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Clinical Investigation

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 Yuan-Hong Gao, MD,*,y Jun-Zhong Lin, MD,*,z Xin An, MD,*,x Jie-Lin Luo, MD,*,z Mu-Yan Cai, MD,*,k Pei-Qiang Cai, MD,*,{ Ling-Heng Kong, MD,*,z Guo-Chen Liu, MD,*,z Jing-Hua Tang, MD,*,z Gong Chen, MD,*,z Zhi-Zhong Pan, MD,*,z and Pei-Rong Ding, MD*,z *State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China; and Departments of yRadiation Oncology, zColorectal Surgery, x Medical Oncology, kPathology, and {Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, PR China Received Feb 12, 2014, and in revised form Jul 10, 2014. Accepted for publication Jul 14, 2014.

Summary This prospective, singleinstitution study evaluated a new strategy of neoadjuvant sandwich treatment, integrating induction chemotherapy, concurrent chemoradiation therapy, and consolidation chemotherapy, in locally advanced rectal cancer. Preliminary results suggest that the strategy of neoadjuvant sandwich

Purpose: Systemic failure remains the major challenge in management of locally advanced rectal cancer (LARC). To optimize the timing of neoadjuvant treatment and enhance systemic control, we initiated a phase 2 trial to evaluate a new strategy of neoadjuvant sandwich treatment, integrating induction chemotherapy, concurrent chemoradiation therapy, and consolidation chemotherapy. Here, we present preliminary results of this trial, reporting the tumor response, toxicities, and surgical complications. Methods and Materials: Fifty-one patients with LARC were enrolled, among which were two patients who were ineligible because of distant metastases before treatment. Patients were treated first with one cycle of induction chemotherapy consisting of oxaliplatin, 130 mg/m2 on day 1, with capecitabine, 1000 mg/m2 twice daily for 14 days every 3 weeks (the XELOX regimen), followed by chemoradiation therapy, 50 Gy over 5 weeks, with the modified XELOX regimen (oxaliplatin 100 mg/m2), and then with another cycle of consolidation chemotherapy with the XELOX regimen. Surgery was performed 6 to 8 weeks after completion of radiation therapy. Tumor responses,

Reprint requests to: Drs. Pei-Rong Ding and Zhi-Zhong Pan, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd East, Guangzhou, 510060, Guangzhou, PR China. Tel: 86-20-87343124; E-mail: [email protected] This work was supported by National Natural Science Foundation of China grant 81101591, Natural Science Foundation of Guangdong Province, China, grants S2011040005278 and 9151008901000157, and Science Int J Radiation Oncol Biol Phys, Vol. 90, No. 5, pp. 1153e1160, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.07.021

and Technology Planning Project of Guangdong Province, China, grant 2010B060900043. Conflict of interest: none. Drs. Gao, Lin, and An contributed equally to this work. AcknowledgmentsdThe authors thank Ke-Jian Gan for assistance in writing and editing the paper.

International Journal of Radiation Oncology  Biology  Physics

1154 Gao et al. treatment using the oxaliplatin plus capecitabine (XELOX) regimen as induction, concomitantly, and consolidation chemotherapy with conventional radiation is well tolerated and highly effective in terms of rates of pathologically complete and nearly complete response.

toxicities, and surgical complications were recorded. Results: All but one patent completed the planned schedule of neoadjuvant sandwich treatment. Neither life-threatening blood count decrease nor febrile neutropenia were observed. Forty-five patents underwent optimal surgery with total mesorectal excision (TME). Four patients refused surgery because of clinically complete response. There was no perioperative mortality in this cohort. Five patients (11.1%) developed postoperative complications. Among the 45 patients who underwent TME, pathologic complete response (pCR), pCR or major regression, and at least moderate regression were achieved in 19 (42.2%), 37 (82.2%), and 44 patients (97.8%), respectively. Conclusions: Preliminary results suggest that the strategy of neoadjuvant sandwich treatment using XELOX regimen as induction, concomitant, and consolidation chemotherapy to the conventional radiation is well tolerated. The strategy is highly effective in terms of pCR and major regression, which warrants further investigation. Ó 2014 Elsevier Inc.

