The current standard of care for patients with stage T3 rectal cancer is adjuvant combined-modality treatment with radiation and fluorouracil (5-FU)-based chemotherapy. Although data from randomized phase III trials comparing
ABSTRACT: The current standard of care for patients with stage T3rectal cancer is adjuvant combined-modality treatment with radiation andfluorouracil (5-FU)-based chemotherapy. Although data from randomized phase IIItrials comparing preoperative and postoperative combined-modality therapy arelacking, preoperative therapy is an option in T3 disease and can be consideredthe standard of care for T4 disease. Given its effects in reducing systemicdisease in stage IV rectal cancer and its potential for radiosensitization oftarget tumors, oxaliplatin (Eloxatin), a new cytotoxic agent from thediaminocyclohexane platinum family, is being evaluated in preoperativecombined-modality regimens in a Cancer and Leukemia Group B (CALGB) phase I/IIstudy (protocol 89901) in T4 disease and an Eastern Cooperative Group (ECOG)phase I study (E-1297) in locally advanced T3 or T4 disease. [ONCOLOGY14(Suppl 11):38-41, 2000]
Colorectal cancer is the third mostfrequently occurring cancer and the third leading cause of cancer death in theUnited States. It is estimated that 36,400 new cases of rectal cancer and8,600 deaths due to rectal cancer will be reported during the current year. Thecurrent standard of care for rectal cancer reflects the findings of a number ofclinical trials of adjuvant therapy conducted over the past 2 decades. Recentresearch programs have focused on the potential role of preoperativechemoradiation in locally advanced rectal cancer and optimal strategies forintegrating new agents such as oxaliplatin (Eloxatin) into preoperativechemoradiation regimens.
The current standard of care for rectal cancer was generallydefined by outcomes from the GI Tumor Study Group (GITSG) report published in1984 and an Intergroup trial reported in 1994. In the GITSG trial, 202patients with rectal adenocarcinoma with extension to perirectal fat or lymphnodes were randomized to fluorouracil (5-FU)/semustine, radiation therapy,combined 5-FU/radiation plus chemotherapy, or surgery alone (control group),with a minimum follow-up of 5 years for surviving patients.
Combined-modality treatment was associated with a significantincrease in disease-free survival (66% compared with 54% for chemotherapy, 52%for radiation therapy, and 45% in control patients; P = .009) and amarginally significant increase in overall survival (56% vs 46%, 46%, and 36%,respectively; P = .07) at 5 years, which became statistically significantwith long follow-up (P = .005). The local recurrence rate forcombined-modality treatment was 11%, compared with 27% for chemotherapy alone,20% for radiation alone, and 24% for control patients. Distant recurrence rateswere 26% for patients receiving the combined-modality therapy, 27% for thosereceiving chemotherapy, 30% for the radiation group, and 42% for the controlgroup.
Subsequently, in 1988, the National Surgical Adjuvant Breast andBowel Project (NSABP) R-01 trial in 555 rectal cancer patients reported that,at 5 years, semustine (methyl-CCNU)/vincristine (Oncovin)/5-FU (MOF)chemotherapy was associated with significantly better disease-free (42% vs 30%and 33%, respectively; P = .006) and overall survival rates (53% vs 43%and 43%; P = .05) than surgery or radiation therapy alone.
In 1991, a North Central Cancer Treatment Group study in 204patients with T3,4 or N1,2 rectal cancer confirmed the effectiveness ofcombined- modality treatment, demonstrating the superiority of a5-FU/semustine/radiation regimen to radiation therapy alone in prolongingdisease-free (58% vs 37%; P = .0016) and overall survival (52% vs 32%; P= .043).
Continuous-Infusion 5-FU vs Bolus
The Intergroup trial in 660 patients with T3,4 or N1,2 cancerreported in 1994 established the superiority of IV continuous-infusion 5-FUover bolus 5-FU during radiation therapy and demonstrated the lack of benefit of5-FU in combination with semustine. Patients were randomized in a 2 ´2 factorial design to (1) bolus 5-FU administered prior to, during, and afterradiation treatment or (2) 5-FU administered by IV continuous-infusion duringradiation therapy, and bolus 5-FU after radiation therapy, with both regimensgiven with or without semustine.
Semustine was stopped after results from the first 445 patientsshowed no significant effect on outcome from the addition of the agent. Patientsreceiving continuous-infusion 5-FU during radiation therapy exhibited asignificantly improved disease-free (63% vs 53%; P = .01) and overallsurvival (70% vs 60%; P = .005) at 4 years, and a significant decrease inthe rate of distant recurrence (31% vs 40%; P = .03). Rates of localrecurrence were comparable in the continuous-infusion and bolus groups (8% vs11%, respectively).
