance ≤ 1 mm), or cT3 carcinomas in the lower third of the rectum. Neither lymph-node status nor EMVI were used as selection criteria. Patients in the low-risk group underwent primary surgery, generally open. 97.5% of the 527 patients with primary resection had a negative histopathologic circumferential resection margin (CRM), and the R0 resection rate was 99.2% (30). After a median follow-up interval of 61 months, the 3-year local recurrence rate was 2.2%, and the rate of distant metastases was 12.5% (29).

In summary, these data indicate that not all patients with UICC stage II/III (middle and lower third) rectal cancer need neoadjuvant radiotherapy. On the basis of MRI-defined selection criteria, this holds, e.g., in the following situations (3, 9, 11, 31) (Figure 3): cT3a/b cN0 CRM- EMVI- (middle third) or cT1/2 CRM- EMVI- with questionable lymph node involvement on MRI (lower and middle third). Appropriate quality assurance with specialized radiological and surgical expertise is a prerequisite for such an approach.

Post-treatment functional disturbances.

Functional disturbances after treatment are common and can arise after neoadjuvant therapy as well as after surgery.

Ideally, such strategies should be validated by controlled trials, e.g., the ongoing ACO/ARO/AIO-18.2 trial (efigure b), in which it is being studied whether neoadjuvant chemotherapy improves disease-free survival in patients with a low local recurrence risk or with a carcinoma in the upper third of the rectum.

eFigure b.

The randomized ACO/ARO/AIO-18.2 trial of the German Rectal Cancer Study Group

Arm A: neoadjuvant chemotherapy with 6 cycles of mFOLFOX6 or, alternatively, 4 cycles of XELOX, no further adjuvant therapy; Arm B: primary resection, followed by risk-adjusted stratification into follow-up care or chemotherapy (*1 = 6 months; *2 = 3 months). The primary endpoint is disease-free survival. Inclusion criteria: see diagram.

R, randomization; 5-FU, 5-fluorouracil

Watch-and-wait strategy without surgical resection

The mesorectal fascia and neoadjuvant treatment.

A critically important criterion determining the indication for neoadjuvant therapy is a close spatial relation of the tumor to the mesorectal fascia.

As mentioned above, the quality of life in the setting of multimodal therapy is affected by the side effects and long-term sequelae of radiotherapy, chemotherapy, and surgical resection (e24 - e29). The typical complications and sequelae of rectal resection include anastomotic insufficiency (10–20%); wound infection (5–10%); impaired micturition, defecation, and sexual function; and the need for fecal deviation (either temporary in the case of TME or permanent in the case of extirpation). Moreover, most patients who have undergone a rectal resection suffer from a functional disturbance called postresection syndrome (or the low anterior resection syndrome, LARS) (e28, e29, e33, e34), which is characterized by impaired continence, defecation urgency, and frequent defecation. Approximately one-third of patients treated with neoadjuvant therapy develop such dysfunction even without surgical resection (e35).

In recent years, therefore, a strategy has increasingly been followed in which, if there has been a clinical complete response (cCR) to neoadjuvant therapy, no oncological resection is performed and the patient is, instead, very closely monitored over the long term (the so-called organ-preserving watch-and-wait strategy). This strategy has met with intense discussion in view of the description of pCR rates in the range of 25–30% after TNT (17– 20). Thus, as many as one-third of patients treated with TNT may theoretically be eligible for a watch-and-wait strategy.

Neoadjuvant radiotherapy.

In patients with locally advanced carcinoma of the middle and lower third of the rectum, both neoadjuvant long-term radiotherapy and short-term radiotherapy significantly lower the locoregional recurrence rate.

As early as 2004, the Brazilian group led by Habr-Gama published the retrospective long-term results of 71 patients treated with a watch-and-wait strategy (32). After a median follow-up interval of almost five years, two patients had developed local regrowth, and three had developed distant metastases. In 2011, the Dutch research group of Maas and colleagues reported their results in a prospectively studied cohort of 21 patients (33): after an average follow-up interval of 25 months, only one patient displayed local tumor regrowth, which was amenable to curative surgical resection.

