Preoperative Chemoradiotherapy in the Management of Localized Rectal Cancer: The New Standard

Abstract

Combined-modality therapy consisting of surgery, radiotherapy, and chemotherapy is the recommended management strategy for patients with stage II and III rectal cancer. Adjuvant radiotherapy has been used to improve upon the historically high pelvic recurrence rates. Both preoperative and postoperative radiation treatment strategies have been extensively studied. However, the recently published 5-year results of the randomized German CAO/ARO/AIO 94 trial of preoperative vs. postoperative chemoradiotherapy support a standard preoperative treatment approach. Randomized trials have also demonstrated that the addition of chemotherapy to preoperative radiotherapy significantly enhances tumor downstaging, pathologic response, and local control over radiation alone. The role of concurrent preoperative chemoradiotherapy, the investigation of novel systemic and biologic agents (capecitabine, oxaliplatin, irinotecan, bevacizumab, and cetuximab) and other key issues in the preoperative treatment of localized rectal cancer are discussed.

Pelvic radiotherapy has remained an integral component of rectal cancer management for patients presenting with stage II (node-negative disease with the primary tumor through the muscle wall) or stage III (positive regional lymph node involvement) disease due to the risk of local failure when treated with surgery alone.^1–3 Two approaches have been explored for the adjuvant administration of pelvic radiotherapy. The first is surgical resection and, if the tumor is stage T3 and/or N1-2, this is followed by postoperative chemoradiotherapy. The second, for patients with ultrasound T3-4 or clinical T4 cancer, is preoperative therapy followed by resection and postoperative chemotherapy.

Several randomized clinical trials have established the role of adjuvant postoperative chemoradiotherapy in locally advanced rectal cancer, including the Gastrointestinal Tumor Study Group Protocol 7175, the North Central Cancer Treatment Group Protocol 79-47-51, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-02.^4–6 These studies demonstrated that (1) adjuvant chemoradiotherapy increases overall survival compared to surgery alone, (2) adjuvant chemoradiotherapy improves overall survival compared to adjuvant radiotherapy alone, and (3) adjuvant chemoradiotherapy improves local control compared to chemotherapy alone.

In recent years, the approach to adjuvant therapy for rectal cancer in the United States and Europe has been shifting toward preoperative therapy to promote sphincter-preserving surgery and decrease acute and late bowel toxicity. This review examines the increasing use of preoperative chemoradiotherapy as a component of combined-modality treatment (CMT) for clinically resectable rectal cancer, which is largely attributable to the published 5-year results of the randomized German Chirurgische Arbeitsgemeinschaft Onkologie/Arbeitsgemeinschaft Radioonkologie/Arbeitsgemeinschaft Internistische Onkologie (CAO/ARO/AIO) 94 trial of preoperative vs. postoperative chemoradiotherapy.⁷ The role of concurrent preoperative chemotherapy, the investigation of novel systemic and biologic agents, and other key issues in the preoperative treatment of locally advanced rectal cancer will be discussed.

POTENTIAL BENEFITS OF PREOPERATIVE THERAPY

Preoperative therapy in the management of rectal cancer has been gaining acceptance in Europe as well as in the United States. Many potential advantages make preoperative therapy an attractive strategy. In theory, preoperative therapy could produce superior local control. This may be attributable, in part, to the fact that tumors are better oxygenated prior to surgery due to their intact vasculature, resulting in enhanced drug perfusion and enhanced radiosensitivity. Tumor cells are significantly more sensitive to an equivalent dose of radiation in the presence of oxygen in contrast to hypoxic conditions. Furthermore, preoperative therapy may also sterilize tumor cells that could be inadvertently released into the regional tissues or bloodstream (“seeding”) during surgery.

Preoperative therapy may also be better tolerated. The volume of tissue that needs to be irradiated may be smaller in the preoperative setting; and greater amounts of normal surrounding tissues, such as the small bowel, may be spared from high-dose radiation. Moreover, because the irradiated tissue is resected, the anastomosis is radiotherapy naïve and free from the adverse effects of exposure. Reducing the amount of small bowel tissue within the high-dose irradiation field and constructing the anastomosis with untreated bowel should contribute to a decreased likelihood of acute and late radiation-induced morbidity.

