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Combined-Modality Therapy of Rectal Cancer with Oxaliplatin-Based Regimens
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Combined-Modality Therapy of Rectal Cancer with Oxaliplatin-Based Regimens Bruce D. Minsky Abstract There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates.There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation. Clinical Colorectal Cancer, Vol. 4, Suppl. 1, S29-S36, 2004 Key words: Chemotherapy, Clinical assessment, Multimodality therapy, Preoperative therapy, Radiation therapy, Sphincter preservation
Introduction There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy.1 The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is uT3/4 and/or node-positive.2
Postoperative Therapy Rationale and Results The National Cancer Institute Consensus Conference concluded in 1990 that combined modality therapy was the standard postoperative adjuvant treatment for patients with T3 and/or N1/2 disease.1 Pelvic radiation therapy decreases local recurrence but does not improve survival. As would be predicted, randomized data do not reveal a survival advantage of pelvic radiation plus elective paraaortic and liver radiation versus pelvic radiation alone.3 Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY Submitted: Nov 6, 2003; Revised: Dec 17, 2003; Accepted: Dec 19, 2003 Address for correspondence: Bruce D. Minsky, MD, Memorial Sloan-Kettering Cancer Center, 127 York Ave, New York, NY 10021-6007 Fax: 212-639-8876; e-mail: [email protected]
The standard design is to deliver 6 cycles of chemotherapy with concurrent radiation during cycles 3 and 4. A randomized trial by Lee et al suggests that radiation should start with cycle 1 rather than cycle 3.4 Although an interesting result, since a number of patients did not receive the treatment arm they were randomized to, further data are needed before recommending a change in sequence. For patients treated with postoperative combined modality therapy and received 5-fluorouracil (5-FU) as a single agent, there was a 10% survival advantage with continuous infusion (CI) 5-FU versus bolus 5-FU.5 The Intergroup (INT 0144) postoperative adjuvant rectal trial reported results at the 39th Annual Meeting of American Society of Clinical Oncology in 2003.6 Patients were randomized to 3 arms. Patients in arm 1 were treated with bolus 5-FU followed by CI 5-FU/radiation therapy (RT) followed by bolus 5-FU. Patients in arm 2 were treated with CI 5-FU followed by CI 5-FU/RT followed by CI 5-FU. Patients in arm 3 were treated with bolus 5-FU/leucovorin (LV)/levamisole followed by bolus 5-FU/LV/levamisole plus RT followed by bolus 5-FU/LV/levamisole. There was a significant decrease in hematologic toxicity of grade ≥ 3 in arm 2; however, there was no significant difference in 3-year survival. Local control data were not reported. Given these results, CI 5-FU with radiation is recommended and either arm 1 or 2 is a reasonable choice. If arm 1 (bolus) is chosen, the chemotherapy-alone segments should be either the Roswell Park (weekly) or the Mayo Clinic regimen (monthly).
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Multimodality Therapy with Oxaliplatin for Rectal Cancer The INT 0114 trial revealed that with longer follow-up the results are not as favorable.7 With a median follow-up of 7.4 years, the 7-year local failure rate was 17% and the survival rate 56%. Patients with high-risk disease (T3 N+ or T4) have lower survival compared with lower-risk disease (T1 N2+ or T3 N0; 45% vs. 70%). Associated with this improvement in local control and survival with postoperative combined modality therapy is an increase in acute toxicity. For example, the incidence of ≥ grade 3 toxicity in the combined modality arms of the Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group (NCCTG) 79-47-51 trials was 25%-50%. Furthermore, the percentages of patients finishing the prescribed 6 cycles of chemotherapy in those trials were only 65% and 50%, respectively. Retrospective data suggest that the acute toxicity with preoperative combined modality therapy may be less than in the postoperative setting8 and sphincter preservation is increased with preoperative therapy.9 These advantages have been confirmed in the German Rectal Cancer Study CAO/ARO/AIO 94 randomized trial of preoperative versus postoperative combined modality therapy.10 The questions of whether preoperative combined modality therapy is more effective than preoperative RT and whether the postoperative chemotherapy component is necessary are being addressed in the recently completed randomized European Organization for Research and Treatment of Cancer trial 22921 and the results are pending.
Patients Who Do Not Require Postoperative Adjuvant Therapy Retrospective data suggest that there may be a subset of patients with T3 N0 disease who may not require adjuvant therapy, as well as patients with stage I disease who should be considered for adjuvant therapy. Retrospective trials examining patients at the Massachusetts General Hospital11 and the Memorial Sloan-Kettering Cancer Center12 have identified favorable subsets of patients with T3 N0 disease who, following surgery alone, had a 10-year actuarial local recurrence rate of < 10%. In addition to other modifications, such as staging smooth nodules in the fat as node-positive and irregular nodules as vascular invasion (VI = microscopic and VI2 = macroscopic), the 6th edition of the American Joint Committee on Cancer staging system subdivides stage III into IIIA (T1/2 N1), IIIB (T3/4 N1), and IIIC (T N2).13 The prognostic validity of this change was supported by both the pooled analysis of the Intergroup and National Surgical Adjuvant Breast and Bowel Project (NSABP) postoperative trials14 and the retrospective analysis of the American College of Surgeons National Cancer Data Base (NCDB).15 The 5-year survival rates by stages IIIA, B, and C in the pooled analysis were 81%, 57%, and 49%, respectively, and in the NCDB database 55%, 35%, and 25%, respectively. Although based on 5-year survival data, radiation does not improve the results of chemotherapy alone in stages T3 N0, T1/2 N1 disease, local control data are needed before recommending chemotherapy alone for this subset of
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patients. If the local control rate without radiation are acceptable, then patients with upper rectal cancers who undergo a total mesorectal excision, have ≥ 12 nodes examined, and have stages T3 N0, T1/2 N1 disease likely do not need radiation therapy.
Preoperative Therapy Rationale Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiation sensitivity because of more oxygenated cells, and enhanced sphincter preservation.2 The primary disadvantage of preoperative radiation therapy is possibly overtreating patients with either early-stage or undetected metastatic disease. In the German CAO/ARO/AIO 94 trial, which used computed tomography and transrectal ultrasound, 18% of patients were overstaged.10 There are 12 modern randomized trials of preoperative radiation therapy (without chemotherapy) for clinically resectable rectal cancer.2 All use low to moderate doses of radiation. Overall, most of the trials showed a decrease in local recurrence, and in 5 of the trials this difference reached statistical significance. Although in some trials a subset analysis has revealed a significant improvement in survival, the Swedish Rectal Cancer Trial is the only one that reported a survival advantage for the total treatment group. Two metaanalyses reported conflicting results. While both reveal a decrease in local recurrence, the analysis by Camma et al16 reported a survival advantage, whereas the analysis by the Colorectal Cancer Collaborative Group17 did not.
