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Preoperative Concurrent Chemoradiotherapy in Locally Advanced Rectal Cancer With High-Dose Radiation and Oxaliplatin-Containing Regimen: The Lyon R0–04 Phase II Trial

Jean-Pierre Gérard, Olivier Chapet, Chantal Nemoz, Pascale Romestaing, Françoise Mornex, Régis Coquard, Nicolas Barbet, Dan Atlan, Patrice Adeleine, Gilles Freyer

From the Department of Radiation Oncology, Lyon Sud Pierre Bénite; Clinique Saint-Jean, and Department of Biostatistics, Hospices Civils Lyon, Lyon; Clinique Denis, Mâcon; Hôpital Européen Georges Pompidou, Paris; and Department of Medical Oncology, Centre Hospitalier Lyon Sud Pierre Bénite, Pierre Bénire, France.

Address reprint requests to Jean-Pierre Gérard, MD, Centre Antoine-Lacassagne, Direction, 33 avenue de Valombrose, 06189 Nice Cedex 2, France; email: jean-pierre.gerard{at}cal.nice.fnclcc.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The combination of radiation, fluorouracil, and oxaliplatin in locally advanced rectal cancer has been shown to be feasible in a phase I trial. The purpose of this phase II trial was to assess tolerance and efficacy of this regimen in a preoperative setting.

Patients and Methods: Between May 2000 and October 2001, 40 operable patients were entered onto the study. Radiotherapy was delivered with a three-field technique to a dose of 50 Gy over 5 weeks with a concomitant boost approach. Two cycles of chemotherapy were given synchronously on weeks 1 and 5, with oxaliplatin 130 mg/m² on day 1 followed by 5-day continuous infusion of fluorouracil 350 mg/m² and L-folinic acid 100 mg/m². Surgery was planned 5 weeks later.

Results: All patients completed treatment without modification except one who experienced grade 3/4 toxicity. Grade 3 toxicity was seen in seven patients. Surgery was performed in all patients after a mean interval time of 5 weeks. An objective clinical response was seen in 30 patients (75%). Sphincter-saving surgery was possible in 26 patients. No postoperative deaths occurred. In four patients (10%), a reoperation was necessary (anastomotic fistula, n = 2; pelvic abscess, n = 2). In six cases the operative specimen was sterilized (15%), and in 12 cases (30%), only few residual cells were detected.

Conclusion: Such a combined preoperative chemoradiotherapy and oxaliplatin-containing regimen is well tolerated with no increase in surgical toxicity. The good response rate observed warrants its use in further clinical trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
SURGERY WILL remain the cornerstone of rectal adenocarcinoma treatment for many years. Since the original description by R.J. Heald,^1,2 most surgeons consider sharp circumferential dissection with total mesorectal excision (TME) as the standard technique of rectal surgery for locally advanced rectal cancer. The Dutch Colorectal Cancer Group randomized trial has clearly demonstrated that even with TME surgery, preoperative irradiation was useful to reduce the risk of local recurrence.³ This trial also gave solid confirmation of data by Quirke et al⁴ showing that circumferential margin involvement was a good predictor of both local control and distant metastases.⁵ Although postoperative chemoradiotherapy is considered standard treatment in many institutions,^6,7 the Uppsala trial has shown that preoperative radiotherapy improves local control and decreases toxicity compared with postoperative radiotherapy.⁸ The best regimen of preoperative irradiation is still under debate. Chemotherapy given concurrently with preoperative irradiation is viewed as standard in some countries but not in most European countries, where the European Organization for Research and Treatment of Cancer Trial 22921 and Fédération Française de Cancérologic Digestive (FFCD) 9203 trial using a fluorouracil (FU) plus leucovorin regimen will determine in 2003 or 2004 whether concurrent chemotherapy is useful. At that time, low-dose bolus FU plus leucovorin may be considered as a nonoptimal chemotherapy regimen to treat systemic micrometastatic disease.⁹

Many different concurrent chemoradiotherapy combinations have been evaluated for rectal cancers during recent years, using FU continuous infusion,^6,7 oral pyrimidine analog,^10–12 or irinotecan.¹³ We have shown in a phase I trial¹⁴ that the regimen with oxaliplatin 130 mg/m² combined with FU 350 mg/m²/d continuous infusion over 5 days, L-folinic acid 100 mg/m²/d over 5 days, for two courses (weeks 1 and 5) and pelvic radiotherapy (45 Gy over 5 weeks, 1.8 Gy/fraction; FOLFOR 1) was well tolerated.