Preoperative therapy can also improve the resectability of tumors, allowing sphincter-preserving procedures that otherwise would not have been possible. This response to preoperative therapy, termed “downstaging,” allows sphincter preservation in almost 25% of patients who would have needed an abdominoperineal resection (APR). The enhanced prospect of sphincter preservation with good functional outcome is of great importance to patients.

Preoperative therapy also provides an opportunity to study innovative agents in combination with pelvic irradiation. Pathologic complete response (pCR) rate at surgery is used to assess response. The primary disadvantage with this strategy, however, is the potential for overtreating patients with stage I or IV disease, because preoperative clinical staging does not perfectly predict the surgical stage. The German CAO/ARO/AIO 94 trial demonstrated that despite excellent endorectal ultrasonography (EUS) clinical staging, pathologic T1-2N0 disease was found in 18% of patients randomized to the postoperative chemoradiotherapy arm.⁷ Further, a recent study from Guillem and colleagues demonstrated that while 19% of patients will be overstaged with magnetic resonance imaging (MRI) or EUS, 22% have undetected mesorectal nodal involvement, even after CMT.⁸ These authors concluded that while there is a risk of overstaging, and thus overtreating, an even greater number of patients are understaged and would require postoperative chemoradiotherapy. In the future, combining imaging techniques such as computed tomography (CT), MRI, and fluorodeoxyglucose positron emission tomography (FDG-PET) with EUS, along with gene expression profiling, may allow more accurate patient selection for preoperative management.

PREOPERATIVE CHEMORADIATION: THE NEW STANDARD

Preoperative Radiotherapy Alone

Over the past 2 decades, several European groups have investigated preoperative radiotherapy alone for stage II and III rectal cancer, most commonly as a short, high-dose-perfraction course. Nineteen randomized trials explored the efficacy of preoperative pelvic radiotherapy; 12 administered 25 Gy in 5 fractions or “short-course” radiotherapy. Most of these trials demonstrated a significant decrease in local recurrence rates with preoperative therapy, but only one study, the Swedish Rectal Cancer trial, showed a survival advantage with this approach.⁹

Other preoperative short-course radiation studies have continued to confirm the local control benefit of pelvic irradiation, even with optimal surgery. The Dutch Commissie Klinisch Vergelijkend Onderzoek (CKVO) 95–04 trial randomized 1,805 patients with operable rectal cancer to short-course preoperative radiotherapy followed 1 week later by total mesorectal excision (meticulous sharp dissection to include the rectal fascia and complete resection of the mesorectal lymphatics at least 4 cm distal to the tumor itself) vs. total mesorectal excision (TME) alone.¹⁰ While there was no significant difference in overall survival rates, the 2-year local recurrence rate was significantly reduced from 8.2% to 2.4% (P < .001) with the addition of preoperative radiotherapy, even with meticulous, centrally reviewed TME surgery.

At the 2006 annual meeting of the American Society of Clinical Oncology (ASCO), Sebag-Montefiore presented preliminary results of the Medical Research Council (MRC) CR07 study, a phase III randomized trial that compared short-course preoperative radiotherapy with selective postoperative chemoradiotherapy in 1,350 patients with clinically resectable rectal cancer.¹¹ Patients were randomized to either routine preoperative short-course radiotherapy (25 Gy in 5 fractions) or postoperative chemoradiotherapy chemoradiotherapy (45 Gy in 25 fractions plus 5-fluorouracil [5-FU]) for patients with involvement of the circumferential margin. All patients underwent centrally reviewed mesorectal excision. Patients with pathologic stage III disease (deemed “high risk”) were to receive postoperative chemotherapy.

The rationale for this study stemmed from the presumption that the risk of pelvic recurrence is low if TME is performed with negative circumferential margins, and that systemic therapy is the primary component of overall survival and should, therefore, be recommended for patients with documented stage III disease. Hence, with mesorectal excision and judicious use of postoperative chemoradiotherapy, potentially excellent local control could be obtained without the risk of overtreatment with preoperative radiotherapy. To their surprise, the investigators found that at 3 years, not only was local recurrence significantly decreased from 11.1% to 4.7% (95% CI, 1.61–3.47) with preoperative radiotherapy, but a significant improvement in 3-year disease-free survival was also demonstrated (79.5% vs.74.9%; 95% CI, 1.02–1.67). Overall survival, however, was not significantly different between treatment groups at the time of this early analysis. These results suggest that even with meticulous TME and appropriate adjuvant chemotherapy, preoperative therapy improves outcomes over adjuvant postoperative chemoradiotherapy for patients with high-risk disease. In concordance with the German data, this study further strengthens the rationale for preoperative therapy.

