over the past decades , considerable advances have been made in the use of long - course crt in rectal cancer . based on a number of pivotal studies in the us which demonstrated positive effects on local control ( lc ) and overall survival ( os ) with the addition of rt and chemotherapy following surgical resection in locally advanced rectal cancer , most clinicians initially favored the use of adjuvant 5-fu based crt ( krook et al . theoretically , rt should be delivered neo - adjuvantly rather than adjuvantly since poor cell oxygenation in the healing tumor bed potentially decreases radiosensitivity . secondary , as the small bowel is not trapped in the pelvic bay by postoperative adhesions , fewer enteric complications are expected with neo - adjuvant rt , where moving loops of small bowel are located on different positions from day to day . lastly , neo - adjuvant downstaging may positively influence the surgical margin status and sphincter preservation rate . strong evidence of the superiority of neo - adjuvant to adjuvant crt in stage ii / iii rectal cancer patients undergoing total mesorectal excision ( tme ) was provided by the 5-year results of the randomized german rectal cancer study ( cao / aro / aio 94 ) , with a significant lower rate of pelvic recurrence in favor of neo - adjuvant crt as compared to adjuvant crt ( 6 versus 13% ) . moreover , the data also showed significant lower rates of toxicity with the use of neo - adjuvant crt ( sauer et al . , 2004 ) . the addition of 5-fu to long - course neo - adjuvant rt is considered standard of care in locally advanced rectal cancer by the evidence of two important phase iii trials , eortc 22921 and ffcd 9203 , which demonstrated the advantages of neo - adjuvant 5-fu based crt over rt alone with respect to pathologic complete remission ( pcr ) and lc , but not with respect to the rate of sphincter - sparing surgery , occurrence of distant metastases , or os ( bosset et al . , 2006 ; grard et al . , those findings led to a shift in the european and us policy of adjuvant crt to neo - adjuvant 5-fu crt , which is now standard of care in stage ii / iii rectal cancer . recently , a non - inferiority phase iii trial of the mannheimer arbeitsgruppe fr gastrointestinale tumoren ( margit ) which compared capecitabine to 5-fu in ( neo-)adjuvant crt of locally advanced rectal cancer provided a growing body of evidence for using capecitabine ( hofheinz et al . , 2011 ) . besides a non - inferiority to 5-fu regarding 5-year os ( 76 versus 67% with 5-fu , p  <  0.05 ) , patients receiving capecitabine experienced equal lc . in concordance with the toxicity profile of capecitabine in the adjuvant treatment of colorectal cancer ( crc ) , less leukopenia but more hand - foot skin reactions and proctitis were recorded compared to 5-fu ( hofheinz et al . , 2011 ) . in view of its advantageous administration profile ( no need for catheter placement and infusion pump ) , those encouraging findings may impact the current standard of administrating 5-fu intravenously during neo - adjuvant rt . despite those improvements , more than one third of the patients undergoing curative treatment of rectal cancer have distant recurrence of this disease . in an effort to further improve the pcr rate , which is considered as a surrogate end point for lc and os , and to decrease the high incidence of distant recurrences , several phase ii and iii trials investigated in addition to neo - adjuvant 5-fu based crt the use of induction chemotherapy and multi - agent systemic therapy by means of other chemotherapeutical drugs ( oxaliplatin ) or biologic agents such as cetuximab and bevacizumab , which are epidermal growth factor receptor ( egfr ) and vascular endothelial growth factor ( vegf ) directed monoclonal antibodies , respectively . an attempt to enhance the outcome after neo - adjuvant crt and tme includes the concept of induction chemotherapy , which has been reported so far only in phase ii setting ( chua et al . , 2010 ; fernandez - martos et al . , 2010 ) . a randomized phase ii spanish trial observed no differences in pcr and r0 resection rate between patients receiving neo - adjuvant crt with capecitabine and oxaliplatin ( capox ) and those receiving induction capox followed by crt with capox ( fernandez - martos et al . , 2010 ) . after a median follow - up of 39  months , similar 3-year disease - free survival ( dfs ) and os rates were recorded in the two treatment arms ( fernandez - martos et al . , 2011 ) . the expert trial , carrying out four cycles of neo - adjuvant capox followed by concomitant capecitabine based crt prior to tme in magnetic resonance imaging ( mri ) defined high - risk rectal cancer patients , reported a promising 20% pcr and 4% r1 rate , with acceptable safety ( chua et al . , 2010 ) . one should however notice the 9 clinically significant cardiotoxic events in 8 out of 77 enrolled patients , of which 4 patients died , before protocol amendment of this trial in january 2004 to exclude patients with recent cardiac morbidity ( chau et al . , 2006 ) . although the impressive number of early fatal events in this trial is not observed in other studies evaluating the safety of induction chemotherapy , acute toxicity is considerable with reported rates of grade 3 acute diarrhea and lymphocytopenia of 20 and 43% , respectively , according to a phase ii study where patients received one cycle of capox followed by capox based crt and surgery ( koeberle et al . , 2008 ) . based on those phase ii data , induction chemotherapy does not seem to be safe and