These randomized trials established that combined-modalitytreatment improved disease-free and overall survival compared with radiationtherapy by decreasing both local and distant disease recurrences. The trialsalso demonstrated that continuous-infusion 5-FU during radiation therapyimproved disease-free and overall survival compared with bolus 5-FU by reducingthe incidence of distant recurrences.
Other 5-FU Modulation Strategies
Intergroup trial 0114 in 1,696 patients with T3,4 or N1,2 rectalcancer assessed the effect of different 5-FU modulation strategies, but foundno differences in local disease control or survival associated with the variousregimens. (Results were published in the Journal of Clinical Oncology in1997.) The study’s treatment arms were (1) 5-FU followed by 5-FU/radiation,(2) 5-FU/leucovorin followed by 5-FU/leucovorin/radiation, (3) 5-FU/levamisole(Ergamisol) followed by 5-FU and radiation, or (4) 5-FU/leucovorin/levamisolefollowed by 5-FU/leucovorin and radiation.
An ongoing Intergroup trial is comparing the effects of (1)standard treatment (bolus 5-FU followed by IV continuous-infusion 5-FU/radiationfollowed by bolus 5-FU) with the results of (2) continuous-infusion 5-FUpreradiation, during, and postradiation therapy, and (3)5-FU/leucovorin/levamisole preradiation and postradiation vs 5-FU/leucovorinduring radiation treatment. Given the lack of benefit associated with theinclusion of levamisole in Intergroup study 0144, no additional benefit isexpected from levamisole in this current Intergroup trial. This trial should,however, be instrumental in establishing the benefit of IV continuous-infusion5-FU before and after radiation therapy.
Recent results from NSABP trial R-02 brought into question thevalue of adding chemoradiation to adjuvant chemotherapy in the management ofpatients with rectal cancer. In this study, 694 patients with T3, T4, ornode-positive rectal cancer were randomized to postoperative chemotherapy aloneor with postoperative radiotherapy. Although there was a statisticallysignificant reduction in the 5-year cumulative incidence of locoregionalrecurrence in patients receiving chemoradiation (from 13% to 8%), there was nosignificant effect on relapse-free, disease-free, or overall survival.
In addition to the NSABP R-02 trial, two recent retrospectiveseries have suggested that certain patients with T3, N0 rectal cancers are atminimal risk of locoregional recurrence.[9,10] These studies have spurred greatdebate among medical, radiation, and surgical gastrointestinal oncologistsregarding the role of chemoradiation in patients with rectal cancer,particularly for those at low risk of locoregional recurrence.
Available evidence[10-12] suggests that preoperativechemoradiation in rectal cancer is associated with greater sphincterpreservation, a lower incidence of acute toxicity, and improved resectability ofT4 tumors. However, there are currently no mature data from randomized trials onthe effect of preoperative chemoradiation in standard fractionation as opposedto postoperative radiation. Important issues regarding its use includedetermining the necessity of postoperative chemotherapy in this setting(particularly in patients with T3 disease), and the potential for overtreatingT1/2 disease with preoperative combined-modality therapy.
Over the past several years, a number of phase II trialsexamined the effect of preoperative chemoradiation. One study of 77 patients atThe University of Texas M. D. Anderson Cancer Center reported a pathologiccomplete response in 29% of patients, with local failure in 4%.
A Duke University study in 43 patients found 51% of patientsachieved a complete clinical response and 27% achieved a pathologic completeresponse, with local failure in 5%. In a Northwestern University study in 30patients, a clinical complete response was observed in 27% and a pathologiccomplete response in 20%, with local failure occurring in 4%. Unfortunately,phase III randomized trial data on the comparative effects of preoperative andpostoperative chemoradiation will not be readily available in the United States.Two randomized trials, the NSABP R03 study and an Intergroup study, have closeddue to poor patient accrual; a German randomized trial is ongoing.
The results of studies[14-19] of preoperative chemoradiation inpatients with T4 tumors are shown in Table 1.The majority of these studies used continuous infusion 5-FU with radiationtherapy in the treatment regimens and some included intraoperative radiation.Complete resection rates ranged from 80% to 97% in these studies, and 3- to5-year overall survival rates have been high.
Evolving treatment algorithms for rectal cancer can besummarized as follows. For T1,N0,M0 disease, treatment consists of localexcision or primary resection. For T2,N0,M0 disease, surgical resection isstandard, although the recent results of a Cancer and Leukemia Group B (CALGB)trial indicate that local excision followed by postoperative chemotherapyproduces good outcomes in appropriately selected patients. For patients with T3,any N, M0 disease, treatment options remain preoperative vs postoperativechemoradiation plus adjuvant 5-FU/leucovorin. Preoperative chemoradiationfollowed by postoperative 5-FU/leucovorin is generally considered the standardof care for T4, any N, M0 disease.