Rationale for Long-Course Preoperative Chemoradiation

While short-course preoperative radiotherapy is favored in parts of Europe, the United States has not adopted this approach because the potential for radiation morbidity and anorectal dysfunction remains a significant concern with hypo-fractionation.^12–16 The Swedish Rectal Cancer trial reported an acute increase in perineal infections and bowel dysfunction with short-course preoperative radiotherapy, as well as increased hospital admissions with long-term follow-up due to bowel obstruction or abdominal pain.^12,15 A questionnaire-based companion study was performed to assess late morbidity in the Dutch CKVO trial. Significant increases in bowel incontinence, anal mucus loss, anal blood loss, and the use of pads were reported.¹⁴

For this reason, investigators in the United States in the 1990s explored conventionally fractionated preoperative radiation in combination with 5-FU in an attempt to promote sphincter-sparing resection by facilitating greater interaction of radiotherapy with radiosensitizing chemotherapy. Phase II studies of preoperative chemoradiotherapy from both Europe and the United States (45–50.4 Gy pelvic radiation at 1.8 Gy per fraction, 5 days a week, with 5-FU) reported pCR rates of 10% to 20%, with approximately 60% to 80% of patients with distal rectal cancers achieving a sphincter-sparing resection with good to excellent sphincter function.^17–22 These investigations led to randomized phase III trials of preoperative vs. postoperative CMT to evaluate the potential value of this approach with regard to sphincter preservation, toxicity, local control, and overall survival.

Phase III Trials of Preoperative vs. Postoperative Chemoradiotherapy

Four randomized trials have evaluated preoperative vs. postoperative adjuvant CMT for clinically resectable stage II and III rectal cancers — the Intergroup 0147 trial and the NSABP RO-03 study in the United States, the CAO/ARO/AIO 94 trial from Germany, and the MRC CR07 trial from the United Kingdom, Canada, South Africa, and New Zealand. The first three studies used long-course 5-FU chemoradiotherapy strategies and required a preoperative surgical assessment affirming the type of resection required prior to neoadjuvant therapy, while the MRC trial used preoperative short-course radiotherapy. Due to limited patient accrual, the two US trials were closed early. An interval analysis at a median follow-up of 1 year of the first 116 patients enrolled into the NSABP RO-03 trial revealed an increase in sphincter preservation favoring the preoperative arm (44% vs. 34%, no P value given), with a similar incidence of postoperative toxicities in both arms.²³ Preliminary 5-year survival results of the 267 enrolled patients presented at the 2004 ASCO meeting revealed significant pathologic tumor downstaging (pCR rate 17%) with preoperative therapy, as well as prolonged overall and disease-free survival, also in favor of the preoperative arm (overall survival, 74% vs. 66%; P = .14; disease-free survival, 64% vs. 53%; P = .08) (Table 1).²⁴ These two failed trials from the United States underscore the importance of the recently published German trial results (CAO/ARO/AIO 94).

Table 1.

Randomized trials of preoperative vs. postoperative chemoradiation with 5-year results.

	NSABP R-0323,24			CAO/ARO/AIO-947
	Preop (%)	Postop (%)	P Value	Preop (%)	Postop (%)	P Value
Number of patients	130	137		405	394
CT given	Bolus 5-FU			CI 5-FU
Received complete RT course	NR	NR	NR	92	54	< .001
Received complete CT course	30	48	NS	89	50	< .001
Any grade 3/4 acute toxicity	34	23	.07	27	40	.001
Postoperative complications	22	22	NS	36	34	NS
Any grade 3/4 ate l toxicity	NR	NR	NR	14	24	.01
Pathologic complete response	17	0	NR	8	0	< .001
Sphincter-p reservation rate	44	34	NS	69	71	NS
				39*	19*	.004
Pelvic recurrence rate	5	9	NS	6	13	.006
Disease-free survival	64	53	.08	65	68	NS
Overall survival	74	66	NS	74	76	NS

Abbreviations: Preop = preoperative; Postop = postoperative; 5-FU = 5-fluorouracil; CI 5-FU = continuous-infusion 5-FU (during 1st and 5th week of RT); NS = not statistically significant; NR = not reported; RT = radiation therapy; CT = chemotherapy; Pts = patients.

