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Department of Rehabilitation, Institute of Rehabilitation in General and Colorectal Surgery at Department of Rehabilitation, J. Pilsudski University of Physical Education, Warsaw, Poland
To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer.
Methods
Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment.
Results
49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II.
Conclusions
The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.
An unresectable primary tumour is commonly defined as a palpably fixed lesion involving adjacent organs or structures. It is diagnosed in approximately 15% of patients with rectal cancer [
]. Chemoradiation aims for tumour shrinkage to allow radical resection. The most frequently used scheme of neoadjuvant chemoradiation involves delivering 45 Gy or 50.4 Gy given in 1.8 Gy per fraction concomitantly with 5-fluorouracil and leucovorin or with capecytabine. The results of such treatment are not satisfactory; the tumour remains unresectable in about 15% of patients, the rate of radical resection is approximately 75%, and 5-year survival is approximately 50% [
]. Therefore, there is a need for exploring more effective schedules of neoadjuvant treatment. A retrospective study has suggested that an addition of oxaliplatin to fluoropyrimidine-based chemoradiation increases efficacy [
Polish and Australian randomized studies have compared short-course preoperative radiation (5 × 5 Gy) and immediate surgery with conventionally fractionated preoperative chemoradiation and delayed surgery in patients with resectable rectal cancer [
Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.
]. Both trials have shown no difference in long-term results between the two treatment-assigned groups. A randomized study comparing conventionally fractionated radiotherapy and simultaneously delivered chemotherapy with conventionally fractionated radiotherapy alone conducted in patients with unresectable cancer has demonstrated benefit in the combined modality group [
]. Based on these three randomized trials, it has been hypothesized that if the interval between short-course radiation and surgery increases allowing for tumour shrinkage [
Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.
Initial results of a randomised controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long term chemoradiotherapy both with delayed surgery.
], and if consolidation chemotherapy is added to short-course radiation in a tight sequence providing an additional cell killing effect, such a combination may be superior to conventionally fractionated chemoradiation. Published data have supported such a concept in both unresectable and resectable rectal cancer [
Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: report of an interim response analysis.
Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases.
Short-course radiation therapy, neoadjuvant bevacizumab, capecytabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: a phase II multicenter study of the Dutch Colorectal Cancer Group.
]. It should be noted that chemotherapy and short-course radiation cannot be delivered simultaneously due to an apprehension of unacceptable acute toxicity; thus, only sequential treatment is possible. The aim of our randomized trial is to test the above hypothesis. Here we present an interim analysis of this trial.
Material and methods
The trial was approved by an ethics committee. Unresectable rectal cancer was defined as a primary or locally recurrent tumour involving or abutting adjacent organs or structures (cT4) or palpably fixed cT3 lesion. The eligibility criteria were as follows: patients with unresectable primary rectal cancer or with an unresectable local recurrence, pathologically proven adencarcinoma, no more than 75 years of age, WHO performance status ⩽2 in patients fit for major surgery and chemotherapy, lower border of tumour ⩽15 cm from anal verge, and signed informed written consent. Exclusion criteria were as follows: distant metastases, tumour imaging indicating that resection will never be possible even after chemoradiation – for example tumour growth into S1–2, active coronary artery disease, cardiac arrhythmia, congestive heart failure, previous radiotherapy to the pelvis, history of peripheral neuropathy, and history of cerebral stroke. Work-up included: colonoscopy or rectoscopy (if a colonoscopy was not carried out before treatment it should be done within 3 months of surgery), pelvic MRI (alternatively pelvic CT was allowed if MRI was not available), CT of the abdomen, chest X-ray or CT, blood count and biochemistry. Other examinations were carried out if necessary, for example cystoscopy for a diagnosis of urinary bladder involvement.
Neoadjuvant treatment
The patients were randomized to receive either preoperative 5 × 5 Gy irradiation over 5 days and consolidation chemotherapy of three cycles of FOLFOX4 or 50.4 Gy in 28 fractions of 1.8 Gy over 5.5 weeks concomitantly with oxaliplatin, 5-fluorouracil and leucovorin. The interval between the start of radiation and surgery was the same (12 weeks) in both groups. Overall neoadjuvant treatment time and the interval between completion of radiotherapy/chemotherapy and surgery were about 6 weeks in both groups (Fig. 1).
