With a median follow-up of This landmark study revealed an entire new concept in rectal cancer management and indicated the potential for organ preservation. Since then, the results have been updated, the treatment schedule has changed and many cancer centres are now sharing their own results and helping to build the evidence.
Functional outcome and quality of life following treatment for rectal cancer
The evidence available comes mainly from retrospective data, with great variations on who has been offered surveillance, including patients characteristics and tumour stage. Furthermore, some studies have used inaccurate and insufficient staging modalities, and others have not even reported on tumour staging at baseline. This heterogeneity limits the interpretation of data. There are patients whose comorbidities or performance status preclude any attempt at radical operation, who are instead offered CRT or short-course radiotherapy as an alternative for definitive treatment.
Some of them appear to achieve a cCR and are being subsequently monitored, even though salvage radical surgery will never be an option in case of tumour regrowth. The essence of active surveillance is in patients who are able to avoid surgery, but to whom the procedure will be considered at a time when we feel we need to intervene. A large number of patients end up being monitored because they decline radical surgery. Most of the time, they receive long-course CRT with or without local excision, and those who achieve a cCR or nearCR enter a surveillance program.
Unfortunately, their baseline characteristics are often poorly recorded, making it difficult to know if they would have normally been offered nCRT on a basis of high-risk tumour at baseline. Patients with early-stage low rectal tumours, without any adverse features, amenable to local excision or transanal endoscopic microsurgery should undergo the procedure without neoadjuvant treatment.
If histopathology confirms the full excision and initial low risk preoperative staging, there is no indication for further treatment, and this approach provides excellent oncological and functional outcomes. However, when high risk features are present, such as third submucosal layer sm3 invasion, positive margin, grade 3, lymphovascular invasion, tumour budding or mucinous subtype, and in cases of pT2 tumours, local resection alone is not sufficient. The standard treatment for completion is radical resection, and since the tumours are low, in the majority of cases it results in a permanent stoma.
In the context of organ preservation, only few studies have included patients with early-stage tumours. Habr-Gama et al. As mentioned above, in the initial study by Habr-Gama [ 10 ], the rate of cCR was Similarly, an Italian group of investigators have cumulated several years of experience in organ preservation in early-stage low rectal cancers. They have reported in the results of a prospective randomised clinical trial comparing endoluminal locoregional resection ELRR with laparoscopic total mesorectal excision TME for early-stage cancers following nCRT [ 13 ].
Patients with lymphovascular or perineural invasion were excluded. The patients in the study received upfront nCRT With a median follow-up of 9. All these studies provide interesting data in favour of nCRT followed by surveillance or local resection in patients with early-stage low cancers, suggesting that these patients might actually be ideal candidates for organ preservation. However, they involve a relatively small number of patients. Although promising, this subject raises an ethical issue.
Unless there is a threatened surgical resection margin, which is considered as a high risk feature, patients with early-stage rectal cancer are not typically considered for neoadjuvant treatment. Offering upfront CRT to these patients, the decision based purely on clinical staging, is risky. At our institution, the initial staging of early low rectal cancer includes a high-resolution pelvic MRI amongst other standard investigations.
The results are discussed in our weekly multidisciplinary meeting where images are reviewed and management options discussed. When the CRM is clear and the tumour amenable to local resection, we tend to favour this approach as first-line intervention and rediscuss the case with the final histopathology report. It has the advantage of providing accurate pathological staging on which to base future management decisions. When further treatment is recommended, we favour discussion with the patients regarding completion radical surgery versus CRT in an attempt at organ preservation with close imaging and clinical surveillance, knowing that the latter is not yet standard.
Although we have reported previously on the good oncological outcomes of patients who decline surgery and undergo adjuvant CRT [ 17 ], we prefer, if available, participation in research trials. In rectal cancer, an incomplete resection is associated with a higher risk of local recurrence and significantly worse outcomes [ 18 , 19 ]. With these factors, the study group was able to propose a predicted risk of pCRM involvement. Based on this data, nCRT is justified in patients with high-risk low tumours. Patients who achieve a cCR or nearCR could be offered organ preservation.
These patients might therefore be candidates for intensified treatment, such as further consolidation chemotherapy or surgery beyond TME with excision of the compartments involved by the treated tumour. Patients with locally advanced rectal cancer typically require nCRT, for its proven benefit on locoregional control [ 2 ]. We have previously discussed the low rectal tumours, but what about the proximal ones, those tumours for which a low anterior resection with sphincter preservation is feasible? There are some pros and cons of a NOM in these cases.
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Firstly, avoiding surgery prevents, at least temporarily, the patient from facing the possible consequences of a triple-modality treatment on bowel, urinary and sexual function and its impact on quality of life [ 24 ]. Several studies have found that nCRT is a significant factor of poorer functional outcomes after surgery. Secondly, a radical procedure such as TME has its risks of surgical complications, morbidities and mortality [ 6 ]. On the other hand, one could argue that salvage surgery might potentially be more challenging than an upfront procedure.
This has been described in anal cancer, where surgery is a salvage strategy and carries a higher risk of complications [ 28 , 29 ]. The late side effects of chemoradiation, including pelvic fibrosis, can complexify the surgical technique. At our institution, we favour imaging modalities in our monitoring protocol, but agree that DRE should not be completely discarded. The response assessment will be further discussed below. However, there are several studies looking at ways to optimise the therapy with the objective of increasing the pCR rate and therefore potentially the rate of organ preservation.
The treatment administered was Organ preservation using this standard combination of RT and 5FU or Capecitabine has shown good outcomes, which will be discussed further below. The median interval between the last fraction and the response assessment was No information was given about the pCR rate with long-course RT. The results of their studies have provided strong evidence supporting the use of CXB in selected cases, with high rates of organ preservation and low rates of local recurrence [ 37 , 38 ].
Sun Myint and colleagues also shared their experience with CXB [ 39 ]. They reported on the rate of local regrowth in a context of organ preservation, in patients treated at their centre between and Again, all these patients either declined surgery or were considered unfit for radical resection, hence the referral for further treatment with CXB. The authors argue in favour of CXB for tumour boost, as it has shown one of the lowest reported rates of local regrowth, but these results need to be interpreted cautiously.
A selection bias might have been introduced, the cohort including potentially only highly radiosensitive and biologically favourable tumours. Another study by Dhadda et al. Hopefully, it will provide answers regarding methods of boost delivery and dose escalation. Several groups have studied the intensification or addition of chemotherapy in the neoadjuvant part of the treatment. The most frequently studied, and possibly the most promising, is the addition of oxaliplatin. Patients with cTNany or cTanyNpositive disease were randomised between two arms.
The standard arm received nCRT The treatment including oxaliplatin was well tolerated, without significantly different side effects than the standard arm. Many other groups have studied the inclusion of oxaliplatin and, in addition to increased toxicities, none has resulted in a statistically significant improvement of the pCR rate [ 43 , 44 , 45 , 46 ]. A group from China performed a meta-analysis on the addition of oxaliplatin to the standard 5FU-based regimen of nCRT [ 48 ]. It also led to an improved disease-free survival and lower rate of distant metastases. They recently retrospectively compared the outcomes of patients with cT2N0 disease in the standard regimen with the extended regimen and found that the extended regimen, which was well tolerated, led to a significant increase in the cCR rate Patients with a significant clinical response to treatment are being management with a non-operative strategy.
While some people investigate the intensification of treatment, others are trying to customise it, for example by studying the feasibility of omitting routine use of radiotherapy in locally advanced rectal cancer. Patients who maintained a stable disease or showed progression proceeded with neoadjuvant radiotherapy prior to radical resection TME , whereas patients who responded to treatment went straight to surgery TME. Four patients needed radiotherapy: 2 patients preoperatively and 2 patients postoperatively for positive resection margins.
The GEMCAD trial investigated the safety and efficacy of neoadjuvant chemotherapy alone capecitabine, oxaliplatin CAPOX and bevacizumab in 46 patients with T3 rectal adenocarcinoma with clear predicted resection margins on MRI, also in that case with a selective use of nCRT for patients with progressive disease only [ 51 , 52 ]. Although interesting, this strategy of offering nCRT only to selected patients after an induction course of chemotherapy is not yet an approved treatment option outside of a clinical trial.
The small number of patients in both studies is a limiting factor to draw any conclusion. If organ preservation is sought, radiotherapy should currently be included in the treatment strategy. We know that there is a strong correlation between dose of radiotherapy and tumour response.
In rectal cancer, the work of Ann Appelt has helped to quantify it [ 53 ]. Her team analysed the data on tumour regression from patients with rectal adenocarcinoma, treated with nCRT, and derived a dose-response relationship. Tumour regression was defined using the Mandard system. Total tumour dose was calculated by adding the brachytherapy component of the treatment to the external radiotherapy dose. They found a strong correlation between total tumour dose and tumour response, with One way of escalating the RT dose is with endorectal brachytherapy.
One of its advantages over external beam RT is that it can deliver high dose of RT to a localised area. The exposure to surrounding healthy tissues is reduced, as the dose decreases with distance from the source. Buckley and colleagues did a systematic review on high-dose-rate brachytherapy HDRB in rectal cancer [ 54 ].
The main limitations of this systematic review were the large variations in patient selection, the lack of long-term outcomes and the significant paucity of data on toxicities. Seventy-eight per cent of patients achieved cCR, and Te Vuong and her team at McGill University have accumulated years of experience in HDRB and have reported good oncological outcomes in selected patients [ 56 , 57 ]. Understandably, it makes sense to aim for dose escalation, knowing that it will likely provide higher tumour regression, but in rectal cancer, caution is advised as the majority of patients will still go to surgery.
Low rectal cancer: current approach based on magnetic resonance imaging
It therefore might be inappropriate to push the dose above a certain level. Patients could face more complex surgeries, with a higher risk of complications and could potentially have to deal with poorer functional outcomes in the long term. There is an ongoing debate on the best interval between treatment completion and response assessment. In order to clarify the optimal timing for restaging after neoadjuvant treatment, we can take a look at what we know so far on timing of surgery and its relation with the pCR rate.
Several retrospective studies have suggested a higher rate of pCR when delaying surgery after nCRT [ 67 , 68 , 69 ]. Since then, multiple prospective trials have been conducted to answer the question on timing, but report conflicting results. The surgeries were equivalent in both groups, without a significant increase rate of complications in either group.
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Automatically, this led to each group with a longer interval between nCRT and surgery: 8. It is reasonable to believe that both the timing and the addition of consolidation chemotherapy had an impact on the pCR rate, but it is impossible to quantify the role of each. In that study, increasing the interval between nCRT and surgery did not lead to a significant difference of pCR rate 15 vs There were no significant statistical differences in the rate of anastomotic leak, perineal healing problems and mean hospital stay between the two groups.
Sun et al. The analysis included 11, patients. Interestingly, the investigators did not find any threshold regarding readmission rate, day mortality rate and overall survival. Another group of investigators has also interrogated the NCDB, over the same period — , and came with different results [ 77 ]. Thirteen studies, of overall medium quality, were included in the analysis. The longer interval led to a higher rate of pCR RR 1. There were no significant difference in the overall survival, disease-free survival, rate of complete resection R0 , rate of sphincter preservation procedure and wound and anastomotic leak events.
Patients who have shown some degree of response might actually benefit from longer waiting and perhaps consolidation chemotherapy in some of them. One of the major challenge in the NOM of rectal cancer is the careful selection of patients suitable for this approach. The objective is being able to identify patients who would have a pCR if operated on, out of all those who achieve a cCR. For the moment, the methods employed have several limitations, and cCR does not correlate perfectly with pCR.
