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10.1245/s10434-006-9102-0
Annals of Surgical Oncology 14:424-431 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Neoadjuvant Chemoradiation Versus Hyperfractionated Accelerated Radiotherapy in Locally Advanced Rectal Cancer

Wim Ceelen, MD1, Tom Boterberg, MD, PhD2, Piet Pattyn, MD, PhD1, Marc van Eijkeren, MD, PhD2, Jean-Marc Gillardin, MD1, Pieter Demetter, MD, PhD3, Peter Smeets, MD4, Nancy Van Damme, PhD5, Els Monsaert, MD5 and Marc Peeters, MD, PhD5

1 Department of Surgical Oncology, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
2 Department of Radiotherapy, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
3 Department of Pathology, Erasmus Hospital, Lenniksebaan 808, B-1070 Brussels, Belgium
4 Department of Radiology, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
5 Department of Hepatogastroenterology, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium

Correspondence: Address correspondence and reprint requests to: Wim Ceelen, MD; E-mail: Wim.ceelen{at}ugent.be


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Neoadjuvant therapy is increasingly used in resectable locally advanced rectal cancer. The exact role of the addition of chemotherapy is not established. We compared neoadjuvant therapy using chemoradiation (CRT) or hyperfractionated accelerated radiotherapy (HART).

Methods: Clinical, pathological, and survival data were obtained from patients with resectable stage II or III rectal cancer within 7 cm from the anal verge. A group of 50 patients was treated with a preoperative dose of 41.6 Gy of radiotherapy (RT) in two daily fractions of 1.6 Gy over 13 days immediately followed by surgery (HART). A second group of 96 patients received 45 Gy of conventionally fractionated RT in 25 daily fractions of 1.8 Gy combined with 5-fluorouracil–based chemotherapy followed by surgery within 4 to 6 weeks (CRT). Both groups were compared in terms of morbidity, pathological downstaging, local recurrence, and survival.

Results: Both groups were comparable in terms of preoperative clinicopathological variables. The mean distance from the anal verge was 5.8 cm (HART) versus 4.9 cm (CRT). Sphincter preservation was possible in 74% (HART) versus 83.5% (CRT) of patients (P = .013). The clinical anastomotic leak rate was 2% (HART) versus 2.2% (CRT). Pathological complete response was observed in 4% (HART) versus 18% (CRT) of the resected specimens (P = .002). A pelvic recurrence developed in 6% (HART) versus 4.4% (CRT) of patients (P = .98). Overall 5-year survival was 58% (HART) versus 66% (CRT) (P = .19); disease-free 5-year survival was 51% (HART) versus 62% (CRT) (P = .037).

Conclusions: Compared with preoperative HART followed by immediate surgery, preoperative CRT followed by a 6-week waiting period enhances pathological response and increases sphincter preservation rate. This could be explained by the addition of chemotherapy or the longer interval between neoadjuvant therapy and surgery. No statistically significant difference was observed in local control or overall survival.

Key Words: Rectal cancer • Neoadjuvant • Total mesorectal excision • Hyperfractionated accelerated therapy • Chemoradiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The annual incidence of fatal cases of colorectal cancer exceeds 200,000 in the European Union alone. The mainstay of therapy in locally advanced rectal cancer remains surgery with negative margins, including the circumferential resection margin. Historically, surgery for rectal cancer has been associated with locally recurrent disease in up to one in four patients.1 Data from a recent systematic review suggest that preoperative radiotherapy (RT) lowers local recurrence rates, provided a biologically equivalent dose of at least 30 Gy is administered.2 On the other hand, attention to surgical technique with precise sharp dissection of the mesorectal plane and total mesorectal excision (TME) in lower-third cancers markedly improved local control in a number of expert series.3–6 The question whether preoperative RT remains effective when optimal surgical technique is systematically implemented was convincingly answered by the results of the Dutch Rectal Cancer Trial.7 After a nationwide surgical training program, preoperative RT further reduced local recurrence rate (2.4% after RT + TME vs. 5.3% in the TME alone group, P < .001).