Introduction Although neoadjuvant chemoradiation therapy (CRT) has substantially reduced the risk of local recurrence, systemic failure remains the major challenge in management of locally advanced rectal cancer (1-7). As has been shown in previous trials, compliance with adjuvant chemotherapy in patients treated with CRT and surgery is suboptimal, with approximately 27% to 35% patients unable to receive adjuvant chemotherapy and 50% of patients unable to receive the planned dose of adjuvant chemotherapy due to toxicities, surgical complications, or good response to CRT (2, 8, 9). Several strategies have been studied to improve systemic control in patients with locally advanced rectal cancer (LARC), including the initial use of an intensified neoadjuvant regimen either before (10-13) or added to oxaliplatin concomitant to conventional CRT (14-16) or chemotherapy extended to the resting period between CRT and surgery (17-19). However, phase 3 trials have consistently demonstrated that addition of oxaliplatin resulted in more toxicities but not efficacy, suggesting that the simple strategy of adding oxaliplatin concomitant to conventional CRT might not be the strategy of choice. To enhance systemic control and improve tolerance to systemic chemotherapy, the strategies of initial use of a more intensified regimen in the neoadjuvant phase might be a promising choice. Currently, several strategies have been tested, including the initial use of a more intense neoadjuvant regimen either before (11, 20), concomitant with (3, 16, 21) conventional chemoradiation, or extending the chemotherapy to the resting period between CRT and surgery (17, 18, 22). Usually, 3 to 4 weeks would be needed before the application of radiation, and meanwhile, 5 to 10 weeks of resting period would be needed before surgery was finally performed. Theoretically there might be a risk of tumor progression because of the delay of treatment in the preparation phase and absence of treatment in the resting period. In order to optimize the timing of neoadjuvant treatment and enhance systemic control, we designed a new strategy of neoadjuvant sandwich treatment that applies 1 cycle of induction chemotherapy (oxaliplatin and capecitabine

[XELOX] regimen), followed by concurrent CRT (with 2 cycles of modified XELOX regimen), and then 1 cycle of consolidation chemotherapy (XELOX regimen), based on our previous pilot study which demonstrated the efficacy and safety profile of induction chemotherapy followed by CRT (13) or CRT followed by consolidation chemotherapy (19). On the basis of those findings, we initiated a phase 2 trial of neoadjuvant sandwich treatment for LARC patients. The purpose of this trial was to evaluate the feasibility and short- and long-term efficacy of this regimen. Here we present preliminary results of this trial, reporting the tumor response, toxicities, and surgical complications.

Methods and Materials Eligibility and pretreatment evaluation Eligibility criteria included ages from 18 to 75 years and histopathologically confirmed rectal adenocarcinoma, with the inferior margin within 12 cm from the anal verge. Patients were considered to have locally advanced rectal cancer (T3-T4 or Nþ) on the basis of both magnetic resonance imaging (MRI) and endorectal ultrasonography. Additional inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status 2 and adequate hematologic, liver, and renal functions. We excluded patients with recurrent rectal cancer, previous radiation therapy to the pelvic region, or previous diagnosis of other malignancies. All patients were required to have a computed tomography (CT) scan of the chest, abdomen, and pelvis and a serum carcinoembryonic antigen (CEA) measurement. The American Joint Committee on Cancer (7th edition) TNM system was used for staging (23). The study protocol was approved by the ethics committee and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained before start of the treatment.

