Capecitabine and Oxaliplatin Before, During, and After Radiotherapy for High-Risk Rectal Cancer

Accepted Manuscript Capecitabine and Oxalipatin Before, During and After Radiotherapy for High-Risk Rectal Cancer F.O. Larsen, A. Markussen, B.V. Jensen, A.L. Fromm, K.K. Vistisen, V.K. Parner, D. Linnemann, R.H. Hansen, H.H. johannesen, J.V. Schou PII:

S1533-0028(16)30147-5

DOI:

10.1016/j.clcc.2016.07.020

Reference:

CLCC 317

To appear in:

Clinical Colorectal Cancer

Received Date: 29 February 2016 Revised Date:

22 July 2016

Accepted Date: 28 July 2016

Please cite this article as: Larsen FO, Markussen A, Jensen BV, Fromm AL, Vistisen KK, Parner VK, Linnemann D, Hansen RH, johannesen HH, Schou JV, Capecitabine and Oxalipatin Before, During and After Radiotherapy for High-Risk Rectal Cancer, Clinical Colorectal Cancer (2016), doi: 10.1016/ j.clcc.2016.07.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Capecitabine and Oxalipatin Before, During and After Radiotherapy for High-Risk Rectal Cancer. F.O.Larsen1, A.Markussen1, B.V.Jensen1, A.L.Fromm1, K.K.Vistisen!, V.K.Parner1, D.Linnemann2, R.H.Hansen3, H.H.johannesen3, and J.V.Schou1

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Department of Oncology, Copenhagen University Hospital, Herlev-Gentofte, Denmark Department of Pathology, Copenhagen University Hospital, Herlev-Gentofte, Denmark Department of Radiology, Copenhagen University Hospital, Herlev-Gentofte, Denmark

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Correspondence: MD, Ph.D. Finn Ole Larsen Department of Oncology

Herlev Ringvej 75 2730 Herlev Denmark

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Phone: +45 38682329

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Herlev and Gentofte Hospital

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e-mail: [email protected]

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Abstract Background: To evaluate the effect of capecitabine and oxaliplatin before, during and after radiotherapy for high-risk rectal cancer.

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Methods: Patients with rectum cancer T4 or T3 involving the mesorectal fascia was included in a prospective phase 2 trial. Liver or lung metastases were accepted if the surgeons found them resectable. The patients received six weeks of capecitabine and oxaliplatin before chemoradiotherapy, continued capecitabine and oxaliplatin during radiotherapy and received four weeks of capecitabine and oxaliplatin after chemo-radiotherapy. The patients received radiotherapy as intensity-modulated radiotherapy. Total mesorectal excision (TME) was planned eight weeks after chemo-radiotherapy. The patients were evaluated with an MRI before start of treatment, after six weeks of chemotherapy and again just before the operation. The EORTC QLQ-CR29 scoring system was used to evaluate adverse events.

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Findings: Fifty-two patients were enrolled between 2009 and 2012. The treatment was well tolerated with only one death during treatment. Eighty percent of the assessable patients had response on MRI to chemotherapy alone, which increased to 94 % after complete oncological treatment. Forty-nine patients had a TME performed all with a R0-resection and with a pathologic complete response of 20 % for patients with T3-tumor and 7 % for patients with T4-tumor. Five patients had metastases at entrance while 47 patients had locally advanced rectal cancer without metastases. Off these 47 patients, overall survival and progression free survival at five year was 72 % and 62 % respectively, with a median follow up of 60 months.

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Funding's: None

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Interpretation: This aggressive approach with capecitabine and oxaliplatin before, during and after radiotherapy for high-risk rectal cancer is safe and feasible and with an impressive response rate on MRI and a promising five year overall survival.