In the original publication from Habr-Gama and colleagues, 8. Other groups have reported even greater discordance. Creavin and colleagues showed that Even in the absence of any residual mucosal abnormality, some people will proceed with random biopsies of the treated scar area, with the hope of being able to document a complete response. When a visible abnormality is suspicious for residual disease, some people would also proceed with biopsy, in that case to confirm the presence of tumour and support the indication for surgery.
These numbers are derived from only three biopsies truly negative and therefore should be taken cautiously. Nevertheless, some people will say that a positive biopsy is enough evidence on its own to proceed with surgery. We disagree, and question the justification of surgery on the basis of a few cells discovered in the sample, without any way of proving their viability. The aspect of timing is also crucial here. That is the reason why we strongly favour the concept of regrowth.
A biopsy reflects the situation at a precise time point. In our opinion, monitoring for regrowth, using imaging modalities and clinical examinations, for example, is a more reliable measure as it takes into account the notion of time. If there is evidence of regrowth, than the residual cells have proven their viability and their ability to proliferate. That is when an intervention, in most cases salvage surgery, should be considered, but a randomised trial is needed if such an approach is to be adopted to ensure that patients are not disadvantaged during this wait period through the development of metastatic disease.
It usually refers to tumours that show a very good response to treatment, but do not fulfil all criteria for a cCR. When a patient presents a nearCR, some people would favour TEM when technically feasible and have described good rates of organ preservation with this approach [ 59 , 62 ]. Proceeding with TEM avoids the geographical miss that is possible with random biopsies, but timing is still an issue.
In a study by Martens et al. Thirty-nine patients presented with a nearCR. The aim of the study was to accurately determine the number of patients with minimal residual disease ypT Out of 51 patients who completed nCRT 50— Twenty-eight per cent of patients who had TEM experienced postoperative complication. The 21 patients with pCR in the CARTS study were obviously overtreated, and we believe that some of the patients with residual disease would probably have pCR as well, if allowed more time to achieve it.
A typical appearance scar is visible, with no evidence of tumour recurrence. We agree that those are helpful tools; however, they are not sufficient on their own. More prominent fibrotic changes could be easily interpreted as residual disease at the site of the primary tumour. Therefore, imaging might be a more robust and less subjective method of assessing response. In a series by Perez et al. TRG1—thin fibrosis, low-density signal on T2-weighted images with no evidence of intermediate signal intensity at the site of the treated disease.
TRG2—dense fibrosis with no macroscopic evidence of intermediate T2 signal intensity Fig. TRG3—predominating low signal fibrosis with macroscopic scattered or local intermediate signal intensity. The tumour borders the intersphincteric plane, therefore the CRM is involved at the level of the distal levators a. Post CRT MRI demonstrates an area of low signal fibrosis at the site of the treated tumour, and no evidence of macroscopic residual intermediate signal suggestive of tumour—mrTRG2 b. This imaging method of assessment response has been tested in a number of international prospective trials and confirmed to be an independent factor of prognosis and also shows to be a reproducible imaging tool [ 87 ].
Furthermore, a recent analysis showed that mrTRG is 10 times more likely to identify patients with complete pathological response when compared with clinical assessment, particularly residual mucosal abnormality [ 88 ]. Supporters of the DW imaging approach are suggesting that residual high signal intensity at the site of the treated tumour on high b-values images is indicative of areas of residual tumour and these patients should not be offered deferral of surgery approach.
Currently, there is no evidence to indicate that apparent diffusion coefficient ADC measurements improve accuracy in detecting patients with a good response to treatment or that it provides any added value when mrTRG is utilised and studies have not yet been able to validate cut-off values or definitions for good versus poor response using DWI or ADC values that can be prospectively tested against survival outcomes [ 90 , 91 , 92 ]. Endoscopic ultrasound, although proven valuable for the initial staging of rectal cancer, is unfortunately not the most helpful in tumour reassessment post treatment.
Further details are available in the protocol, including chemoradiotherapy regimen, chemotherapy agents and number of cycles. Several investigators have tried to determine and better understand factors that may predict response to CRT. This is an attractive field of research, as it has the potential to help clinicians select the appropriate candidates for organ preservation. A group of investigators has developed a nomogram to predict pCR post nCRT in locally advanced rectal cancer [ 95 ].
Other researchers have developed similar nomograms, using different factors [ 96 , 97 ]. This is interesting and could indeed give us an idea of the likelihood of achieving pCR, but these nomograms will always remain imperfect. Rectal cancers represent a group of diverse tumours, with inherent characteristics that can potentially influence the outcome of the treatment. Histology is one of them.
The vast majority of tumours are adenocarcinoma, but subtypes include mucinous cancers which come with poorer outcomes and relative resistance to CRT [ 98 ]. Also, tumours that macroscopically look similar can express a wide range of different mutations. Furthermore, there is intratumoral heterogeneity, which illustrates the danger of supporting a management strategy and predict pCR on a biopsy sample only. Similarly, two rectal cancer patients with the same overall burden of disease can express different carcinoembryonic antigen CEA levels.
Several studies have found the CEA level, either prior to any treatment or after nCRT before radical surgery, to be a strong factor of tumour regression and pCR [ , , ]. The location of the tumour within the rectum, its size, its circumferential extent, have all been recognised as possible predictive factors of response [ , ]. There are many characteristics of the host that could potentially influence the outcome of the treatment. Examples include the immune system, the presence of chronic disorders such as inflammatory bowel disease or diabetes and active cigarette smoking.
Medication might be an important confounder, for example immunosuppressor agents like cyclosporin, tacrolimus or even simple corticosteroids. There is not much data on medication and response to treatment, but researchers have found that the use of statins increases tumour regression with CRT [ , , ]. Similar to the CEA level, the link between the neutrophil-lymphocyte ratio NLR or other inflammatory markers and tumour regression is being studied and is promising [ , , ].
The treatment administered, including the modality, the dose, the delays or interruptions, obviously has an impact on the outcomes. Timing, discussed in details earlier, has also a major influence on the response to treatment. Other possible confounders, on which there is paucity of data, include other interventions, like trauma from multiple biopsies, for example.
Could it have an impact on the risk of regrowth? There are differences between monitoring residual disease and monitoring a cCR. As discussed above, at our institution, we favour the surveillance for absence of regrowth, irrespective of residual tumour.
We have said earlier that, from our point of view, biopsies are unnecessary and we also believe they might actually be harmful. Unless we find a way of proving viability of tumour cells, waiting and monitoring for regrowth is preferable. Some people are sceptical of this approach and argue that there is a risk of distant metastasis with residual tumour.
Since the NOM approach in rectal cancer is fairly recent, little is known regarding the functional outcomes and quality of life of patients being managed with this strategy. Some authors have attempted comparing it with anal cancer, in which the first-line treatment is definitive chemoradiation, but such a comparison is inadequate. This is mostly due to the different chemotherapy regimen, radiation fields, doses and dose distribution.
The concomitant chemotherapy was oral tegafur-uracil. Faecal incontinence was recorded at every visit. The median score at baseline 38 patients was 9. As mentioned in a previous section, Martens and colleagues prospectively studied a cohort of patients who received standard nCRT, achieved a cCR and were consequently offered an organ preservation strategy [ 60 ]. Faecal incontinence was assessed using the Vaizey score. A total of patients entered the program. The CCII score was 2. It will provide precious information on functional outcomes and QoL.
They analysed the combined evidence on rate of local regrowth and salvage therapy and compared the rates of relapse and survival outcomes between patients managed with NOM and patients managed with surgery. They defined local regrowth as evidence of intraluminal tumour detected clinically, endoscopically or radiologically. Nodal disease was considered as non-regrowth recurrence, which also included any non-luminal intrapelvic disease or distant metastatic disease.
The final analysis included 23 studies, with a total of patients. The pooled rate of local regrowth was For those patients undergoing salvage surgery, the rate of sphincter preservation was Kong et al. They measured the rate of local regrowth, salvage surgery, disease-free and overall survival.
They defined local recurrence as any evidence of relapse after surgery, either immediate surgery or salvage surgery. The rate of tumour regrowth was The rate of distant recurrence without tumour regrowth was 1. The reasons for not undertaking salvage surgery was equal about a third each between: presence of distant metastases, patients unfit for surgery and patients declining surgery.
With a median follow-up time of 2. The future is promising with regard to organ preservation in rectal cancer, and interest is growing fast. Despite some major advances in the last few years, there are still many challenges and aspects of the strategy that need refinement. The selection of patients, the identification of accurate predictors of response and the increase in response rates by intensifying treatment yet offering an acceptable toxicity profile are all examples of exciting areas of development.
With the evidence we have so far, we could reasonably predict that the treatment of rectal cancer is likely to be tailored and risk-adapted to each specific patient. For example, patients who show some response to nCRT could be monitored and be allowed longer delays in order to let them achieve the best possible response. On the other hand, patients who do not respond to treatment are unlikely to benefit from longer waiting period and should proceed with surgery at a time point that allows a safe and successful procedure.
Alternatively, they might be the ideal candidates for further chemotherapy. However, this database seems to combine a heterogeneous group of patients, stages, assessments and monitoring protocols that may lead to inaccuracy of results. This article does not contain any studies with human or animal subjects performed by any of the authors. Skip to main content Skip to sections. Advertisement Hide. Download PDF.
Open Access. First Online: 07 March Purpose of Review Pathological complete response is seen in approximately one fifth of rectal cancer patients following neoadjuvant chemoradiation. Recent Findings The major challenges in interpreting the data on watch-and-wait are the significant heterogeneity of patients selected for this approach and of methods employed to identify them. Summary There is currently not enough and not robust enough evidence to support watch-and-wait as a standard approach, outside a clinical trial, for patients achieving clinical complete response following neoadjuvant chemoradiation.
Introduction The standard treatment for high-risk non-metastatic rectal adenocarcinoma is neoadjuvant chemoradiation nCRT followed by total mesorectal excision TME with or without adjuvant chemotherapy. Patients Not Fit for Radical Resection There are patients whose comorbidities or performance status preclude any attempt at radical operation, who are instead offered CRT or short-course radiotherapy as an alternative for definitive treatment. Patients with Early-Stage Low Tumours Patients with early-stage low rectal tumours, without any adverse features, amenable to local excision or transanal endoscopic microsurgery should undergo the procedure without neoadjuvant treatment.
Patients with High-Risk Low Tumours In rectal cancer, an incomplete resection is associated with a higher risk of local recurrence and significantly worse outcomes [ 18 , 19 ]. Patients with Advanced Cancer Patients with locally advanced rectal cancer typically require nCRT, for its proven benefit on locoregional control [ 2 ]. The limitations of the data we have so far are related to the lack of accurate staging or standardisation of selection policies for CRT.
Figure 1 summarises our current institutional policy for rectal cancer management, including organ preservation strategies. Open image in new window. Addition of Consolidation Chemotherapy vs Neoadjuvant Chemotherapy Several groups have studied the intensification or addition of chemotherapy in the neoadjuvant part of the treatment. On endoscopic and clinical evaluation, a whitening of the rectal mucosa can be observed, with or without associated telangiectasia Fig. The rectal wall can also show loss of pliability. Possible signs of incomplete response are, on endoscopy, the observation of any residual ulcer deep or superficial, with or without a necrotic centre , significant stenosis and on digital examination the palpation of any residual nodule.