Multiple reviews and meta-analyses have been published on this topic recently (e36 - e39). The underlying studies involved selected and markedly heterogeneous patient cohorts, yet their findings suggest overall that most patients with cCR do not develop local tumor regrowth after neoadjuvant therapy, and that most cases of recurrent tumor can be treated with secondary curative surgery. The analysis of an international multicenter registry revealed a 2-year cumulative incidence of local tumor regrowth of 25.2% in 880 patients after a median follow-up of just under 3 years, with 88% of the recurrences being diagnosed in the first 2 years (e40). A recent review (e39) found no support for the initial concern that a watch-and-wait strategy would increase the patients’ risk of developing distant metastases (e40, e41). Nor was any long-term adverse effect of a watch-and-wait strategy on outcome seen in the recently published OPRA trial, in which patients with rectal cancer who had been randomized to one of two TNT arms were treated either with an oncologic resection or with a watch-and-wait strategy, depending on their response to TNT (21).

Adjuvant therapy after neoadjuvant therapy.

There is currently no clear recommendation for or against adjuvant therapy after neoadjuvant therapy and surgical resection.

Employing a watch-and-wait strategy after cCR is still controversial (34– 39, e42). This innovative concept, is, of course, particularly relevant to patients whose tumors are at a site incompatible with a sphincter-preserving resection. Such an approach necessitates careful selection of patients who will be willing to undergo regular, close follow-up (reliable adherence). The recommendations for aftercare that are contained in an international expert consensus statement are presented in eTable 4 (37). Documented expertise in the pertinent techniques of diagnostic radiology and surgical endoscopy is essential as well. Clearly, the use of molecular biomarkers would be very helpful to a watch-and-wait strategy (e43 - e46). According to a joint statement of the AIO, ACO, and ARO, such a strategy for suitable patients (among other treatment options) should be critically discussed, both in interdisciplinary board conferences and with the patients themselves (40). Moreover, the organ-preserving approach in patients for whom TNT has led to a cCR is now being prospectively studied in the ongoing ACO/ARO/AIO-18.1 trial (efigure a).

Overview and future prospects

Total neoadjuvant therapy.

TNT consists of a further type of systemic neoadjuvant therapy (oxaliplatin-containing chemotherapy) given in addition to neoadjuvant radio(chemo)therapy.

The sphere of applicability of total neoadjuvant therapy.

According to current recommendations, TNT should be used for patients with locally highly advanced rectal cancer.

The current treatment of rectal cancer is a prime example of the interdisciplinary, multimodal therapeutic approach. While in the past the emphasis lay on improving long-term oncological outcomes, it now increasingly lies on preserving the patients’ quality of life, and on the functional aspects of the different treatment modalities. A definitive evaluation of innovative concepts such as TNT or the organ-preserving watch-and-wait strategy must await the treatment of suitable patients in randomized controlled clinical trials.

Complete remission after total neoadjuvant therapy.

It is now being studied whether patients with a complete clinical remission (cCR) after neoadjuvant therapy can be spared surgical resection (the organ-preserving watch-and-wait strategy).

Supplementary Material

eMethods

Comparison of resection techniques

Open surgical resection for rectal carcinoma has been compared with laparoscopic techniques in a number of randomized trials (table 1), and one randomized trial has compared laparoscopic with robot-assisted rectum resection (table 1). All of these trials excluded advanced T3 tumors (i.e., those adjacent to the mesorectal fascia) and T4 tumors.