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Introduction

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Rectal cancer is a frequent and deadly malignant disease in the western world.1,2 Locally advanced rectal cancer (LARC) constitutes up to 50 % of all rectal cancers and includes non-resectable and borderline resectable tumors. Before the 21th century, local relapse was reported in up to 25 % of patients after conventional resection.3,4 After the introduction of total mesorectal excision (TME) local relapse has decreased to less than 10 %.5 TME surgery removes the rectal cancer and the surrounding rectal fat tissue including all local draining lymph nodes in one intact resection specimen. Due to preoperative radiotherapy and by addition of fluoropyrimidines chemotherapy to radiotherapy the local recurrence rate has fallen further.6,7 Despite having achieved good local control many patients with LARC still get distant metastases.6 In a retrospective analysis of 500 patients with LARC only 4·8 % had local recurrence but 25·5 % had distant recurrence.8 Given that systemic relapse is responsible for the majority of deaths in patients with rectal cancer, there is a strong clinical rationale for upfront chemotherapy, particularly in patients with high-risk disease. By definition, patients with high-risk disease have involved or threatened mesorectal fascia and are at increased risk of both local and distant recurrences with an associated poorer prognosis. The idea of giving chemotherapy up front, has been investigated in other trials, either with chemotherapy before chemo-radiotherapy (CRT) 9–16 or after CRT.17 Both strategies showed promising results. We wanted to evaluate the effect of combining both strategies with six weeks of chemotherapy before CRT and four weeks of chemotherapy after CRT. With this strategy, we hoped to be able to achieve high response rates, to reduce the local and distant recurrence rates and improve overall survival for this group of high-risk patients.

Methods Patients

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From August 2009 to June 2012, 52 patients were included in this prospective phase 2 trial. Patients could be included if they had a verified adenocarcinoma in the rectum. Further the patients should have either a T3 rectum cancer involving the mesorectal fascia or a T4 rectum cancer defined by MRI. T3 rectum cancers with ≥ 1 mm to the mesorectal fascia were not included. Liver or lung metastases at entry were accepted if the liver/lung surgeon considered them resectable (table 1). All patients were evaluated by a multidisciplinary team with a radiologist, pathologist, oncologist and a rectum surgeon. In case of metastases to the liver or lung the relevant surgeons were consulted. The patients should be in a good performance status (0 or 1 in ECOG score) and have a good kidney, liver and bone marrow function. The study was designed to add cetuximab to capecitabine and oxaliplatin if the patients were KRAS wild-type. After the presentation of the COIN study at ESMO in September 2009 showing a detrimental effect of adding cetuximab to capecitabine and oxaliplatin, 18 this aspect was closed. Therefore only one patient received cetuximab. The primary end point was response rate to chemotherapy alone and after complete chemo- and radiotherapy, evaluated by MRI. Secondary end points were number of R0 resections, pathological downstaging/regression, adverse events (immediately and persistent), overall survival (OS) and progression free survival (PFS). This study is registered with ClinicalTrials.gov, number NCT00964457. Procedures

The patients received three cycles of chemotherapy with capecitabine and oxaliplatin before CRT. One cycle included oxaliplatin 85 mg/m2 every second week with capecitabine 650 mg/m2 twice a day continuously without break. This continuously regime was used as we had good experience with low toxicity to the regime in our institution. When planning radiotherapy, the patients had a CT-scan of the pelvis, as well as a MRI made, which were merged. Radiotherapy was given with 54 Gy in 27 fractions, five fractions a week, to the tumor bed and 48·6 Gy in 27 fractions five fractions a week to the regional lymph nodes extending to the promontoria. Radiotherapy was planned with intensity-modulated radiotherapy (IMRT), concomitant with capecitabine 650 mg/m2 twice a day continuously without break and oxaliplatin 50 mg/m2 every week. After end of CRT further two cycles of oxaliplatin and capecitabine was given in the same schedule as before CRT. The patients were planned to TME surgery eight weeks after end of CRT. In

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case of neurotoxicity, oxaliplatin doses were reduced or stopped. In case of severe diarrhea or palmar-plantar erythema, capecitabine doses were reduced or stopped. If a patient stopped capecitabine, oxaliplatin was stopped as well. The patients were planned to receive cetuximab 500 mg/m2 every second week, three cycles before, three cycles during and two cycles after radiotherapy. As mentioned earlier, only one patient received cetuximab.

