Lanorec study: Lateral Nodal Recurrence in rectal Cancer

The complexity of rectal cancer treatment increases towards the level of the
sphincter. Tapering of the mesorectum imposes that the circumferential
resection margin (CRM) is more easily involved (R1 resections) than in higher
tumors. In addition, the pelvic nerves, the sphincter complex and reproductive
organs are close by in low rectal cancers, which can lead to morbidity and
reduced quality of life. Oncological and functional outcomes are highly
dependent on available expertise and cooperation within the multi-disciplinary
team.
Distal, locally advanced, rectal cancer has the tendency to spread to lateral
lymph nodes. Previous research has shown that patients with enlarged lateral
lymph nodes have a considerable chance of local recurrence, e.g. 19.5% in 5
years1. Western surgeons have always relied on (chemo)radiotherapy ((C)RT) to
sterilize the lateral compartment containing the internal iliac and obturator
lymph nodes. Eastern surgeons however treat enlarged lateral lymph nodes with a
lateral lymph node dissection (LLND), which is technically challenging to
perform and associated with nerve function disorders. Furthermore, most Western
clinicians consider lateral nodal disease to represent metastatic disease, not
amendable to cure2. Recently, the Lateral Node Study consortium undertook a
multi-center study with 12 centers from seven countries, collecting data over a
5-year period, including all consecutive patients operated for a cT3 or cT4
rectal cancer1,3. In all patients, MRI*s were re-reviewed by a standardized
protocol, examining lateral pelvic nodes, defining these according to size and
the presence of malignant features and relating these to the development of
locally recurrent disease.

In the first publication of the consortium with a total of 1216 patients, it
was shown that a pre- treatment lateral lymph node (LLN) size of * 7 mm results
in an unacceptably high incidence of lateral local recurrence of 19.5%, despite
(C)RT with total mesorectal excision (TME)1. Within the consortium, several
centers performed LLND*s after (C)RT, which resulted in a significantly lower
rate of lateral local recurrence of 5.7% in nodes * 7 mm (p = 0.042).
Furthermore, LLN enlargement did not influence distant metastases rate,
suggesting it is a local issue, which requires to be addressed through targeted
treatment in the pelvis, rather simply representing a marker of poor prognosis
and distant disease.
To assess the value of restaging MRI, patients who underwent (C)RT and had a
restaging MRI were then selected, leaving 741 for analyses: 651 had (C)RT+TME,
90 underwent (C)RT+TME+LLND. In total, 96 patients (14.7%) had nodes * 7 mm in
short-axis on primary MRI (pre-SA). At 3 years after surgery, there were no
lateral local recurrences in 28 patients (29.2%) with nodes that had a
short-axis of * 4 mm on restaging MRI (post-SA). There was an important
difference between the nodes that had a short-axis of * 4 mm on restaging MRI
(post-SA). And, there was an important difference between the nodes located in
the internal iliac compartment versus the ones in the obturator compartment. In
the internal iliac nodes, there was only a 22% chance of becoming * 4 mm.
Pre-SA * 7 mm, post-SA > 4 mm in the internal iliac compartment resulted in a
5-year lateral local recurrence rate of 52.3%. Adding LLND to (C)RT+TME in
these malignant internal nodes, resulted in a significantly lower 8.7% lateral
recurrence rate (p = 0.0071). In the nodes in the obturator compartment, the
chance of becoming * 4 mm was 36%, but even in the nodes * 6 mm (63%) there was
a 0% chance of lateral local recurrence. If the nodes however remained post-SA
> 6 mm, the chance of lateral local recurrence was 17.8%. This was reduced to
0% after a LLND3.