^*Sphincter-preservation rates among 194 patients in whom abdominoperineal resection was initially thought to be necessary.

In the CAO/ARO/AIO 94 study, Sauer et al randomly assigned 805 patients with clinical stage II or III rectal cancer to preoperative or postoperative regimens of chemoradiotherapy.⁷ Standard-of-care clinical staging (EUS), radiotherapy (50.4 Gy preoperative and 54 Gy postoperative), chemotherapy (continuous infusion 5-FU during the first and fifth weeks of radiotherapy), and surgery (TME technique with mandatory central quality assurance) were all employed. Patients in both arms received four cycles of adjuvant chemotherapy with bolus 5-FU. At a median follow-up of 4 years, no significant differences between the two approaches were reported in the primary end point of 5-year overall survival (Table 1). However, treatment compliance, grade 3/4 acute and late toxicity profile, tumor and nodal downstaging, and rates of pelvic recurrence, all favored the preoperative chemoradiotherapy arm. In addition, sphincter-preservation rates in the 194 patients with low-lying tumors declared by the surgeon prior to randomization as requiring an APR were enhanced with preoperative treatment (39% vs. 19%, P = .004). The effect of preoperative chemoradiotherapy on anorectal function is also an important consideration; reports on these outcomes are still pending from this trial. Based on the German trial results, preoperative chemoradiotherapy is now considered to be the current standard adjuvant practice in the United States for patients with stage II and III rectal cancer.

Value of Concurrent Chemotherapy with Preoperative Radiation

Whether the addition of 5-FU chemotherapy to a preoperative long-course radiation strategy is more efficacious than preoperative radiotherapy alone has recently been addressed in four randomized European trials: the European Organization for the Research and Treatment of Cancer (EORTC) trial 22921, the Fondation Française de Cancérologie Digestive (FFCD) trial 9203, the Groupe de Recherche Chirurgical dans le Cancer du Rectum (GRECCAR) trial also from France, and a Polish Colorectal Study Group multicenter effort. In contrast to the German trial, these trials lacked mandated EUS clinical staging and central quality assurance of TME.

In EORTC 22921, 1,011 patients with resectable stage T3 or T4 rectal cancers were randomized according to a 2×2 factorial design as follows: preoperative long-course radiotherapy (45 Gy in 5 weeks) with or without concurrent bolus 5-FU and then to four cycles of adjuvant chemotherapy (5-FU + folinic acid) vs. none. Although acute toxicity data revealed a slight increase in the frequency and severity of gastrointestinal and hematologic toxicity with preoperative chemoradiotherapy vs. radiotherapy alone,²⁵ patients treated with preoperative chemoradiotherapy benefited from significantly enhanced tumor and nodal downstaging and enhanced pCR (14% vs. 5.3% with preoperative radiotherapy alone, P < .0001) (Table 2).²⁶ The rate of sphincterpreserving surgery also favored the addition of chemotherapy to preoperative radiotherapy (55.3% vs. 52.8%, P = .05). The rate of 5-year overall survival in both groups was 65%.²⁷ However, the administration of chemotherapy concurrently with neoadjuvant radiotherapy significantly decreased the risk of local recurrence at 5 years (17.1% radiotherapy alone vs. 8.7% chemoradiotherapy, P = .0016). In terms of the role of adjuvant 5-FU therapy after preoperative treatment and surgery, preliminary analysis at 5 years reveals no survival benefit; however, longer follow-up data are necessary.

Table 2.

Randomized trials of preoperative chemoradiation vs. radiation alone.