For patients with bulky tumors, possibly invaded lateral resection margins, or tumors close to the sphincter apparatus, several approaches to intensify preoperative RT have been used. The addition of chemotherapy to preoperative RT builds on the favorable results obtained with postoperative chemoradiation (CRT) and preoperative CRT for irresectable disease.8

Several phase II trials with preoperative CRT in resectable rectal cancer have shown a promising pathological complete response rate and a high rate of sphincter preservation.9,10

The aim of hyperfractionated regimens is to separate early and late radiation effects, with the goal of improving local control while limiting late tissue toxicity.11 In head and neck cancer, a randomized trial by the European Organization for the Research and Treatment of Cancer (EORTC) demonstrated far better local control after hyperfractionated RT compared with a conventionally fractionated regimen.12 In colorectal cancer, cell kinetic studies that used biomarkers have demonstrated rapid proliferation of clonogens, with a small potential doubling time (Tpot) that could cause local tumor recurrence.13–15 Moreover, because of potential rapid re-growth of subclinical tumor deposits during RT, limiting total treatment time is important to achieve a high probability of local control.16 Theoretically, therefore, rectal tumors would benefit from hyper-fractionated accelerated radiotherapy (HART).

We retrospectively compared two neoadjuvant therapy regimens in patients with resectable locally advanced rectal cancer. Group 1 was treated with HART immediately followed by surgery. Group 2 received neoadjuvant 5-fluorouracil–based CRT followed by surgery after a 4- to 6-week interval.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
All patients with resectable rectal cancer stage cT3–4 N0 or cT1–4 with nodal disease were offered neoadjuvant therapy. Patients with possibly resectable lung or liver metastases were also included. From 1994 until July 2000, all patients received pre-operative HART. After this period, given the results from various phase 2 trials in both resectable and irresectable rectal cancer, neoadjuvant CRT was introduced. Mean follow-up time for both groups was therefore different. Because most local recurrences after rectal cancer surgery occur within 2 years after surgery and no major changes were applied in surgical technique, we considered a comparison of both protocols appropriate when looking at down-staging and local control as end points.

Preoperative Workup
Preoperative clinical staging included clinical assessment, liver ultrasound or computed tomographic scan, chest x-ray or computed tomographic scan, full blood analysis including carcinoembryonic antigen, and colonoscopy with biopsy. Routine use of magnetic resonance imaging before and after neoadjuvant therapy was introduced in 2002 and performed in 42 patients (30%). Endoscopic ultrasonography of the tumor was performed in 52% of the patients.

Radiotherapy
All patients were treated on a 25 MV Elekta linear accelerator. The treatment was delivered in prone position with a three-field technique (one posterior and two opposite lateral fields) on the pelvis. The upper border was set at the L5–S1 interspace. If an abdominoperineal resection was to be performed, the perineum was included in the fields. The anterior border of the lateral fields was set just posterior of the symphysis; the posterior border included the sacrum. Adequate blocking was used to exclude excessive amounts of small intestine. The dose was prescribed at the isocenter. A combination of wedged and open fields was used, depending on which resulted in the most optimal dose distribution, with a homogeneity within 5% of the prescribed dose, according to the International Commission on Radiation Units and Measurements (ICRU) rules. The patients in the HART group were treated twice daily, 5 days a week, with an interval of at least 6 hours. The dose per fraction was 1.6 Gy. Twenty-six fractions were delivered, resulting in a cumulative dose of 41.6 Gy. The patients in CRT group were treated once daily, 5 days a week, with a dose of 1.8 Gy. Twenty-five fractions were delivered, resulting in a cumulative dose of 45 Gy.