In the COREAN trial, which was conducted in South Korea, patients who had previously been treated with neoadjuvant radiochemotherapy were recruited over the years 2006–2009 (e47 - e49). A major difference between the open-surgery and laparoscopy groups was the longer duration of surgery in the latter group; this was seen in the other trials as well (table 1). The two groups did not differ, however, with respect to oncologic endpoints or the quality of life. In the COLOR II trial, whose patients were recruited from Europe, Canada, and South Korea from 2004 to 2010, the two types of surgery yielded similar outcomes with respect to morbidity, mortality, and oncological endpoints (e50, e51). As in the COREAN trial, laparoscopy was associated with a slightly earlier recovery of bowel function and a slightly shorter hospital stay (table 1). Interestingly, follow-up studies did not reveal any relevant differences between the two types of surgery with respect to the quality of life or the occurrence of urogenital dysfunction or incisional hernia (e52 - e54). In two other trials, a “successful resection” was taken as the primary endpoint, as a kind of surrogate parameter for the long-term oncologic outcome. Most of the patients treated in the ACOSOG Z6051 trial (U.S. and Canada, (2008–2013) had previously undergone neoadjuvant radiotherapy or radiochemotherapy (e55, e56). Laparoscopic procedures were found to take longer than open surgery in this trial as well, but there was no difference in the length of hospital stay (table 1); nor did the two types of surgery differ with respect to achievement of the primary endpoint (“successful resection”). The long-term outcomes published later on were comparable as well. In the ALaCaRT trial (Australia and New Zealand, 2010–2014) (e57, e58), laparoscopic mobilization of the left colonic flexure was permitted in the open surgery group. Laparoscopy was found to take longer than open surgery, but there were no differences with respect to the length of hospital stay or complication rates (table 1). The two types of surgery did not differ, either, in the rate of “successful resection,” and the long-term oncologic outcomes were comparable as well.

There have not been any controlled trials comparing open with robot-assisted surgery, but there has indeed been a trial comparing laparoscopy with robot-assisted surgery. In the ROLARR trial (Europe, U.S., South Korea, Australia, and Singapore, 2011-2014) (e59), the primary endpoint was the rate of conversion to open surgery in the setting of TME. Robot-assisted TME displayed an overall benefit that was not statistically significant (table 1). The two procedures had comparable effects on other endpoints as well, such as the postoperative complication rate, the length of hospital stay, and the positivity of the circumferential resection margin. Unfortunately, the long-term oncologic outcomes remain unknown.

In summary, these trials indicate that the functional and oncologic outcomes of open and laparoscopic rectal surgery are similar, under the key condition of “appropriate surgical expertise and patient selection,” as stated in the guideline (3). The same appears to be true of robot-assisted surgery, although only one large-scale randomized trial of this technique has been conducted to date, with as yet unpublished long-term oncologic results. It was stated in the guideline that “this method should be considered experimental at present,” but, in the meantime, this is no longer true (3, e60). Finally, it should be pointed out once more that there is no evidence from controlled trials to support the use of minimally invasive surgery for advanced T3 and T4 carcinomas, and that special surgical expertise (learning curve, case numbers, team) remains a prerequisite for all minimally invasive procedures.

Further information on CME.

• Participation in the CME certification program is possible only via the Internet: cme.aerzteblatt.de. This unit can be accessed until 21 August 2023. Submissions by letter, e-mail, or fax cannot be considered.

• The completion time for all newly started CME units is 12 months. The results can be accessed 4 weeks following the start of the CME unit. Please note the respective submission deadline at: cme.aerzteblatt.de.

• This article has been certified by the North Rhine Academy for Continuing Medical Education. CME points can be managed using the “uniform CME number” (einheitliche Fortbildungsnummer, EFN). The EFN must be stated during registration on www.aerzteblatt.de (“Mein DÄ”) or entered in “Meine Daten”, and consent must be given for results to be communicated. The 15-digit EFN can be found on the CME card (8027XXXXXXXXXXX).

CME credit for this unit can be obtained via cme.aerzteblatt.de until 21 August 2023. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

Which tumor marker should be measured before the treatment of rectal carcinoma?

1. CEA

2. AFP

3. PSA

4. CA 15–3

5. CA 125

Question 2

What percentage of colorectal carcinomas are located in the rectum?

1. ca. 15%

2. ca. 30%

3. ca. 45%

4. ca. 60%

5. ca. 75%

Question 3

What is the most suitable study for the exclusion of simultaneous colorectal second malignancies?