Trial/Preoperative Treatment	RT Total Dose	% pCR	% 5-year LR	% SPS	% 5-year OS
EOR TC 22921
RT alone	45 Gy (1.8 Gy)	5.3	17.1	52.8	65
Chemo-RT*	45 Gy (1.8 Gy)	14	8.7	55.3	65
P value		<.0001	.0016	.05	NS
FFCD 9203
RT alone	45 Gy (1.8 Gy)	3.7	16.5	51.7	66.6
Chemo-RT	45 Gy (1.8 Gy)	11.7	8	52.6	67.8
P value		<.05	NR	NS	NS
Polish Trial
RT alone	25 Gy (5 Gy)	1	NR	61	NR
Chemo-RT	50.4 Gy (1.8 Gy)	16	NR	58	NR
P value		NR	NR	NS	NS
GRECCAR 1
RT alone	63 Gy (1.8 Gy)	NR	NR	83	NR
Chemo-RT	45 Gy (1.8 Gy)	NR	NR	86	NR
P value		NR	NR	NS	NS

Abbreviations: RT = radiation therapy; Gy = gray; pCR = pathologic complete response; LR = local recurrence; SPS = sphincter-preserving surgery; OS = overall survival; NS = not statistically significant; NR = not reported.

^*The local recurrence rates compare RT alone vs. concurrent and/or adjuvant chemotherapy.

Preliminary results from the FFCD 9203 study of 762 patients with resectable T3 or T4 rectal cancers receiving preoperative bolus 5-FU–based chemoradiotherapy vs. radiotherapy alone were presented at the 2004 and 2005 ASCO meetings.^28,29 The use of preoperative chemoradiotherapy resulted in significantly increased pCR rates (11.7% vs. 3.7% with radiotherapy alone, P < .05), albeit with increased grade 3/4 acute toxicity (15% vs. 3%, P < .05) as seen in the EORTC study (Table 2). At 69 months median follow-up, overall survival and disease-free survival were similar for both arms. A significant improvement in local recurrence rate was seen, however, with the addition of concurrent chemotherapy to preoperative radiotherapy (8% vs. 16.5%, P value not given). In the French trial, the addition of preoperative chemotherapy did not increase the rates of sphincter-sparing surgery (52% for both arms).

Another French randomized phase III trial, GRECCAR 1, compared sphincterpreservation sphincterpreservation rates for preoperative radiotherapy with and without chemotherapy.³⁰ Entry criteria included patients with stage T3 or N1 rectal cancer with a distance between the tumor and levator ani of < 2 cm. Preliminary results were presented at the 2006 ASCO meeting. Two hundred seven patients were randomized to 45 Gy pelvic radiotherapy with continuous infusion 5-FU vs. radiotherapy alone (45 Gy + 18 Gy boost). Overall, 85% of patients were able to undergo a sphincter-preserving resection with no difference between the two randomized groups (Table 2). However, there appeared to be a trend toward greater morbidity with high-dose radiation alone.

The Polish Colorectal Study Group multicenter phase III trial randomized 311 patients with resectable T3 or T4 disease to receive short-course hypofractionated radiation alone (5 Gy×5) followed by surgery 1 week later or standard 50.4 Gy in 1.8 Gy daily fractions of pelvic radiotherapy with bolus 5-FU followed 2 to 12 weeks later by surgery.³¹ While the EORTC 22921 and FFCD trials were evaluating survival as their primary end point, this trial, similar to the GRECCAR study, was designed to evaluate sphincter preservation. Despite a significant improvement in pCR of 16% vs. 1% with the addition of chemotherapy to long-course preoperative radiotherapy (no P value given) as well as enhanced tumor and nodal downstaging and negative radial margin status, the addition of chemotherapy did not increase the rate of sphincter preservation (58% vs. 61%, P = .57) (Table 2). The authors noted that in some situations, a sphincter-sparing operation was not performed even in the setting of a CR, rendering interpretation of this result difficult. Of note, this is the only trial thus far to compare the two most commonly used preoperative strategies: European “short-course” radiotherapy alone vs. “longcourse” chemoradiotherapy. Longer follow-up is required to evaluate local control and survival end points for these two approaches.

In summary, the addition of chemotherapy to neoadjuvant radiation in the EORTC, FFCD, and Polish trials was associated with significant improvements in tumor downstaging, pCR rates, and local control. Survival rates appeared to be similar with and without concurrent bolus 5-FU. The lack of a marked sphincterpreservation enhancement with the addition of preoperative chemotherapy (notably in the GRECCAR I trial) appears perplexing. However, there was a lack of TME surgical quality assurance in all four trials, in contrast to the German preoperative vs. postoperative trial. Also noteworthy, the poor compliance with chemotherapy administration as prescribed after surgical resection (ranging from approximately 50% in both the FFCD and Polish trials to 66.7% in the EORTC report) again stresses the importance of a preoperative radiation-plus-chemotherapy approach.