The irradiation technique was identical in both groups. The clinical target volume (CTV) included the primary tumour with at least 15 mm margin, regional lymph node metastases, and uninvolved regional nodes: mesorectal nodes with the upper limit set at the sacral promontory, obturator, internal iliac and lower common iliac nodes. Irradiation of external iliac nodes was not recommended because there is no evidence indicating benefit from such treatment [
T4 rectal cancer treated with preoperative chemoradiation to the posterior pelvis followed by multivisceral resection: patterns of failure and limitations of treatment.
]. In case of a very low-lying lesion or when the anal canal was involved, the lower border of the CTV was located at least 2 cm distally from the tumour. Otherwise, the lower limit of the CTV was located at the pelvic floor or at least 4 cm below the lowest part of the tumour in case of a high lesion. A single fraction boost dose of 4 Gy in the experimental group or 5.4 Gy in three fractions in the control group was given in case of involvement of lymph nodes (>1 cm) not routinely removed during surgery, for example internal iliac or obturator nodes. A three-dimensional planning and the use of at least a 6 MV linear accelerator were recommended. The dose was specified at the intersection of the axes of the fields. In order to protect the small bowel, irradiation with a distended urinary bladder was advised. A belly-board device was also recommended.
Patients allocated to the experimental group received three cycles of FOLFOX4. The first cycle was planned to start a week after the completion of radiation. However, in the case of radiation toxicity, the onset of chemotherapy was postponed until recovery. Each cycle comprised a 2-h infusion of 85 mg/m2 of oxaliplatin on day 1, given simultaneously with 200 mg/m2 of leucovorin through a Y catheter. Next, a bolus of 400 mg/m2 5-Fu was given and then 600 mg/m2 of 5-Fu in a 22-h continuous infusion every 14 days, for three cycles. If the second or third cycle of chemotherapy was delayed, the interval between delivering the first and last dose of chemotherapy was limited to 7 weeks. Doses of chemotherapy which were not given within this time were missed. Patients allocated to the control group received two 5-day cycles of 5-Fu 325 mg/m2/day and leucovorin 20 mg/m2/day intravenous bolus simultaneously with irradiation during the first and fifth week of irradiation. Additionally, 5 one-day infusions of oxaliplatin 50 mg/m2 were given once a week at 1, 8, 15, 22, and 29 days of irradiation. Postoperative chemotherapy in both groups was optional. Early toxicity of neoadjuvant treatment was defined as toxicity occurring during radio(chemo)therapy or within the interval to surgery. In the experimental group, toxicity occurring during irradiation, after irradiation (within interval between irradiation and chemotherapy) and within or after chemotherapy was recorded separately. The NCI CTCAE v. 3 scale was used [
A second pelvic MRI or CT was not recommended routinely prior to surgery as those examinations are not reliable in the assessment of pathological response [
Morphological assessment of the interface between tumor and neighboring tissues, by magnetic resonance imaging, before and after radiotherapy in patients with locally advanced rectal cancer.
Morphological assessment of the interface between tumor and neighboring tissues, by magnetic resonance imaging, before and after radiotherapy in patients with locally advanced rectal cancer.
], and for this reason, the protocol stipulated that tumour resection should be attempted regardless of clinical response. In case of the involvement of neighbouring organs, multivisceral en bloc resection was recommended. The extent of the resection had to be decided at a multidisciplinary meeting based on a pre-treatment pelvic MRI or CT. A favourable clinical tumour response did not negate the need for an en bloc resection. This is because even in case of a favourable response, cancer cells might be present in the pre-treatment tumour volume. For tumours located in the low or mid rectum, a total mesorectal excision was carried out, and for tumours located in the upper rectum, a subtotal mesorectal excision was done; i.e. the mesorectum was excised 4 cm below the tumour. The distal bowel margin was at least 1 cm. Extralevator type of an abdominoperineal resection was required [
]. In the case of an anterior resection, the decision to create a defunctioning stoma was left to the surgeon. Enlarged internal iliac or external iliac lymph nodes were resected. Resection was categorized as microscopically non-radical when cancer cells were seen within 1 mm from surgical margin. Macroscopically non-radical surgery (R2) was confirmed by a pathologist. Postoperative complications were defined as those occurring within 30 days after surgery.