Intensive Short-Course Preoperative Radiation The Swedish Rectal Cancer Trial is the only randomized trial of preoperative radiation therapy to report a significant improvement in survival. Patients with clinically resectable (T1-3) rectal cancer were randomized to receive 25 Gy in 1 week followed by surgery 1 week later versus surgery alone.18 Those who received preoperative radiation had a significant decrease in local recurrence (12% vs. 27%) and a corresponding significant improvement in 5-year survival (58% vs. 48%). It is important to analyze these positive results in context with the remainder of the literature. First, given that the other 11 randomized trials of preoperative radiation therapy do not report a survival benefit, these data clearly need to be confirmed by additional studies. The most recent trial to report results was the Dutch CKVO 95-04 trial, which randomized 1805 patients with clinically resectable (T1-3) disease to surgery alone (with a total mesorectal excision [TME]) or intensive short-course preoperative radiation therapy followed by TME.19 Although radiation significantly decreased local recurrence (8% vs. 2%), there was no dif-
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Bruce D. Minsky ference in 2-year survival (82%). With longer follow-up, 5year local failure was higher with TME (12%); however, it was still significantly decreased to 6% with preoperative radiation therapy.20 Second, even if future trials confirm a survival benefit, there are other equally important endpoints in rectal cancer that need to be addressed. These include acute toxicity, sphincter preservation and function, and quality of life (QOL). For example, acute toxicity in the Dutch CKVO 95-04 trial included 10% neurotoxicity, 29% perineal wound complications, and 12% postoperative leaks.21 In the patients who developed postoperative leaks, 80% required surgery resulting in 11% mortality. The presence of a positive circumferential margin is an important negative prognostic sign. In the Dutch CKVO trial, 17% had positive circumferential margins. In this subset, they received 50 Gy postoperatively. Postoperative radiation did not compensate for positive margins.22 Unfortunately, few centers in the United States performed the necessary pathologic examination to detect positive circumferential margins. Data from Beets-Tan et al suggest that preoperative magnetic resonance imaging (MRI) can identify patients who will have positive margins and can be used to better select patients for preoperative therapy.23 It is not possible to accurately compare the local control and survival results of intensive short-course radiation with conventional preoperative combined modality therapy. This is due to selection bias in favor of the series using intensive short-course radiation. The conventional preoperative combined modality therapy regimens are limited to patients with clinical T3 disease, whereas most trials that use intensive short course preoperative radiation include patients with clinical T1-3 disease.
Sphincter Preservation with Preoperative Radiation A major goal of preoperative therapy is sphincter preservation. From the viewpoint of sphincter preservation, the advantage of preoperative therapy is to decrease the volume of the primary tumor. When the tumor is located in close proximity to the dentate line, this decrease in tumor volume may allow the surgeon to perform a sphincter-conserving procedure that would not otherwise be possible. However, if the tumor directly invades the anal sphincter, sphincter preservation is unlikely even when a complete response is achieved. One of the most important controversies with preoperative therapy is whether the degree of downstaging is adequate to enhance sphincter preservation. Furthermore, if preoperative radiation therapy is effective, what regimen (intensive short course versus conventional course) is preferred? An analysis of 1316 patients treated on 2 previously published Scandinavian trials of intensive short course of radiation revealed that downstaging was most pronounced when the interval between the completion of radiation and surgery was ≥ 10 days.24 In the Dutch CKVO 95-04 trial, where the interval was 1 week, there was no downstaging.25 None of the other randomized trials of preoperative intensive short-course radiation address the issue of sphincter preservation, and it is not an endpoint of the trials.
When the goal of preoperative therapy is sphincter preservation, conventional doses and techniques of radiation are recommended. These include multiple field techniques to a total dose of 45-50.4 Gy at 1.8 Gy/fraction. Surgery should be performed 4-7 weeks following the completion of radiation. Unlike the intensive short-course radiation regimen, this conventional design allows for 2 important events to occur. First is the recovery from the acute side effects of radiation and second is the allowance of adequate time for tumor downstaging. Data from the Lyon R90-01 trial of preoperative radiation suggest that an interval > 2 weeks following the completion of radiation increases the chance of downstaging.26 Whether increasing the interval between the end of intensive short-course radiation and surgery to ≥ 4 weeks will increase downstaging is not known. This question is being addressed in an ongoing randomized trial from Sweden, the Stockholm III trial.
Preoperative Prospective Clinical Assessment The most accurate method of determining whether preoperative therapy increases sphincter preservation is to perform a prospective clinical assessment. In this setting, the operating surgeon examines the patient prior to the start of preoperative therapy and declares the type of operation required. It should be noted that this assessment is based on an office examination and may not accurately reflect the assessment when the patient is relaxed under general anesthesia. The only method by which to account for this potential bias is to perform a randomized trial of preoperative versus postoperative therapy. The German CAO/ARO/AIO 94 randomized trial of preoperative versus postoperative combined modality therapy, which was stratified by a surgeon, reported that this assessment is accurate in 80% of patients.10
Clinical Experience with Sphincter Preservation Eight nonrandomized trials reported results in patients with clinically resectable rectal cancer who underwent a prospective clinical assessment by a surgeon prior to the start of preoperative therapy and were declared to need an abdominoperineal resection (APR). All used conventional doses and techniques of radiation therapy. Three used radiation therapy alone,9,26,27 and 4 used combined modality therapy.28-32 The incidence of sphincter preservation is only 23% in the NSABP series28 and 44% in the Lyon series.26 In the remaining 5 series it is approximately 70%. A valid concern of surgeons is that in order to perform sphincter preservation in those patients who would otherwise require an APR, the distal resection margin may be suboptimal (≤ 1 cm). Can preoperative therapy compensate for this? Retrospective data from Moore et al reveal that with preoperative combined modality therapy the 3-year local control rates were similar regardless of whether the margins were > 2 cm, < 2 cm, > 1 cm, or < 1 cm, providing they were negative.33 Sphincter preservation without good function is of questionable benefit. In a series of 73 patients who underwent sur-
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Multimodality Therapy with Oxaliplatin for Rectal Cancer gery, Grumann and associates reported that the 23 patients who had an APR had a more favorable QOL compared with the 50 who underwent a low anterior resection.34 Although preoperative combined modality therapy may adversely affect sphincter function, the impact is most likely less than postoperative combined modality therapy.35 In 4 of the 8 preoperative series discussed previously that report functional outcome, the majority (approximately 75%) have good to excellent sphincter outcome. Functional results continue to improve up to 1 year after surgery.