Evaluation Evaluation of response on MRI

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When the patients were included in this trial, a new MRI was made to evaluate the volume of the rectum tumor. The MRI was repeated after six weeks of chemotherapy and just before the TME operation. The second MRI was done to evaluate the effect of chemotherapy alone to the rectal cancer and the last to evaluate the full effect of both chemotherapy and radiotherapy. In this study volume of the rectum has been used and not the diameter of the tumor as we believe it better describes the size of the tumor. The MRIs were performed on the same Philips 1· 5 T Achieva system with a protocol including a paratransversal T2-weighted high resolution sequence planned perpendicularly to the long axis of the tumor and with no gaps between the slices. Therefore it was possible to gauge the volume of the tumor by adding the tumor areas delineated by hand using the free-hand contouring tool in the nordicICE software package (Nordic Neuro Lab, Oslo, Norway), on the relevant slices and multiplying by the slice thickness of 3 mm. There was a loss of scans in the running MRI evaluation. Some MRI was not done due to claustrophobia. Some MRI was done, but not assessable, mainly due to spasms or metal implants, rendering the images too noisy for evaluation. Radiological response was calculated from the intention-to-treat population as well as in the assessable patients. A tumor volume decrease of 30 % was considered as response and a tumor volume increase of 20 % was considered as progression. The deepness of response was defined as the rate of reduction from the baseline MRI. Evaluation of pathological down-staging, regression and complete response

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The pathological down-staging was evaluated by comparing T and N staging in baseline MRI with the pathological staging. This part can be problematic as the MRI not necessary tells the truth particularly not with lymph nodes. Tumor regression grade (TRG) was evaluated by a pathologist in accordance to Mandard (five tier).19 TRG 1: No residual cancer cells. TRG 2: Rare cancer cells. TRG 3: Fibrosis outgrowing residual cancer. TRG 4: Residual cancer cells outgrowing fibrosis. TRG 5: Absence of regressive change. Pathologic complete response was defined as absence of any detectable residual tumor cells within the resected specimen. Evaluation was calculated from the intention-to-treat population. Evaluation of adverse events

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The patients were requested to evaluate symptoms in an EORTC QLQ-CR29 scoring system. Before each visit the patient completed a report of adverse events which was used for evaluation. The patient could report adverse events as no, few, some, or severe. In addition the doctor interviewed the patients about adverse events in accordance to common toxicity criteria, version 3·0, and reported them in the journal.

Evaluation of overall survival and progression free survival The patients were followed with blood samples and CT-scans every three months for the first year. Subsequently every six months for the next two years and finally once every twelve months the last two years, to a final follow up with CTscans of five years. After five years, PFS and OS were followed through their electronic medical record. The database was closed for analysis in November 2015. When the analysis was completed all patients alive had been evaluated with a CT-scan at three years after surgery. Data for OS were calculated from the date of entry until death from any cause or censored at last follow-up. Data for PFS were calculated from the date of entry until disease progression, recurrence or

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death from any cause or censored at last follow-up. OS and PFS were analyzed with the use of Kaplan-Meier curves calculated and plotted using R, the R survival package and the ggplot2 package. Evaluation was calculated from the intention-to-treat population and in the same group with exclusion of the five patients with distant metastases at inclusion.

Results Feasibility

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Fifty-two patients with advanced rectal cancer were included. The median age was 64·4 years (41-77) with 31 male and 21 female. All patients were in a good performance status with 42 (81%) in performance status 0 and 10 (19%) in performance status 1 in ECOG score. The treatment was well tolerated with few adverse events (table 2). All but one dead patient (98 %) completed radiotherapy (fig. 1). Forty-eight patients (92 %) completed the six weeks of chemotherapy before CRT. Thirty-seven (71 %) completed capecitabine treatment and 33 (63%) completed oxaliplatin treatment during radiotherapy. Post-chemotherapy was given to 28 patients (54 %). Diarrhea was the main reason for stopping capecitabine and increased during treatment. This resulted in nearly half the patients did not receive consolidation chemotherapy. One patient known to have five liver metastases upon entering the study experienced progression in the liver metastases during treatment. The patient therefore never received a rectum resection, leaving 50 patients for rectum resection. During operation one patient with a T4-rectum tumor was found too advanced for resection, while the remaining 49 patients all had an R0-resection (fig. 1). All patients had a TME resection with nine patients needing an extended resections of neighboring organs. Response rate by MRI

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Patients with LARC had an excellent response to neoadjuvant chemotherapy with a response rate in tumor volume in the assessable patients of 80 % on MRI which increased to 94 % after completed treatment. Eight patients (20 %) did not have response to the initial chemotherapy alone. Of these eight, six were evaluated after full chemo and radiotherapy. We found that five of the six had an excellent response to full chemo and radiotherapy, despite no response to the initial chemotherapy (fig 2). In the intension to treat population the response rate was 62 % and 65 % respectively (table 3). The deepness of response rate to chemotherapy alone and to complete chemotherapy plus radiotherapy, is shown in a waterfall-plot (fig 2). The deepness of response to chemotherapy alone is shown in increasing order, together with the corresponding response to complete chemotherapy + radiotherapy. Three patients had deepness of response measured after complete chemotherapy plus radiotherapy, but not after chemotherapy alone, and are therefore not included in the waterfall plot. A deepness of response up to 80 % was achieved with chemotherapy alone.

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Pathological down-staging and regression

Tumor down-staging was found in thirty-two patients (62 %) and down-staging in lymph nodes was observed in thirtyone patients (60 %). Regression in TRG was found in forty-eight patients (92 %). Complete pathological response was found in seven (13 %), five with T3 tumor (20 %) and two with T4 tumor (7 %), (table 4). Quality of life

The patients’ adverse events were evaluated through doctors´ reports and through patients´ reports from the EORTC QLQ-CR29 scoring system (table 2). During treatment, diarrhea and neurotoxicity were the main adverse events and were equally reported in the doctors´ and patients´ reports. After end of treatment the patients reported more adverse events and more severe adverse events in the EORTC QLQ-CR29 scoring system than reported in the doctors´ journals. Particularly neurotoxicity was more severe in the EORTC QLQ-CR29 scoring system with more than half of the patients reporting persisting problems. Thirty-eight patients filled out patients´ reports. Some patients refrained from answering the sexually related questions. One man did not answer the question about impotence while nearly half the

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women did not answer the question about discomfort during intercourse. Impotence was a severe problem in half of the men.

Survival and relapse

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With a median follow-up time of 60 months (44-75), 19 deaths were observed (table 5). Two deaths were seen in the first year and could be related to the treatment. The first patient was brought to the hospital two days after starting CRT with exacerbation in COPD and pneumonia. The patient died after one week. He was not neutropenic, but the chemotherapy might have weakened him. The second patient died 10 days after the TME operation. No complications to the operation were registered and the operation showed complete remission. The patient was discharged from hospital but died suddenly three days later. No cause of death was registered but one possibility might be a deep venous thrombosis following the operation, resulting in a fatal lung embolus.

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Four deaths were due to non-rectum-cancer and non-treatment reasons. One patient developed malign melanoma one year after end of treatment. Two patients developed cerebral apoplexy two and three years after end of treatment. The last patient died a sudden death two years after end of treatment. None of these patients had recurrence of their rectum cancer. Thirteen patients died after 15 to 63 months due to their rectum-cancer. All five patients who had liver or lung metastases at inclusion died from their rectum-cancer. The remaining eight deaths (three with T3- and five with T4tumors) were observed in patients with LARC without metastases when entering the study (Table 5).

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Of the 47 patients with LARC without metastases when entering the study, 13 had relapsed (28%). Two patients had local relapses (both T4-tumors) and 11 had distant relapses. All 11 patients with distant relapses had relapses in the lungs (100 %), while five patients had relapsed in the liver as well (45 %). Seven of the eleven patients have been resected in the lungs. Three patients with lung metastases only, remain disease free at 30, 44 and 45 months follow up since operation. One with both lung and liver metastases remains disease free five months since last operation. The last three patients, who were resected, had relapsed.

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Discussion

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OS and PFS at five years for the entire population were 65 % and 56 % respectively, with a median follow up of 60 months (44-75). As no other trials have included patients with distant metastases, we also made a calculation of OS and PFS where the five patients with distant metastases at inclusion, were excluded. This was done to have a more comparable group to other trials. OS and PFS at 5-year for the 47 patients with LARC without distant metastases at inclusion was 72 % and 62 % respectively (fig 3).

In the last decade radiotherapy has been changed to IMRT allowing a better distribution of radiotherapy compared to conventional radiotherapy. Hopefully this could further reduce the local recurrence rate and reduce adverse events. As most recurrences today are distant metastases, it is important to try to reduce the risk of distant metastases. This might be achieved with upfront chemotherapy. The treatment given in our trial, with chemotherapy before, during and after radiotherapy was feasible and safe with only one death occurring during treatment. Except for this single fatality, all patients completed radiotherapy. The treatment was well tolerated, but in adverse events, diarrhea during treatment and consistent neurotoxicity cannot be neglected. More than half of the patients, reported neurotoxicity after one year, in the EORTC QLQ-CR29 scoring system. Ninety-two percent fulfilled the induction chemotherapy but only half the patients in our trial received consolidation chemotherapy mainly due to diarrhea. This is far less than found in a Chinese study with similar strategy. 20 Our strategy with continuously capecitabine but in a lower dose did not seem to reduce the risk of diarrhea in this trial. Other trials have found no benefit to the rectum cancer of adding oxaliplatin during CRT, but

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found that diarrhea grad 3-4 increased from 4 % with 5-FU to 15 % with 5-FU + oxaliplatin.21 From these observations our strategy for future trials would be induction chemotherapy with capeox, but only capecitabine as concurrent therapy. With this strategy maybe more patients could receive consolidation chemotherapy.

