BACKGROUND:Developments in the quality of care of patients with colon cancer have improved surgical outcome and thus the need for adjuvant chemotherapy.
OBJECTIVE:To investigate the recurrence rate ...in a large population-based cohort after modern staging, surgery, and pathology have been implemented.
DESIGN:This was a retrospective registry study.
SETTINGS:Data from patients included in the Swedish Colorectal Cancer Registry covering 99% of all cases and undergoing surgery for colon cancer stages I to III between 2007 and 2012 were obtained.
PATIENTS:In total, 14,325 patients who did not receive any neoadjuvant treatment, underwent radical surgery, and were alive 30 days after surgery were included.
MAIN OUTCOME MEASURES:Tumor and node classification and National Comprehensive Cancer Network–defined risk factors for recurrence were used to assess overall and stage-specific 5-year recurrence rates.
RESULTS:The median follow-up of nonrecurrent cases was 77 months (range, 47–118 mo). The 5-year recurrence rate was 5% in stage I, 12% in stage II, and 33% in stage III patients. In patients classified as having pT3N0 cancer with no or 1 risk factor, the 5-year recurrence rates were 9% and 11%. Risk factors for shorter time to recurrence were male sex, more advanced pT and pN classification, vascular and perineural invasion, emergency surgery, lack of central ligature, short longitudinal resection margin, postoperative complications, and, in stage III, no adjuvant chemotherapy.
LIMITATIONS:The registry does not contain some recently identified factors of relevance for recurrence rates, and some late recurrences may be missing.
CONCLUSIONS:The recurrence rate is less than that previously observed in historical materials, but current, commonly used risk factors are still useful in evaluating recurrence risks. Stratification by pT and pN classification and the number of risk factors enables the identification of large patient groups characterized by such a low recurrence rate that it is questionable whether adjuvant treatment is motivated. See Video Abstract at http://links.lww.com/DCR/A663.
Staging and treatment of rectal cancer have evolved over several decades with considerably fewer locoregional recurrences but no marked improved survival since systemic recurrence risks remain ...virtually unchanged. This development will briefly be summarised followed by a thorough discussion of two recent developments.
A systematic approach towards the literature is aimed at focusing on organ preservation and the delivery of all non-surgical treatments prior to surgery or total neoadjuvant treatment (TNT).
Organ preservation, that is to defer surgery if the tumour happens to disappear completely after any pre-treatment given to locally advanced tumours to decrease recurrence risks has increased in popularity and is, if not universally, widely accepted. To give neo-adjuvant treatment to intentionally obtain a clinically complete remission to avoid surgery is practised in some environments but is mostly still experimental. TNT, that is to provide both radiotherapy and chemotherapy aimed at killing microscopic disease in the pelvis or elsewhere has been subject to several trials. Collectively, they show that the chance of achieving a complete response, pathologically or clinically, has approximately doubled, increasing the chance for organ preservation, and the risk of distant metastasis has decreased at least in some trials. The best schedule remains to be established.
To obtain substantial progress and also improve survival, the systemic treatments need to be improved even if preoperative delivery is more effective and better tolerated than postoperative. The locoregional treatment may be further optimised through better risk prediction.
Preoperative radiotherapy (RT) or chemoradiotherapy (CRT) is often required before rectal cancer surgery to obtain low local recurrence rates or, in locally advanced tumours, to radically remove the ...tumour. RT/CRT in tumours responding completely can allow an organ-preserving strategy. The time from the end of the RT/CRT to surgery or to the decision not to operate has been prolonged during recent years. After a brief review of the literature, the relevance of the time interval to surgery is discussed depending upon the indication for RT/CRT. In intermediate rectal cancers, where the aim is to decrease local recurrence rates without any need for down-sizing/-staging, short-course RT with immediate surgery is appropriate. In elderly patients at risk for surgical complications, surgery could be delayed 5-8 weeks. If CRT is used, surgery should be performed when the acute radiation reaction has subsided or after 5-6 weeks. In locally advanced tumours, where CRT is indicated, the optimal delay is 6-8 weeks. In patients not tolerating CRT, short-course RT with a 6-8-week delay is an alternative. If organ preservation is a goal, a first evaluation should preferably be carried out after about 6 weeks, with planned surgery for week 8 if the response is inadequate. In case the response is good, a new evaluation should be carried out after about 12 weeks, with a decision to start a 'watch-and-wait' programme or operate. Chemotherapy in the waiting period is an interesting option, and has been the subject of recent trials with promising results.
...inclusion of all cT3 tumours among those given preoperative chemoradiotherapy is today thought to be substantial overtreatment.11 To give patients with early cT3 tumours chemoradiotherapy with a ...fluoropyrimidine risks overtreatment; to add oxaliplatin based on the results of this trial could result in further overtreatment for minimal absolute gains (1-2% at best). ...since many aspects of rectal cancer care have improved we see better overall results and better results in all stages, or stage migration.
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.
A pathology atlas of the human cancer transcriptome Uhlen, Mathias; Zhang, Cheng; Lee, Sunjae ...
Science (American Association for the Advancement of Science),
08/2017, Letnik:
357, Številka:
6352
Journal Article
Recenzirano
Odprti dostop
Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We ...used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.
Summary Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under ...debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4–8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4–8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov , number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2–62·2) in the short-course radiotherapy group and 19·3 months (8·5–39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8–114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 95% CI 0·41–5·11; long-course radiotherapy with delay 2·24 0·71–7·10; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 50% of 129 patients in the short-course radiotherapy group; 48 38% of 128 patients in the short-course radiotherapy with delay group; 50 39% of 128 patients in the long-course radiotherapy with delay group; odds ratio OR vs short-course radiotherapy: short-course radiotherapy with delay 0·59 95% CI 0·36–0·97, long-course radiotherapy with delay 0·63 0·38–1·04, p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 53% of 355 vs 188 41% of 357; OR 0·61 95% CI 0·45–0·83 p=0·001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. Funding Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.
•5-FU and leucovorin are standard therapy in metastatic colorectal cancer.•Systemic chemotherapy agents can increase the efficacy of 5-FU-based treatments.•Optimising route of administration, dosage ...and folate metabolism improves efficacy.•Recent research has focused on addressing variability in folate metabolism.•Agents that do not require metabolic conversion are promising candidate therapies.
Notwithstanding recent treatment advances in metastatic colorectal cancer (mCRC), chemotherapy with a combination of a fluoropyrimidine and a folate agent, often 5-fluorouracil (5-FU) and leucovorin, remains the backbone of treatment regimens for the majority of patients with mCRC. This is despite a recent focus on molecular-targeted treatments and patient stratification according to mutational status or expression levels of specific genes. Intracellular folate concentration was discovered to be pivotal in the cytotoxic efficacy of 5-FU, paving the way to the current standard combination therapy approach. Subsequent discovery that systemic chemotherapy agents, such as irinotecan and oxaliplatin, can further increase the efficacy of 5-FU-based treatments led to the development of several combination chemotherapy regimens, including FOLFOX, FOLFIRI and FOLFOXIRI. Subsequent efforts to optimise 5-FU-based treatments have focused on 5-FU analogues, initially capecitabine and the combination drug tegafur/gimeracil/oteracil (S-1) and then TAS-102, which has recently been evaluated in phase 3 clinical trials for refractory colorectal cancer. Further approaches taken to improve the efficacy of 5-FU chemotherapy regimens have focused on optimising the route and dosing schedules and regulating folate metabolism. Pharmacokinetic variability caused by the requirement for metabolic conversion of leucovorin has been central to recent research, and the development of agents such as arfolitixorin which bypass the need for metabolic conversion remains promising for future therapeutic candidates. In this review, we summarise the evidence leading to the current treatment regimens employing 5-FU and leucovorin, focusing on recent approaches taken to optimise and refine treatments to improve clinical outcomes in patients with mCRC.
The cell surface proteins CD133, CD24 and CD44 are putative markers for cancer stem cell populations in colon cancer, associated with aggressive cancer types and poor prognosis. It is important to ...understand how these markers may predict treatment outcomes, determined by factors such as radioresistance. The scope of this study was to assess the connection between EGFR, CD133, CD24, and CD44 (including isoforms) expression levels and radiation sensitivity, and furthermore analyze the influence of AKT isoforms on the expression patterns of these markers, to better understand the underlying molecular mechanisms in the cell. Three colon cancer cell-lines were used, HT-29, DLD-1, and HCT116, together with DLD-1 isogenic AKT knock-out cell-lines. All three cell-lines (HT-29, HCT116 and DLD-1) expressed varying amounts of CD133, CD24 and CD44 and the top ten percent of CD133 and CD44 expressing cells (CD133high/CD44high) were more resistant to gamma radiation than the ten percent with lowest expression (CD133low/CD44low). The AKT expression was lower in the fraction of cells with low CD133/CD44. Depletion of AKT1 or AKT2 using knock out cells showed for the first time that CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. There were several genes in the cell adhesion pathway which had significantly higher expression in the AKT2 KO cell-line compared to the AKT1 KO cell-line; however important genes in the epithelial to mesenchymal transition pathway (CDH1, VIM, TWIST1, SNAI1, SNAI2, ZEB1, ZEB2, FN1, FOXC2 and CDH2) did not differ. Our results demonstrate that CD133high/CD44high expressing colon cancer cells are associated with AKT and increased radiation resistance, and that different AKT isoforms have varying effects on the expression of cancer stem cell markers, which is an important consideration when targeting AKT in a clinical setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