NOVEL SYSTEMIC AND BIOLOGIC AGENTS

The addition of systemic therapy to standard fractionated or long-course pelvic radiation allows for enhanced local tumor shrinkage. Although 5-FU–based chemotherapy has been the standard for adjuvant CMT for rectal cancer, a number of novel chemotherapeutic and biologic agents (capecitabine, oxaliplatin, irinotecan, bevacizumab, and cetuximab) are currently undergoing phase II and III evaluation in combination with radiation, as well as in the adjuvant setting (Table 3).

Table 3.

Select trials of novel preoperative chemoradiation combinations.

Study	N	Preop Therapy*	Type Surgery	Postop Therapy	Pathologic Complete Response (%)
Dunst37	90	Capecitabine	NS	NS	4
Mohiudden43	59	CI 5-FU Irinotecan	NS	NS	26
Ryan 47	44	CI 5-FU Oxaliplatin	TME	5-FU leucovorin	25
Willett49	6	CI 5-FU Bevacizumab	TME	NS	5/6 had only microscopic disease
Chung51	20	CI 5-FU Cetuximab	NS	NS	12

^*All drugs given concurrently with external beam radiation therapy dose of 50.4 Gy.

Abbreviations: Preop = preoperative; Postop = postoperative; CI 5-FU = continuous-infusion 5-fluorouracil; TME = total mesorectal excision; NS = not specified.

Capecitabine

The oral fluoropyrimidine capecitabine (Xeloda) is an attractive alternative to protracted infusion 5-FU, as it eliminates the burden of central venous catheter placement and the need for an infusion pump. Capecitabine has proven equivalence in efficacy to 5-FU for the treatment of patients with metastatic colorectal cancer.^32,33 In a large randomized study, the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, capecitabine was shown to be equivalent to bolus 5- FU/leucovorin (Mayo regimen) in the adjuvant setting for patients with stage III colon cancer.³⁴ For neoadjuvant treatment in rectal cancer, a matched pair comparison in patients receiving preoperative radiotherapy and capecitabine or radiotherapy with concurrent continuous infusion 5-FU demonstrated no significant differences in morbidity, pathologic response, sphincter preservation, and local recurrence rates.³⁵ In fact, preclinical data suggest that capecitabine may be an even more effective radiation sensitizer.³⁶ Sawada and co-workers found that radiation upregulates thymidine phosphorylase, the enzyme involved in the intracellular conversion of capecitabine to 5-FU. They reported enhanced radiosensitization with capecitabine when compared to 5-FU in colon cell lines. In a phase II trial of 98 patients with locally advanced rectal cancer treated with capecitabine 825 mg/m² twice daily and 50.4 Gy radiation, the clinical response rate was 61% and R0 resection rate 89% in 59 evaluable patients (Table 3).³⁷ Diarrhea, the most common adverse event, was reported in 46% of patients; grade 3 or 4 diarrhea was noted in 7%. Other phase I/II studies using a similar strategy have reported pCR rates up to 31% and sphincter-preservation surgery in approximately 70%.^38–40

Capecitabine is under phase III investigation in the current NSABP R-04 trial randomizing 1,460 patients with clinically resectable rectal cancer to preoperative 50.4 Gy pelvic radiotherapy with infusional 5-FU or capecitabine, with or without oxaliplatin.⁴¹ This drug appears to serve as an acceptable alternative to infusional 5-FU for preoperative chemoradiotherapy in patients with rectal cancer, and as such, capecitabine and pelvic radiotherapy are the current investigational preoperative backbone in the study of additional novel systemic and biologic agents.