Randomized Trials Four randomized trials of preoperative versus postoperative therapy for clinically resectable rectal cancer have been performed. The Uppsala trial used intensive short-course radiation (preoperative 25.5 Gy in 5 fractions) versus postoperative conventional course 60 Gy.36 The preoperative arm revealed a significant decrease in local failure (13% vs. 22%) but no difference in survival (42% vs. 38%). The other 3 randomized trials were limited to patients with T3/4 disease, used conventional doses and techniques of radiation therapy and concurrent 5-FUbased chemotherapy, and required a preoperative clinical assessment declaring the type of operation required. Two are from the United States (INT 0147, NSABP R0-3) and 1 from Germany (CAO/ARO/AIO 94). Unfortunately, low accrual resulted in early closure of both the NSABP R-03 and INT 0147 trials. A preliminary report of the NSABP R-03 trial (with a median follow-up of only 1 year) revealed that the percent of patients who underwent sphincter-sparing surgery and were without evidence of disease was higher in the preoperative versus the postoperative arm (44% vs. 34%).37 The German CAO/ARO/AIO 94 trial completed the planned accrual of over 800 patients and randomized patients with ultrasound-staged T3/4 and/or node-positive rectal cancers ≤ 16 cm from the anal verge to preoperative radiation plus CI 5-FU followed by surgery and postoperative bolus 5FU/LV versus the same regimen postoperatively.10 In order to help remove surgical bias, patients were stratified by surgeon. Compared with postoperative combined modality therapy, patients who receive preoperative therapy had a significant decrease in local failure (6% vs. 12%, P = 0.006), acute toxicity (28% vs. 40%, P = 0.005), chronic toxicity (10% vs. 23%, P = 0.04), and in those 194 patients judged by the surgeon to require and APR, a significant increase in sphincter preservation (39% vs. 20%, P = 0.004). With a median follow-up of 40 months there was no difference in 5-year survival (74%). Given the improved local control, acute and long-term toxicity profile, and sphincter preservation reported in the German trial, patients with T3 rectal cancer who require combined modality therapy should receive it preoperatively. However, data from the NCDB15 and the Intergroup pooled analysis14 suggest that patients with N0 tumors may not require postoperative pelvic radiation. In the German CAO/ARO/AIO 94 trial, 18% of patients who were clinically staged as uT3/4 and/or node-positive preoperatively and underwent surgery without preoperative therapy were pT1/2 N0. Therefore, those
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patients would have been overtreated if they had received preoperative therapy. Although pretreatment MRI can help predict patients who may have positive circumferential margins,23,38 neither MRI or any other imaging modality or clinicopathologic factor can accurately identify patients with N+ disease. As preoperative therapy gains acceptance, the development of more accurate imaging techniques and molecular markers to identify N+ disease are necessary.
Predicting the Response of the Primary Tumor Although some series show no correlation,39,40 most series suggest that there is improved outcome with increasing pathologic response to preoperative therapy.41-47 Analysis of biopsies examining selected molecular markers such as c-K-ras,48 thymidylate synthase,49 p27kip1,50 p53,51-54 apoptosis,55,56 DCC,54 EGFR,57 TP53,52 and Ki-6758 have had varying success in helping to select patients who may best respond to preoperative therapy. Since all of the studies are limited retrospective trials and most did not examine multiple markers, at this time the need for adjuvant therapy should still be based solely on T and N stage. Fortunately, the new Intergroup rectal trials will prospectively collect tissues for these and other markers. In the future, molecular markers may help predict patients with lymph node–positive disease.
Novel Combined-Modality Regimen A number of new chemotherapeutic agents have been developed for the treatment of patients with colorectal cancer (CRC). Phase I/II trials are examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting. Selected agents include uracil and tegafur (UFT),59 raltitrexed,60 oxaliplatin,61-68 irinotecan,69,70 gefitinib,71 and capecitabine72 with pelvic radiation therapy. Clinical trials of combined modality therapy in combination with novel targeted agents such as with bevacizumab and cetuximab are under development. 73 Phase III trials are needed to determine whether these regimens offer an advantage compared with 5-FU– based combined modality therapy regimens.
Oxaliplatin-Based Regimens Based on the in vitro evidence of radiation sensitization with oxaliplatin74 as well as the survival advantage of oxaliplatinbased chemotherapy in patients with metastatic CRC75-77 there is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. A number of phase I/II trials combining oxaliplatin with radiation therapy have been reported. As seen in Table 1, most have used concurrent oxaliplatin, pelvic radiation therapy, and either bolus 5-FU,61 CI 5-FU,62-68,78 or capecitibine.63,79,80 One trial used raltitrexed81 and another used UFT.82 Induction FOLFOX followed by combined radiation plus capecitibine83 or tegafur84 has also been reported (Table 2). Most were phase I trials and the dose of oxaliplatin was escalated. The recommended dose level of oxaliplatin and,
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Bruce D. Minsky Table 1
Concurrent Oxaliplatin-Based Preoperative Combined-Modality Therapy Regimens Patients Treated at RDL
Regimen*
Grade ≥ 3 Toxicity
pCR
25
Oxaliplatin 130 mg/m2, days 1,19, 38 Tomudex 3 mg/m2 45 Gy radiation + 5.4 Gy boost
20% (Total)
38%
20
Oxaliplatin 130 mg/m2, days 2, 30 5-FU bolus 350 mg/m2 and LV 20 mg/m2, days 1-5, 29-33 45 Gy radiation
33% (Diarrhea)
14%
Gerard et al62 Phase II
40
Oxaliplatin 130 mg/m2 days 1, 29 CI 5-FU 350 mg/m2 days 1-5, 29-33 LV 100 mg/m2 days 1, 29 50 Gy radiation + 1 Gy weekly boost
18% (Total)
15%
Landry et al63,78 Phase I
6
Oxaliplatin 85 mg/m2, days 1, 15, 29 CI 5-FU 225 mg/m2 daily
–
58%†
Rodel et al79 Phase II
26
Oxaliplatin 50 mg/m2 days 1, 8, 22, 29 Capecitabine 825 mg/m2 days 1-14, 22-35 50.4 Gy radiation
8% (Diarrhea and skin)
19%
Aschele et al64 Phase I
18
Oxaliplatin 60 mg/m2 weekly CI 5-FU 225 mg/m2 daily 50.4 Gy radiation
13% Diarrhea
29%
Ngan et al65 Phase I
7
Oxaliplatin 85 mg/m2 weeks 1, 3, 5 CI 5-FU 200 mg/m2, days 1-5 weekly 50.4 Gy radiation
–
–
Glynne-Jones et al80 Phase I
6
Oxaliplatin 130 mg/m2, days 1, 29 Capecitabine 650 mg/m2 twice a day, daily 45 Gy radiation
17% Proctitis
31%
Fernandez-Martos et al82 Phase I
-
Oxaliplatin 85 mg/m2, days 1, 15, 29 UFT 450 mg/m2 days 1-5 weekly 50 Gy radiation
RDL not yet reached
–
Eric et al66 Phase I
-
Oxaliplatin 30-80 mg/m2 weekly for 5 weeks CI 5-FU 225 mg/m2 daily 45 Gy radiation
RDL not yet reached
31% (5 of 16)
22
Oxaliplatin 25 mg/m2 LV 20 mg/m2 CI 5-FU 375 mg/m2 days 1-4, weeks 1, 5, 9 Oxaliplatin 50 mg/m2 week 3
27% 1 Neutropenic death
19% (3 of 16)
6
Oxaliplatin 130 mg/m2, day 1 LV 100 mg/m2 CI 5-FU 350 mg/m2 days 1-5, weeks 1, 5 45 Gy radiation
0
25% (2 of 8)
Study/Phase Valentini et al81 Phase II
Sebag-Montefiore et al61 Phase I
Carraro et al67 Phase II
Freyer et al68 Phase I
*Recommended dose level of oxaliplatin if the trial was phase I. †Includes microscopic residual cancer. Abbreviations: CI 5-FU = continuous infusion 5-fluorouracil; LV = leucovorin; pCR = pathologic complete response; RDL = recommended dose level; UFT = uracil/tegafur
where available, the numbers of patients treated at the recommended dose level and the associated acute toxicity in these trials are listed in Table 161-68,78-82 and Table 2.83-84 Although not a randomized comparison, standard preopera-
tive regimens using radiation and bolus or continuous 5-FU alone report a 10% pathologic complete response (CR) rate,10 whereas most of the trials that add oxaliplatin report rates of ≥ 20%.85,86
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Multimodality Therapy with Oxaliplatin for Rectal Cancer Oxaliplatin-Based Neoadjuvant Chemotherapy Followed by Non–Oxaliplatin-Based Preoperative Combined-Modality Therapy
Table 2
Patients Treated at RDL
Study
7. Regimen
pCR 8.