After this phase I trial, we initiated a phase II trial to evaluate this concurrent chemoradiotherapy with slight modifications (FOLFOR 2) in a preoperative setting. The main objective of this study was to evaluate the early postoperative complication rate of this regimen.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Patients entering the study had histologically proven rectal adenocarcinoma, either T3–4, M0 (International Union Against Cancer, 1997) or T2 with a more than 10% risk of local relapse (circumferential T2, poorly differentiated type, T2N > 0, inferior location: < 5 cm from the anal margin). All patients were initially considered operable. We included men or women younger than 76 years of age with World Health Organization/Eastern Cooperative Oncology Group performance status 2 and acceptable hematologic, renal, and liver function: neutrophils 1,500/µL, platelets 100,000/µL, creatinine 130 µmol/L, liver AST less than twice the upper limit of normal, and bilirubinemia less than 1.5 times the upper limit of normal. Written informed consent was systematically required.

Patients were excluded from the trial for previous anticancer treatment; synchronous colic tumor; any previous history of malignant tumor except in situ carcinoma of the cervix, cutaneous basocellular carcinoma, and in situ carcinoma of the bladder; inflammatory bowel disease; ischemic heart disease; psychiatric disorders; other severe pathology; lack of effective contraception; and pregnancy. The Lyon University Independent Ethics Committee reviewed and approved the study protocol in May 2000.

Work-Up
The pretreatment work-up included biopsy, careful digital rectal examination and rigid rectoscopy in the knee-chest position, colonoscopy, transrectal ultrasound, pelvic computed tomography scan, liver ultrasound, chest x-ray, carcinoembryonic antigen assay, complete blood cell counts, blood electrolytes, serum creatinine and urea, blood glucose, calcium, liver AST, alkaline phosphatase, total bilirubin, prothrombin time, partial thromboplastin time, fibrinogen, and ECG. We established the tumor-node-metastasis staging with maximum possible accuracy, always including ultrasonographic tumor-node-metastasis staging, except when transrectal ultrasound could not be performed because of rectal tumor stenosis.

Treatment
Radiotherapy. Patients received external-beam radiotherapy. Treatment planning and field positioning were performed with orthogonal film simulation and contrast barium in the rectum. We used a three-field wedge technique with the patient in prone position using a linear accelerator with a photon beam of 10 MV. The treated volume included the macroscopic tumor and its potential extensions within the rectum, the mesorectum, and the perirectal lymph nodes. It extended 6 cm above and 4 cm below the tumor margins. The anus was not irradiated unless the tumor extended into the anal canal. The treated volume extended 3 cm laterally and anteroposteriorly around the macroscopic limits of the tumor. We did not irradiate the external iliac lymph nodes.

The posterior field measured an average 14 x 12 cm and did not extend outside the pelvic rim. Lateral fields involved the sacrum’s posterior surface. They measured an average 14 cm vertically (as for the posterior field) and 10 to 12 cm anteroposteriorly. The upper limit of the fields was never above the promontorium. No shielding was recommended. The treated volume encompassed by the 95% isodose never exceeded 2 L.

All patients received a total dose of 45 Gy in daily fractions of 1.8 Gy calculated at the International Commission of Radiation Units reference point, at the intersection of the central axes of the three or four beams. All fields were treated every day. In addition, a boost limited to the macroscopic tumor with a 2-cm peripheral margin was given. This boost delivered a dose of 1 Gy, once a week for 5 weeks, with a 6-hour minimum interval between the pelvic irradiation and the local boost. This bifractionated irradiation was delivered on Friday.

Chemotherapy. We administered two cycles of oxaliplatin, FU, and L-folinic acid (FOLFOR 2); the first cycle was administered on days 1 to 5 of the external-beam radiotherapy and the second cycle was administered on days 29 to 33. The cycle consisted of a 2-hour oxaliplatin infusion 130 mg/m² on the first day of each sequence, followed by five daily infusions of L-folinic acid 100 mg/m²/d over 30 minutes, and a continuous infusion of FU 350 mg/m²/d over the same 5 days (Fig 1). Patients could receive a second cycle of chemotherapy at day 29 without dose reduction if they had 1,500 neutrophils/µL and 100,000 platelets/µL. For patients with between 1,000 and 1,500 neutrophils/µL and/or platelets between 80,000 and 100,000/µL, doses were reduced to oxaliplatin 100 mg/m² and FU 200 mg/m²/d. For patients with levels below those limits, we did not perform the second chemotherapy cycle, which was never delayed.