Pathology
The pathological examination was based on the Quirke method [
Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision.
]. The assessment of the circumferential resection margin (CRM) was mandatory. Positive CRM was diagnosed when cancer cells were seen within 1 mm of the surgical margin. Staging was based on the 6th version of the UICC/AJCC TNM classification. For a diagnosis of complete tumour response, five samples had to be taken from the pre-treatment tumour volume. If cancer was still not found, an additional three slides had to be cut from each of these samples. Pathological complete response was defined as the absence of cancer cells both at the primary site and regional lymph nodes. Central quality control for radiotherapy, chemotherapy, surgery, and pathology was not carried out.
Statistics
A microscopically radical resection rate was chosen as the main endpoint of the trial, because in the Nordic randomized study on unresectable rectal cancer, this variable was shown to be correlated with both, the type of neoadjuvant treatment and long-term disease-free survival [
]. The assumed microscopically radical resection rate in the conventionally fractionated chemoradiation group was 75%. To detect at least a 10% benefit in the short-course group, 540 patients are needed assuming the use of two-sided chi-square test with a significance level of 0.05% and 80% power.
Randomization was performed by telephone to the central trial office and was based on the minimization method. The patients were stratified according to the centre and type of the tumour (primary cT3 or cT4 or recurrent cancer). The trial is registered with ClinicalTrials.gov number NCT00833131.
As little is known about toxicity of short-course radiation combined with sequential chemotherapy, an interim analysis of the first 100 patients was planned. Apart from early toxicity, microscopically radical resection rate and pathologic response to preoperative treatment were also evaluated, as one cannot exclude that due to the lack of synergistic interaction (radiosensitization) between sequentially given chemotherapy and radiation in the experimental arm, the tumourcidal effect may be inferior to that produced by simultaneously given chemoradiation. Termination of the study was planned in case of major differences between the study groups in the above endpoints. The stopping rules were not defined. As the primary aim of the current interim analysis was to assess toxicity, the analyses were performed according to the schedule of radiotherapy actually given. Statistical tests were not performed as this was planned after the completion of accrual.
Results
Between November 2008 and January 2010, 100 patients from 20 Polish hospitals were enrolled. Three patients were excluded, 49 patients received short-course irradiation with consolidation chemotherapy and 48 patients received chemoradiation (Fig. 2). The patients in both groups were well balanced with respect to the pre-treatment characteristics (Table 1). The majority of patients (72%) had cT4 primary tumour.
Details of neoadjuvant treatment and surgery are given in Table 2. All patients in the experimental group received the planned total dose of irradiation, whereas, in the control group, the dose was reduced in six patients (13%) due to toxicity. The toxic effect of short-course radiation occurred more often after treatment (i.e. during the one week interval between radiation and chemotherapy) than during treatment (Table 2). Sacral pain was the most common toxic effect occurring during irradiation, whereas diarrhoea and proctitis were the most common toxic effects occurring after irradiation. Overall (both during and after short-course radiation) grade 1–2 toxicity occurred in 26 patients (53%) and grade 3 toxicity (maximal) occurred in two patients (4%). Due to this toxicity consolidation chemotherapy was postponed in four patients (8%). Intraoperative irradiation was not given in either group.
Table 2Treatment related parameters.
5 + 5 Gy + chemotherapy N = 49
Chemoradiation N = 48
Radiotherapy dose reduction due to toxicity
Yes
0 (0)
6 (13)
No
49 (100)
41 (87)
Chemotherapy dose reduction due to toxicity
Yes
5 (10)
12 (25)
No
44 (90)
36 (75)
Chemotherapy cycle delay due to toxicity (without dose reduction)
Surgery was not carried out for the following reasons: the experimental group – in two patients distant metastases were detected after neoadjuvant treatment and two patients did not consent for surgery; the control group – two patients died shortly after chemoradiation and two patients did not consent for surgery.