Treatment Radiation therapy All patients were immobilized using an AIO bellyboard and pelvic solution system (AIO Solution; Orfit Industries,

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Wijnegem, Belgium). Radiation therapy was carried out using the linear accelerator equipped with the PreciseBeam volumetric-modulated arc therapy (VMAT) linear accelerator control system (Elekta Medical Systems, Crawley, UK). Optimization and dose calculation were performed using the Monaco treatment-planning system (version 3.0 [Elekta]) with a Monte Carlo algorithm. Simulations were obtained with patients in the prone position, with arms up and a full bladder. CT-based simulation with 3-mm-slice thickness was performed. Target volumes were delineated according to the guidelines of the International Commission on Radiation Units and Measurements reports 50 ICRU. Prescribing, recording, and reporting photon beam therapy. ICRU Report 50, 1993. and 62 ICRU. Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU Report 50). ICRU Report 62, 1999. The gross tumor volume (GTV) was the macroscopic tumor and the enlarged lymph nodes visible on CT or MRI. The clinical target volume (CTV) covered the GTV with a radial margin of 2 cm, a craniocaudal margin of 2.5 to 3 cm and lymphatic drainage basin, including anterior sacral lymphatic drainage, iliac lymph drainage, obturator lymph drainage, and the true pelvis internal iliac lymph drainage area. In lymph node-positive disease, the superior border was typically at the L4-L5 interspace, whereas for lymph nodenegative disease, it was at the L5-sacrum level. Planning target volume (PTV) was defined as the CTV or GTV with uniform margins of 6 mm. The prescribed irradiation dose

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of 46 Gy was delivered to PTVCTV (PTV2, CTVþ6mm) and 50 Gy to PTVGTV (PTV1, GTVþ6mm) in 25 fractions; 8-MV photons were adapted with VMAT. All the patients were treated with one fraction daily for 5 days per week. A representative treatment plan for LARC with IMRT is shown in Figure 1. The hierarchy of dose prescription and dose constraints was as follows: first, small bowel; second, PTV; third, bladder. The irradiation plans were accepted when the PTV95 was 46 Gy for PTVCTV and 50 Gy for PTVGTV, the dose received by 5% of the small bowel was 50 Gy, the minimal dose to the PTV was 35 Gy, and maximal dose to the small bowel was 55 Gy. For the bladder, including a maximal dose of 55 Gy and a minimal dose received by 5% of the bladder of 50 Gy were accepted. There was no specific rectum or external volume constraints. Chemotherapy Patients received 1 cycle of induction chemotherapy with the standard XELOX regimen (oxaliplatin, 130 mg/m2 on day 1, plus capecitabine, 1000 mg/m2 twice daily on days 1 to 14) 3 weeks before radiation. Then 2 cycles of modified XELOX regimen (oxaliplatin, 100 mg/m2 on day 1, plus capecitabine, 1000 mg/m2 twice daily on days 1 to 14) were administered on days 1 to 14 and on days 21 to 34 of radiation. One week after completion of CRT, patients received one additional cycle of chemotherapy with standard XELOX regimen. Adverse events during neoadjuvant treatment were recorded using Common Terminology Criteria for Adverse Events Version 3.0. Simple tumor response assessment was

Fig. 1. Representative treatment plan for locally advanced rectal cancer with IMRT. A radiation dose of 50 Gy to PTVGTV and 46 Gy to PTVCTV with 25 fractions during 5 weeks, using simultaneous, integrated boost by IMRT. The PTVGTV was covered with 100% of the prescription dose of 50 Gy, and PTVCTV was covered with 98.3% of the prescription dose of 46 Gy. The minimum, maximum, and mean doses were 2.08 Gy, 48.6 Gy, and 22.9 Gy, respectively, to small bowel. The minimum, maximum, and mean doses were 25.8 Gy, 53.1 Gy, and 43.2 Gy, respectively, to bladder. IMRT Z intensity modulated radiation therapy; PTVGTV Z GTVþ6mm margin.

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performed at 1 week after completion of CRT, with complete physical examination and digital rectal examination to rule out progression of tumor. Comprehensive tumor response assessment was performed at 4 to 5 weeks from radiation completion, including complete physical examination, digital rectal examination, CEA levels; CT scan of the chest, abdomen, and pelvis; and endoscopic ultrasonography and/ or MRI of the pelvis. Toxicities were assessed weekly in clinic. In addition to physical examination, complete blood count and liver and renal function tests were also administered weekly during CRT. Complete blood count results were obtained weekly, whereas liver and renal function test results were obtained every 3 weeks during consolidation chemotherapy. Patients received another assessment 1 week after completion of all neoadjuvant treatment. Surgery was scheduled 6 to 8 weeks after completion of radiation therapy. Patients received radical rectal resection according to the principles of total mesorectal excision (TME). The treatment schedule is shown in Figure 2.