View larger version (30K): [in this window] [in a new window]   Fig 1. Concomitant chemoradiotherapy: fluorouracil, L-folinic acid, oxaliplatin, and pelvic radiation (the FOLFOR 2 regimen).

Surgery. Surgery was planned after a 5-week rest period. A total mesorectal excision was planned according to the technique described by Heald et al.¹ The type of surgery (sphincter preservation or abdomino-perineal resection) was left to the surgeon’s discretion, but a minimal distance of 2 cm between the inferior margin of the tumor and the limit of resection was strongly recommended. A complete exploration of the pelvis and abdomen was systematically performed to look for lymph nodes and/or liver metastases.

Operative Specimen Pathologic Examination
Distal as well as lateral resection margins, residual tumor, and lymph nodes were carefully examined by the pathologist, but the Quirke procedure^4,5 was not routinely performed. Pathologic complete response was defined as the absence of any residual tumor cells detected in the operative specimen.

Patient Monitoring and Follow-Up
During study treatment, we monitored patients by weekly clinical examination with full hematology assessment. Blood biochemistry and liver function tests were performed before each cycle of chemotherapy. After surgery, all patients were followed-up with clinical examination every 3 months.

Study Design
The aim of the study was to evaluate the feasibility of this preoperative regimen. The main end point was early surgical complications. To rule out more than 10% of patients requiring subsequent surgery for postoperative complication, 40 patients were required for the study.

Our secondary objectives were immediate toxicities assessed by the National Cancer Institute Common Toxicity Criteria version 2, clinical response rate (as determined by rigid rectoscopy) 4 weeks after completion of chemoradiotherapy, and pathologic response rate after surgery.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Accrual
Between May 2000 and October 2001, 40 patients were enrolled onto the trial by four different radiotherapy departments. Table 1 lists the characteristics of the study population. All tumors were easily felt on digital rectal examination and were located in the lower or middle rectum. Transrectal ultrasound was not informative in only one patient with a circumferential tumor.

Acute Toxicity
Table 2 lists all acute toxicities occurring during the preoperative combined chemoradiotherapy for the 40 patients. Grade 3/4 toxicity was seen in seven patients (17%) for a total of 16 different toxicities. Patient radiation interruption was necessary for a week for only one patient. This patient presented with fever, diarrhea, rectitis, grade 3 neutropenia, and grade 4 mucositis. He fully recovered and underwent surgery without any surgical complication. A dihydropyrimidine dehydrogenase deficiency was not detected in this patient, who was the only one to experience severe toxicity.

Surgery
Surgery was performed in all 40 patients, with a median interval time after chemoradiotherapy of 5 weeks (range, 4 to 7 weeks). Eleven surgeons performed the operations. There was no supervision of the surgical technique, which was described in all cases as a total circumferential mesorectal excision. Anterior resection was performed in 25 patients, abdomino-perineal resection was performed in 14 patients, and an endo-anal full thickness dissection was performed in one patient. A diverting stoma was deemed necessary in nine of the 25 patients who underwent anterior resection. In all cases, a total gross tumor resection with no macroscopic residual disease was possible.

Pathologic Examination of Operative Specimens
In six patients, no residual cancer cells could be identified and tumor was staged pathologic (p) T0N0 (15%). In 12 patients, only a few residual cells with questionable viability were detected (30%). This was associated in six patients with the presence of mucoid deposits. These deposits and residual cells could be found either in the muscularis propria (pT2) or in the perirectal fat (pT3). Combining six pT0N0 patients and 12 patients with few residual cells gave a complete or nearly complete pathologic response in 18 patients or 45% (95% confidence interval, 29% to 61%). Positive lymph node metastases were present in 10 patients (25%). Circumferential mesorectal margin was examined in all patients and was free of cancer cells in 38 patients and involved (R1) in two patients. An involvement of distal margin was never present.

Surgical Complication
There were no postoperative deaths (death during the 60 days after surgery). In four patients, a complication required a reoperation (10%; 95% confidence interval, 2.8% to 23.7%). Anastomotic fistula was present in two patients and pelvic abscess was present in two patients. There were no medical complications. The median hospital stay was 13 days.

Follow-Up
The follow-up is still short for most of the patients, but at time of analysis (March 2002), no local recurrences, no distant metastases, and no deaths have been observed. Anorectal function for patients with a sphincter-saving surgery and no diverting stoma was considered to be not significantly affected by the preoperative chemoradiotherapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This phase II trial was initiated after the phase I Lyon R97–03 trial. The only modification in the FOLFOR 2 regimen was an increase of the radiation dose from 45 to 50 Gy. This radiation dose increase was intended to improve the downsizing of the tumor. A concomitant, bifractionated boost was selected according to the M.D. Anderson Cancer Center approach.¹⁵

The main end point of this trial was to assess the early surgical toxicity and complication rate of this new regimen. It is possible to state that the rate of surgical complication seems acceptable, with no postoperative deaths and 10% of patients requiring reoperation for either anastomotic fistulae (8%) or pelvic abscess. In one patient, we observed a supra-anastomotic necrotic area that may not be directly related to chemoradiotherapy but might be due to a failure of the surgical procedure itself.

In the Dutch TME trial in the radiotherapy group, the rate of perineal complication after abdomino-perineal resection was 26%, and the rate of anastomotic leakage after anterior resection was 12%.³ In most series of patients with rectal cancer treated with preoperative radiotherapy and anterior resection, the rate of anastomotic fistula varies between 6% and 16%.^15–18

As in our prior phase I trial, the acute toxicity of this regimen was good in all the patients except one who experienced severe toxicities after the first chemotherapy cycle. Complete clinical recovery was observed after 10 days and irradiation was completed, but the patient did not receive the second chemotherapy cycle. In this patient, we performed a dihydropyrimidine dehydrogenase (a key enzyme in the catabolism of FU) assay, but the result showed no significant abnormality. The most frequent side effect was grade 1 oxaliplatin-related dysesthesiae. The radiation dose increase to 50 Gy did not seem to modify either the early surgical toxicity or the immediate acute toxicity of this regimen. It must be emphasized that the treated volume was limited to the posterior pelvis only and remained less than 2 L. In no patients were the external iliac nodes, which are seldom involved in these cancers, included in the clinical target volume. It is well recognized that small irradiated volume is a key point for good tolerance of pelvic irradiation.^19–23

Before surgery, an objective tumor response was noticed by the radiation oncologist or the surgeon in a large majority of patients. No tumor progression was observed. Sphincter-saving surgery was performed in 65% of patients, which is a rather high rate for tumor of the low or middle rectum accessible to digital rectal examination. It is possible that some of these conservative surgeries were related to the downsizing of the tumor.^24–27 The rate of anterior resection in the Dutch TME trial, with immediate surgery after radiotherapy, was identical in both arms (65%, with 30% of tumors located > 10 cm from the anal verge in the upper rectum).

The response rate, or downsizing or downstaging as it can be analyzed on the operative specimen, is a good end point to evaluate the efficacy of a preoperative radiotherapy or chemoradiotherapy approach.¹³ This end point heavily depends on the pathologic technique used to analyze the operative specimen. Ideally, a Quirke procedure^4,5 with transaxial sections of the operative specimen and serial section of the various slices is required. In our study, different departments performed the pathologic examination and the procedure was not standardized. A careful analysis of the specimen was performed for all patients, and the distal and lateral circumferential margins were examined in all cases to assess the R0 or R1 states of the surgical specimen. The rate of pathologic complete response also closely depends on the number of sections performed and the quality of search for residual cancer cells. The definition of viable cells can also be a source of discrepancy. In the German Chirurgie Assoziation Onkologie/Assoziation Ratiotherapy Onkologie phase III trial with preoperative chemoradiotherapy,²⁷ the rate of pathologic complete response was only 9%. This lower-than-expected response rate may be due to a strict and careful search for residual viable cancer cells.