Chau et Phase II
al83
17
Induction Capecitabine 1000 mg/m2, days 1-4 every 3 weeks Oxaliplatin 130 mg/m2, every 3 weeks
9. 29% (4 of 14)
Chemotherapy/RT Capecitabine 825 mg/m2 twice daily 50.4-54 Gy radiation Calvo et al84 Phase II
52
Induction FOLFOX4 × 2 cycles Tegafur 1200 mg/m2 daily 45-50.4 Gy radiation
10.
11.
29%
Abbreviations: FOLFOX4 = 5-fluorouracil/leucovorin/oxaliplatin; pCR = pathologic complete response; RDL = recommended dose level; RT = radiation therapy
12. 13. 14.
The ideal oxaliplatin-based preoperative combined modality regimen has not been determined. The preliminary data reveal encouraging high CR rates following preoperative therapy. However, it should be emphasized that the higher CR rates need to be confirmed in randomized trials. Given the advantage of CI versus bolus 5-FU in the Mayo/NCCTG 86-4751 postoperative rectal adjuvant trial5 as well as in the INT 0114, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is CI 5-FU or capecitabine and pelvic radiation.
15. 16. 17. 18. 19.
Conclusion For patients with rectal cancer selected to receive combined modality therapy, it should be delivered preoperatively. Oxaliplatin-based preoperative regimens report encouraging response rates with acceptable toxicity profiles.
20.
21.
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Long term oncologic and functional results. Dis Colon Rectum 2002; 45:305-315. Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum. A progress report of the National Surgical Adjuvant Breast and Bowel Project protocol R0-3. Dis Colon Rectum 1997; 40:131-139. Valentini V, Coco C, Cellini N, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys 1998; 40:1067-1075. Grann A, Feng C, Wong D, et al. Pre-op combined modality therapy (CMT) for uT3 rectal cancer. Proc Am Soc Clin Oncol 2000; 19:249a (Abstract #967). Kuvshinoff B, Maghfoor I, Miedema B, et al. Distal margin requirements after preoperative chemoradiotherapy for distal rectal carcinomas: Are < 1 cm distal margins sufficient? Ann Surg Oncol 2001; 8:163-169. Mehta VK, Cho C, Ford JM, et al. Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 2003; 55:132-137. Moore HG, Riedel E, Minsky BD, et al. Adequacy of 1-cm distal margin after restorative rectal cancer resection with sharp mesorectal excision and preoperative combined modality therapy. Ann Surg Oncol 2003; 10:80-85. Grumann MM, Noack EM, Hoffman IA, et al. Comparison of quality of life in patients undergoing abdominoperineal extirpation or anterior resection for rectal cancer. Ann Surg 2001; 233:149-156. Kollmorgen CF, Meagher AP, Pemberton JH, et al. The long term effect of adjuvant postoperative chemoradiotherapy for rectal cancer on bowel function. Ann Surg 1994; 220:676-682. Pahlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: Report from a randomized multicenter trial. Ann Surg 1990; 211:187-195. Roh MS, Petrelli N, Weiand H, et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABP R-03). Proc Am Soc Clin Oncol 2001; 20:123a (Abstract #490). Beets-Tan RGH, Beets GL: Rectal cancer: how accurate can imaging predict the T stage and the circumferential resection margin? Int J Colorec Dis 2003; 18:385-391. Onaitis MW, Noone RB, Fields R, et al. Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival. Ann Surg Oncol 2001; 8:801-806. Stein DE, Mahmoud NN, Anne PR, et al. Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma. Dis Colon Rectum 2003; 46:448-453. Janjan NA, Crane C, Feig BW, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001; 24:107-112. Mohiuddin M, Hayne M, Regine WF, et al. Prognostic significance of postchemoradiation stage following preoperative chemotherapy and radiation for advanced/recurrent rectal cancers. Int J Radiat Oncol Biol Phys 2000; 48:1075-1080. Read TE, Ogunbiyi OA, Fleshman JW, et al. Neoadjuvant external beam radiation and proctectomy for adenocarcinoma of the rectum. Dis Colon Rectum 2001; 44:1778-1790. Hiotis SP, Weber SM, Cohen AM, et al. Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg 2002; 194:131-136. Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, et al. A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum 2003; 46:298-304. Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg 2002; 236:75-81. Valentini V, Coco C, Picciocchi A, et al. Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long term analysis of 165
patients. Int J Radiat Oncol Biol Phys 2002; 53:664-674. 48. Luna-Perez P, Segura J, Alvarado I, et al. Specific c-K-ras gene mutations as a tumor-response marker in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Ann Surg Oncol 2000; 7:727-731. 49. Villafranca E, Okruzhnov Y, Dominguez MA, et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001; 19:1779-1786. 50. Esposito G, Pucciarelli S, Alaggio R, et al. p27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer. Ann Surg Oncol 2001; 8:311-318. 51. Elsaleh H, Robbins P, Joseph D, et al. Can p53 alterations be used to predict tumor response to pre-operative chemo-radiotherapy in locally advanced rectal cancer? Radiother Oncol 2000; 56:239-244. 52. Kandioler D, Zwrtek R, Ludwig C, et al. TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer. Ann Surg 2002; 235:493498. 53. Schwander O, Bruce HP, Broll R. p21, p27, cyclin D1, and p53 in rectal cancer: immunohistology with prognostic significance? Int J Colorec Dis 2002; 17:11-19. 54. Saw RPM, Morgan M, Koorey D, et al. p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 2003; 46:192-202. 55. Adell GCE, Zhang H, Evertsson S, et al. Apoptosis in rectal cancer. Prognosis and recurrence after preoperative radiotherapy. Cancer 2001; 91:1870-1875. 56. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 2002; 52:294-303. 57. Giralt J, Eraso A, Armengol M, et al. Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2002; 54:1460-1465. 58. Adell G, Zhang H, Jansson A, et al. Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys 2001; 50:659-663. 59. Fernandez-Martos C, Aparicio J, Bosch C, et al. Preoperative therapy (PT) with oral uracil and tegafur (UFT) and concomitant irradiation (RT) in operable rectal cancer (RC). Preliminary results of a multicenter phase II study. Proc Am Soc Clin Oncol 2001; 20:148a (Abstract #590). 60. James RD, Botwood N, Vernon CC, et al. Raltitrexed plus radiotherapy for the treatment of unresectable/recurrent rectal cancer: a phase I study. Ann Oncol 2003; 14:570-573. 61. Sebag-Montefiore D, Glynne-Jones R, Falk S, et al. Preoperative radiation and oxaliplatin in combination with 5-fluorouracil (5-FU) and low-dose leucovorin (LV) in locally advanced rectal cancer. Proc Am Soc Clin Oncol 2002; 21:146a (Abstract #580). 62. Gerard JP, Chapet O, Nemoz C, et al. Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with highdose radiation and oxaliplatin-containing regimen: yhe Lyon R0-04 phase II trial. J Clin Oncol 2003; 21:1119-1124. 63. Rosenthal DI, Catalano P, Haller DG, et al. ECOG 1297: a phase I study of preoperative radiation therapy (RT) with concurrent protracted continuous infusion 5-FU and dose escalating oxaliplatin followed by surgery, adjuvant 5-FU, and leucovorin for locally advanced (T3/4) rectal adenocarcinoma. Proc Am Soc Clin Oncol 2003; 22:273 (Abstract #1094). 64. Aschele C, Friso ML, Pucciarelli S, et al. A phase I-II study of weekly oxaliplatin (OXA) 5-fluorouracil (FU) continuous infusion (CI) and preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC). Proc Am Soc Clin Oncol 2002; 21:132a (Abstract #527). 65. Ngan S, Rischin D, Michael M, et al. A phase I trial of radiotherapy, oxaliplatin and infusional 5-fluorouracil (5FU) for patients with rectal cancer not suitable for curative resection. Proc Am Soc Clin Oncol 2003; 22:291 (Abstract #1169). 66. Eric F, Marc Y, Michel D, et al. A phase I study of 5-fluorouracil continuous infusion (5FU CI), weekly oxaliplatin (OXA) and ra-