should therefore not be recommended outside clinical trials . four randomized phase iii studies , the studio terapia adiuvante retto ( star)-01 trial , prodige 2-accord-12/405 trial , the national surgical adjuvant breast and bowel project ( nsabp ) r-04 trial and the german cao / aro / aio-04 trial evaluated the tolerability and efficacy of the addition of oxaliplatin to 5-fu based crt as neo - adjuvant treatment of locally advanced rectal cancer ( grard et al . , 2010 ; aschele et al . , 2011 ; roedel et al . , 2011 ; roh et al . , no improvement in the pcr rate was noted as compared to 5-fu based crt alone in the star-01 trial , with reported rates of 16% in both arms ( aschele et al . , 2011 ) . furthermore , no differences in r0 resection rates circumferential resection margin ( crm ; > 1  mm ) were observed with the addition of oxaliplatin ( 93 versus 96% ; aschele et al . , 2011 ) . longer follow - up is needed in this study to assess the impact on the primary endpoint , os . in similarity , the prodige 2-accord-12/405 trial displayed no differences in pcr ( 19 versus 14% , p  =  0.09 ) , the primary endpoint , or crm involvement ( 7.7 versus 12.7% , p  =  0.17 ) with the addition of oxaliplatin to capecitabine based crt ( grard et al . those findings were confirmed by first results from the nsabp r-04 trial , randomizing 1680 rectal cancer patients between four treatment groups : neo - adjuvant continuous infusion 5-fu crt with or without oxaliplatin or neo - adjuvant capecitabine crt with or without oxaliplatin , showing no differences in downstaging , sphincter preservation rate or pcr ( roh et al . , 2011 ) . the cumulative incidence of distant recurrence of 36% in the neo - adjuvant arm of the german rectal cancer study ( sauer et al . , 2004 ) led to a comparison of this regimen to an arm that incorporates oxaliplatin during both neo - adjuvant 5-fu crt and 5-fu adjuvant chemotherapy in the german cao / aro / aio - o4 randomized phase iii trial , which was powered to detect a 7% difference in 3-year dfs as primary endpoint ( roedel et al . , 2011 ) . first results of this trial showed no significant differences in grade 3 acute toxicity ( 22% for 5-fu versus 23% for 5-fu / oxaliplatin arm ) , rates of sphincter preserving surgery , and r0 resection , whereas a slight but significant improvement was found in terms of pcr with the addition of oxaliplatin ( 17 versus 13% , p  =  0.045 ; roedel et al . , 2011 ) . it should be noticed that their regimen , unlike the other trials , included a chemotherapy gap during the third week of rt which may explain the similar toxicity rates and improved compliance rates ( roedel et al . , 2011 ) . 2012 ) presented the clinical outcomes after a median follow - up time of 36  months of the 598 patients included in the prodige 2-accord-12/405 trial , and they observed no differences in lc , dfs , or os between the group of patients who received neo - adjuvant capox based crt as compared to those who underwent neo - adjuvant capecitabine crt . not surprisingly with intensified multi - agent chemotherapy , side effects may be enhanced significantly . first results from the nsabp r-04 trial displayed a more than twofold excessive risk of grade 3 diarrhea with the addition of oxaliplatin to 5-fu based crt ( roh et al . the star-01 and prodige 2-accord-12/405 trial reported a significant increase in grade 3 acute toxicity , with reported rates of 25% in patients receiving oxaliplatin compared to 811% for the groups receiving 5-fu based crt alone ( grard et al . , 2010 ; aschele et al . , 2011 ) . given the activity of oxaliplatin in combination with 5-fu based chemotherapy in the adjuvant and metastatic setting of colon cancer and the well established radiosensitizing effects of another platinum - based drug , cisplatin , in the treatment of lung cancer and cervical cancer , its clinical additive effect to 5-fu based crt in the neo - adjuvant setting of rectal cancer is disappointing . regarding its active launch into clinical combined modality trials , with the first phase i study of oxaliplatin in neo - adjuvant crt of rectal cancer already 11  years ago ( freyer et al . , 2001 ) , solid biological data with respect to the radiosensitizing activity of oxaliplatin are quite limited and not conclusive . only in abstract form , oxaliplatin was shown to sensitize crc cell cultures to radiation in vitro ( blackstock et al . , 2000 , 2002 ) . in combination with 5-fu in vitro , exposure of human crc cell line ht29 to oxaliplatin indicated synergistic effects to radiation , whereas in vivo it failed to improve the growth inhibitory response induced by fractionated radiation doses of 2  gy plus capecitabine in ht29 colorectal tumor xenografts ( folkvord et al . , 2008 ) . on the basis of the scarcity of this preclinical evidence , further experimental in vivo studies are warranted to determine the radiosensitizing properties of oxaliplatin in neo - adjuvant crt of rectal cancer and to provide a strong preclinical knowledge which is critical before moving on to further phase iii trials . moreover , the primary goal in those phase iii trials is of crucial concern in the era of 5-fu based crt , where local recurrences after tme are already reported to occur in less than 5% of the patients and where surrogate end points such as pcr are debatable . given that one third of the patients with resected rectal cancer develop metastatic disease despite the very high lc after neo - adjuvant crt and tme , the focus should be on the eradication of subclinical metastatic disease . however , with current clinical end points such as dfs and os , the large number of patients to be enrolled and long time period before analysis within phase iii studies do not allow a quick answer on the systemic efficacy of a new medical treatment in the neo - adjuvant setting of rectal cancer . in conclusion , the addition of oxaliplatin to 5-fu based crt can not be considered a standard approach in the neo - adjuvant management of locally advanced rectal cancer , but the long - term follow - up data of those phase iii trials should be awaited . in a randomized phase ii study , the expert - c trial addressed the addition of weekly cetuximab to the concept of induction capox and concurrent capecitabine crt , as used in the expert trial ( chua et al . , 2010 ) , in high - risk rectal cancer patients ( dewdney et al . , 2011 ) . no differences were found in pcr , progression - free survival ( pfs ) and os for the all treated population ( dewdney et al . , 2011 ) . in subgroup analysis , kras and braf wild type patients displayed significantly improved 3-year os with the addition of cetuximab once per week throughout treatment compared to those who received induction chemotherapy and crt alone ( 96 versus 81% , p  =  0.04 ; dewdney et al . , interestingly , there was no significant difference in pcr ( 7 versus 11% ) in the wild type patients receiving cetuximab compared to those not receiving cetuximab ( dewdney et al . , 2011 ) . the low pcr rate may in part be explained by the eight patients displaying a pcr but with insufficient tissue for kras and braf analysis , of which six patients received cetuximab . grade 3 + skin rash was , as expected , increased with the use of cetuximab as well as the rates of diarrhea in patients receiving cetuximab , the latter only during crt ( dewdney et al . , 2011 ) . in a pooled analysis of 10 phase i / ii trials incorporating cetuximab in neo - adjuvant crt of rectal cancer , an overall pcr rate and r1 resection rate of 9 and 7% were reported ( glynne - jones et al . , 2010 ) . based on those first results , adding cetuximab to neo - adjuvant crt does not seem to improve pcr , with respect to an overall pcr rate of 13% seen after 5-fu based crt ( glynne - jones et al . , 2010 ) . possible reasons for the disappointing results on the early endpoint of pcr include a less crucial role for repopulation in adenocarcinoma of the rectum in the presence of continuous exposure to 5-fu and rt ( brierley et al . , 1996 ; glynne - jones et al . , 2010 ) in addition , cetuximab could potentially abolish the additive effects of 5-fu by blockade of s phase entry , as cells which fail to progress through s phase do not accumulate additive effects from the combination of 5-fu and radiation ( lawrence et al . the optimum sequence of cetuximab in addition to 5-fu crt remains unclear and should be explored before moving on to phase iii trials . furthermore , biomarkers such as kras and braf mutational status , which are predictive for lack of response to anti - egfr therapy in metastatic crc , have to be integrated in those trials , finally to help us in selecting out appropriate patients which may benefit from neo - adjuvant crt in combination with cetuximab . in a phase i / ii trial in rectal cancer patients receiving bevacizumab and crt , willett et al . ( 2004 ) provided direct evidence of the antivascular effect of anti - vegf treatment by functional , cellular , and molecular investigations . briefly , bevacizumab decreases the tumor vascular density , tumor perfusion , tumor interstitial fluid pressure , and the number of viable circulating endothelial and progenitor cells , which results into a significant increase in apoptosis of cancer cells ( willett et al . , 2004 ) . several phase i / ii trials reported on the feasibility of adding bevacizumab to 5-fu based crt in the neo - adjuvant setting of locally advanced rectal cancer , and provided encouraging pcr rates with moderate toxicity ( willett et al . , 2009 ; crane et al . , the reported incidence of postoperative wound complications in up to 36% of the patients is however concerning and consistent with other reports utilizing bevacizumab with crt before a major surgical procedure ( dipetrillo et al . , 2012 ) . recently , a systematic review identified between 2000 and 2011 15 trials which incorporated bevacizumab in neo - adjuvant crt and calculated a pooled pcr rate of 21% , which is not superior than those reported with 5-fu based crt ( shaalan beg et al . , taking into account the lack of phase iii data in the neo - adjuvant setting of rectal cancer , the similar response rates as compared to 5-fu based crt alone and the considerable treatment - related toxicities , bevacizumab as a radiation sensitizer in combination with 5-fu based crt does not seem to provide additional benefits in the neo - adjuvant treatment of locally advanced rectal cancer . in conclusion , 5-fu based crt still remains the standard of care in the neo - adjuvant treatment of locally advanced rectal cancer . intensifying this regimen by the concept of induction chemotherapy , concurrent multi - agent chemotherapy or the addition of biologic agents does not seem to improve treatment efficacy in terms of pcr , sphincter preservation , or crm negative resection rate , and is therefore not recommended outside clinical trials in locally advanced rectal cancer . the impact of those strategies on the occurrence of distant metastases and os remains unclear until additional follow - up is achieved . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .