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Randomized Phase III Study Comparing Preoperative Radiotherapy With Chemoradiotherapy in Nonresectable Rectal Cancer

Morten Brændengen, Kjell M. Tveit, Åke Berglund, Elke Birkemeyer, Gunilla Frykholm, Lars Påhlman, Johan N. Wiig, Per Byström, Krzysztof Bujko, Bengt Glimelius

From the Departments of Medical Oncology and Surgery, Norwegian Radium Hospital; Ullevål University Hospital, Cancer Centre, Oslo, Norway; University of Oslo, Oslo; Division of Hematology and Oncology, Stavanger University Hospital, Stavanger; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Oncology and Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Radiology, and Clinical Immunology, University of Uppsala; Department of Surgery, Uppsala University Hospital, Uppsala, Sweden; and the Department of Radiotherapy, M. Sklodowska-Curie Memorial, Warsaw, Poland

Corresponding author: Morten Braendengen, MD, Ullevål University Hospital, Cancer Centre, 0407 Oslo, Norway; e-mail: morten.braendengen{at}ulleval.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate.

Patients and Methods The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109).

Results The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity.

Conclusion CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients with rectal cancer have traditionally been separated into resectable and nonresectable cases. Nonresectable cancer, constituting 10% to 15% of primary rectal cancers,¹ was present if the tumor was palpably fixed to adjacent nonresectable structures such as the proximal sacrum, pelvic side wall, pelvic floor, prostate, or base of the urinary bladder, or was a large nonmobile tumor. More lately, the terms "early" and "locally advanced" rectal cancer have been used. The locally advanced tumors, likely constituting at least 50% of the cases, also include the nonresectable ones. These were, however, excluded from recent trials comparing different treatments in locally advanced rectal cancer.^2-5 Most recently, three groups—low, intermediate, and high risk—have been introduced on the basis of magnetic resonance imaging (MRI).^6-8 The proportions in these groups are not known, but the nonresectable cancers likely constitute only a fraction of the high-risk group.

In the nonresectable cases, preoperative radiotherapy (RT) was used early to sterilize peripherally located disease and induce tumor shrinkage to allow subsequent radical surgery.⁹ RT, either pre- or postoperatively, was also used in the "resectable" cases, but then with the primary aim to decrease high local failure rates (approximately 30%) by sterilizing tumor cells left during surgery.^9,10 Because there was no need for a decrease in size or stage of the primary tumor, short-course schedules (such as 5 x 5 Gy) with immediate surgery was explored,¹¹ in addition to the fractionated regimens (1.8 or 2 Gy/fraction).

To improve the results, the radiosensitizing effects of chemotherapy have been explored with RT. Postoperatively, the addition of fluorouracil (FU) reduced local failure rates and improved survival compared with RT alone.^12,13 Preoperatively, on the contrary, no benefit of chemotherapy could be detected, although the randomized trials were underpowered.^14-16 With this limited evidence, we considered RT alone as standard preoperative therapy in nonresectable rectal cancers. A randomized trial was initiated with the aim to investigate if chemotherapy, within a combined modality treatment, could improve survival and reduce recurrence rates in these cancers. Patients with previously nonirradiated local recurrence were also included because they have a poor prognosis and were rarely resectable without prior RT.^17-20

	PATIENTS AND METHODS

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Patients
Between March 1996 and November 2003, 209 patients with primary, nonresectable or locally recurrent rectal adenocarcinoma (after major surgery) were randomly assigned. Tumors were considered nonresectable if digital examination and rigid rectoscopy revealed a fixed tumor, and (after 1999) if computed tomography (CT) or MRI indicated overgrowth to the sacrum, pelvic side wall/floor, base of the bladder, or prostate gland.

Other inclusion criteria were age 75 years or younger, WHO performance status 0 to 2, no distant metastases, hemoglobin of at least 100 g/L, WBC of at least 3.0 x 10⁹/L, platelet count of at least 100 x 10⁹/L, creatinine less than 150 µmol/L, and bilirubin less than 30 µmol/L. Patients with another malignancy (except for nonmelanoma skin cancer), previous RT to the pelvis, or medical contraindication to the planned treatment were excluded.

Randomization and Stratification
The ethical committees in all three countries approved the trial. After signing written informed consent, the patients were randomly assigned to preoperative chemoradiotherapy (CRT) or preoperative RT alone. The patients were stratified according to (1) department, (2) primary versus recurrent disease and, after an amendment in June 1999, (3) whether pelvic MRI or CT showed tumor infiltration into adjacent organs/structures.

Pretreatment Investigations
CT scan or MRI of the pelvis were recommended before 1999, but mandatory thereafter. Furthermore, digital examination, rectoscopy, colonoscopy or double-contrast barium enema, ultrasound, CT or MRI of the liver, and chest x-ray were performed. Laboratory investigations included hemoglobin, WBC, platelet count, liver function tests, electrolytes, creatinine, and carcinoembryonic antigen.

RT
The RT specifications were defined in guidelines at each department. A three- or four-beam technique (alternatively two beams in special cases) was used. The patient was treated in the prone position. Energies between 8 and 21 MV were allowed. A daily fraction of 2.0 Gy was administered 5 days a week. The clinical target volume 1 (CTV1), defined as the gross tumor volume (GTV; identified by palpation, x-ray, CT, MRI) plus a 2-cm margin, received 50 Gy. The CTV2, defined as CTV1 plus lymph node areas in the dorsal pelvis, received 46 Gy. Whether the external iliac lymph nodes were included in CTV2 depended on the extent of the tumor. All patients’ treatment should be individually planned using a three-dimensional dose-planning system.

In typical cases, the lateral margins of the anterior-posterior beams were 1 cm lateral to the bony pelvis. The anterior margin of the lateral beams was about 2.5 cm in front of the promontory, and the posterior margin 1 cm behind the sacrum. The superior margin was at the sacral promontory, and the inferior margin at the perineum or at least 5 cm below the lower tumor margin. The beams deviated from this description if the tumor extension in one or several directions made it necessary.

The dose homogeneity within the planning target volume (PTV) should be less than ± 5%. In case of an unplanned split lasting more than 1 week, this should be compensated for by one or two extra fractions of 2 Gy.

Chemotherapy
Patients randomly assigned to chemotherapy received bolus (3 minutes) FU 400 mg/m² concomitant with RT preoperatively, and 500 mg/m² postoperatively, followed by leucovorin 100 mg 20 to 30 minutes later on 2 consecutive days every 2 weeks (Nordic schedule). The FU injection was administered 30 to 40 minutes before RT fractions 1 to 2, 11 to 12, and 21 to 22.²¹

In the CRT group, all patients were scheduled to receive adjuvant chemotherapy starting 4 to 6 weeks postoperatively and continuing for eight cycles, irrespective of pathologic stage. We permitted administration of postoperative chemotherapy to patients in the RT group who had stage III disease.

Surgery
Surgery was performed 5 to 8 weeks after the last radiation treatment. Standard exploratory laparotomy with thorough examination of the intraperitoneal content was performed. The choice of surgical procedure was left to the discretion of the operating surgeon. Anterior and abdominoperineal resections and Hartmann's procedure were all permitted. Total mesorectal excision was recommended. Pelvic organs with cancer involvement were resected en bloc if possible, to achieve an R0 resection.

Follow-Up
Follow-up investigations were scheduled every 3 months during 2 years, then every 6 months for 2 years, and thereafter annually. Evaluation included patient's history, clinical examination, rectoscopy, blood tests, quality-of-life questionnaire (data not presented), and WHO toxicity score. Imaging was performed when signs or symptoms indicated recurrent disease.

Statistical Considerations
The primary hypothesis was that chemotherapy improved 5-year survival from 15% to 35%. With a significance level of 0.05 and power of 0.9, 200 patients should be included. Secondary end points were reduction of relapse rates (distant and local), local control, toxicity, and quality-of-life.

The data were analyzed using Statistica Software (Statsoft, Tulsa, OK), version 7.1. Time to treatment failure (TTF), overall survival (OS), and cancer-specific survival (CsS) were calculated by the Kaplan-Meier method, and differences tested using the log-rank test. All tests were two sided. TTF and survival times were calculated from the date of random assignment. A treatment failure was defined as no or nonradical (R2) resection, local recurrence, distant metastases, or death from rectal cancer. For the calculation of the actuarial incidence of local recurrence, the data from patients who were alive and free from local recurrence, or who died without local recurrence, were censored. Comparison of proportions was made using the ² test (trend test for resection margin, T and N stage). All analyses were performed according to intention to treat.

	RESULTS

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Patient Characteristics
Between 1996 and 2003, 98 patients were randomly assigned to the CRT group and 111 to the RT group. Two patients were ineligible (Fig 1). One hundred four patients were included from five hospitals in Norway, 82 patients from eight hospitals in Sweden, and 21 patients from one hospital in Poland. All tumors were histologically verified. Patient characteristics, well balanced between groups, are shown in Table 1. The majority of the primary cancers were stage T4 according to clinical staging and CT or MRI.

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Flow chart of the study.

An R0 resection was achieved more often in the CRT group, 82 (84%) patients versus 74 (68%) in the RT group (P = .009; Table 4). An R0 + R1 resection was achieved in 85 (87%) and 81 (74%) patients in the CRT and RT groups, respectively (P = .03).