(depending on size of lesions) full thickness sections are sampled and stained with hematoxylin and eosin for evaluation of tumor regression. In case of diagnostic uncertainties, more sections would be sampled for further evaluation.

Adjuvant chemotherapy Patients who underwent an R0 resection received adjuvant chemotherapy with XELOX regimens for four cycles at 3 to 8 weeks after surgery. Oxaliplatin was administered on day 1 of each cycle at a dose of 130 mg/m2. Capecitabine was administered daily at a dose of 2000 mg/m2 for 14 days every 21 days.

Pathologic examination Specimens were examined by two pathologists who specialized in gastrointestinal cancers. The macroscopically visible tumor or suspected areas were localized, and specimens were embedded in paraffin. Serial 3- to 5-mm

Study endpoints and statistics The primary endpoint of this study was rate of pathologic complete response (pCR) defined as the absence of any residual tumor cells detected in the primary lesions or sampled lymph nodes. A one-stage design, as proposed by A’Hern (24) and Fleming (25), was used to estimate the number of patients required to be enrolled in the study. Using a and b errors of 0.05 and 0.20, respectively, the study required 48 patients to decide whether the pCR rate was less than or equal to 15% (null hypothesis) or greater than or equal to 30% (alternative hypothesis). If the number of pCR was 12 or more, the hypothesis that the pCR rate 15% was rejected with a target error rate of 0.050 and an actual error rate of 0.048. If the number of responses was 11 or less, the hypothesis that the pCR rate 30% was rejected with a target error rate of 0.200 and an actual error rate of 0.181. The secondary endpoints were tumor regression grade, R0 resection rate, toxicities related to CRT/chemotherapy, surgical complication rates, local recurrence rate, and recurrence free survival at 3 years. Tumor regression after preoperative treatment was semiquantitatively evaluated according to Dworak regression grading system (26). Categorical variables are presented as frequencies (percentages) and continuous variables as means with standard deviations or medians with ranges. Statistical analyses were performed with SPSS statistical software version 15.0 (SPSS Inc., Chicago, IL) for Windows (Microsoft, Redmond, WA). pCR

Fig. 2. Schedules of neoadjuvant sandwich chemoradiation in locally advanced rectal cancer. Patients received one cycle of chemotherapy with standard XELOX regimen (oxaliplatin, 130 mg/m2 on day 1, plus capecitabine, 1000 mg/m2 twice daily on days 1 to 14) 3 week before radiation. Then, two cycles of a modified XELOX regimen (oxaliplatin, 100 mg/m2 on day 1, plus capecitabine, 1000 mg/m2 twice daily on days 1 to 14) were administered on days 1 to 14 and days 21 to 34 of radiation. One week after completion of CRT, patients received one additional cycle of chemotherapy with the standard XELOX regimen. Then, patients underwent radical rectal surgery 6 to 8 weeks after radiation therapy, followed by adjuvant chemotherapy for 3 to 6 weeks thereafter. CRT Z chemoradiation therapy; XELOX Z oxaliplatin and capecitabine.

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was defined as the absence of any residual tumor cells detected in the primary lesions or sampled lymph nodes.

Table 2

Rate of acute toxicity (nZ49) No. of patients with acute toxicity grades shown (%)

Results Toxicity

Clinicopathological characteristics From January 2012 to March 2013, 51 patients were enrolled in the study. Two patients were excluded because of distant metastasis before treatment. Clinicopathological features of the patients included in this study are summarized in Table 1. The median age at diagnosis was 53.5 years old (range 25-72 years). The median distal tumor margin from anal verge was 6 cm (range 2-12 cm). Thirtyone patients (63.3%) had a tumor located in the low rectum (6 cm from the anal verge). Median time from end of CRT to surgery was 55 days (range 45-83 days). Forty-five patients underwent optimal surgery with TME, among which, 33 patients (73.3%) received a sphincter-saving procedure. R0 resection of primary tumor was obtained in all surgical patients, with negative distal and radial margins. The median number of retrieved lymph nodes was 5 (range 0-20 nodes) per specimen. Four patients were considered to have complete clinical response and refused surgery.