Irinotecan

Irinotecan is a plant alkaloid shown to inhibit DNA replication, transcription, and repair by blocking topoisomerase I function. Irinotecan is approved for metastatic colon cancer but has not demonstrated utility in the adjuvant setting. Based on an initial phase I/II study showing a pCR in 25% of patients with stage T3-4 rectal cancer receiving preoperative chemoradiotherapy consisting of weekly irinotecan (maximum tolerated dose 50 mg/m²) in combination with 5-FU (225 mg/m²/d) and 54 Gy radiation (1.8 Gy daily fractions),⁴² the Radiotherapy Oncology Group initiated RTOG 0012. This phase II trial randomized 106 patients with stage T3-4 rectal cancer to irinotecan, 5-FU, and concomitant daily radiation vs. 5-FU alone with twice daily radiation followed by surgical resection 4–10 weeks later (Table 3).⁴³ The overall resectability rate was 93%. Tumor downstaging was observed in 78% of patients in both arms. For patients who had surgery, the pCR rate was 28% in both arms. Acute and late toxicity was also similar. Grades 3 and 4 acute hematologic and nonhematologic toxicity developed in 13% and 38% in arm 1 and 12% and 45% in arm 2, respectively.

Oxaliplatin

Oxaliplatin is a third generation 1,2 diaminocyclohexane platinum analogue that intercalates with DNA to prevent normal activities of replication and transcription. This drug has an established role in the adjuvant therapy of stage II and III colon cancer.⁴⁴ Given the superior 3-year disease-free survival of 5-FU/leucovorin/oxaliplatin (FOLFOX) over 5-FU/leucovorin in this trial, the Gastrointestinal Intergroup initiated a phase III effort (ECOG 3201) to examine combination chemotherapy in the adjuvant setting for rectal cancer. Patients with stage II or III rectal cancer after undergoing surgery and receiving adjuvant chemoradiotherapy were randomized to postoperative chemotherapy consisting of 5-FU + leucovorin or 5-FU + leucovorin and irinotecan (FOLFIRI) or FOLFOX. This trial closed when the Gastrointestinal Intergroup developed another trial investigating the addition of bevacuzimab. However, the toxicity data from the 225 accrued patients of the planned 3,150 were recently reported at the 2006 ASCO meeting.⁴⁵ There were no significant differences in morbidity among the three arms, apart from increased diarrhea with the use of FOLFIRI after postoperative chemoradiotherapy. Based on these data, FOLFOX is the new investigational platform for adjuvant rectal trials, and some oncologists are beginning to use this combination for the adjuvant therapy of high-risk rectal cancer patients.

Oxaliplatin is also under investigation in the preoperative chemoradiotherapy setting. In the Lyon R0-04 trial, 40 patients with locally advanced rectal cancer received oxaliplatin 130 mg/m² with 5-day continuous-infusion 5-FU 350 mg/m²/day and leucovorin 100 mg/m² during weeks 1 and 5 of radiation (50 Gy over 5 weeks with a concomitant boost).⁴⁶ All patients underwent surgery, and 65% of patients underwent a sphincter-preserving procedure. The clinical response rate was 75%, with a pCR of 15%. In Cancer and Leukemia Group B (CALGB) 89901, the maximally tolerated dose of oxaliplatin was 60 mg/m² in combination with 5-FU 200 mg/m²/day and radiation, yielding a pCR of 25% (Table 3).⁴⁷ Based on these results, RTOG developed the ongoing 0247 phase-II trial randomizing 141 patients with locally advanced rectal cancer to receive preoperative capecitabine and either irinotecan or oxaliplatin with standard 50.4 Gy radiation. Similarly, the German CAO/ARO/AIO-05 phase II trial has been initiated, randomizing 110 patients to 5-FU and 50.4 Gy radiation preoperatively vs. capecitabine and oxaliplatin with the same dose of radiotherapy. The neoadjuvant role of oxaliplatin is also being evaluated in the current NSABP R-04 trial.