TTF and Survival
Median follow-up in January 2007 for living individuals was 61 months. TTF was statistically significantly different (log-rank P = .003), with 63% failure-free in the CRT group compared with 44% in the RT group at 5 years (Fig 2). CsS was also statistically significantly different (log-rank P = .02) at 72% versus 55% at 5 years. OS favored RCT, 66% versus 53%, but the difference was not statistically significant (log-rank P = .09).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curves comparing the chemoradiotherapy (CRT) group (n = 98) and the radiotherapy-alone (RT) group (n = 109). (A) Cancer-specific survival; (B) overall survival; and (C) time to treatment failure.

Local Tumor Control
Local control was higher in the CRT group compared with the RT group (Table 4). In patients obtaining an R0 or R1 resection, the local recurrence rate was 5% and 7% in the CRT and RT groups, respectively.

Acute and Late Toxicity
The most frequent acute toxicity was diarrhea grade 1 and 2 (Table 5). There was more grade 3 or 4 toxicity in the CRT group, 27 (28%) of 98, compared with the RT group, six (6%) of 109 (P = .001). The greatest difference was seen in grade 3 to 4 diarrhea. There were no toxic deaths.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
It is generally agreed that patients with locally advanced nonresectable rectal cancer should receive fractionated preoperative RT with 1.8 or 2 Gy per fraction up to a dose of about 50 Gy, with surgery 5 to 8 weeks later. The purpose of the RT is to obtain downstaging of the primary tumor to permit an R0 resection, and to sterilize the pelvic area at risk, reducing local recurrence rate and improving survival. The value of concomitant and adjuvant chemotherapy in these cases has previously not been proven in randomized trials, although there were indications from phase II studies of better efficacy from such combinations. The studies showed downstaging with pCR of more than 15% after preoperative CRT compared with approximately 5% after RT alone.^22,23 This randomized phase III study confirms that the addition of chemotherapy to RT improves outcome both concerning local and systemic control.

The results from this study in nonresectable cancers should be compared with two recent randomized trials, similarly comparing preoperative RT with CRT, however, in resectable cases. The trials^4,5 included patients with locally advanced cancers, but excluded the most locally advanced, nonresectable ones. The three trials reach basically the same results, namely that local control is significantly better in the combined modality groups, but with no significant gain in overall survival. However, in this, but not in the other trials, a gain in TTF and CsS was seen. The trials also conclude that CRT is more toxic than RT alone, but still safe before major rectal cancer surgery. The trials contribute substantial knowledge to the treatment of rectal cancer.

It should be noted that in resectable tumors it is not known whether the long-course or the short-course 5 x 5 Gy regimen should be used.^3,24 This question is addressed in an ongoing Stockholm III trial.¹¹

The trials do not give an answer to whether the addition of chemotherapy mainly works as a radiosensitizer, improving local control, or if it has an effect of its own. Actually, in the European Organisation for Research and Treatment of Cancer (EORTC) study, the favorable effect on local control was seen whether the chemotherapy was given concomitantly with the RT or postoperatively.⁴ In the Locally Advanced Rectal Cancer Study (LARCS), the effects on overall relapses tended to be more pronounced than those with local control. Our trial was not designed to answer separately the relevance of concomitant or sequential chemotherapy, whereas the EORTC trial intended to give an answer, although with no conclusive results.^4,25

The addition of chemotherapy resulted in LARCS in more sphincter-preserving procedures although this was not an end point in the study. In several trials,^2-5,24 some of which had sphincter-preserving surgery as an end point,^2,5 this was not seen in the CRT groups when all randomly assigned patients were analyzed.²⁶

When the study was planned, local recurrences were common at many centers, and these patients were included because of a poor prognosis after RT.^17,18,20 However, local recurrences became much less prevalent with improved surgery and increased use of perioperative RT. They therefore contributed to only a minor fraction of the trial population. Exclusion of the locally recurrent cases did not change the overall results.

Rectal cancer imaging and preoperative staging were not optimal during most of the trial period. The quality of imaging, particularly MRI, has developed considerably during the last 5 years.^6-8,27,28 Attempts to retrospectively evaluate the images, to get information beyond what was stated in the case report forms, did not add relevant information. As a group, the patients included in this trial, compared with other randomized trials^2-5,24 were clearly more advanced, although such intertrial comparisons are difficult. The resectability rates (R0-R1) in the Fédération Francophone de Cancérologie Digestive⁵ and EORTC⁴ trials, where only resectable cancers were eligible (90% cT3, 10% cT4), were higher in both groups (RT 93% to 94%, CRT 94%) than in LARCS (10% cT3, 83% cT4; RT 74%, CRT 87%), reflecting a less advanced local stage. In those resected, however, the local recurrence rates did not differ. Actually, in the RT group, they were lower in LARCS (6%) than in the other trials (16% to 17%). Five-year disease-free and OS did not differ.