The major drawback from this multi-center study is its retrospective nature.
The institutional protocols stated that the lateral nodal compartments would
always be included in the irradiation volume in these types of rectal cancers.
However, whether this was practiced for each individual patient was impossible
to find out. It might be that the internal iliac were not always included in
the irradiation volume, explaining the low response rate and the high lateral
local recurrence rate. Also, although it was reconstructed from the operation
reports that all patients had a complete formal LLND, surgery was not
standardized, not guaranteeing clearance of all nodes with formal anatomical
landmarks and boundaries of the dissection. So, we don*t know which part of the
high local recurrence rates in enlarged nodes is due to inadequate application
of radiotherapy, and which part is due to not performing (adequate) lateral
lymph node dissections. Moreover, functional outcome and quality of life data
are not known for this cohort of patients. Therefore, a national prospective
registration study is presented here, aiming to standardize radiotherapy and
surgery, and to assess quality of life outcome after this treatment.

To investigate whether a standardized multidisciplinary treatment of rectal
cancer patients with enlarged lateral lymph nodes will decrease the amount of
local recurrences.

Secondary outcomes are morbidity, quality of life and functional outcomes.

Please also see the flowchart in the protocol.

Briefly, patients with rectal cancer and 1/more LNN of >7.0mm in the internal
iliac or obturator compartment can be included. They will undergo standardised
radiotherapy and chemotherapy, according protocol. After 6 weeks a new MRI scan
will be made, and the short-axis of the LNN in the internal iliac/obturator
compartment will be measured again.

If a LLN in the internal iliac compartment <4mm and a clinical complete
response (cCR) => Watch & Wait + FU
If a LLN in the internal iliac compartment <4mm and NO clinical complete
response (cCR) => TME
If a LLN in the internal iliac compartment > 4mm and NO clinical complete
response (cCR) => TME + referral to VUmc for LLND

If a LLN in the obturator compartment <6mm and a clinical complete response
(cCR) => Watch & Wait
If a LLN in the obturator compartment <6mm and NO clinical complete response
(cCR) => TME
If a LLN in the obturator compartment >6mm and NO clinical complete response
(cCR) => TME + referral to VUmc for LLND

Patients with extensive tumors and/or lateral nodal disease which means that
they cannot undergo minimally invasive TME surgery and/or nerve sparing LLND
surgery will drop out of the main study cohort and enter the registration
study. They require invasive and extensive surgery to ensure goed resection
margins. These patients will be followed in the registration cohort.

Patients will undergo follow-up according to local protocol, except that they
will have an additional MRI after 2yrs (this appointment is not extra, but the
MRI imaging is suggested instead of other options such as X-thorax/endoscopy).
Before irradiation and after 6, 12, 36 months a quality of life questionnaire
will be obtained

Standardised radiotherapy and selective lateral lymph node dissection in high
risk patients.

The potential benefit resulting from participation is improvement in
oncological outcome, mainly by the reduction of lateral local recurrence. A
local recurrence is associated with significant morbidity and disease related
mortality. More than half of the patients with a local recurrence can only be
treated palliatively. Another advantage is that patients will be closely
monitored with frequent follow-up visits, with one extra MRI for local
recurrence monitoring.

The potential risks are mostly associated with the performance of a LLND. The
main peroperative complication is bleeding. In the last years, this was mainly
performed via open surgery, but nowadays laparoscopic LLND is gaining interest.
A recent meta-analysis showed that laparoscopic LLND has similar efficacy in
oncological outcomes and postoperative complications to conventional (open)
surgery. Yet, laparoscopic LLND resulted also in advantages of reduced
intraoperative blood loss and shorter postoperative hospital stay.

The most important postoperative complication is a LLND is urinary dysfunction,
caused by autonomic nerve injury during surgery. However, complete preservation
of autonomic nerves during LLND reduces the incidence of dysfunction by 4-8%.
Moreover, recent research showed no significant difference in percentages of
urogenital dysfunction between patients who underwent TME + LLND and patients
who underwent TME alone (i.e. 79% vs 68% in 343 patients).

The main goal of this study is to ensure quality control of LLND*s, by
performance of the procedure by experienced surgeons and video analysis. As
described in chapter 5.4, surgery will be centralized and surgeons will go
through an intensive training and proctoring program, to ensure a standardized
procedure is performed to reduce per- and postoperative complications.

The burdens for patients taking part in this study are not great that patients
who do not take part, except if they undergo a LLND procedure (see above). Then
there are added positives that the local recurrence chance should be reduced.