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diotherapy (RT) in advanced rectal cancer. Proc Am Soc Clin Oncol 2003; 22:344 (Abstract #1381). Carraro S, Roca EL, Cartelli C, et al. Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: A Phase II IATTGI study. Int J Radiat Oncol Biol Phys 2002; 54:397-402. Freyer G, Bossard N, Romestaing P, et al. Addition of oxaliplatin to continuous infusion fluorouracil, l-folinic acid, and concomitant radiotherapy in rectal cancer: the Lyon R 97-03 phase I trial. J Clin Oncol 2001; 19:2433-2438. Levine EL, Gollins S, Susnerwala S, et al. Phase I/II study of irinotecan (CPT-11), 5-fluorouracil and concurrent radiotherapy for the treatment of T3-T4 locally advanced inoperable rectal cancer. Proc Am Soc Clin Oncol 2003; 22:345 (Abstract #1384). Mitchell EP, Anne PR, Fry RD, et al. Chemoradiation with CPT-11, 5FU, in neoadjuvant treatment of locally advanced or recurrent adenocarcinoma of the rectum: a phase I/II study update. Proc Am Soc Clin Oncol 2003; 22:262 (Abstract #1052). Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20:1512-1521. Dunst J, Reese T, Hoelscher T, et al. Capecitabine combined with radiotherapy as neoadjuvant treatment of locally advanced rectal cancer. Proc Am Soc Clin Oncol 2003;22:277 (Abstract #1113). Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 2003; 22:252 (Abstract #1012). Blackstock AW, Hess S, Chaney S: Oxaliplatin: in vitro evidence of its radiation sensitizing activity - pre-clinical observations relevant to clinical trials. Int J Radiat Oncol Biol Phys 1999; 45:S253. Goldberg RM, Morton RF, Sargent DJ, et al. N9741: Oxaliplatin (Oxal) or CPT-11 + 5-fluorouracil (5-FU)/Leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life. Proc Am Soc Clin Oncol 2003; 22:252 (Abstract #1009). Rothenberg MA, Oza A, Burger B, et al. Final results of a phase III trial of 5-FU/leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal cancer following irinotecan. Proc Am Soc Clin Oncol 2003; 22:252 (Abstract #1011). Rothenberg MA, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy
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78.
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alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21:2059-2069. Landry JC, Rosenthal D, Spitz FR, et al. ECOG 1297: A phase I study of preoperative radiation therapy (RT) with concurrent protracted continuous infusion 5-FU and dose escalating oxaliplatin followed by surgery, adjuvant 5-FU, and leucovorin for locally advanced (T3/4) rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 2003; 57:S179. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003; 21:3098-3104. Glynne-Jones R, Sebag-Montefiore D, McDonald A, et al. A phase I study of preoperative radiation and capecitabine in combination with oxaliplatin in locally advanced rectal cancer. Proc Am Soc Clin Oncol 2003; 22:292 (Abstract #1174). Valentini V, Morganti AG, Gambacorta MA, et al. Raltitrexed (Tomudex) and oxaliplatin (Tomox) preliminary results of a phase II study of chemoradiation with preoperative treatment of stage II/III resectable rectal cancer. Proc Am Soc Clin Oncol 2002; 21:151a (Abstract #603). Fernandez-Martos C, Aparicio J, Bosch C, et al. Combined modality treatment with oxaliplatin, oral uracil and tegafur (UFT) and concomitant irradiation (RT) in rectal cancer. A dose finding study. Proc Am Soc Clin Oncol 2003; 22:322 (Abstract #1293). Chau I, Cunningham D, Tait D, et al. Twelve weeks of neoadjuvant capecitabine (cap) and oxaliplatin (ox) followed by synchronous chemoradiation (CRT) and total mesorectal excision (TME) in MRI defined poor risk locally advanced rectal cancer resulted in promising tumor regression and rapid symptomatic relief. Proc Am Soc Clin Oncol 2003; 22:271 (Abstract #1087). Calvo FA, Serrano F, Gomez-Espi M, et al. Induction oxaliplatin + 5-FU improves further the incidence of pT0 downstaged surgical specimens in > cT3 rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2003; 57:S178. Klautke G, Kirchner R, Hopt U, et al. Continuous infusion of 5-FU and weekly irinotecan with concurrent radiotherapy as neoadjuvant treatment for locally advanced or recurrent rectal cancer. Proc Am Soc Clin Oncol 2001; 20:140a (Abstract #555). Mitchell EP, Anne P, Fry R, et al. Combined modality therapy of locally advanced or recurrent adenocarcinoma of the rectum: report of a phase I trial of chemotherapy (CT) with CPT-11, 5-FU and concomitant irradiation (RT). Proc Am Soc Clin Oncol 2001; 20:131a (Abstract #519).
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Combined-Modality Therapy of Rectal Cancer with Oxaliplatin-Based Regimens Bruce D. Minsky Abstract There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates.There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation. Clinical Colorectal Cancer, Vol. 4, Suppl. 1, S29-S36, 2004 Key words: Chemotherapy, Clinical assessment, Multimodality therapy, Preoperative therapy, Radiation therapy, Sphincter preservation
Introduction There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy.1 The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is uT3/4 and/or node-positive.2
Postoperative Therapy Rationale and Results The National Cancer Institute Consensus Conference concluded in 1990 that combined modality therapy was the standard postoperative adjuvant treatment for patients with T3 and/or N1/2 disease.1 Pelvic radiation therapy decreases local recurrence but does not improve survival. As would be predicted, randomized data do not reveal a survival advantage of pelvic radiation plus elective paraaortic and liver radiation versus pelvic radiation alone.3 Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY Submitted: Nov 6, 2003; Revised: Dec 17, 2003; Accepted: Dec 19, 2003 Address for correspondence: Bruce D. Minsky, MD, Memorial Sloan-Kettering Cancer Center, 127 York Ave, New York, NY 10021-6007 Fax: 212-639-8876; e-mail: [email protected]
The standard design is to deliver 6 cycles of chemotherapy with concurrent radiation during cycles 3 and 4. A randomized trial by Lee et al suggests that radiation should start with cycle 1 rather than cycle 3.4 Although an interesting result, since a number of patients did not receive the treatment arm they were randomized to, further data are needed before recommending a change in sequence. For patients treated with postoperative combined modality therapy and received 5-fluorouracil (5-FU) as a single agent, there was a 10% survival advantage with continuous infusion (CI) 5-FU versus bolus 5-FU.5 The Intergroup (INT 0144) postoperative adjuvant rectal trial reported results at the 39th Annual Meeting of American Society of Clinical Oncology in 2003.6 Patients were randomized to 3 arms. Patients in arm 1 were treated with bolus 5-FU followed by CI 5-FU/radiation therapy (RT) followed by bolus 5-FU. Patients in arm 2 were treated with CI 5-FU followed by CI 5-FU/RT followed by CI 5-FU. Patients in arm 3 were treated with bolus 5-FU/leucovorin (LV)/levamisole followed by bolus 5-FU/LV/levamisole plus RT followed by bolus 5-FU/LV/levamisole. There was a significant decrease in hematologic toxicity of grade ≥ 3 in arm 2; however, there was no significant difference in 3-year survival. Local control data were not reported. Given these results, CI 5-FU with radiation is recommended and either arm 1 or 2 is a reasonable choice. If arm 1 (bolus) is chosen, the chemotherapy-alone segments should be either the Roswell Park (weekly) or the Mayo Clinic regimen (monthly).