1. palpation of the abdomen

2. abdominal x-ray

3. abdominal ultrasonography

4. total colonoscopy

5. digital rectal examination

Question 4

What is the current gold standard among staging techniques to assess the anatomical relation of the tumor to the mesorectal fascia?

1. computerized tomography

2. magnetic resonance imaging

3. endosonography

4. positron emission tomography-computerized tomography

5. transabdominal ultrasonography

Question 5

Which finding implies a high-risk constellation and thereby contraindicates local excision of rectal carcinoma?

1. infiltration of the muscularis propria (T2 carcinoma)

2. moderately differentiated tumor (G2)

3. no lymphatic vessel invasion (L0)

4. tumor diameter 2 cm

5. R0 resection

Question 6

According to the German clinical practice guideline, what studies suffice for the evaluation of potential distant metastases in colon carcinoma?

1. tumor markers and physical examination

2. magnetic resonance imaging and positron emission tomography-computerized tomography.

3. (c) endosonography and physical examination

4. (d) positron emission tomography-computerized tomography and ultrasonography

5. (e) abdominal ultrasonography and chest x-ray

Question 7

What is the probability of lymph node metastasis in T1 rectal carcinoma?

1. 10–20%

2. 20–30%

3. 30– 40%

4. 40–50%

5. 50–60%

Question 8

What is NOT a typical side effect of radiochemotherapy for rectal carcinoma?

1. painful proctitis

2. acute diarrhea

3. bone marrow depression

4. chronic diarrhea

5. rotary vertigo

Question 9

Which surgical principle should be followed in oncologic rectal resection?

1. The primary tumor should be resected with an adequate safety margin; there is no need to resect the lymph nodes as well.

2. The procedure should be open surgical, rather than minimally invasive.

3. With carcinomas in the upper third of the rectum, colostomy can usually be avoided.

4. The quality of the surgical TME specimen does not affect the outcome to any relevant degree.

5. TME need not spare the pelvic autonomic nerves, as postoperative dysfunction is rare in any case.

Question 10

According to the joint position statement of the AIO, ACO, and ARO, what is the preferred treatment for patients with locally highly advanced rectal carcinoma?

1. intensified chemotherapy without radiotherapy

2. hyperthermic intraoperative chemotherapy (HIPEC)

3. postoperative chemotherapy

4. radiotherapy alone

5. total neoadjuvant therapy

?Participation is possible only via the Internet: cme.aerzteblatt.de

eTable 3. Recommendations for the follow-up of patients in UICC stage II oder III, modified from (3).

	Months
	3	6	9	12	18	24	36	48	60
History, physical examination, serum CEA		×		×	×	×	×	×	×
Colonoscopy		×*1		×*2					×*2
Abdominal ultrasonography		×		×	×	×	×	×	×
Sigmoidoscopy/rektoscopy*3		×		×	×	×
Computerized tomography*4	×
Chest x-ray				×		×	×	×	×

*¹ if a complete colonoscopy has not been performed preoperatively

*² if findings are unremarkable (no adenoma, no carcinoma), next colonoscopy in five years

*³ without neoadjuvant or adjuvant radiochemotherapy

*⁴ three months after completion of tumor-specific therapy, as a baseline study

CEA, carcinoembryonic antigen

eTable 4. Recommendations for the follow-up of patients being managed with a watch-and-wait strategy because of clinical complete remission after neoadjuvant therapy, according to international expert consensus; modified from (37).

	Year 1	Year 2	Year 3	Year 4
Serum CEA	3 months	3 months	3 months	6 months
Digital rectal examination	3–4 months	3–4 months	6 months	6 months
Endoscopy	3–4 months	3–4 months	6 months	6 months
MRI of the pelvis	3–4 months	3–4 months	6 months	6 months
Chest and/or abdominal CT	6–12 months	annually	annually	annually

CEA, carcinoembryonic antigen; CT, computerized tomography; MRI, magnetic resonance imaging