Magnetic resonance imaging MRI is a powerful tool to assess tumour response. In any case, MRI should be of high quality to enable visualisation of fine details of the tumour spread as well as assessment of tumour response. According to mrTRG grading system patients are categorised in 5 groups: TRG1—thin fibrosis, low-density signal on T2-weighted images with no evidence of intermediate signal intensity at the site of the treated disease TRG2—dense fibrosis with no macroscopic evidence of intermediate T2 signal intensity Fig.
The findings defined for each modality are used to divide patients between complete responders, near complete responders and incomplete responders. This assessment protocol is currently being tested and validated in the MSKCC phase II multi-institutional trial mentioned earlier [ 49 ]. We do not take into account DRE and endoscopy findings at this point. Patients who then fulfil the criteria for good responders enter the same surveillance program. Patients still deemed poor responders are referred for radical surgery.
Endoscopy and DRE are used in the surveillance protocol, and their findings are taken into account when there is suspicion of regrowth. The trial flowchart is summarized in Fig. Tumour-Related Factors Rectal cancers represent a group of diverse tumours, with inherent characteristics that can potentially influence the outcome of the treatment. Patient-Related Factors There are many characteristics of the host that could potentially influence the outcome of the treatment.
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External Factors The treatment administered, including the modality, the dose, the delays or interruptions, obviously has an impact on the outcomes. Its follow-up schedule is summarised in Table 1. Of note, biopsies should not be done routinely, but only if regrowth is suspected and should be taken only after MRI and PET-CT are performed to reduce the rate of false-positive finding on imaging. Table 1 Follow-up schedule in the Deferral of Surgery trial.
Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Sauer R, et al. To facilitate the design of personalised therapeutic strategies for CRC patients, it is therefore important to identify biomarkers which are able to accurately predict the sensitivity of patients to the potential therapies and to estimate the likely course of the illness. Recent advances in the fields of genomics and proteomics have contributed to our understanding of CRC at the molecular level by evaluating the expression profiles of genes and proteins in tissues and body fluids.
To date, some of the candidate biomarkers have yielded somewhat contradictory results. On the other hand, several studies have identified candidate molecular biomarkers that may help to predict the response to cytotoxic chemotherapy and guide treatment selection. We should also consider other markers which it has been suggested may be useful for predicting patient responses to biological agents, in particular anti-epidermal growth factor receptor EGFR monoclonal therapy.
EGFR is a member of the transmembrane tyrosine kinase receptor family ErbB, involved in tumour cell proliferation, inhibition of apoptosis, invasion, migration and angiogenesis [ 59 - 60 ]. When a ligand binds the EGFR homo or hetero-dimers are formed with other ErbB family members, initiating two main intracellular cascades, which are important for cell survival, proliferation and migration.
Abnormal expression of EGFR has been demonstrated in many advanced tumours, including in breast cancers, gliomas and lung cancer. For these reasons, researchers started to explore therapeutic strategies to disrupt EGFR function. However, its exact role in the CRC metastatic cascade has not yet been characterised due to controversial results obtained with anti-EGFR antibody therapy.
In fact, it has been shown that the response to this therapy is independent of EGFR expression in tumour tissue [ 63 ]. These findings prompted an effort to identify alternative predictive molecular biomarkers that could help to select patients more likely to benefit from anti-EGFR agents. When the KRAS protein is bound to GTP, it relays signals of cellular proliferation and inhibition of apoptosis, acting as a typical oncogene. Specifically, mutations in codons 12 and 13 of exon 2 have been demonstrated to predict low response rate to EGFR monoclonal antibodies-targeted therapy [ 65 ].
For instance, the reported frequency of NRAS mutations is 2. Patients with tumours with these mutations had a significantly poorer response rate to anti-EGFR therapy [ 68 ], although no significant differences were seen in overall survival between patients with wild-type and mutant NRAS. In a retrospective study, Di Nicolantino et al.
Moreover, De Roock et al. However, because the number of patients with these mutations is very low in most studies, there is a need for controlled trials to assess whether the use of BRAF and PIK3CA mutation analysis as predictors of anti-EGFR therapy efficacy improves clinical outcomes [ 70 ]. VEGF is overexpressed in CRC and the level of expression is directly correlated with the development of metastasis [ 72 ]. Although several groups have focused their research efforts on finding a biomarker to accurately predict the clinical benefit of adding bevacizumab to therapy, no predictive molecules have yet been identified.
Several candidate predictive biomarkers similar to the KRAS mutation for cetuximab, have been proposed for bevacizumab, but they have remained elusive [ 73 ]. Another candidate is Ang-2, a regulator of angiogenesis that exerts context-dependent effects on endothelial cells. Although this ligand binds the endothelial-specific receptor tyrosine kinase 2 TIE2 and acts as a negative regulator of angiogenesis, recent data from analysis of tumours indicate that, under certain conditions, Ang-2 can stimulate endothelial cells, acting as an anti-apoptotic agent in these cells [ 76 ].
In this context, serum Ang-2 has been proposed as a candidate biomarker due to the fact that patients having low pre-therapeutic Ang-2 serum levels was significantly associated with response rate after receiving bevacizumab-containing treatment, though results should be further validated [ 77 ]. Recently, the development of quantitative predictive biomarkers has led to the increased use of imaging in the evaluation of tumour angiogenesis. Although it is difficult to evaluate the subtle changes occurring during bevacizumab treatment, correlations between tumour grade, microvessel density and VEGF expression in clinical trials of angiogenesis inhibitors have led to DCE-MRI parameters being proposed as biomarkers of drug efficacy [ 73 ].
Lastly, some authors have investigated changes in plasma cytokines and angiogenic factors during treatment as potential markers of therapeutic response and resistance [ 78 ]. Due to the genetic heterogeneity of CRC, many authors agree that it is likely to be necessary to assemble a panel of biomarkers to obtain high enough sensitivity to use these types of biomarkers as a screening test in clinical practice [ 48 , 52 ]. To date, however, a limited number of markers have been identified in CRC, and their individual use has led to conflicting results. In this context, advances in genomic techniques, such as DNA microarrays allowing high-throughput analysis of genes , are very important as they provide large volumes of data which increases the probability of uncovering potential biomarkers.
If validated, these signatures will quantify the likelihood of differential treatment benefit from 5-FU-based therapy [ 79 ]. Further, DNA microarray-based gene expression profiling provides a strategy to search systematically for molecular markers of colon cancer. Gene expression analysis studies have already resulted in many new insights into cancer biology and mRNA expression analysis is turning out to be a very useful tool for disease outcome prediction [ 80 - 81 ].
The current treatment recommendations for mCRC indicate that therapeutic approach should be multidisciplinary [ 82 ], as surgery plus perioperative treatment offers better survival than surgery alone in patients with resectable or potentially resectable disease. Thus, whereas primary surgery is the gold standard for individuals with a single mestatasis, it seems that for multinodular disease, neoadyuvant chemotherapy followed by surgery may be more appropriate [ 83 ].
Though in cases of unresectable aggressive disease, treatment should be decided on a case-by-case basis adapting the strategy to the characteristics of the patient , a multidisciplinary approach should be taken to planning treatment from the outset. In fact, in select unresectable patients chemotherapy allows subsequent rescue surgery and achieves a significant increase in five-year survival rates [ 39 ]. An essential aspect of the treatment strategy for advanced CRC is the consideration of treatment as a continuum.
Thus, sequential administration of conventional drug combinations based on fluoropyrimidines plus oxaliplatin or irinotecan, results in longer survival. The development of new drugs that selectively target specific molecular pathways involved in tumour progression targeted therapy has resulted in one of the most important advances in mCRC in the last decade, with biological agents today being a commonly used weapon in the armamentarium against mCRC, particularly in chemorefractory patients and those who are not initially suitable liver resection candidates [ 87 ].
GFs have been identified as important targets [ 88 ]and the development of targeting biological agents, directed to block effects of GFs on tumour cells, and their integration with cytotoxic chemotherapy regimens has resulted in significant improvements in efficacy outcomes.
One of the most important effects of some GFs is the promotion of angiogenesis, an essential mechanism for both primary tumour growth and metastasis. Due to this, novel therapeutic approaches have focused on the role of angiogenesis-targeting inhibitors. So far, three antiangiogenic biological agents have been approved for the treatment of patients with mCRC: bevacizumab, cetuximab and panitumab.
The first successful targeting agent was bevacizumab; today, there is clear evidence to recommend addition of this anti-VEGF antibody to cytotoxic therapy irrespective of the selected chemotherapy regimen in both the first- and second-line treatment, this significantly increasing overall survival [ 75 ]. In addition, it is also important to note that in patients with mCRC on a bevacizumab-containing regimen who show disease progression and hence need a change in the chemotherapy regimen, maintenance therapy with bevacizumab appears to be associated with significantly longer overall survival than the same regimen without bevacizumab [ 90 ]; this fact highlights the importance of bevacizumab therapy beyond disease progression in patients with mCRC, although this use is not currently recommended outside clinical trials.
The other two antiangiogenenic biological agents, cetuximab and panitumumab target the ligand-binding domain of EGFR. Signalling of this receptor appears to modulate angiogenesis via the upregulation of VEGF and other angiogenic factors [ 60 ]. In fact, as described previously, BRAF and codon 12 KRAS mutations are predictive of adverse outcome in CRC patients receiving cetuximab, being associated with a shorter time to progression and poor survival [ 91 ].
In contrast, it has been demonstrated that the combination of chemotherapy, such as irinotecan or FOLFIRI, and cetuximab as a first line in patients with wild-type KRAS significantly improves survival [ 67 , 92 ]. Cetuximab is also indicated as a monotherapy in such patients following failure of both irinotecan- and oxaliplatin-based chemotherapy [ 93 ], while panitumumab is also a valid second-line option for wild-type KRAS patients, as a monotherapy or combined with FOLFIRI [ 94 ], though the addition of this EGFR inhibitor to oxaliplatin-based chemotherapy in first-line treatment of mCRC did not improve survival or response rate [ 95 ].
In an attempt to increase anti-tumour activity by simultaneously blocking both VEGF and EGFR pathways, some randomised studies have explored the combination of cetuximab or panitumumab with bevacizumab plus chemotherapy, but no benefits were observed, and in some cases the outcome was actually poorer with a greater toxicity, so this type of combination is not recommended for mCRC [ 64 ]. In relation to toxicity, treatment with these biological agents is associated with a wide range of adverse events that sometimes require discontinuation of treatment; these include severe hypersensitivity and skin toxicities, in the case of EGFR mAbs, and hypertension, thromboembolic events, bleeding and proteinuria, with bevacizumab treatment [ 93 ].
Despite the aforementioned advances, the targeted biological agents currently available are only effective in a small subset of patients for example, less than half of the KRAS-wild type patient population benefits from anti-EGFR strategies [ 96 ]and their overall impact on the treatment of mCRC has been relatively modest beneficial effects only lasting on the order of weeks to a few months. These limited results, coupled with the undesirable effects, has led to intensification of the search for novel antiangiogenic therapies to increase the anti-tumour activity in advanced CRC.
Like aflibercept, ramucirumab is currently being evaluated in combination with FOLFIRI in a phase III trial for the second-line treatment of mCRC patients for whom prior oxaliplatin- and bevacizumab-containing initial therapy has failed [ ]. In a recent phase III study CORRECT trial , regorafenib has been found to improve survival in mCRC patients who progressed after all standard therapies, making it the first small-molecule multikinase inhibitor to have demonstrated survival benefits in such patients [ ].