4 (8)
4 (8)
Exploratory laparotomy; pelvic tumour was still unresectable
6 (12)
4 (8)
Exploratory laparotomy; distant metastases were found at surgery
1 (2)
0
R2 resection
0
1 (2)
Microscopically non-radical resection
2 (4)
5 (10)
Microscopically radical resection
36 (73)
34 (71)
Adjacent organs were resected
Yes
14 (37)
17 (43)
No
24 (63)
23 (57)
No tumour resection
11
8
Type of surgery
Anterior resection
14 (37)
19 (48)
Abdominoperineal resection
15 (39)
16 (40)
Hartmann’s procedure
9 (24)
5 (12)
No tumour resection
11
8
Postoperative complications
Requiring re-operation
4 (9)
3 (7)
Treated conservatively
8 (18)
4 (9)
No complications
33 (73)
36 (84)
No data
–
1
No surgery
4
4
Hospital stay post surgery in days, median (range)
8.0 (5–23)
8.5 (4–50)
No data
3
6
Numbers in the table denote number of patients (%) unless otherwise stated.
Abbreviation use: n.a., no applicable.
a Surgery was not carried out for the following reasons: the experimental group – in two patients distant metastases were detected after neoadjuvant treatment and two patients did not consent for surgery; the control group – two patients died shortly after chemoradiation and two patients did not consent for surgery.
b Delay of chemotherapy was not allowed by the protocol; all chemotherapy had to be given during irradiation
c Interval between completion of 5 × 5 Gy and start of chemotherapy longer than two weeks was recorded in 7 patients (15%).
The protocol stipulated the delivery of chemotherapy one week after the completion of short-course radiation. However, it was most often 10 days, as irradiation ended on a Friday and chemotherapy started on a Monday. Oxaliplatin was not given in 1 patient (2%) in the experimental group and in 7 patients (15%) in the control group. Overall, grade 3 or higher acute toxicity of neoadjuvant treatment was recorded in 26% of patients in the experimental group and in 25% in the control group (Table 2). Diarrhoea and c toxicity were most common side effects in both groups. There were two sudden deaths shortly after completion of chemoradiation in the control group, probably due to a thromboembolic event. There were no toxic deaths in the experimental group. Chemotherapy dose reduction (mostly oxaliplatin) due to toxicity was needed less often in the experimental group than in the control group (10% vs. 25% of patients). However, when both the need for chemotherapy dose reduction and the need for chemotherapy cycle delay were taken into account, the rates were similar - 26% of patients in the experimental group and 25% in the control group. This was because, in the experimental group chemotherapy could be delayed, whereas in the control group, chemotherapy doses not given during irradiation were missed.
Staging laparoscopy and laparoscopic ultrasound investigation were not performed before embarking on excision. The overall resection rate and microscopically radical resection rate were 77% and 73% in the experimental group vs. 83% and 71% in the control group (Table 2). Postoperative complications were observed in 27% of patients in the experimental group and in 16% of patients in the control group; complications requiring re-operation were recorded in 9% and 7% of patients, respectively. There was no postoperative mortality in either group.
A pathological complete response was observed in 21% of patients in the experimental group and in 8% in the control group (Table 3). A downstaging effect was observed in 71% and 73% of patients, respectively. A positive circumferential margin was recorded in 5% and 15% of patients, respectively. A distal bowel margin was negative in all patients.
The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated neoadjuvant treatments. So, the trial is continued. Our data contribute to the growing evidence showing that short-course radiation combined with consolidation chemotherapy is a promising management [
Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: report of an interim response analysis.
Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases.
Short-course radiation therapy, neoadjuvant bevacizumab, capecytabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: a phase II multicenter study of the Dutch Colorectal Cancer Group.
]. This opinion is, however, based mainly on the early assessment of efficacy, namely on the radical resection rate and on the rate of pathological complete response (Table 4). Long-term oncological results are unknown as they were reported only in 15 patients [
Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.
Table 4Short-course radiotherapy and long interval to surgery in advanced rectal cancer. The rate of pathological complete response in relation to the delivery of consolidation chemotherapy.
Initial results of a randomised controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long term chemoradiotherapy both with delayed surgery.
Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases.
Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.
Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: report of an interim response analysis.
Short-course radiation therapy, neoadjuvant bevacizumab, capecytabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: a phase II multicenter study of the Dutch Colorectal Cancer Group.