In addition to a total mesorectal excision, many patients underwent en bloc resection of an adjacent organ. The policy among the participating surgeons was to resect all previously involved tissues, even if tumor regression was present. Even if this was not always the case, this policy, and the surgeons’ long experience in operating rectal cancer, can explain the high R0 resectability rate and the low local recurrence rate, despite the advanced tumors. The generally high quality of the surgery can be one explanation why the outcome in this trial (predominantly cT4) was not much worse than in the two parallel trials (predominantly cT3).^4,5

The quality of the pathologic examination in LARCS, performed in routine care, was not sufficient according to standards discussed recently.²⁹ Therefore, the pCR rates should be regarded with caution, although we have no reason to doubt that the difference between the groups is real. A retrospective evaluation by a blinded pathologist, performed according to Dworak,³⁰ confirmed the difference, although poor sampling of material for histology could not be compensated for.

In conclusion, this randomized trial adds further evidence in favor of CRT in nonresectable rectal cancer. The preoperative part of the treatment with concurrent CRT is probably most important, although the postoperative chemotherapy may also have played a role. Altogether, the CRT improved resectability and local control, and after a median follow-up of 5 years, there was a difference in disease-free survival and CsS. More acute grade 3 or 4 toxicity was seen in the CRT group, but the treatment was generally well tolerated. There was no difference in late toxicity.

However, many questions remain, and controversies regarding optimal treatment will likely also remain. The most straightforward conclusion is that, whenever long-course preoperative RT is indicated, the addition of FU results in significantly better local tumor control without being too toxic, and should be the reference treatment. Presently, much interest is focused on the use of combinations of drugs, particularly combinations including capecitabine, oxaliplatin, or irinotecan concomitant with RT.^31-33 Most recently, targeted drugs have also been investigated.³⁴ These combinations need to undergo phase III evaluation to prove superior efficacy compared with FU chemotherapy.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Kjell Magne Tveit, Lars Påhlman, Johan N. Wiig, Bengt Glimelius

Administrative support: Morten Brændengen, Kjell Magne Tveit, Åke Berglund, Bengt Glimelius

Collection and assembly of data: Morten Brændengen, Kjell Magne Tveit, Åke Berglund, Elke Birkemeyer, Gunilla Frykholm, Per Byström, Krzystzof Bujko, Bengt Glimelius

Data analysis and interpretation: Morten Brændengen, Kjell Magne Tveit, Åke Berglund, Bengt Glimelius

Manuscript writing: Morten Brændengen, Kjell Magne Tveit, Bengt Glimelius

Final approval of manuscript: Morten Brændengen, Kjell Magne Tveit, Åke Berglund, Elke Birkemeyer, Gunilla Frykholm, Lars Påhlman, Johan N. Wiig, Per Byström, Krzystzof Bujko, Bengt Glimelius

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Kaplan-Meier curves of time to treatment failure (TTF) in patients with (A) primary and (B) recurrent cancer, comparing chemoradiotherapy (CRT; primary n = 88, recurrent n = 10) and radiotherapy-alone (RT; primary n = 99, recurrent n = 15).

	ACKNOWLEDGMENTS

 
We thank Eva Skovlund for statistical knowledge and advice; Inger Hjertström Östh and Bente Kvisgaard for endless support with the databases and with secretarial functions; and the following clinicians who contributed patients to the trial: Elke Birkemeyer (Stavanger), Gunilla Frykholm, Stein Sundstrøm (Trondheim), Kjell Magne Tveit (Ullevål, Oslo), Morten Brændengen, Johan N. Wiig (Radiumhospitalet, Oslo), Norway, Bengt Glimelius, Per Byström, Jan-Erik Frödin, Christer Svensson (Stockholm), Bengt Glimelius, Åke Berglund, Lars Påhlman (Uppsala), Eva Fernebro (Lund), Henrik Grönberg (Umeå), Hans Starkhammar (Linköping), Bengt Ernström (Örebro), Åke Arwidi (Malmö), Sweden, Krzysztof Bujko (Warsaw), Poland.

	NOTES

 
Supported by the Swedish Cancer Society, Stockholm Cancer Society, and the Norwegian Cancer Society and through the regional agreement on medical training and clinical research between Stockholm county council and the Karolinska Institutet.

Presented in part at the 13th Annual European Cancer Conference, October 30–November 3, 2005, Paris, France.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted December 4, 2007; accepted April 16, 2008.

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