the Geisinger Cancer Institute, Wilkes-Barre
    Radiation Therapy Oncology Group Headquarters
    Thomas Jefferson University, Philadelphia
    Reading Hospital and Medical Center, Reading, PA
    University of Maryland Medical Center, Department of Surgical Oncology, Baltimore, MD
    Bay Medical Regional Cancer Center, Panama City, FL
    Ingalls Memorial Hospital, Harvey, IL
    Santa Fe Cancer Center, Santa Fe, NM
    Duke University Medical Center, Durham, NC

    ABSTRACT

    PURPOSE: To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a randomized phase II study

    PATIENTS AND METHODS: Patients with clinical T3/T4 distal rectal cancers were randomly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection. Patients were randomly assigned to receive continuous venous infusion (CVI) fluorouracil (FU) 225 mg/m2 per day, 7 days per week, plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid (arm 1) or CVI FU 225 mg/m2 per day Monday to Friday, 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day (arm 2). Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy. The primary end point of this study was pathologic complete response (pCR). Secondary end points included acute and late normal tissue morbidity.

    RESULTS: A total of 106 patients were entered onto the study, with 103 assessable for response. The overall resectability rate was 93%. The median time to surgery was 7 weeks. Tumor downstaging was observed in 78% of patients in both arms. The pCR rate for all assessable patients was 26% in each arm. For patients who had surgery, the pCR rate was also the same (28%) in both arms. Acute and late toxicity was also similar. Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13% and 38% in arm 1 and 12% and 45% in arm 2, respectively.

    CONCLUSION: Although the overall complete response rate and toxicity seems similar in both arms, this is the first multi-institutional study to establish a relatively high (28%) pCR rate after neoadjuvant therapy.

    INTRODUCTION

    Rectal cancer management remains a significant oncologic challenge in the United States. There are an estimated 36,400 new cases of cancer of the rectum annually, with an overall 5-year survival of 55% to 60%.1 Although the prognosis in patients with early tumors is excellent, patients with tumors in the distal rectum and those with higher stage of disease (T3 to T4 or N+) seem to have significantly worse outcomes. Several cooperative group studies have validated the benefits of adjunctive postoperative chemoradiation in improving survival in patients with advanced cancers (> T3).2,3 However, postoperative radiation therapy (RT) may be associated with significant bowel toxicity and compromised bowel function.4

    Recently, several European studies have indicated that preoperative RT may be a potentially better approach to treatment of rectal cancers both in terms of improved local control and reduced toxicity.5,6 Previous randomized studies, using preoperative RT in rectal cancer, had generally used lower total doses of RT (< 45Gy) and had failed to find a survival benefit.7-10 More recent institutional studies have used higher doses of preoperative RT with improved resectability rates, increased options for sphincter preservation, reduced local recurrence, and a suggestion of improved survival.11,12 Several studies have also extrapolated from the postoperative experience by combining chemotherapy with RT in the neoadjuvant setting.13-16

    Recent reports indicate that pathologic complete response (pCR) rates after preoperative chemoradiation have improved compared with RT alone, and range from 10% to 30%.17-19 However, several of these studies have used different patient selection criteria, different combinations of cytotoxic agents, and a variety of RT dose/time schedules. Reporting of treatment-related toxicity is also variable; therefore, it is difficult to determine the most effective regimen in the neoadjuvant management of this disease.

    This Radiation Therapy Oncology Group 0012 study was undertaken to determine the efficacy of neoadjuvant therapy in the management of locally advanced distal rectal cancer in a multi-institutional setting and to compare the results of RT dose intensification (55 to 60 Gy) using a hyperfractionated RT schedule and fluorouracil (FU) to a chemotherapy intensification approach using two drugs, irinotecan (CPT-11) and FU, with a standard RT schedule (50 to 54 Gy). The primary end point of the study was to assess the pCR. One of the secondary end points, toxicity of treatment, is included in this report. Survival and patterns of treatment failure will be reported in the future.

    PATIENTS AND METHODS

    Patients with clinical T3/T4 distal rectal cancers located 0 to 9 cm from the dentate line were randomly assigned in a phase II study to receive combined neoadjuvant preoperative chemoradiation followed by surgical resection of the disease. The treatment schema is shown in Figure 1. Patients were stratified by clinical stage and randomly assigned to receive either continuous venous infusion (CVI) FU 225 mg/m2/d, 7 days per week, plus hyperfractionated pelvic RT to a dose of 45.6 Gy at 1.2 Gy bid ( 6-hour interval between fractions) and a boost of 9.6 Gy for T3 and 14.4 Gy for T4 cancers (arm 1); or CVI FU 225 mg/m2 per day Monday through Friday (120 h/wk) plus irinotecan 50 mg/m2 once weekly x 4 weeks, plus pelvic RT to a dose of 45 Gy (1.8 Gy/d with a boost to the tumor of 5.4 Gy for T3 and 9 Gy for T4 cancers; arm 2). Surgery was performed 4 to 10 weeks after completion of assigned treatment. Although total mesorectal excision was recommended for all patients, it was not required.