Chemoradiation
In 85 patients (93%), chemotherapy consisted of bolus 5-fluorouracil (325 mg/m2) and folinic acid (10 mg/m2) provided during days 1 to 5 and 29 to 33 of RT. In six patients (7%), concomitant chemotherapy consisted of oxaliplatin (50 mg/m2) weekly for 5 weeks and capecitabine (825 mg/m2) twice a day, 5 days a week, for 5 weeks, according to the capecitabine, oxaliplatin, radiotherapy, and excision protocol (CORE).17

Surgery
All patients underwent nerve-sparing TME. The decision to perform a sphincter-sparing procedure was made peroperatively, and not before initiation of neoadjuvant therapy. Technical details included division of the inferior mesenteric artery and vein at 1 cm from its origin, routine mobilization of the splenic flexure, and washout of the rectal stump with an iodine solution before completion of the anastomosis. Creation of a temporary loop ileostomy was performed in selected cases as judged necessary by the operating surgeon.

The criteria for sphincter preservation were acceptable sphincter function and absence of direct invasion of the sphincter apparatus. These criteria remained unchanged throughout the treatment period.

Follow-up
During treatment, patients were seen weekly, and acute toxicity was scored according to the World Health Organization scale. Late toxicity was evaluated at least 12 months after surgery. Node-positive (stage III) patients were proposed to receive six cycles of adjuvant chemotherapy.

Statistical Analysis
Data are expressed as mean (standard error), unless indicated otherwise. Differences between means of continuous variables were analyzed with the two-tailed t-test or, when a nonnormal data distribution was observed, with the Mann-Whitney U-test. Differences between fractions were analyzed with the {chi}2 or Fisher’s exact test where appropriate. Actuarial survival curves were generated with the Kaplan-Meier method and compared by the log rank test. Statistical significance was assumed at an alpha value <.05. All calculations were performed by SPSS 12.0 for Windows (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathological Variables
No statistically significant differences were present between both groups regarding demographic variables, clinical tumor stage, or distance between tumor and the anal verge (Table 1Go). One-third of patients in both groups had a tumor within 3 cm from the anal verge. More than half of the patients had clinically node-positive disease, and hepatic metastases deemed resectable were present in approximately 10% of patients in both groups.


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  		TABLE 1. Comparison of preoperative clinicopathological variables
 
Neoadjuvant Therapy Acute Toxicity
Acute gastrointestinal, urogenital, and hematological toxicity was more pronounced in the group of patients receiving CRT, whereas cutaneous toxicity was comparable (Table 2Go). Grade 3 toxicity was seen in only one patient, who received CRT and developed a severe skin reaction. No grade 4 toxicity was observed.


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  		TABLE 2. Comparison of World Health Organization acute toxicity episodes
 
Details and Outcome of Surgery
Surgery was performed after a mean time interval of 3 days (HART) versus 6 weeks (CRT). More sphincter-preserving procedures were performed in patients who received CRT. No difference was observed in clinical anastomotic leak rate. Both early postoperative overall morbidity and late radiation-induced toxicity, however, were more pronounced in group 1 (HART) patients. In the HART group, eight patients (16%) developed late radiation sequelae. Five patients (10%) needed surgery for severe late radiation induced bowel damage (radiorectitis n = 2, radioenteritis n = 1, rectovaginal fistula n = 2). Another three patients in the HART group developed radiorectitis but were managed medically. The median time interval between primary and reoperative surgery was 15 months (range, 2–34 months). In the CRT group, two patients (2.2%) developed radio-enteritis but did not undergo reoperation (Table 3Go).


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  		TABLE 3. Details and results of the surgical procedure
 
Pathology Data
Pathological details and downstaging rates are illustrated in Table 4Go. Both tumor and node down-staging were more pronounced in group 2 (CRT). The pathological complete response rate was higher in patients who received CRT. Downsizing of the resected tumor was observed in both groups compared with the preoperative tumor size. In the CRT group, however, tumors were smaller after neoadjuvant therapy compared with the HART group. Mucinous differentiation was observed in 18% of patients in both groups.