]. This toxicity occurred in approximately half of the patients. Such toxicity is not observed when surgery takes place immediately after the delivery of 5 × 5 Gy. This is because the rectum (the organ at risk of acute adverse effect) is excised before damage occurs.
A week point of the trial is that initial pelvic MRI was not used in all patients (only in 64%, Table 1). This was because, in Poland in many centres there is a long waiting list for this examination. For this reason, palpably fixed cT3 lesion was used as the entry criterion instead of threatened mesorectal fascia diagnosed by using MRI. It should be stressed that tumour fixity is not always representative of very locally advanced unresectable lesion. Other weakness of the study is that administration of cetuximab or bevacizumab was not considered in patients with recurrent tumour. A drawback of the study design is a lack of strictly predefined stopping rules for interim analysis. Other weak point of the study design is the uncertainty whether the addition of chemotherapy to short-course radiation improves local efficacy. In order to answer this question, a literature search was carried out. Pathological complete response in patients with advanced rectal cancer treated with short-course radiation and long interval to surgery [
Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.
Initial results of a randomised controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long term chemoradiotherapy both with delayed surgery.
Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: report of an interim response analysis.
Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases.
Short-course radiation therapy, neoadjuvant bevacizumab, capecytabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: a phase II multicenter study of the Dutch Colorectal Cancer Group.
]. Pooled results showed 8.9% of pathological complete response in patients treated with short-course radiation alone and 23.7% in patients treated with combination of short-course radiation and consolidation chemotherapy, chi-square p < 0.001 (Table 4). Thus, this cross-study comparison suggests a beneficial effect of the addition of chemotherapy. Another uncertain point of the study design is the addition of oxaliplatin to 5-Fu based chemotherapy when combined with radiation. At the time the protocol was being written, a panel of experts proposed the addition of oxaliplatin to chemoradiation for unresectable rectal cancer [
The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007.
]. The rationale for such a proposal was that this strategy may lead to a higher regression rate and thus a higher resectability. Results of four randomized trials comparing fluoropyrimidine-based chemoradiation with or without oxaliplatin were recently published [
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.
Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase III trial.
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.
]. It should be noted, however, that all four trials were carried out in resectable rectal cancer. In contrast to the aforementioned randomized trials, a retrospective analysis of a series of patients with unresectable cancer suggested benefit in cancer specific survival with addition of oxaliplatin to chemoradiation [
]. Thus, the role of oxaliplatin in unresectable rectal cancer is still uncertain.
In conclusion, our interim analysis suggests that early results after short-course irradiation and consolidation chemotherapy in unresectable rectal cancer are not worse than those achieved after conventionally fractionated chemoradiation. Thus, short-course irradiation and consolidation chemotherapy may be considered in a case of logistic problems; for example a long waiting list for radiation.
Conflict of interest
There was no financial and personal relationship with other people and organizations that could inappropriately influence (bias) this work.
Acknowledgements
The study was supported by grant No. NN403 580538 from the Polish Ministry of Science and Higher Education. The study sponsor had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
References
Eriksen M.T.
Wibe A.
Hestvik U.E.
Haffner J.
Wiig J.N.
Surgical treatment of primary locally advanced rectal cancer in Norway.
Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.
Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity.
Initial results of a randomised controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long term chemoradiotherapy both with delayed surgery.
Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: report of an interim response analysis.
Upfront systemic chemotherapy and preoperative short-course radiotherapy with delayed surgery for locally advanced rectal cancer with distant metastases.
Short-course radiation therapy, neoadjuvant bevacizumab, capecytabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: a phase II multicenter study of the Dutch Colorectal Cancer Group.
T4 rectal cancer treated with preoperative chemoradiation to the posterior pelvis followed by multivisceral resection: patterns of failure and limitations of treatment.
Morphological assessment of the interface between tumor and neighboring tissues, by magnetic resonance imaging, before and after radiotherapy in patients with locally advanced rectal cancer.
Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision.
The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007.
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.
Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase III trial.
☆Presented at European Multidisciplinary Colorectal Cancer Congress 2012, April 2012, Prague, Czech Republic and at 31st Meeting of European Society for Therapeutic Radiology and Oncology, Barcelona, Spain, 2012.
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