    All patients were without evidence of distant metastasis and had a Zubrod performance status of 0 to 1. Patients were required to have a WBC count greater than 4,000/mL and platelet count greater than 130,000/mL. They were also required to have satisfactory liver and renal function tests and a bilirubin  1.5x the upper limit of normal. All patients were required to have a chest x-ray and a computed tomography scan of the abdomen and pelvis to determine the location, extent, and size of the pretreatment disease. An endorectal ultrasound was performed for TNM staging of mobile cancers. A magnetic resonance imaging scan of the pelvis for corroboration of TNM staging was optional. Patients were required to sign the study-specific informed consent before random assignment.

    The initial RT treatment was delivered to the whole pelvis. All patients were treated with megavoltage RT ( 6 MV) using anteroposterior/posteroanterior and two lateral fields. The superior border of the treatment volume was at the L5-S1 junction with the inferior border a minimum of 5 cm inferior to the distal-most extent of the tumor or the anal verge as identified by a marker on simulation. Laterally, the field extended 2 cm lateral to the boney pelvis at its widest point. The anterior border of the lateral fields covered the lower common and external iliac nodes to 1 cm anterior to the symphysis for anterior wall lesions and to the mid-symphysis for posterior lesions. The posterior border included the entire sacrum with a 1-cm margin posteriorly. The boost fields were planned with a 3-cm margin around the tumor but included the whole of the sacral hollow. Chemotherapy was started on day 1 of the RT treatment and continued until the completion of RT.

    Chemotherapy and RT were interrupted if grade more than 3 toxicity was encountered. Chemotherapy and RT were restarted when toxicity had resolved to grade 1. A dose modification of chemotherapy was undertaken for subsequent cycles. The dose of FU was decreased by 25% and irinotecan was decreased to 40 mg/m2.

    Postoperative chemotherapy was recommended for all patients with pathologic residual disease. Patients with a CR could have their postoperative chemotherapy omitted at the discretion of the treating physician.

    End points of the study were measurement of both acute and late toxicity of treatment, as well as pCR rate, which was defined as absence of identifiable cancer cells in the specimen after surgical resection of the tumor. Secondary end points included sphincter preservation rate, survival, and local recurrence.

    Statistical Considerations

    This study was designed to evaluate the pCR rate for patients with cancer of the rectum treated with preoperative combined-modality chemoradiotherapy. A pCR rate of less than 20% would not merit additional study. With a one-sided type I error of 5% and 90% power, if there are at least 14 pCRs of the first 45 assessable patients in a given arm, the conclusion will be that the true pCR rate for that arm is more than 20%. Patients who die or have disease progression before surgery will be considered not to have a pCR and will be included in the denominator. The balance of pretreatment characteristics between the treatment arms was evaluated using 2 tests.

    RESULTS

    Patient Characteristics

    Fifty-two patients were entered in arm 1 and 54 patients were entered in arm 2 between February 1, 2001, and January 22, 2003. Three patients were excluded for the following reasons: withdrawn consent (n = 1), no protocol treatment received (n = 1), and ineligibility because the carcinoembryonic antigen was not performed within the eligibility time frame; the remaining 103 patients were analyzable for CR (50 in arm 1 and 53 in arm 2). The distributions of pretreatment characteristics of the patients in the two arms of the listed are shown in Table 1. Pretreatment characteristics were well balanced, with the exception of sex. There were more males in arm 1 than in arm 2 (78% v 55%, respectively; P =.013). The presence of T4 tumors was slightly higher in arm 1, although the value was not statistically significant (32% in arm 1 and 25% in arm 2).