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The primary endpoint was response rate on MRI to chemotherapy alone and after complete chemo- and radiotherapy. A high response rate of 80 % in the assessable patients was found after only six weeks of chemotherapy. This increased to 94 % after receiving the complete oncological treatment. These high response rates are in accordance with earlier studies 10,13 and were also found in a neoadjuvant trial with capecitabine and oxaliplatin for colon cancer.22 Unfortunately 23 % of the patients were not assessable for response to induction chemotherapy and 31 % to neoadjuvant treatment which is a limitation of this study. In the few tumors that did not respond well to the initial chemotherapy, we observed a promising response rate to the following CRT treatment. We see this as an indication that the proposed treatment could be highly beneficial for the patients who respond to chemotherapy. But it might also be acceptable to patients not responding to the initial chemotherapy, as they have a good opportunity of responding to the following CRT. In a pilot trial, Schrag et al 23 investigated whether radiotherapy was always necessary in T2,N+/T3 rectum tumors, or if chemotherapy alone could be sufficient. The results were so encouraging, that a randomized trial now is proceeding in USA. Our trial support the idea, that chemotherapy alone might be sufficient in down staging some T2,N+/T3 rectum tumors for TME-resection.

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The pathological complete response in our trial was 20 % for T3-tumors and 7 % for T4-tumors. This is similar to the findings of other studies that focus on the same tumor stages. In a retrospective review of 17 trials on 3105 patients with LARC, a pathological complete response of 16 % was found (T1: 58%, T2: 28%, T3:16%, T4: 12%).24 In our trial, patients had more advanced stages than found in other trials, with half the patients having T4-tumor and the other half advanced T3-tumor involving the mesorectal fascia. T3-tumors are a heterogeneous group with very different prognoses. An earlier trial found, that patients with T3-tumors with extramural spread ≤ 5 mm have a 5-year cancerrelated OS of 85·4 % compared with those tumors > 5mm, which have a 5-year OS of 54·1 %.25 Patients in our trial with T3-tumors had an excellent outcome. All of these patients achieved an R0 resection with no local relapses. Further, only three patients died due to distant metastases. Taking the advanced stage of T4-tumors into account, these patients achieved reasonable results. Only one of these patients died during treatment and all but one achieved an R0 resection. Two local relapses with one death occurred and three deaths due to distant metastases. For the five patients with distant metastases upon entering the study, no one was cured. Maybe patients with a solitary metastasis could be candidates for this treatment. However, four of our patients had more than one metastasis and should have been treated using a different strategy. Of the thirteen relapses observed in our study, two patients had local recurrence (both T4-tumors) and 11 patients had distant recurrence. The lungs were the primary location of the distant recurrences, occurring in all 11 patients. Only five recurrences to the liver were observed. Of the 11 patients with recurrences in the lungs, seven have been resected in the lungs and four are still disease free. Three are disease free after 30, 44 and 45 months. The forth has been resected in both the lungs and in the liver and is disease free at five months since last operation. This indicates, that resection of lung metastases is meaningful. The five year OS in the 47 patients with LARC, without distant metastases at entering the study, was 72 % which is a promising result. We conclude that the aggressive approach with capecitabine and oxaliplatin before, during and after radiotherapy for LARC is safe and feasible. We found an impressive high response rate on MRI both after six weeks of chemotherapy and after complete oncological treatment. As our study is a non-randomized single-arm study, these results are only hypothesis generating for future randomized trials. We do not know to which degree the four components of induction, concurrent or consolidation chemotherapy or the higher dose of radiation is responsible for the effect. As a high response rate on MRI was found after induction chemotherapy we would recommend this in future trials but due to diarrhea, omit oxaliplatin concurrent.