This FGF signalling blockade may represent an important advantage, since it has been suggested that resistance to bevacizumab is associated with increased expression of FGF [ 78 ], and hence brivanib could have antiangiogenic activity in bevacizumab-resistant patients.
These aforementioned data provide the rationale for targeting this pathway therapeutically in CRC patients. The mTOR inhibitors are analogues of rapamycin, including everolimus and temsirolimus, which are being investigated in clinical trials in combination with irinotecan, cetuximab, FOLFOX, bevacizumab or panatimumab in patients with mCRC progressing on prior chemotherapy [ ].
Current expert opinion suggests that mTOR inhibitors may represent an attractive anti-tumour target in combination with strategies to target other pathways that may overcome resistance [ ]. In relation to this, it has been demonstrated that addition of the multikinase inhibitor, sorafenib, enhances the therapeutic effect of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs [ ].
In addition, it has been suggested that mTOR inhibition by metformin an antidiabetic drug , via activation of the AMP-activated protein kinase AMPK pathway, which functions as a sensor for cellular nutrient and energy levels, could be a new option for CRC [ ]. Autophagy is a multistep process of sequestration and subsequent elimination of cytosolic proteins, damaged organelles and protein aggregates in autophagosomes [ ]. This self-degradation, via the lysosome, is responsible for the maintenance of intracellular homeostasis and enables cell survival under stress conditions. In the cancer cell, autophagy can be used as a strategy of self-adaption to generate nutrients and energy during tumour progression and in periods of hypoxia and stress, such as induced by chemotherapy, leading to development of drug resistance.
The role of autophagy after chemotherapy remains controversial, it having been suggested that autophagy induction may increase efficacy of other anti-tumour agents, while most evidence suggests that the inhibition of autophagy is what can increase the effectiveness of these agents. Given that HCQ induces ocular toxicities, such as retinopathy, novel autophagy inducers, such as Lys05, are currently being investigated in CRC [ ]. Proteasome inhibitors have also been described as autophagy inducers. It has been shown that proteasome inhibition generates a stress response through alteration of the protein milieu, which, in turn, induces endoplasmic reticulum stress; this causes an accumulation of misfolded proteins in the endoplasmic reticulum lumen and, consequently, induction of cellular stress responses, such as the unfolded protein response and autophagy to maintain endoplasmic reticulum homeostasis [ ].
Bortezomib, the main proteasome inhibitor, was shown to induce autophagy in CRC cells [ ]. However, in a randomised phase II study in relapsed or refractory CRC, bortezomib alone or in combination with irinotecan was not effective [ ]. There are current trials examining combinations of bortezomib with other chemotherapies, such as oxaliplatin, 5-FU and leucovorin, in patients with advanced CRC [ ].
In view of the limited results with autophagy inducers, some authors have suggested that optimal anti-tumour efficacy might be achieved by the combination of proteasome inhibitors and autophagy inhibitors [ ]. Cancer stem cells CSCs are a subpopulation of tumour cells that possess the capacity to self-renew and to give rise to the heterogeneous lineages of cancer cells that comprise the tumour, and it is believed that they could be crucial in controlling and curing cancer [ ].
Specifically, there is increasing evidence that CSCs play an important role in the occurrence, growth, and progression of tumours, as well as possibly in the initiation of distant metastases. In addition, CSCs are also involved in resistance to conventional chemotherapeutic drugs, novel tumour-targeted drugs, and radiation therapy [ ]. In fact, it has been suggested that CRC stem cells are responsible for tumour relapse, because conventional drugs fail to eliminate the CSC reservoir [ ].
Due to this important clinical feature, CRC stem cells have recently been identified as a rational therapeutic target. Several CSC-targeted therapies have been proposed, including microbial- and plant-derived biomolecules; therapies directed at CSC-specific surface markers; some classical drugs, such as tranilast, curcumin and thioridazine; and reversal of their resistance to anti-tumour agents; so far, however, the toxicity of some of these approaches in normal stem cells and treatment resistance remain important limitations [ ].
Among these, Wnt, stands out for being particularly active in the majority of CRCs, and hence is the first being investigated for therapeutic targeting in CRC. Despite the importance of this pathway, few compounds have progressed beyond preclinical development. Efforts have been made to investigate the inhibition of a number Wnt genes, including the matrix metalloproteinases MMPs , which play an important role in the degradation of extracellular matrix component, crucial for invasion and metastasis. Further, several therapeutic MMP inhibitors have been developed, but so far they have failed to produce a survival benefit and, in addition, they have been associated with adverse effects, such as musculoskeletal syndrome.
The development of more selective MMP inhibitors is seen as a possible way forward [ ]. The results from preclinical trials and its ability to kill therapy-resistant cancer cells make salinomycin a promising anticancer drug [ ]. It has been suggested that combinations of these agents and conventional therapy could significantly reduce tumour growth, metastasis and recurrence [ ]. CSCs are characterised by two main properties of normal stem cells, self-renewal and differentiation. Given this, the induction of differentiation using retinoids would be a plausible therapeutic strategy.
In addition, in combination with 5-FU, an additive effect was observed in in vitro studies [ ]. In in vivo experiments, ATRA also reduced tumour progression, though it failed to increase survival, both alone and in combination with 5-FU unpublished data. Although surgical excision of tumour tissue remains the only potentially curative treatment for CRC-LM, several other techniques are now being developed to be used when surgery is not feasible or to improve surgical results.
The list of possible new therapeutic techniques for CRC-LM seems likely to increase over the next five years, including:. Surgical approaches focused on increasing the size of the liver lobes staged surgery or portal branch ligatures , as the percentage of remnant liver after hepatectomy is a limiting factor in many patients.
Techniques for percutaneous tumour ablation, which can reduce CRC-LM volume and allow surgery or at least delay the progression of the illness. Nanoparticles NPs to selectively deliver drugs to tumour cells or induce local hyperthermia. Initially, strategies for such cases were focused on selectively increasing the liver mass of liver lobes free of tumour. However, the clinical benefit of this procedure is not clear and, as there were also reports of tumour progression due to hepatectomy, it has not been widely adopted.
In patients who have inadequate FLR to undergo disease clearance with a single hepatectomy, two-stage hepatectomy for bilobar liver metastases in combination with selected use of portal venous embolization is feasible. It offers the best chance of achieving adequate FLR hypertrophy, better than a strategy involving PVE before a single hepatectomy. Surgical strategies must be individualised after careful assessment of disease distribution and its relationship to key underlying vascular and biliary structures. Thus, the majority of authors perform the first surgical stage focused on the minor hepatectomy and concurrent procedures as required.
When necessary, ligature or embolization of the portal vein is carried out, to enhance the hepatic regeneration response induced by hepatectomy [ ]. Nowadays, embolization is preferred to avoid surgical manipulation of the porta hepatis prior to major hepatectomies, and to achieve segment IV total portal inflow occlusion if a right hepatectomy is planned. Hypertrophy after PVE is maximal in the first three weeks, and tends to plateau after this period [ ]. The time interval between hepatectomies must be long enough for adequate recovery from the first hepatectomy and liver hypertrophy, but not so long as to enable disease progression, since tumour volume may still increase within the occluded liver [ ].
This interval is not well defined but is believed to be around eight to sixteen weeks. In the second-stage operation, the liver surgery usually is complex, often involving other procedures such as radiofrequency ablation. Nevertheless, when performed in referral centres for hepatic surgery the mortality rate is low 2. Given this survival benefit and the feasibility of the surgery, this two-stage approach can be justified in suitably selected patients.
More recently, in situ liver transection with portal vein ligation has been proposed as a useful alternative for patients who have some segments of the left liver free of tumour, but an FLR that is too small [ ]. In a first surgical intervention, arterial vessels and veins draining the lobes containing metastases are dissected and marked with vessel loops; then, the portal branches to those lobes are severed most commonly, all right portal branches and segment I and IV branches.
A quite different approach is percutaneous tumour ablation, an old design that is continuously being refined and improved with new technical developments. Initially, ablation of liver metastases was achieved by alcoholisation ethanol injection , this being used as a downstaging procedure prior to surgery, then came radiofrequency thermoablation [ 42 ], and this was soon followed by microwave thermoablation. These procedures proved to be useful tools to reduce tumour volume, but only provided a transient effect when applied to CRC-LM. More recently, laser tumour ablation and cryoablation have gone through experimental trials in animals and are now being tested in patients, but still limited to primary liver tumours.
As with previous treatments, if and when they prove to be useful in hepatocarcinomas, they will be tried in CRC-LM [ ]. A different, perhaps more subtle, approach is embolization of the arterial vessels supplying the tumour. This classic technique was improved by adding selective transarterial chemotherapy prior to embolisation, which allowed higher doses of chemotherapy with fewer side effects [ ].
One of the problems in treating CRC-LM is the low tolerance of the liver parenchyma to radiation [ ]. An elegant solution to overcome this limitation is known as selective internal radiation therapy and consists in the administration of 90 Y-resin microspheres through the arterial branches supplying the tumour. First applied to non-resectable hepatocarcinoma patients, achieving a reduction in tumour burden, relief of symptoms and increase in survival, it is now being tested in CLR-LM with promising results.
However, the type of radiolabelled microspheres, indications and dosing schedules have to be better defined [ ]. A novel approach has been the use of precharged particles to chemoembolise liver tumours. These spheres are delivered to the vascular tumour bed where they are widely and uniformly seeded; then the drug is released and exerts its effect specifically on the tumour tissue, while the spheres block further blood supply.
Preliminary reports have been quite promising, and may lead to the procedure being applied in CRC-LM [ ]. All these techniques can, however, only be applied to selected macroscopic liver metastases, leaving untreated residual microfoci responsible for tumour recurrence. We need therapeutic tools to attack individual cancer cells seeded throughout the whole liver parenchyma from the primary colorectal tumour. Currently, one of the most promising avenues is radioimmunotherapy, with ongoing preclinical and clinical studies in CRC.
This type of therapy involves the administration of radiolabeled mAbs that are directed specifically against tumour-associated antigens or against the tumour microenvironment. More recently, new studies are being undertaken to assess the safety and efficacy of combining anti-CEA-RIT and kinase inhibitors, such as imatinib, to increase antibody distribution in CRC tumours [ ].
Watch-and-Wait as a Therapeutic Strategy in Rectal Cancer
On the other hand, the new field of nanosystems for cancer diagnostics and treatment is highly promising [ ]. NPs, which easily escape detection and destruction by our immune system, are being used to deliver drugs directly to the tumour bed and selectively destroy cancer cells. It has been suggested that this strategy may be able to overcome tumour resistance and reduce toxicity in healthy organs. Tumour tissue tends to retain NPs, probably due to its particular characteristics abnormally leaky endothelium and underdeveloped lymphatic drainage [ ], and this could explain the tendency of NPs to accumulate in liver metastases more than in normal liver parenchyma when administered through the hepatic artery, as we have recently shown [ ].
Further, in order to decrease the severe dose-limiting toxicity of 5-FU and to enhance the concentration of this agent in the tumour mass, some researchers are investigating the use of 5-FU-loaded biodegradable NPs, and have already shown a significant improvement in the anticancer activity of the drug in an in vitro CRC model [ ]. Finally, magnetic NPs are being investigated in combination with high-frequency magnetic fields to induce local hyperthermia in the tumour, promising results having been obtained in experimental settings CRC-LM in rats [ ].
Liver metastases are a common undesirable development in CRC and represent the leading cause of death in this high-prevalence disease.