Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation.
Patients with radiologically staged ...T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with
-wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat.
Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all
< .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351),
< .001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% 118/699
21.5% 76/354; rate ratio, 0.72 95% CI, 0.54 to 0.98;
= .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair-deficient tumors.
Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.
Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The ...role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio OR, 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage.
Over recent years, patient outcomes after colon cancer resection have not improved to the same degree as for rectal cancer. Japanese D3 resection and European complete mesocolic excision (CME) with ...central vascular ligation (CVL) are both based on sound oncologic principles. Expert surgeons using both techniques report impressive outcomes as compared with standard surgery. We aimed to independently compare the physical appearances and quality of specimens resected using both techniques in major institutions in Japan and Germany.
A series of resections for primary colon cancer from one European and two Japanese centers were independently assessed in terms of the plane of surgery, physical characteristics, and lymph node yields.
Mesocolic plane resection rates from both series were high; however, Japanese D3 specimens were significantly shorter (162 v 324 mm, P < .001), resulting in a smaller amount of mesentery (8,309 v 17,957 mm(2), P < .001) and nodal yield (median, 18 v 32, P < .001). The distance from the high vascular tie to the bowel wall (100 v 99 mm, P = .605) was equivalent.
Both techniques showed high mesocolic plane resection rates and long distances between the high tie and the bowel wall. The extended longitudinal resection after CME with CVL increased the nodal yield but did not increase the number of tumor involved nodes. Both series were oncologically superior to recently reported series from other countries and confirm the wide variation in colonic cancer surgery and the need for further standardization and optimization following the approach undertaken in improving rectal cancer outcomes.
Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on ...routine histology slides faster and less expensively than molecular assays. However, clinical application of this technology requires high performance and multisite validation, which have not yet been performed.
We collected H&E-stained slides and findings from molecular analyses for MSI and dMMR from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (N = 6406 specimens) and validated in an external cohort (n = 771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC).
The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound, 0.91; upper bound, 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC of 0.95 (range, 0.92–0.96) without image preprocessing and an AUROC of 0.96 (range, 0.93–0.98) after color normalization.
We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using H&E-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens.
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The prognostic relevance of preoperative high-resolution magnetic resonance imaging (MRI) assessment of circumferential resection margin (CRM) involvement is unknown. This follow-up study of 374 ...patients with rectal cancer reports the relationship between preoperative MRI assessment of CRM staging, American Joint Committee on Cancer (AJCC) TNM stage, and clinical variables with overall survival (OS), disease-free survival (DFS), and time to local recurrence (LR).
Patients underwent protocol high-resolution pelvic MRI. Tumor distance to the mesorectal fascia of ≤ 1 mm was recorded as an MRI-involved CRM. A Cox proportional hazards model was used in multivariate analysis to determine the relationship of MRI assessment of CRM to survivorship after adjusting for preoperative covariates.
Surviving patients were followed for a median of 62 months. The 5-year OS was 62.2% in patients with MRI-clear CRM compared with 42.2% in patients with MRI-involved CRM with a hazard ratio (HR) of 1.97 (95% CI, 1.27 to 3.04; P < .01). The 5-year DFS was 67.2% (95% CI, 61.4% to 73%) for MRI-clear CRM compared with 47.3% (95% CI, 33.7% to 60.9%) for MRI-involved CRM with an HR of 1.65 (95% CI, 1.01 to 2.69; P < .05). Local recurrence HR for MRI-involved CRM was 3.50 (95% CI, 1.53 to 8.00; P < .05). MRI-involved CRM was the only preoperative staging parameter that remained significant for OS, DFS, and LR on multivariate analysis.
High-resolution MRI preoperative assessment of CRM status is superior to AJCC TNM-based criteria for assessing risk of LR, DFS, and OS. Furthermore, MRI CRM involvement is significantly associated with distant metastatic disease; therefore, colorectal cancer teams could intensify treatment and follow-up accordingly to improve survival outcomes.
It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch ...repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy.
Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial.
Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% 25 of 218 v 26% 438 of 1,695 recurred; risk ratio RR, 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% 150 of 542 v 21% 219 of 1,041; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy.
MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.
The plane of surgery in colonic cancer has been linked to patient outcome although the optimal extent of mesenteric resection is still unclear. Surgeons in Erlangen, Germany, routinely perform ...complete mesocolic excision (CME) with central vascular ligation (CVL) and report 5-year survivals of higher than 89%. We aimed to further investigate the importance of CME and CVL surgery for colonic cancer by comparison with a series of standard specimens.
The fresh photographs of 49 CME and CVL specimens from Erlangen and 40 standard specimens from Leeds, United Kingdom, for primary colonic adenocarcinoma were collected. Precise tissue morphometry and grading of the plane of surgery were performed before comparison to histopathologic variables.
CME and CVL surgery removed more tissue compared with standard surgery in terms of the distance between the tumor and the high vascular tie (median, 131 v 90 mm; P < .0001), the length of large bowel (median, 314 v 206 mm; P < .0001), and ileum removed (median, 83 v 63 mm; P = .003), and the area of mesentery (19,657 v 11,829 mm(2); P < .0001). In addition, CME and CVL surgery was associated with more mesocolic plane resections (92% v 40%; P < .0001) and a greater lymph node yield (median, 30 v 18; P < .0001).
Surgeons in Erlangen routinely practicing CME and CVL surgery remove more mesocolon and are more likely to resect in the mesocolic plane when compared with standard excisions. This, along with the associated greater lymph node yield, may partially explain the high 5-year survival rates reported in Erlangen.
To assess magnetic resonance imaging (MRI) and pathologic staging after neoadjuvant therapy for rectal cancer in a prospectively enrolled, multicenter study.
In a prospective cohort study, 111 ...patients who had rectal cancer treated by neoadjuvant therapy were assessed for response by MRI and pathology staging by T, N and circumferential resection margin (CRM) status. Tumor regression grade (TRG) was also assessed by MRI. Overall survival (OS) was estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging of good and poor responders on MRI or pathology and survival outcomes after controlling for patient characteristics.
On multivariate analysis, the MRI-assessed TRG (mrTRG) hazard ratios (HRs) were independently significant for survival (HR, 4.40; 95% CI, 1.65 to 11.7) and disease-free survival (DFS; HR, 3.28; 95% CI, 1.22 to 8.80). Five-year survival for poor mrTRG was 27% versus 72% (P = .001), and DFS for poor mrTRG was 31% versus 64% (P = .007). Preoperative MRI-predicted CRM independently predicted local recurrence (LR; HR, 4.25; 95% CI, 1.45 to 12.51). Five-year survival for poor post-treatment pathologic T stage (ypT) was 39% versus 76% (P = .001); DFS for the same was 38% versus 84% (P = .001); and LR for the same was 27% versus 6% (P = .018). The 5-year survival for involved pCRM was 30% versus 59% (P = .001); DFS, 28 versus 62% (P = .02); and LR, 56% versus 10% (P = .001). Pathology node status did not predict outcomes.
MRI assessment of TRG and CRM are imaging markers that predict survival outcomes for good and poor responders and provide an opportunity for the multidisciplinary team to offer additional treatment options before planning definitive surgery. Postoperative histopathology assessment of ypT and CRM but not post-treatment N status were important postsurgical predictors of outcome.
To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) status in metastatic colorectal cancer (mCRC).
A pooled analysis of four ...phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data.
The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAF(MT). BRAF(MT) was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P < 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors HR, 1.33; 95% confidence interval (CI), 1.12-1.57 and HR, 1.35; 95% CI, 1.13-1.61, respectively), and for patients with BRAF(MT) compared with BRAF wild-type (BRAF(WT)) tumors (HR, 1.34; 95% CI, 1.17-1.54 and HR, 1.91; 95% CI, 1.66-2.19, respectively). PFS and OS were significantly decreased for patients with BRAF(MT) within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAF(WT) or BRAF(MT).
Prevalence of dMMR and BRAF(MT) in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAF(MT) status.
Activating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We ...wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.
The Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.
Three hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio HR, 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).
KRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.
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