In the literature, the rate of complete sterilization of the operative specimen varies between 5% and 32%.^{10–12,15,24} The higher rates are observed with protocols using higher radiation doses, longer intervals before surgery, concurrent chemotherapy, and rectal tumors of smaller size or lower stage. The rate of nearly complete sterilization or few residual cells is also often reported in the literature and varies between 15% and 48%.^10,15,18,24 This end point also seems somewhat subjective and, like sterilization, is dependant on the treatment protocol and the stage of the tumor. For all of these reasons, without randomization it is difficult to demonstrate that this present or any other specific regimen is clearly more efficient than another in terms of pathologic tumor response or complete sterilization. Given that 36 of 40 patients have been staged as having T3 or T4 disease with endorectal sonography, the present FOLFOR 2 regimen seems to provide a significant rate of pathologic response, with a 15% rate of complete sterilization and overall 52% of operative specimens being sterilized or with only few viable residual cells. It is interesting to note that the circumferential resection margin was positive in only two patients (5%) compared with 11% in the Dutch Colorectal Group TME Trial. According to Kapiteijn et al³ and Hall et al,⁵ circumferential margin is considered positive (R1) when the tumor has encroached to within 1 mm of the inked resection margin. Such a definition, which was not used in our practice, seems to be one of the best predictors of local relapse and survival.

This preoperative chemoradiotherapy regimen seems tolerable and efficient. It could be compared in the near future with bolus FU and leucovorin in a phase III trial. Some modifications of this regimen can also be discussed, such as the use of oral fluoropyrimidine^10–12 or a weekly schedule of oxaliplatin.²⁸ Radiation dose escalation with conformal three-dimensional radiotherapy¹⁶ or endocavitary irradiation^29,30 may also be of interest.

In conclusion, the Lyon R0–04 phase II trial is a new step in the direction of an optimal multimodality approach to treat locally advanced rectal cancer. It demonstrates the feasibility and efficiency of a preoperative regimen using high-dose irradiation in a limited pelvic volume concurrently with oxaliplatin and continuous FU infusion. Adjuvant chemotherapy and new molecular targeting in rectal cancer also warrant attention in light of the improved local control rate. Phase III trials will be needed soon to define a standard approach that takes into consideration local control, sphincter preservation, survival, and quality of life.

	NOTES

 
Supported by grants from Ligue Contre le Cancer, Comité du Rhône et de Saône et Loire, France.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke experience of total mesorectal excision—1978–1997. Arch Surg 133:894–899, 1998[Abstract/Free Full Text]

2. Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181:335–346, 1995[Medline]

3. Kapiteijn E, Marijnen CAM, NagtegaaI ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646, 2001[Abstract/Free Full Text]

4. Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996–999, 1986[CrossRef][Medline]

5. Hall NR, Finan PJ, Al-Jaberi T, Brown et al: Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent: Predictor of survival but not local recurrence? Dis Colon Rectum 41:979–983, 1998[CrossRef][Medline]

6. O’Connell M, Mailliard J, Kahn M, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246–250, 1997[Abstract/Free Full Text]

7. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. J Am Med Assoc 264:1444–1450, 1990[Abstract/Free Full Text]

8. Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564–572, 1993[CrossRef][Medline]

9. Bosset JF, Pavy JJ, Hamers HP, et al: Determination of the optimal dose of 5-fluorouracil when combined with low dose D, L-leucovorin and irradiation in rectal cancer: Results of three consecutive phase II studies. Eur J Cancer 29:1406–1410, 1993

10. Kim JS, Cho MJ, Song KS, et al: Preoperative chemoradiation using capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 54:403–408, 2002[CrossRef][Medline]

11. Calvo FA, Marcos P, Gomes-Espi M, et al: Pathologic downstaging of T3-4 Nx rectal cancer after chemoradiation: 5 FU vs tegafur. Int J Radiat Oncol Biol Phys 48:122, 2000 (abstr 23)

12. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983–3991, 2002[Abstract/Free Full Text]

13. Glimelius B: Chemotherapy for rectal cancer: Is there an optimal combination? Ann Oncol 12:1039–1043, 2001[Abstract/Free Full Text]

14. Freyer G, Bossard N, Romestaing P, et al: Addition of oxaliplatin to continuous fluorouracil l-folinic acid and concomitant radiotherapy in rectal cancer: The Lyon R97-03 phase I trial. J Clin Oncol 19:2433–2438, 2001[Abstract/Free Full Text]

15. Janjan NA, Khoo VS, Abbruzzese J, et al: Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: The M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 44:1027–1038, 1999[CrossRef][Medline]

16. Valentini V, Cocco C, Cellini N, et al: Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: Acute toxicity, tumor response, sphincter preservation. Int J Radiat Oncol Biol Phys 45:1175–1184, 1999[CrossRef][Medline]

17. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980–987, 1997[Abstract/Free Full Text]