Bevacizumab and Cetuximab

Biologic agents targeting vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) were approved by the FDA in 2004 for patients with metastatic colorectal cancer. The VEGF inhibitor bevacizumab has been approved in combination with 5-FU–based chemotherapy for metastatic disease.⁴⁸ Bevacizumab (5 mg/kg) has been administered to patients with locally advanced rectal cancer prior to and in combination with 5-FU and radiation (Table 3).⁴⁹ In this phase I/II effort, tumor blood flow, interstitial pressure, and mean vessel density decreased 12 days after bevacizumab induction therapy. Encouraging tumor downstaging was also reported. The Gastrointestinal Intergroup is currently conducting a phase III trial of adjuvant FOLFOX with or without bevacizumab after preoperative chemoradiotherapy and surgery (ECOG 5201). The chimeric anti-EGFR monoclonal antibody cetuximab was approved for metastatic disease in combination with irinotecan following irinotecan failure.⁵⁰ Investigators at the Memorial Sloan-Kettering Cancer Center recently reported their preliminary safety results of a pilot trial of cetuximab in combination with standard neoadjuvant protracted infusion 5-FU and radiotherapy in ultrasound T3-4, clinical T4, or locally recurrent rectal adenocarcinoma (Table 3).⁵¹ Twenty patients were treated with acceptable toxicity, and a pCR of 12% was observed. Radiation field dermatitis was seen in only 5%. Additionally, a phase I/II study evaluating the combination of cetuximab with capecitabine, oxaliplatin, and radiotherapy is ongoing in Germany.

CONFORMAL RADIATION TECHNIQUES

Generally, preoperative chemoradiotherapy strategies are well tolerated. However, it is possible that the continued addition of more aggressive agents to a preoperative chemoradiotherapy regimen may increase the acute side effects associated with therapy. Highly conformal radiation techniques, such as intensity modulated radiotherapy (IMRT) offer the potential to reduce the spectrum of side effects associated with radiotherapy by decreasing the volume of normal tissue receiving radiation. One study from investigators at the Royal Marsden Hospital demonstrated that IMRT reduces the amount of small bowel receiving high doses of radiation.⁵² Such sparing of normal tissues may translate into decreased morbidity. This may be of particular importance with the intensification of concurrent systemic and/or biologic agents.

RISK-ADAPTED TREATMENT STRATEGIES

Significant tumor and individual heterogeneity may exist among patients with rectal cancer. Therefore, selective or “tailored” treatment strategies may be warranted on the basis of an individual’s risk for local and distant failure as well as survival. For example, patients at low risk for local and distant failure may be candidates for less intense preoperative and adjuvant regimens, while patients at high risk for distant disease may be candidates for more aggressive adjuvant chemotherapy combinations such as FOLFOX. Clinical and pathologic factors that predict relapse and death are therefore helpful in the design of risk-adapted tailored treatment approaches.

Investigators at The University of Texas M. D. Anderson Cancer Center performed univariate and multivariate analyses to identify predictive factors in 470 patients with rectal cancer treated with mesorectal excision and either neoadjuvant or adjuvant chemoradiotherapy with a median followup interval of over 5 years.⁵³ Pathologic T3-4 and N1-2 disease significantly predicted for poorer pelvic control, distant metastasis-free survival, and overall survival on multivariate analysis. In a rectal cancer pooled analysis of phase III North American trials, both overall survival and disease-free survival were dependent on TN stage, NT stage, and treatment method.⁵⁴ Three risk groups of patients were defined: intermediate (T1-2N1, T3N0), moderately high (T1-2N2, T3N1, T4N0), and high (T3N2, T4N1, T4N2). Patients with a single high-risk factor (T1-2N1, T3N0) had better overall survival, diseasefree survival, and local disease control than patients with both high-risk factors. These and other predictive factors will play an important role in the future development of risk-adapted investigative trial design.

CONCLUSIONS

Preoperative chemoradiotherapy now represents the standard adjuvant care for patients with clinical stage II or III rectal cancer. The recently published 5-year results of the German CAO/ARO/AIO 94 trial of preoperative vs. postoperative chemoradiotherapy, using modern chemoradiotherapy and TME techniques, clearly demonstrate marked improvements in treatment compliance, grade 3/4 toxicity, tumor downstaging, rates of sphincter preservation for patients with low-lying tumors, and rates of pelvic recurrence in favor of preoperative therapy. Moreover, the EORTC, FFCD, and Polish randomized studies emphasize the importance of concurrent systemic therapy with preoperative radiation, as the addition of chemotherapy is associated with significant improvements in tumor downstaging, pCR rates, and local control over radiation alone. Ongoing randomized phase II and III investigations incorporating novel systemic and biologic agents may refine our current preoperative chemoradiotherapy and adjuvant therapy strategies, and likely lead to future trials of risk-adapted management.