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  		TABLE 4. Comparison of pathological details and tumor (T) and node (N) downstaging
 
Although the percentage of patients in both groups receiving adjuvant chemotherapy was similar, all patients in group 1 (HART) received a regimen of 5-fluorouracil alone, whereas in group 2 (CRT), the regimen contained oxaliplatin or irinotecan in 42% of patients.

Local Control and Survival
Mean follow-up time was 67 months in group 1 (HART) and 28 months in group 2 (CRT) (P < .001). No patients were lost to follow-up. Overall local recurrence rate was 6% in group 1 (HART) and 4.4% in group 2 (CRT) (P = .98). In group 1, all three local recurrences were isolated. Two of these patients had a pT4 tumor and developed a presacral recurrence; in the third patient, a lymph node recurrence developed along the left iliac artery. In group 2, three of the local recurrences were seen in patients with systemic disease, whereas isolated local recurrence was present in only one patient who presented with pT4 disease with bilateral ureteral obstruction. The isolated local recurrence rate was therefore 3% in group 1 versus 1.1% in group 2 (P = .13). As far as distant failure is concerned, 24% of pretreatment clinically M0 patients developed metastases in group 1 (HART) and 11% in group 2 (CRT) (P = .02).

Overall 5-year survival was 58% in group 1 and 66% in group 2 (P = .19). Disease-free 5-year survival was 51% in group 1 and 62% in group 2 (P = .037).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A multimodal approach has become the standard of care in locally advanced resectable rectal cancer. The addition of chemotherapy to RT is firmly grounded in the principles of enhanced tumor response and spatial cooperation (local vs. systemic activity).18 Several theoretical considerations favor preoperative CRT over postoperative CRT, and this was clinically demonstrated in the recent German rectal cancer trial.19 We retrospectively compared neoadjuvant HART immediately followed by surgery with neoadjuvant CRT with surgery performed after a 6-week period. Several nonrandomized and randomized studies have compared RT alone with CRT in the preoperative therapy of rectal cancer (Table 5Go). From the EORTC 22921 and the French FFCD 9203 trials, only preliminary data are available. Taken together, the results of these studies indicate that the addition of chemotherapy greatly improves tumor response, although acute toxicity is usually worse. Interestingly, the increase in pathological downstaging was translated into enhanced sphincter preservation in only one of the four randomized studies. This finding may be explained by the reluctance of surgeons to perform a low anastomosis with tissue that was cancer invaded before initiation of CRT. Moreover, the observed increase in tumor response did not improve disease-free or overall survival.


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  		TABLE 5. Studies comparing preoperative radiotherapy alone with preoperative chemoradiation in rectal cancer
 
Our results confirm an increased tumor response with CRT, with increased downstaging of both tumor and node status. The difference in downsizing and downstaging between both groups is probably mainly because of the different waiting period between the completion of RT and surgery. In our experience, this was translated into more sphincter-preserving procedures, although we cannot exclude the influence of other variables such as refinements in surgical technique, allowing more very low anastomoses to be performed. In keeping with others, we found that preoperative RT in either schedule increases the incidence of mucinous carcinomas.20

The anastomotic leak rate was not affected by neoadjuvant therapy, confirming experimental data indicating that neither RT nor CRT affect colonic anastomotic healing provided only one limb of the anastomosis is irradiated.21,22 The low clinical anastomotic leak rate in the present series is partly explained by the liberal use of a deviating ileostomy. Although presence of an ileostomy temporarily adversely affects quality of life,23 it has been shown to reduce the incidence of clinical leakage and to mitigate the consequences of a leak.24 On the other hand, early (30 day) postoperative overall morbidity (major and minor) was more pronounced in patients treated with HART, reflected by a far longer hospital stay. It is possible, however, that a more liberal use of a diverting ileostomy in CRT patients is confounding the difference in the 30-day morbidity rate.