18. Gérard JP, Chapet O, Morignat E, et al: La radiothérapie preoperatoire du cancer du rectum: Expérience lyonnaise de 1985 à 1996—Etude pronostique à propos de 312 patients. Ann Chir 53:1003–1010, 1999[Medline]

19. Minsky BD, Conti JA, Huang Y, et al: The relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 13:1409–1416, 1995[Abstract]

20. Cedermark B, Johanson H, Rutqvist LE, et al: The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. Cancer 75:2269–2275, 1995[CrossRef][Medline]

21. Martling A, Holm T, Johansson H, et al: The Stockholm II trial on preoperative radiotherapy in rectal carcinoma. Cancer 92:896–902, 2001[CrossRef][Medline]

22. Cho KH, Lee CKK, Levit SH: Proctitis after conventional external radiation therapy for prostate cancer: Importance of minimizing posterior rectal dose. Radiology 195:699–703, 1995[Abstract/Free Full Text]

23. Kollmorgen CF, Meagher AP, Wolff B, et al: The long term effect of adjuvant post operative chemotherapy for rectal carcinoma on bowel function. Ann Surg 220:676–682, 1994[Medline]

24. François Y, Nemoz CJ, Baulieux J, et al: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter saving surgery for rectal cancer: The Lyon R 90.01 randomized trial. J Clin Oncol 17:2396–2402, 1999[Abstract/Free Full Text]

25. Hyam SDM, Manounas EP, Petrelli N, et al: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: A progress report of NSABP Protocol R-03. Dis Colon Rectum 40:131–139, 1997[CrossRef][Medline]

26. Gérard A, Buyse M, Nordlinger B, et al: Preoperative radiotherapy in Duke’s B and C carcinoma of the rectum and rectosigmoid: A randomized multicenter study. Ann Surg 208:606–614, 1988[Medline]

27. Sauer R, Fietkav R, Martus P, et al: Adjuvant and neoadjuvant radiochemotherapy for advanced rectal cancer: First results of a German multicenter phase III trial. Int J Radiat Oncol Biol Phys 48:119, 2000 (abstr 17)[Medline]

28. Aschele C, Friso M, Pucciarelli S, et al: A phase I study of weekly oxaliplatin (OXA), 5-fluorouracil (5-FU) continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Eur J Cancer 37:A253, 2001 (abstr 253; suppl 6)

29. Gérard JP, Chapet O, Ramaioli A, et al: Long-term control of T2–T3 rectal adenocarcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys 54:142–149, 2002[Medline]

30. Vuong T, Belliveau PJ, Michel RP, et al: Conformal preoperative endorectal brachytherapy treatment for locally advanced rectal cancer: Early results of a phase I/II study. Dis Colon Rectum 45:1486–1495, 2002[CrossRef][Medline]

Submitted October 7, 2002; accepted December 10, 2002.

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				A. De Paoli, S. Chiara, G. Luppi, M. L. Friso, G. D. Beretta, S. Del Prete, L. Pasetto, M. Santantonio, E. Sarti, G. Mantello, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study Ann. Onc., February 1, 2006; 17(2): 246 - 251. [Abstract] [Full Text] [PDF]

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				J.-P. Machiels, L. Duck, B. Honhon, B. Coster, J.-C. Coche, P. Scalliet, Y. Humblet, S. Aydin, J. Kerger, V. Remouchamps, et al. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study Ann. Onc., December 1, 2005; 16(12): 1898 - 1905. [Abstract] [Full Text] [PDF]

				A Hartley, K F Ho, C McConkey, and J I Geh Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials Br. J. Radiol., October 1, 2005; 78(934): 934 - 938. [Abstract] [Full Text] [PDF]

				C. Aschele, M. L. Friso, S. Pucciarelli, S. Lonardi, L. Sartor, G. Fabris, E. D. L. Urso, P. Del Bianco, G. Sotti, M. Lise, et al. A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer Ann. Onc., July 1, 2005; 16(7): 1140 - 1146. [Abstract] [Full Text] [PDF]

				B. M. Ghadimi, M. Grade, M. J. Difilippantonio, S. Varma, R. Simon, C. Montagna, L. Fuzesi, C. Langer, H. Becker, T. Liersch, et al. Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy J. Clin. Oncol., March 20, 2005; 23(9): 1826 - 1838. [Abstract] [Full Text] [PDF]

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