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References

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581-92 Bray F, Sankila R, Ferlay J, Parkin DM. Estimates of cancer incidence and mortality in Europa in 1995. Eur J Cancer 2002; 38: 99-166 Havenga K, Enker WE, Norstein J et al. Improved survival and local control after total mesorectal excision or D3 lymphadnectomi in the treatment of primary rectal cancer: an international analysis of 1411 patients. Eur J Surg Oncol 1999; 25: 368-74 Nesbakken A, Nygaard K, Westerheim O, Mala T, Lunde OC. Local recurrence after mesorectal excision for rectal cancer. Eur J Surg Oncol 2002: 28:126-34 Kapiteijn E, Putter H, van de Velde CJ. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in the Netherlands. Br J Surg 2002; 89: 1142-49 Sauer R, Becker H, Hohenberger W et al. Preoperative versus postpoerative chemo radiotherapy for rectal cancer. N Engl J Med 2004; 351:1731-40 Kapiteijn E, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345:638-46 Cienfuegos JA, Baixauli J, Pastor C et al. Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases. Rev Esp Enferm Dig 2015; 107: 34046 Calvo F, Serrano F, Diaz-Gonzalez J et al. Improved incidence of pT0 down staged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Annals of oncol 2006: 17; 1103-10. Chau I, Brown G, Cunningham D et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging. Defined poor-risk rectal cancer. JCO 2006: 24; 668-74. Chua Y, Barbachano Y, Cunnigham D et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiation and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 2010: 11; 241-48 Schou J, Larsen F, Rasch L et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Annals of oncology 2012: 23; 2627-33 Dewdney A, Cunningham D, Tabernero J et al. Multicenter randomized phase II trial comparing neoadjuvant oxaliplatin, capecitabine and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT C). JCO 2012: 30; 1620-27.

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14. Marechal R, Vos B, Polus M et al. Short course chemotherapy followed by concomitant chemo radiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Annals of Oncol 2011: 23; 1525-30 15. Fernandez-Martos C, Garcia-Albeniz X, Pericay C et al. Chemo radiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemo radiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial. Annals of Oncol 2015: 26; 1722-28. 16. Cercek A, Goodman K, Hajj K et al. Neoadjuvant chemotherapy first followed by chemo radiation and then surgery, in the management of locally advanced rectal cancer. JNCCN 2014: 12; 513-18 17. Garcia-Aguilar J, Chow O, Smith D et al. Effect of adding mFOLFOX6 after neoadjuvant chemo radiation in locally advanced rectal cancer: a multicentre phase 2 trial. Lancet of oncol 2015: 16; 957-66 18. Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomized phase 3 MRC COIN trial. Lancet 2011: 377; 2103-14. 19. Mandard AM, Dalibard F, Mandard JC et al. Pathologic assessment of tumor regression after preoperative chemo radiotherapy of esophageal carcinoma. Cancer 1994: 73; 2680-86. 20. Gao Y-H, Lin J-Z, An X et al. Neoadjuvant sandwich treatment with oxaliplatin and capecitabine administered prior to, concurrently with, and following radiation therapy in locally advanced rectal cancer: A prospective phase 2 trial. International Journal of Radiation Oncology 2014: 90; 1153-1160. 21. Aschele C, Cionini L, Lonardi S et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: Pathologic results of the STAR-01 randomized phase III trial. JCO 2011: 29; 2773-2780. 22. Dam C, Lund-Rasmussen V, Pløen J, Jakobsen A, Rafaelsen SR. Computed tomography assessment of early response to neoadjuvant therapy in colon cancer. Danish Medical Journal 2015: 62; 103-08. 23. Schrag D, Weiser M, Goodman K et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: A pilot trial. JCO 2014; 32: 513-18. 24. Maas M, Nelemans P, Valentini V et al. Long-term outcome in patients with a pathological complete response after chemo radiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010: 11; 835-45. 25. Merkel S, Mansmann U, Siassi M et al. The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 2001; 16:298-304.

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Clinical practical points:

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1. That the strategy with capeox as induction, concurrent and consolidation chemotherapy for rectum cancer is safe. 2. That a high response rate on MRI with induction chemotherapy with capeox is found. 3. That even without response on capeox many patients response to chemoradiation.

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Due to these reason some rectum tumors may not need chemoradiation but could settle with chemotherapy alone and some large tumors may have a better chance for cure with intensive chemotherapy up front.