Colorectal cancer (CRC) is the third most common cancer worldwide and the second most
common in tumor-related mortality by Global Cancer Statistics 2020 (1). Recent data
show that the incidence and mortality of CRC in China are increasing (2-4), with the
number of new cases and deaths reaching 607,900 and 261,777 in 2019. The Chinese Society
of Clinical Oncology (CSCO) published the first version guidelines in April 2017 and
updated annually according to the latest clinical data and the changes in China’s
national conditions (5-8). Here we present the main updates of the 2022 version compared
with the previous version.
Updated highlights of guidelines from version 2021 to 2022
In general, this year’s guideline updates are limited, mainly involving imaging diagnosis,
postoperative adjuvant chemotherapy, palliative second-line and third-line immunotherapy
for patients with high microsatellite instability (MSI-H)/deficient mismatch repair
(dMMR), and postoperative circulating tumor deoxyribonucleic acid (ctDNA) monitoring.
Imaging diagnosis
After discussion by the expert panel of the guidelines, in the diagnosis of CRC, class
I recommendation was modified to “high-resolution plain computed tomography (CT) or
contrast-enhanced CT of the chest and enhanced CT of the abdominal/pelvic cavity”
for the staging diagnosis of patients diagnosed by colonoscopy. For patients with
iodine contrast agent allergy, class II recommendation “high-resolution plain chest
CT and enhanced abdominal/pelvic magnetic resonance imaging (MRI)” could be used.
Considering the imaging diagnosis of lung, peritoneal and ovarian metastasis, continuous
thin transverse, coronal, and sagittal reconstruction images could be used for differential
diagnosis of lung metastasis of CRC if possible (9); enhanced abdominal and pelvic
CT was recommended to diagnose ovarian metastasis and peritoneal implantation metastasis.
When CT does not confirm the diagnosis of ovarian metastasis, pelvic MRI or gynecological
ultrasound was recommended to assist the diagnosis. MRI was suggested including T2-weighted,
diffusion-weighted imaging (DWI) and multiphasic T1-weighted enhanced imaging sequences
(10).
Postoperative adjuvant chemotherapy
In adjuvant therapy after radical resection of CRC, the description of low-risk stage
II patients was changed from “T3N0M0, dMMR” to “T3N0M0, dMMR, regardless of the clinical
high-risk factors such as poor histological differentiation, lymphatic/vascular invasion,
nerve invasion, preoperative intestinal obstruction or perforation of tumor site,
positive resection margin or insufficient safety distance, less than 12 lymph nodes
dissected (11)”. In addition, based on results of the International Duration Evaluation
of Adjuvant Chemotherapy (IDEA) collaboration, 3 months of CapeOX (capecitabine +
oxaliplatin) adjuvant chemotherapy was recommended for all high-risk stage II patients,
and 6 months of CapeOX was no longer emphasized for T4N0M0 patients (12).
Second-line and third-line palliative treatment for MSI-H/dMMR patients
In the second-line and third-line palliative treatment for MSI-H/dMMR patients, class
II recommendation was modified from “programmed cell death protein 1 (PD-1) inhibitors
with no restriction on the types” to “PD-1/ programmed cell death ligand 1 (PD-L1)
inhibitors”. Meanwhile, because pembrolizumab, nivolumab and envafolimab have been
approved for the treatment of unresectable or metastatic MSI-H/dMMR patients with
solid tumors, including advanced CRC patients who failed to respond to standard treatments
(13,14), the above three PD-1/PD-L1 inhibitors were preferentially recommended for
second-line and third-line therapies.
Postoperative ctDNA monitoring during follow-up of CRC
Recent studies have shown that dynamic ctDNA monitoring is helpful for early warning
of postoperative recurrence and metastasis (15-17), but whether it should be routinely
used for postoperative follow-up and guidance of treatment remains controversial and
requires further evidence.