Toxicity The most common toxicities during neoadjuvant treatment are described in Table 2. All patents completed the planned dose of induction chemotherapy and concurrent CRT. One

Table 1 Patient and disease characteristics and treatment compliance Characteristic Median age at diagnosis (range) No. of patients by sex (%) Female Male Median distal tumor margin from anal verge (range) No. of patients with pre-CRT T stage (%) T2 T3 T4a No. of patients with cN stage (%) N negative N positive No. of patients with CEA (%) >5 ng/ml 5 ng/ml No. of patients who received full dose of radiation (%) No. of patients who received full dose of chemotherapy (%)

Value 53.5 (25-72) 13 (26.5) 36 (73.5) 6 cm (2-12 cm)

1 (2.0) 33 (67.3) 15 (30.6) 15 (30.6) 34 (69.4) 21 (42.9) 28 (57.1) 49 (100) 48 (98.0)

Abbreviations: CEA Z carcinoembryonic antigen; CRT Z chemoradiation therapy.

Hematologic toxicity Anemia Leucopenia Thrombocytopenia Nonhematologic toxicity Nausea or vomiting Diarrhea Proctitis Radiation dermatitis Hand-foot syndrome Peripheral neuropathy

Grades1-2

Grades 3-4

1 (2.0) 30 (61.2) 10 (20.4)

e 1 (2.0) 5 (10.2)

21 21 15 19 28 36

4 1 2 2

(42.9) (42.9) (30.6) (38.7) (57.2) (73.5)

e (8.2) (2.0) (4.1) (4.1) e

patient was unable to complete the consolidation chemotherapy because of grade 3 diarrhea. Overall, 1 patient (2.0%) developed grade 3 leucopenia; 5 patients (10.2%) developed grade 3 thrombocytopenia; 4 patients (8.2%) developed grade 3 diarrhea; 1 patient (2.0%) developed grade 3 proctitis; 2 patients (4.1%) developed grade 3 radiation dermatitis; and 2 patients (3.9%) developed grade 3 hand-foot syndrome. No grade 3 or 4 toxicities were recorded for other toxicities. Neither life-threatening blood count decrease nor febrile neutropenia was observed. Grade 1 to 2 leucopenia, thrombocytopenia, nausea or vomiting, diarrhea, proctitis, radiation dermatitis, hand-foot syndrome, and peripheral neuropathy occurred in 30 patients (61.2%), 10 patients (20.4%), 21 patients (42.9%), 21 patients (42.9%), 15 patients (30.6%), 19 patients (38.7%), 28 patients (57.2%), and 36 patients (73.5%), respectively.

Surgical complications There was no perioperative mortality in this cohort. Five of the 45 patients (11.1%) developed postoperative complications, including obstruction/ileus (2.2%), anastomosis leakage (2.2%), superficial surgical site infection (2.2%), perineal wound dehiscence (2.2%), and deep vein thrombosis (2.2%).

Pathological and clinical response Details of pathologic findings are presented in Table 3. Nineteen patients (42.2%) achieved pCR (ypT0N0). Only microscopic residual tumor foci (grade 3 tumor regression or major regression) were present in another 18 patients (40.0%). Seven patients (15.6%) achieved moderate regression (grade 2 tumor regression), and 1 patient (2.2%) achieved minimal regression (grade 1 tumor regression). By comparing baseline clinical staging with final pathological T and N stages (Table 4), 10 patients (22.2%) were

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Surgical results and pathologic findings No. of patients (%)