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Multimodality Therapy with Oxaliplatin for Rectal Cancer The INT 0114 trial revealed that with longer follow-up the results are not as favorable.7 With a median follow-up of 7.4 years, the 7-year local failure rate was 17% and the survival rate 56%. Patients with high-risk disease (T3 N+ or T4) have lower survival compared with lower-risk disease (T1 N2+ or T3 N0; 45% vs. 70%). Associated with this improvement in local control and survival with postoperative combined modality therapy is an increase in acute toxicity. For example, the incidence of ≥ grade 3 toxicity in the combined modality arms of the Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group (NCCTG) 79-47-51 trials was 25%-50%. Furthermore, the percentages of patients finishing the prescribed 6 cycles of chemotherapy in those trials were only 65% and 50%, respectively. Retrospective data suggest that the acute toxicity with preoperative combined modality therapy may be less than in the postoperative setting8 and sphincter preservation is increased with preoperative therapy.9 These advantages have been confirmed in the German Rectal Cancer Study CAO/ARO/AIO 94 randomized trial of preoperative versus postoperative combined modality therapy.10 The questions of whether preoperative combined modality therapy is more effective than preoperative RT and whether the postoperative chemotherapy component is necessary are being addressed in the recently completed randomized European Organization for Research and Treatment of Cancer trial 22921 and the results are pending.
Patients Who Do Not Require Postoperative Adjuvant Therapy Retrospective data suggest that there may be a subset of patients with T3 N0 disease who may not require adjuvant therapy, as well as patients with stage I disease who should be considered for adjuvant therapy. Retrospective trials examining patients at the Massachusetts General Hospital11 and the Memorial Sloan-Kettering Cancer Center12 have identified favorable subsets of patients with T3 N0 disease who, following surgery alone, had a 10-year actuarial local recurrence rate of < 10%. In addition to other modifications, such as staging smooth nodules in the fat as node-positive and irregular nodules as vascular invasion (VI = microscopic and VI2 = macroscopic), the 6th edition of the American Joint Committee on Cancer staging system subdivides stage III into IIIA (T1/2 N1), IIIB (T3/4 N1), and IIIC (T N2).13 The prognostic validity of this change was supported by both the pooled analysis of the Intergroup and National Surgical Adjuvant Breast and Bowel Project (NSABP) postoperative trials14 and the retrospective analysis of the American College of Surgeons National Cancer Data Base (NCDB).15 The 5-year survival rates by stages IIIA, B, and C in the pooled analysis were 81%, 57%, and 49%, respectively, and in the NCDB database 55%, 35%, and 25%, respectively. Although based on 5-year survival data, radiation does not improve the results of chemotherapy alone in stages T3 N0, T1/2 N1 disease, local control data are needed before recommending chemotherapy alone for this subset of
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patients. If the local control rate without radiation are acceptable, then patients with upper rectal cancers who undergo a total mesorectal excision, have ≥ 12 nodes examined, and have stages T3 N0, T1/2 N1 disease likely do not need radiation therapy.
Preoperative Therapy Rationale Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiation sensitivity because of more oxygenated cells, and enhanced sphincter preservation.2 The primary disadvantage of preoperative radiation therapy is possibly overtreating patients with either early-stage or undetected metastatic disease. In the German CAO/ARO/AIO 94 trial, which used computed tomography and transrectal ultrasound, 18% of patients were overstaged.10 There are 12 modern randomized trials of preoperative radiation therapy (without chemotherapy) for clinically resectable rectal cancer.2 All use low to moderate doses of radiation. Overall, most of the trials showed a decrease in local recurrence, and in 5 of the trials this difference reached statistical significance. Although in some trials a subset analysis has revealed a significant improvement in survival, the Swedish Rectal Cancer Trial is the only one that reported a survival advantage for the total treatment group. Two metaanalyses reported conflicting results. While both reveal a decrease in local recurrence, the analysis by Camma et al16 reported a survival advantage, whereas the analysis by the Colorectal Cancer Collaborative Group17 did not.
Intensive Short-Course Preoperative Radiation The Swedish Rectal Cancer Trial is the only randomized trial of preoperative radiation therapy to report a significant improvement in survival. Patients with clinically resectable (T1-3) rectal cancer were randomized to receive 25 Gy in 1 week followed by surgery 1 week later versus surgery alone.18 Those who received preoperative radiation had a significant decrease in local recurrence (12% vs. 27%) and a corresponding significant improvement in 5-year survival (58% vs. 48%). It is important to analyze these positive results in context with the remainder of the literature. First, given that the other 11 randomized trials of preoperative radiation therapy do not report a survival benefit, these data clearly need to be confirmed by additional studies. The most recent trial to report results was the Dutch CKVO 95-04 trial, which randomized 1805 patients with clinically resectable (T1-3) disease to surgery alone (with a total mesorectal excision [TME]) or intensive short-course preoperative radiation therapy followed by TME.19 Although radiation significantly decreased local recurrence (8% vs. 2%), there was no dif-
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Bruce D. Minsky ference in 2-year survival (82%). With longer follow-up, 5year local failure was higher with TME (12%); however, it was still significantly decreased to 6% with preoperative radiation therapy.20 Second, even if future trials confirm a survival benefit, there are other equally important endpoints in rectal cancer that need to be addressed. These include acute toxicity, sphincter preservation and function, and quality of life (QOL). For example, acute toxicity in the Dutch CKVO 95-04 trial included 10% neurotoxicity, 29% perineal wound complications, and 12% postoperative leaks.21 In the patients who developed postoperative leaks, 80% required surgery resulting in 11% mortality. The presence of a positive circumferential margin is an important negative prognostic sign. In the Dutch CKVO trial, 17% had positive circumferential margins. In this subset, they received 50 Gy postoperatively. Postoperative radiation did not compensate for positive margins.22 Unfortunately, few centers in the United States performed the necessary pathologic examination to detect positive circumferential margins. Data from Beets-Tan et al suggest that preoperative magnetic resonance imaging (MRI) can identify patients who will have positive margins and can be used to better select patients for preoperative therapy.23 It is not possible to accurately compare the local control and survival results of intensive short-course radiation with conventional preoperative combined modality therapy. This is due to selection bias in favor of the series using intensive short-course radiation. The conventional preoperative combined modality therapy regimens are limited to patients with clinical T3 disease, whereas most trials that use intensive short course preoperative radiation include patients with clinical T1-3 disease.