Combination of PD-1 inhibitors and anti-angiogenetic tyrosine kinase inhibitors (TKIs)
was not included in 2022 version of CSCO guidelines
A phase Ib trial (REGONIVO, EPOC 1603) which applied the combination therapy of regorafenib
and nivolumab to metastatic colorectal cancer (mCRC) patients who had failed to respond
to standard treatments was first reported by Japanese researchers at the American
Society of Clinical Oncology (ASCO) 2019 annual meeting (18). The treatment regimen
was regorafenib (80−160 mg once daily for 21 d on/7 d off, every 4 weeks) combined
with nivolumab (3 mg/kg intravenously every 2 weeks). Twenty-four CRC patients with
microsatellite stablility (MSS) achieved 33.3% objective response rate (ORR). The
median progression-free survival (PFS) in CRC patients was 7.9 months and 12-month
PFS rate was 41.8%. These prominent data held great promise to improve the efficacy
of immunotherapy in mCRC patients with MSS status. Since then, several similar single-arm
exploratory trials were published in large international conferences including ASCO,
European Society of Medical Oncology (ESMO) and ASCO-Gastrointestinal Cancers Symposium
(ASCO-GI). At the 2021 ASCO meeting, Fakih et al. reported a phase II trial (NCT04126733)
based on North American population, in which regorafenib and nivolumab were used.
Among the 70 MSS mCRC patients who failed to standard treatments, only 7.1% ORR was
achieved, with a disease control rate (DCR) of 38.6% at 40 weeks, a median PFS of
8.0 weeks and a median overall survival (OS) of 51.8 weeks. Among them, ORR in patients
with liver metastasis was 0, which was significantly different from the previous REGONIVO
study in the Japanese population.
A phase Ib trial (NCT03903705) of fruquintinib plus sintilimab, reported by Prof.
Li at the 2021 ASCO meeting, showed that fruquintinib (with two different administration
regimens: 3 mg once daily continuously; 5 mg once daily for 14 d on/7 d off, every
3 weeks) combined with sintilimab (200 mg intravenously every 3 weeks) in 44 mCRC
patients who failed to standard treatments achieved 22.7% ORR and 86.4% DCR, with
a median PFS of 5.6 months and a median OS of 11.8 months, among which the 5 mg fruquintinib
group had better data.
The REGOTORI study (NCT03946917) (19), reported by Prof. Xu at the 2020 ESMO meeting,
included 42 mCRC patients with MSS who had received ≥2 previous lines of chemotherapy.
Among 33 patients with at least one imaging tumor assessment, ORR and DCR were 15.2%
and 36.4%, respectively, when using the combination of regorafenib (80 mg once daily
for 21 d on/7 d off, every 4 weeks) and toripalimab (3 mg/kg intravenously every 2
weeks). A median PFS of 2.1 months and a median OS of 15.5 months were reported.
The LEAP-005 study (NCT03797326), presented at the 2021 ASCO meeting, showed that
pembrolizumab (200 mg intravenously every 3 weeks) combined with lenvatinib (20 mg
once daily continuously) resulted in 22% ORR and 47% DCR with a median PFS of 2.3
months and a median OS of 7.5 months in the third-line treatment of MSS mCRC patients.
According to the results of the above single-arm trials, the combination of PD-1 inhibitors
with anti-angiogenetic TKIs in patients with late line MSS mCRC who failed to the
standard treatments was highly inconsistent. Even though using the same combination
regimen, inconsistent data were obtained from different populations. The scheduled
phase III trials of regorafenib combined with nivolumab in comparison with regorafenib
have not initiated due to various reasons, and currently only one phase III clinical
trial LEAP-017 (NCT04776148) is ongoing. The LEAP-017 study is a 1:1 randomized controlled
phase III trial scheduled to enroll 434 patients with non-MSI-H/proficient mismatch
repair (pMMR) who have failed to standard treatments from 117 centers of 15 countries.
The experimental group was treated with pembrolizumab (400 mg intravenously every
6 weeks) combined with lenvatinib (20 mg once daily continuously), while the control
group was treated with standard third-line drug regorafenib (160 mg once daily for
21 d on/7 d off, every 4 weeks) or TAS-102 (trifluridine and tipiracil hydrochloride,
35 mg/m2 twice a day for d 1−5, d 8−12, repeated every 4 weeks). The primary endpoint
was OS, and the secondary endpoints were PFS, ORR, DCR and safety. Therefore, experts
in the guideline group decided, based on the current data, not to add the combined
regimen of PD-1 inhibitor and anti-angiogenetic TKIs to the third-line palliative
treatment in 2022 version CSCO guidelines for the time being, pending the results
of phase III clinical trial of LEAP-017.
Footnote
Conflicts of Interest: The authors have no conflicts of interest to declare.