The rationale for HART in rectal cancer is based on the observation of the relatively early occurrence of locally recurrent disease in most patients. At the origin of a local recurrence are rapidly proliferating clonogens with a small potential doubling time (Tpot).14–16 Limiting the total treatment time by accelerating RT and reducing the delay with surgery could therefore enhance the effect on local recurrence after rectal cancer surgery. Clinical experience with preoperative HART in rectal cancer is limited. Coucke et al.25 reported on two phase 1 trials in 20 patients treated with postoperative 41.6 Gy of HART and 23 patients treated with 41.6 Gy of preoperative HART. Acute toxicity after preoperative HART was acceptable in this report, and small bowel toxicity was much lower compared with postoperative HART. There was only one case of late bowel toxicity in the group treated preoperatively. The same group recently reported a phase 1 study combining preoperative 41.6 Gy of HART with concomitant CPT-11 in locally advanced rectal cancer.26 Major complications after surgery were seen in 25% of patients with a considerable anastomotic leak rate of 22%.

Hyperfractionation is aimed at limiting late tissue toxicity while achieving an identical or enhanced local control. In head and neck cancer, a randomized trial comparing a hyperfractionated (twice daily 1.15 Gy) with a conventional (daily 2 Gy) regimen has shown a marked increase in local control (59% vs. 40% at 5 years) with no increase in late toxicity. We could not demonstrate the late toxicity sparing of HART; on the contrary, we found an increase in late radiation sequelae, with 10% of patients needing further surgery as a direct consequence of radiation-induced bowel damage. Certainly, this conclusion has to be interpreted with caution and may even be premature, given the difference in follow-up time between both groups.

Overall and isolated local recurrence rates were low with both treatment modalities and in keeping with recent clinical literature. More specifically, no influence of limiting total treatment time was noted on the incidence of local recurrence.

One of the important questions in low-lying rectal cancer is how the time interval between preoperative therapy and surgery, tumor downstaging, and sphincter preservation rate are related. In the Polish randomized study comparing preoperative CRT with 5 x 5 Gy of preoperative RT, the observed increase in tumor response was not translated into enhanced sphincter preservation.27 This was explained by the fact that the surgeon’s decision to perform a sphincter-saving procedure was based on the pretreatment tumor volume. We chose to rely on the posttreatment clinical stage, with acceptance of a peroperative free distal resection margin of >5 mm when confirmed by analysis of frozen sections. This policy resulted in a statistically significantly higher percentage of sphincter-saving procedures in CRT patients (83.5% vs. 74%, P = .013).

Survival and recurrence data are to be interpreted with caution because the mean follow-up time between both groups is very different. Moreover, routine preoperative magnetic resonance imaging to define the circumferential margin was performed only in the CRT group, which could lead to stage migration. Because most patients were followed for more than 2 years, we considered it useful to provide the disease-free and overall actuarial survival data (Figs. 1Go and 2Go). Overall 5-year survival was not different between the two treatment modalities. Disease-free 5-year survival, however, was better in the CRT group (62% vs. 51%, P = .037). This is explained by a statistically significantly lower occurrence of systemic failure after CRT (11% vs. 24%, P = .02) confirming the effectiveness of the systemic component of this neoadjuvant regimen in patients who may already have micrometastatic disease at presentation. However, differences in the adjuvant therapy regimen in stage III patients could partly account for the observed difference in disease free survival and distant metastasis rate.


Figure 1
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  		FIG. 1. Comparison of overall survival. HART, hyperfractionated accelerated radiotherapy; CRT, chemoradiation.

 

Figure 2
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  		FIG. 2. Comparison of disease-free survival. HART, hyperfractionated accelerated radiotherapy; CRT, chemoradiation.

 
In conclusion, preoperative CRT increases tumor downsizing and downstaging compared with pre-operative HART. This translates into a higher sphincter preservation rate at the expense of a moderately increased acute toxicity. Postoperative early and late complications are far more pronounced after HART. Both regimens, when combined with precise surgery, result in excellent local control. Systemic relapse was more common and disease-free survival worse after HART, but overall survival was not different.

Received for publication April 11, 2006. Accepted for publication May 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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