Results Surgical results No. of days from the end of CRT to surgery (range) No. of patients undergoing sphincter-saving surgery Preventive ileostomy R0 resection of primary tumor Median no. o lymph nodes examined (range) Pathologic tumor response pCR Few residual cells (TRG 3) TRG 2 TRG 1 Pathologic T stage T0 Tis T2 T3 T4a Pathologic N stage N0 N1 N2

55 (45-83) 33 (73.3%) 0 (0%) 45 (100%) 5 (0-20) 19 18 7 1

(42.2) (40.0) (15.6) (2.2)

19 1 8 13 4

(42.2) (2.2) (17.8) (28.9) (8.9)

39 (86.7) 5 (11.1) 1 (2.2)

Abbreviations: CRT Z chemoradiation therapy; pCR Z pathologic complete response; TRG Z tumor regression grading.

downstaged for T only, 6 (13.3%) were downstaged for N only, and 21 (46.7%) were downstaged for both T and N stages. As a result, 37 of 45 patients (82.2%) who underwent TME had some type of downstaging from neoadjuvant treatment. Another four patients achieved complete clinical response and refused surgical resection.

Discussion Our findings demonstrate for the first time the feasibility of neoadjuvant sandwich treatment with XELOX regimen administered as induction, concomitant, and consolidation chemotherapy with conventional radiation therapy in locally advanced rectal cancer.

Table 4 Comparison of baseline clinical staging to pathological T and N staging in resected patients (nZ45) Baseline staging cT2 cT3 cT4 cN negative cN positive

Pathological T staging pN pN pT0 pTis pT2 pT3 pT4 negative positive 1 13 5 -

0 1 0 -

0 5 3 -

0 9 4 -

0 2 2 -

12 27

1 5

Abbreviations: c Z clinical (in this case assessed by imaging); p Z assessed pathologically.

The current study achieved a pCR rate of 42.2% and a major regression rate of 40.0%. Considering the patients who did not receive surgery, the complete response (clinical and pathological) rate was 51.1%. The pCR rate seems more impressive than that in other studies using a strategy of conventional CRT, a strategy with CRT followed by consolidation chemotherapy (17, 18, 22), a strategy with induction chemotherapy followed by CRT (10, 11, 20), or even a strategy with target agents added to CRT (3, 16, 21). Furthermore, the major regression rate was also fairly high, suggesting that the strategy might work widely for most of the patients in the cohort. The initial intention of the strategy of neoadjuvant sandwich treatment is to enhance systemic control and reduce the possibility of tumor spread in the preoperative phase. Results of the current study suggest that the strategy might also have a substantial impact on the primary tumor. There are several explanations for this. First, it could be a result of the application of both induction chemotherapy and consolidation chemotherapy. The application of short-term induction chemotherapy might shrink the tumor and improve the oxygen supply of local tumor, which might further enhance the effect of CRT (11). Meanwhile, extending chemotherapy to the resting period might also allow further exposure of irradiated tumor cells to chemotherapy and eradicate the minimal residual tumor cells (17). Several studies have investigated alternative strategies in neoadjuvant treatment of LARC. Chua et al (10) assessed the approach of induction chemotherapy with capecitabine and oxaliplatin followed by CRT and TME in MRI-defined poor-risk rectal cancer in a phase 2 trial. The approach achieves a favorable long-term outcome (70% RFS and 80% OS at 5 years) and acceptable safety profiles. However, another phase 2 randomized clinical trial (11) do not show superior local control or survival compared to the conventional CRT, which questions the efficacy of the strategy with induction chemotherapy. Habr-Gama et al (17) first reported the strategy of consolidation chemotherapy in the resting period between completion of CRT and surgery. In the cohort, 14 patients (48%) achieved complete clinical response, and 5 patients (17%) achieved pCR of primary lesion after full-thickness local excision. Recently, Garcia-Aguilar et al (18) further showed that CRT followed by consolidation chemotherapy (with two cycles of Oxaliplatin and 5-fluorouracil/ leucovorin) resulted in a modest increase in pCR rate without increasing complications compared to the strategy of conventional CRT in patients with LARC. Although results appeared promising, the follow-up is still too short, and the cohort is too small to come to the final conclusion that this strategy is better than conventional CRT. Second, the intensified chemotherapy regimen using concomitant radiation therapy might also have had an impact on the efficacy. In the current study, the regimen of concurrent chemotherapy was modified in two aspects compared to the strategy of conventional CRT. First,