    Response Rate

    Seven patients did not undergo the planned surgery (four in arm 1 and three in arm 2) because of either disease progression or patient/physician refusal, which produced an overall resectability rate of 93%. The median time to surgery was 7 weeks. The statistical conclusion regarding the pCR rate for each arm is based on the number of pCRs of the first 45 assessable patients in each arm. The pCR rate for the first 45 assessable patients, as determined on surgical review, was 29% (13 of 45) in arm 1 and 31% (14 of 45) in arm 2. Of all eligible patients who started treatment, the pCR rate, as determined on surgical review, was 26% (13 of 50) in arm 1 and 26% (14 of 53) in arm 2 (Table 2). Of patients who had surgery, the pCR rate was also similar in both arms, 13 of 46 (28%) in arm 1 compared with 14 of 50 (28%) in arm 2. For T3 cancers, 22 of 69 (32%) patients achieved pCR compared with five of 27 (18%) for T4 cancers. The overall tumor downstaging rate was 80% in both arms of the study and is listed in Table 3.

    Toxicity

    In general, the treatment was well tolerated in both arms of the study; 90% of patients completed the planned course of treatment as per protocol. There was one death in each arm attributed to complications of protocol surgery. In the FU plus RT arm 1, 11 of 50 (22%) patients had a delay in RT ranging from 2 to 22 days. On the FU plus RT plus irinotecan arm 2, 24 of 53 (45%) patients had a delay in RT ranging from 2 to 21 days. Chemotherapy and acute RT toxicity (grade  3) was reported for 42% (20 of 47) of arm 1 patients and 51% (26 of 51) of arm 2 patients. Selected acute toxicities are shown in Table 4. The GI toxicity was slightly higher in arm 2 compared with arm 1. Similarly, late toxicity, listed in Table 5, was reported in 4% (two of 45) of arm 1 patients and 8% (four of 50) in arm 2 patients. The worst toxicities are listed in Table 6. The worst overall toxicity grade  3 was slightly higher in arm 2 than in arm 1 (54% v 42%, respectively).

    DISCUSSION

    Historically, preoperative RT for the treatment of locally advanced rectal cancer has been used primarily for its ability to downstage disease and allow for surgical resection in marginally resectable or unresectable cancers. Several randomized studies undertaken in the 1980s had shown that although preoperative RT can cause tumor shrinkage and some improvement in local control of disease after surgery, there was no clear benefit in terms of survival of patients.7-10 Many of these studies have used moderate to low doses of RT to avoid surgery-related complications. More recently, however, studies in Europe have shown that preoperative RT can not only improve local control of disease but also survival of patients in both early and late stages of the disease.5,6 Significant pathologic downstaging of disease has been observed, with CR rates between 5% and 30%. However, the rate of distant metastasis still remains high, and this has led to the incorporation of systemic chemotherapy into many neoadjuvant treatment programs.

    Combined chemotherapy and RT has become well established in the postoperative adjuvant treatment of rectal cancer. The addition of concurrent FU not only enhances the effect of RT in decreasing local recurrence, but also leads to a decrease in the incidence of distant metastasis and improvement in overall survival in patients with stage II and III cancers.2,3 The synergistic effects of FU and RT are well established in in vitro studies and in animal models.20-22

    The combined use of FU and RT has become routine in the treatment of a variety of GI malignancies; however, strategies for optimally combining FU and RT continue to evolve. Initially, FU was administered as a bolus intravenous weekly injection and subsequently evolved into continuous, short, 3- to 5-day intravenous infusions given concurrent with RT during the first and last weeks of treatment. Recent Intergroup data suggest that prolonged low-dose CVI FU at 225 mg/m2/d for the duration of the RT treatment (5 to 6 weeks) seems to yield the best results both in terms of lower toxicity and improved efficacy.23

    These findings have been extrapolated to the use of CVI FU in the neoadjuvant setting for the treatment of rectal cancer as well. Several authors have reported a significantly greater downstaging of disease with the addition of chemotherapy.24-26 Chan et al27 reported a downstaging rate of 68% (pathologic T0-2) in patients with initially tethered or fixed (clinical T3-4) cancers treated with FU at the beginning and end of treatment and RT to a dose of 50.4 Gy. Using protracted venous infusion of 300 mg/m2 of FU for 5 days a week for 5 weeks together with an RT dose of 45 Gy, Rich et al25 reported a downstaging rate of 64% (pT0 or T1-2) for clinical uT3 cancers. Mohiuddin et al26 reported downstaging in 78% of patients with advanced T3-T4 cancers treated with RT doses of 55 to 60 Gy and CVI FU 225 mg/m2 7 days a week for 6 weeks. Recent reports suggest that with improved tumor downstaging, a significant proportion of patients have CR of disease; 10% to 30% of patients have no evidence of residual cancer at the time of surgery.25-32

    However, the addition of chemotherapy to RT has also caused enhanced GI, mucosal, and hematologic toxicities. Several authors have reported GI toxicity ranging from 21% to 44% (grade  3) with combined-modality treatment. The question therefore remains whether the price of enhanced toxicity is worth the increased tumor downstaging and pCR observed with combined-modality treatment.