Sphincter Preservation with Preoperative Radiation A major goal of preoperative therapy is sphincter preservation. From the viewpoint of sphincter preservation, the advantage of preoperative therapy is to decrease the volume of the primary tumor. When the tumor is located in close proximity to the dentate line, this decrease in tumor volume may allow the surgeon to perform a sphincter-conserving procedure that would not otherwise be possible. However, if the tumor directly invades the anal sphincter, sphincter preservation is unlikely even when a complete response is achieved. One of the most important controversies with preoperative therapy is whether the degree of downstaging is adequate to enhance sphincter preservation. Furthermore, if preoperative radiation therapy is effective, what regimen (intensive short course versus conventional course) is preferred? An analysis of 1316 patients treated on 2 previously published Scandinavian trials of intensive short course of radiation revealed that downstaging was most pronounced when the interval between the completion of radiation and surgery was ≥ 10 days.24 In the Dutch CKVO 95-04 trial, where the interval was 1 week, there was no downstaging.25 None of the other randomized trials of preoperative intensive short-course radiation address the issue of sphincter preservation, and it is not an endpoint of the trials.
When the goal of preoperative therapy is sphincter preservation, conventional doses and techniques of radiation are recommended. These include multiple field techniques to a total dose of 45-50.4 Gy at 1.8 Gy/fraction. Surgery should be performed 4-7 weeks following the completion of radiation. Unlike the intensive short-course radiation regimen, this conventional design allows for 2 important events to occur. First is the recovery from the acute side effects of radiation and second is the allowance of adequate time for tumor downstaging. Data from the Lyon R90-01 trial of preoperative radiation suggest that an interval > 2 weeks following the completion of radiation increases the chance of downstaging.26 Whether increasing the interval between the end of intensive short-course radiation and surgery to ≥ 4 weeks will increase downstaging is not known. This question is being addressed in an ongoing randomized trial from Sweden, the Stockholm III trial.
Preoperative Prospective Clinical Assessment The most accurate method of determining whether preoperative therapy increases sphincter preservation is to perform a prospective clinical assessment. In this setting, the operating surgeon examines the patient prior to the start of preoperative therapy and declares the type of operation required. It should be noted that this assessment is based on an office examination and may not accurately reflect the assessment when the patient is relaxed under general anesthesia. The only method by which to account for this potential bias is to perform a randomized trial of preoperative versus postoperative therapy. The German CAO/ARO/AIO 94 randomized trial of preoperative versus postoperative combined modality therapy, which was stratified by a surgeon, reported that this assessment is accurate in 80% of patients.10
Clinical Experience with Sphincter Preservation Eight nonrandomized trials reported results in patients with clinically resectable rectal cancer who underwent a prospective clinical assessment by a surgeon prior to the start of preoperative therapy and were declared to need an abdominoperineal resection (APR). All used conventional doses and techniques of radiation therapy. Three used radiation therapy alone,9,26,27 and 4 used combined modality therapy.28-32 The incidence of sphincter preservation is only 23% in the NSABP series28 and 44% in the Lyon series.26 In the remaining 5 series it is approximately 70%. A valid concern of surgeons is that in order to perform sphincter preservation in those patients who would otherwise require an APR, the distal resection margin may be suboptimal (≤ 1 cm). Can preoperative therapy compensate for this? Retrospective data from Moore et al reveal that with preoperative combined modality therapy the 3-year local control rates were similar regardless of whether the margins were > 2 cm, < 2 cm, > 1 cm, or < 1 cm, providing they were negative.33 Sphincter preservation without good function is of questionable benefit. In a series of 73 patients who underwent sur-
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Multimodality Therapy with Oxaliplatin for Rectal Cancer gery, Grumann and associates reported that the 23 patients who had an APR had a more favorable QOL compared with the 50 who underwent a low anterior resection.34 Although preoperative combined modality therapy may adversely affect sphincter function, the impact is most likely less than postoperative combined modality therapy.35 In 4 of the 8 preoperative series discussed previously that report functional outcome, the majority (approximately 75%) have good to excellent sphincter outcome. Functional results continue to improve up to 1 year after surgery.
Randomized Trials Four randomized trials of preoperative versus postoperative therapy for clinically resectable rectal cancer have been performed. The Uppsala trial used intensive short-course radiation (preoperative 25.5 Gy in 5 fractions) versus postoperative conventional course 60 Gy.36 The preoperative arm revealed a significant decrease in local failure (13% vs. 22%) but no difference in survival (42% vs. 38%). The other 3 randomized trials were limited to patients with T3/4 disease, used conventional doses and techniques of radiation therapy and concurrent 5-FUbased chemotherapy, and required a preoperative clinical assessment declaring the type of operation required. Two are from the United States (INT 0147, NSABP R0-3) and 1 from Germany (CAO/ARO/AIO 94). Unfortunately, low accrual resulted in early closure of both the NSABP R-03 and INT 0147 trials. A preliminary report of the NSABP R-03 trial (with a median follow-up of only 1 year) revealed that the percent of patients who underwent sphincter-sparing surgery and were without evidence of disease was higher in the preoperative versus the postoperative arm (44% vs. 34%).37 The German CAO/ARO/AIO 94 trial completed the planned accrual of over 800 patients and randomized patients with ultrasound-staged T3/4 and/or node-positive rectal cancers ≤ 16 cm from the anal verge to preoperative radiation plus CI 5-FU followed by surgery and postoperative bolus 5FU/LV versus the same regimen postoperatively.10 In order to help remove surgical bias, patients were stratified by surgeon. Compared with postoperative combined modality therapy, patients who receive preoperative therapy had a significant decrease in local failure (6% vs. 12%, P = 0.006), acute toxicity (28% vs. 40%, P = 0.005), chronic toxicity (10% vs. 23%, P = 0.04), and in those 194 patients judged by the surgeon to require and APR, a significant increase in sphincter preservation (39% vs. 20%, P = 0.004). With a median follow-up of 40 months there was no difference in 5-year survival (74%). Given the improved local control, acute and long-term toxicity profile, and sphincter preservation reported in the German trial, patients with T3 rectal cancer who require combined modality therapy should receive it preoperatively. However, data from the NCDB15 and the Intergroup pooled analysis14 suggest that patients with N0 tumors may not require postoperative pelvic radiation. In the German CAO/ARO/AIO 94 trial, 18% of patients who were clinically staged as uT3/4 and/or node-positive preoperatively and underwent surgery without preoperative therapy were pT1/2 N0. Therefore, those
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patients would have been overtreated if they had received preoperative therapy. Although pretreatment MRI can help predict patients who may have positive circumferential margins,23,38 neither MRI or any other imaging modality or clinicopathologic factor can accurately identify patients with N+ disease. As preoperative therapy gains acceptance, the development of more accurate imaging techniques and molecular markers to identify N+ disease are necessary.