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oxaliplatin was added to the concurrent chemotherapy and was delivered using the XELOX regimen schedule in which 1 dose of oxaliplatin was administered every 3 weeks. Second, dose and schedule of capecitabine concomitant to the radiation therapy was also administered exactly the same schedule as the XELOX regimen (1000 mg/m2 twice daily, 2 weeks on, 1 week off). Although the advantage of adding oxaliplatin to conventional CRT remains controversial, a recent meta-analysis suggests that adding oxaliplatin might both improve pCR rate and reduced perioperative metastatic rate (27). The reason for the discrepancy probably lies in the different strategies of drug delivery. In most studies, oxaliplatin was added to the conventional CRT without changing the schedule of fluoropyramidine delivery (3, 21), which inevitably results in more toxicities and less tolerance to treatment. Consequently, significantly fewer patients in the combination arm received full dose of chemotherapy and radiation, ultimately compromising the local effect of CRT. Unlike most of the previous reports (3, 11), the current study adopted a strategy of drug delivery similar to that of the German AIO04 trial (16), which scheduled 1 week that was chemotherapy free in the middle of radiation. The modification of schedule probably accounted for good tolerance and favorable short-term outcome. Although significant, the efficacy of the above strategies, either induction chemotherapy or intensified concurrent CRT or consolidation chemotherapy, seems modest. In stark contrast to the modest improvement in pCR rate in the above-mentioned strategies (8-10, 12-14, 17, 19-21), the current approach achieves higher pCR and major regression rates than in previous reports (10, 11, 14-18, 20, 22, 28), which suggests that the strategy of combining induction chemotherapy, intensified concurrent CRT, and consolidation chemotherapy might result in better outcome. The concern of adding oxaliplatin concomitant to conventional CRT is that it might significantly increase the toxicities with approximately 50% of patients ending up not receiving the complete chemotherapy (2, 8, 9) and 13% to 16% of patients not receiving the complete dose of radiation (14-16, 28). Induction and consolidation chemotherapy might even exacerbate the toxicities, decrease the tolerance to radiation, and compromise the treatment effect. As a matter of fact, the current strategy was well tolerated. All patients completed the induction chemotherapy and CRT, and all but one patient were able to complete the consolidation chemotherapy. Grades 3 to 4 toxicities and surgical complications were also comparable to those in other series using conventional 5-fluorouracil-based CRT. The low toxicities and high compliance to treatment might attribute to the strategy of drug delivery (mentioned above) as well as racial differences. It has been shown that tolerance of capecitabine is remarkably variable among different regions worldwide. Asian population seems to tolerate capecitabine better than the US population (29). The TREE trial (30) also demonstrated that even though it

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is used in chemotherapy alone (not in combination with radiation therapy), lower capecitabine doses (specifically 850 mg/m2 twice daily on days 1-14 of a 3-week schedule) needs to be used in a US population. In stark contrast to the poor capecitabine tolerability of the US population, the current cohort received the standard dose of capecitabine (1000 mg/m2 twice daily on days 1-14 of a 3-week schedule) with acceptable toxicities and compliance, reinforcing the previous findings and might also account for the high efficacy. Use of the intensity modulated radiation therapy (IMRT) technique might also have contributed to the lower toxicities and high tolerance in the current cohort. The modern highly conformal radiation therapy planning and delivery techniques could potentially reduce the radiation dose to the bowel and, consequently, reduce gastrointestinal side effects. IMRT has been demonstrated to be effective in reducing small bowel dose and resultant gastrointestinal toxicity in patients with other pelvic malignancies (cervical, endometrial, prostate) and rectal cancer previously (31). Urbano et al (31) found the small bowel volume irradiated to 45 and 50 Gy was significantly reduced (by 64%) with IMRT, resulting in less bowel toxicity, which might consequently translate into better tolerance to the treatment and even improved outcome. The current study is subject to several limitations. First, tumor response (pCR and major regression rate) is used as a surrogate endpoint for efficacy. Although pCR has not yet been recommended as a surrogate endpoint for longterm survival in the current guidelines, most studies demonstrate that pCR is associated with a favorable prognosis (28, 32). Notably, in a pooled analysis with individual patient data, Maas et al (33) enrolled 14 LARC patients who were treated with CRT and showed that patients with pCR have significantly better prognosis than those without pCR. The results reinforce the fact that pCR might be a proper surrogate endpoint for long-term outcome. Nevertheless, longer follow-up is needed to determine the definite role of this strategy on local control and survival. Second, the number of lymph nodes is relatively low compared to the reported phase 3 trials on the same setting. One of the possible explanations is the inadequate sampling of lymph nodes. However, the number of lymph nodes might not have a significant impact on the results, as we expect in the setting of surgery alone. First, it is widely accepted that patients who receive preoperative chemoradiation therapy should be expected to have a lower lymph node yield (34). Second, more recent data from the Cleveland Clinic demonstrate that lower yield of lymph node may be a marker of better tumor response and is associated with decreased local relapse rate (35). As a result, the favorable response in the current cohort might be one of the reasons that a small number of lymph nodes was sampled. Third, this is a small sample sized study. There might be selection bias. Consequently, randomized control trials are needed to determine the definite role of the current strategy.

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International Journal of Radiation Oncology  Biology  Physics

Conclusions

16. Rodel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 2012;13:679-687. 17. Habr-Gama A, Perez RO, Sabbaga J, et al. Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum 2009;52:1927-1934. 18. Garcia-Aguilar J, Smith DD, Avila K, et al. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 2011;254:97-102. 19. Gao YH, Zhang X, An X, et al. Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer. Strahlenther Onkol 2014;190:158-164. 20. 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. J Clin Oncol 2006;24:668-674. 21. Bria E, GR, Raftopoulos H, et al. Comparing two methods of metaanalysis in clinical researchdindividual patient data-based (IPD) and literature-based abstracted data (AD) methods: analyzing five oncology issues involving more than 10,000 patients in randomized clinical trials (RCTs) [abstr 6512]. J Clin Oncol 2007;25:325s. 22. Zampino MG, Magni E, Leonardi MC, et al. Capecitabine initially concomitant to radiotherapy then perioperatively administered in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2009;75: 421-427. 23. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. 24. A’Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med 2001;20:859-866. 25. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982;38:143-151. 26. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19-23. 27. An X, Lin X, Wang FH, et al. Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: a meta analysis. Eur J Cancer 2013;49:843-851. 28. Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum [abstr 3503]. J Clin Oncol 2011;29. 29. Grothey A. A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer. Nat Clin Pract Oncol 2009;6:10-11. 30. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008;26:3523-3529. 31. Guerrero Urbano MT, Henrys AJ, Adams EJ, et al. Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels. Int J Radiat Oncol Biol Phys 2006;65:907-916. 32. Lee WS, Yun SH, Chun HK, et al. Clinical usefulness of chest radiography in detection of pulmonary metastases after curative resection for colorectal cancer. World J Surg 2007;31:1502-1506. 33. MacMahon H, Austin JHM, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005;237:395-400. 34. Miller ED, Robb BW, Cummings OW, et al. The effects of preoperative chemoradiotherapy on lymph node sampling in rectal cancer. Dis Colon Rectum 2012;55:1002-1007. 35. de Campos-Lobato LF, Stocchi L, de Sousa JB, et al. Less than 12 nodes in the surgical specimen after total mesorectal excision following neoadjuvant chemoradiation: it means more than you think!. Ann Surg Oncol 2013;20:3398-3406.

Preliminary results suggest that the strategy of neoadjuvant sandwich treatment using the XELOX regimen as induction, concomitant, and consolidation regimen to the conventional radiation is well tolerated. This strategy is associated with high pCR and major regression rates. The promising results warrant further investigation of this strategy in future clinical trials.

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