    Recent reports show that improved downstaging of cancer after neoadjuvant therapy also leads to improved survival of patients. Mohiuddin et al28 found that patients downstaged to pT0 or T1-T2 tumors had a 5-year survival of 100% compared with 78% in patients who remain T3 or N positive after neoadjuvant therapy. Similar results have also been reported by Roh,30 Kaminsky-Forrett,31 and Valentini.32 Several recent reports also show that RT dose is a significant factor in the degree of downstaging of disease. Mohiuddin et al26 found that patients treated to a dose of  50 Gy even in the presence of chemotherapy had a downstaging rate of 67% and a pCR rate of 3%, compared with a downstaging rate of 89% and a pCR rate of 45% at doses of  55 Gy (P =.05). Similarly in a subsequent analysis of the patients, they found that patients treated with hyperfractionated RT plus CVI FU had a higher incidence of pCR compared with patients treated with once-daily fractionation. Hyperfractionated RT may have allowed for greater sensitization with a CVI FU schedule.

    Meanwhile, several new drugs have been found to be effective in the treatment of colorectal cancer.33,34 Irinotecan has been found to be effective in FU-refractory patients and in combination with FU has been shown to double the response rate in metastatic disease.33 Mitchell et al35 used combined irinotecan plus FU with RT as neoadjuvant treatment and reported a pCR rate of 25% with conventional RT dose fractionation.

    The Radiation Therapy Oncology Group therefore undertook a randomized study to assess the effectiveness of a RT dose-intensification approach (55 to 60 Gy) using a hyperfractionated RT schedule with CVI FU and compared it with a chemotherapy dose-intensification approach using two drugs, irinotecan and FU, with conventional once-daily RT (50 to 54 Gy). The end points of the study were to determine both the pCR rate and the potential GI, hematologic, and other toxicities of the individual treatments. Results of the study indicate that the rate of tumor downstaging is high (80%) with either RT dose intensification or with chemotherapy dose-intensification. Patients treated in arm 1 received a dose of 55.6 Gy for T3 cancers and 60 Gy for T4 cancers, which are considerably higher than doses that have been used in most studies with neoadjuvant therapy. However, this did not result in compromise of tumor respectability or in higher surgical or wound complications. The pCR rate of 28% in this study with either RT or chemotherapy dose intensification seems higher than most other institutional studies and may be due to the more moderate dose (45 to 50.4 Gy) used in these studies. Overall acute toxicity of treatment, which was similar in both arms of the study, seems to compare favorably with other reports (15% to 40%). The late toxicity of 6% seen in this study seemed to be considerably lower than that reported in other studies. The pCR for T3 tumors in the study was 33%, and seems better than the 18% response seen in T4 tumors. This may be related to tumor volume and would therefore suggest a dose/volume response, which may indicate the need for further dose escalation with either additional RT or chemotherapy intensification using new drugs such as oxaliplatin or a molecular targeted agent for the T4 cancers.

    In summary, neoadjuvant chemoradiation for rectal cancer seems to be safe, with an acceptable rate of acute toxicity during the course of treatment and a low incidence of late toxicity. The rate of tumor downstaging is high (80%) and a complete pCR rate of 28% is achievable with either RT or chemotherapy dose intensification. The outcome of the current trial with regard to tolerance, pCR, and downstaging would be an acceptable baseline for comparison with similar outcomes in treatment arms of future neoadjuvant trials for patients with T3 rectal cancer. For T4 cancers, additional dose escalation should be considered to improve results.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Collection and assembly of data: Mohammed Mohiuddin, Kathryn Winter, Edith Mitchell, Nader Hanna, Albert Yuen, Charles Nichols, Robert Shane, Cherie Hayostek, Christopher Willett

    Data analysis and interpretation: Mohammed Mohiuddin, Kathryn Winter, Edith Mitchell, Nader Hanna, Albert Yuen, Charles Nichols, Robert Shane, Cherie Hayostek, Christopher Willett

    Manuscript writing: Mohammed Mohiuddin, Kathryn Winter, Edith Mitchell, Nader Hanna, Albert Yuen, Charles Nichols, Robert Shane, Cherie Hayostek, Christopher Willett

    Final approval of manuscript: Mohammed Mohiuddin, Kathryn Winter, Edith Mitchell, Nader Hanna, Albert Yuen, Charles Nichols, Robert Shane, Cherie Hayostek, Christopher Willett

    NOTES

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

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