Predicting the Response of the Primary Tumor Although some series show no correlation,39,40 most series suggest that there is improved outcome with increasing pathologic response to preoperative therapy.41-47 Analysis of biopsies examining selected molecular markers such as c-K-ras,48 thymidylate synthase,49 p27kip1,50 p53,51-54 apoptosis,55,56 DCC,54 EGFR,57 TP53,52 and Ki-6758 have had varying success in helping to select patients who may best respond to preoperative therapy. Since all of the studies are limited retrospective trials and most did not examine multiple markers, at this time the need for adjuvant therapy should still be based solely on T and N stage. Fortunately, the new Intergroup rectal trials will prospectively collect tissues for these and other markers. In the future, molecular markers may help predict patients with lymph node–positive disease.
Novel Combined-Modality Regimen A number of new chemotherapeutic agents have been developed for the treatment of patients with colorectal cancer (CRC). Phase I/II trials are examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting. Selected agents include uracil and tegafur (UFT),59 raltitrexed,60 oxaliplatin,61-68 irinotecan,69,70 gefitinib,71 and capecitabine72 with pelvic radiation therapy. Clinical trials of combined modality therapy in combination with novel targeted agents such as with bevacizumab and cetuximab are under development. 73 Phase III trials are needed to determine whether these regimens offer an advantage compared with 5-FU– based combined modality therapy regimens.
Oxaliplatin-Based Regimens Based on the in vitro evidence of radiation sensitization with oxaliplatin74 as well as the survival advantage of oxaliplatinbased chemotherapy in patients with metastatic CRC75-77 there is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. A number of phase I/II trials combining oxaliplatin with radiation therapy have been reported. As seen in Table 1, most have used concurrent oxaliplatin, pelvic radiation therapy, and either bolus 5-FU,61 CI 5-FU,62-68,78 or capecitibine.63,79,80 One trial used raltitrexed81 and another used UFT.82 Induction FOLFOX followed by combined radiation plus capecitibine83 or tegafur84 has also been reported (Table 2). Most were phase I trials and the dose of oxaliplatin was escalated. The recommended dose level of oxaliplatin and,
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Bruce D. Minsky Table 1
Concurrent Oxaliplatin-Based Preoperative Combined-Modality Therapy Regimens Patients Treated at RDL
Regimen*
Grade ≥ 3 Toxicity
pCR
25
Oxaliplatin 130 mg/m2, days 1,19, 38 Tomudex 3 mg/m2 45 Gy radiation + 5.4 Gy boost
20% (Total)
38%
20
Oxaliplatin 130 mg/m2, days 2, 30 5-FU bolus 350 mg/m2 and LV 20 mg/m2, days 1-5, 29-33 45 Gy radiation
33% (Diarrhea)
14%
Gerard et al62 Phase II
40
Oxaliplatin 130 mg/m2 days 1, 29 CI 5-FU 350 mg/m2 days 1-5, 29-33 LV 100 mg/m2 days 1, 29 50 Gy radiation + 1 Gy weekly boost
18% (Total)
15%
Landry et al63,78 Phase I
6
Oxaliplatin 85 mg/m2, days 1, 15, 29 CI 5-FU 225 mg/m2 daily
–
58%†
Rodel et al79 Phase II
26
Oxaliplatin 50 mg/m2 days 1, 8, 22, 29 Capecitabine 825 mg/m2 days 1-14, 22-35 50.4 Gy radiation
8% (Diarrhea and skin)
19%
Aschele et al64 Phase I
18
Oxaliplatin 60 mg/m2 weekly CI 5-FU 225 mg/m2 daily 50.4 Gy radiation
13% Diarrhea
29%
Ngan et al65 Phase I
7
Oxaliplatin 85 mg/m2 weeks 1, 3, 5 CI 5-FU 200 mg/m2, days 1-5 weekly 50.4 Gy radiation
–
–
Glynne-Jones et al80 Phase I
6
Oxaliplatin 130 mg/m2, days 1, 29 Capecitabine 650 mg/m2 twice a day, daily 45 Gy radiation
17% Proctitis
31%
Fernandez-Martos et al82 Phase I
-
Oxaliplatin 85 mg/m2, days 1, 15, 29 UFT 450 mg/m2 days 1-5 weekly 50 Gy radiation
RDL not yet reached
–
Eric et al66 Phase I
-
Oxaliplatin 30-80 mg/m2 weekly for 5 weeks CI 5-FU 225 mg/m2 daily 45 Gy radiation
RDL not yet reached
31% (5 of 16)
22
Oxaliplatin 25 mg/m2 LV 20 mg/m2 CI 5-FU 375 mg/m2 days 1-4, weeks 1, 5, 9 Oxaliplatin 50 mg/m2 week 3
27% 1 Neutropenic death
19% (3 of 16)
6
Oxaliplatin 130 mg/m2, day 1 LV 100 mg/m2 CI 5-FU 350 mg/m2 days 1-5, weeks 1, 5 45 Gy radiation
0
25% (2 of 8)
Study/Phase Valentini et al81 Phase II
Sebag-Montefiore et al61 Phase I
Carraro et al67 Phase II
Freyer et al68 Phase I
*Recommended dose level of oxaliplatin if the trial was phase I. †Includes microscopic residual cancer. Abbreviations: CI 5-FU = continuous infusion 5-fluorouracil; LV = leucovorin; pCR = pathologic complete response; RDL = recommended dose level; UFT = uracil/tegafur
where available, the numbers of patients treated at the recommended dose level and the associated acute toxicity in these trials are listed in Table 161-68,78-82 and Table 2.83-84 Although not a randomized comparison, standard preopera-
tive regimens using radiation and bolus or continuous 5-FU alone report a 10% pathologic complete response (CR) rate,10 whereas most of the trials that add oxaliplatin report rates of ≥ 20%.85,86
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Multimodality Therapy with Oxaliplatin for Rectal Cancer Oxaliplatin-Based Neoadjuvant Chemotherapy Followed by Non–Oxaliplatin-Based Preoperative Combined-Modality Therapy
Table 2
Patients Treated at RDL
Study
7. Regimen
pCR 8.
Chau et Phase II
al83
17
Induction Capecitabine 1000 mg/m2, days 1-4 every 3 weeks Oxaliplatin 130 mg/m2, every 3 weeks
9. 29% (4 of 14)
Chemotherapy/RT Capecitabine 825 mg/m2 twice daily 50.4-54 Gy radiation Calvo et al84 Phase II
52
Induction FOLFOX4 × 2 cycles Tegafur 1200 mg/m2 daily 45-50.4 Gy radiation
10.
11.
29%
Abbreviations: FOLFOX4 = 5-fluorouracil/leucovorin/oxaliplatin; pCR = pathologic complete response; RDL = recommended dose level; RT = radiation therapy
12. 13. 14.
The ideal oxaliplatin-based preoperative combined modality regimen has not been determined. The preliminary data reveal encouraging high CR rates following preoperative therapy. However, it should be emphasized that the higher CR rates need to be confirmed in randomized trials. Given the advantage of CI versus bolus 5-FU in the Mayo/NCCTG 86-4751 postoperative rectal adjuvant trial5 as well as in the INT 0114, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is CI 5-FU or capecitabine and pelvic radiation.
15. 16. 17. 18. 19.
Conclusion For patients with rectal cancer selected to receive combined modality therapy, it should be delivered preoperatively. Oxaliplatin-based preoperative regimens report encouraging response rates with acceptable toxicity profiles.
20.
21.
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