Treatment of Systemic Disease
European studies[21,22] have reported the effectiveness ofoxaliplatin in the treatment of systemic disease in patients with stage IVdisease; US studies are currently establishing its efficacy. The rationaleincluding oxaliplatin in the preoperative regimens of patients with rectalcancer is based on the effect of cisplatin (Platinol) in tumorradiosensitization and the recent demonstration that the addition of oxaliplatinresulted in a two- to threefold increase in the effect of radiation in HT-29colon cancer cell lines and a reduction in systemic metastases. Twocooperative group studies in the United States have been initiated to determinethe suitable dose and schedule for oxaliplatin in combination with radiation and5-FU therapy.
Determining the Maximum Tolerated Dose
The CALGB protocol 89901 is a phase I/II study assessing themaximum tolerated dose (MTD) of preoperative oxaliplatin when deliveredconcurrently with 5-FU and external beam radiation in patients with T4 rectaladenocarcinoma. A secondary objective is to determine the pathologic completeresponse rate after preoperative therapy. Patients must have a fixed orimmovable tumor on physical examination and T4 disease with invasion of adjacentstructures, consisting of the pelvic sidewall, sacrum, pelvis, bladder, orprostate. Focal invasion of the posterior vagina or uterus is not accepted asthe sole determinant of T4 disease. Documentation by computed tomography (CT)scan is required, with ultrasound or magnetic resonance imaging (MRI)documentation being optional. Patients must have no evidence of distantmetastatic disease and cannot have received any prior therapy.
The treatment schema consists of oxaliplatin on day 1 or 2,continuous- infusion 5-FU at 200 mg/m2 on days1 to 7, and radiation therapy on days 1 to 5 during study weeks 1 to 6. Theradiation dose is 45 Gy to the tumor bed and nodes with a 5.4-Gy boost.Oxaliplatin will be given at four dose levels, beginning at 30 mg/m2and increasing in 10- mg/m2 increments to 60mg/m2. Enrollment will consist of 9 to 15patients in the phase I portion of the study, with 3 to 6 patients per doselevel, and an additional 19 patients in the phase II portion, with a target of25 at the recommended phase II dose. Dose-limiting toxicities (DLTs) are definedas any grade 4 neutropenia, any grade 4 thrombocytopenia, and any grade 3 or 4nonhematologic toxicity, excluding alopecia, that requires a treatmentinterruption exceeding 7 days.
The Eastern Cooperative Oncology Group (ECOG) has initiated aphase I study (E-1297) of preoperative concurrent radiation, protractedcontinuous infusion of 5-FU, and dose-escalating oxaliplatin and postoperativeoxaliplatin plus 5-FU/leucovorin in patients with T3 and T4 rectaladenocarcinoma with no distant metastases. Study objectives are to (1) identifythe MTD and DLTs of oxaliplatin in the preoperative regimen; (2) evaluate theresection rates for T4 tumors, pathologic complete response rate, and theexpected vs actual type of resection used; (3) make preliminary observations ofpatient survival and patterns of recurrence; and (4) evaluate anastomotic andsphincter function following preoperative therapy.
Preoperative therapy will consist of radiation at 50.4 Gy,continuous infusion of 5-FU at 200 mg/m2 daily,and oxaliplatin on day 1 of weeks 1, 3, and 5. Oxaliplatin is given at threedose levels of 55 mg/m2, 70 mg/m2,and 85 mg/m2. At 4 to 6 weeks after surgery,patients receive four cycles of oxaliplatin at 130 mg/m2on day 1, 5-FU at 285 mg/m2 on days 1 to 5, andleucovorin at 20 mg/m2 on days 1 to 5. The DLTsare defined as grade 4 neutropenia or platelet abnormalities and grade 3nonhematologic toxicity, including diarrhea for more than 14 days, anastomoticbreakdown in more than 1 patient, and grade 3 neuropathy not resolving beforethe next dose. The study plans to add 10 patients at the MTD. Cohorts of fivepatients will each receive escalating doses of oxaliplatin until the MTD isreached; additional patients are treated at this dose.
Randomized studies have established that adjuvant chemoradiationand chemotherapy are the standard of care for patients with stage II and IIIrectal cancer. Future studies in rectal cancer will focus primarily on twoissues: the integration of new agents such as oxaliplatin and irinotecan(Camptosar) in the adjuvant therapy of rectal cancer, and the additive benefitof chemoradiation to chemotherapy for patients at low risk for locoregionalrecurrence. It is hoped that the CALGB and ECOG studies will help to determinewhether oxaliplatin enhances the effects of radiation therapy in T3 and T4rectal adenocarcinomas, and whether integration of oxaliplatin reduces bothlocal and distant disease recurrence. Data from these studies may also indicatewhether oxaliplatin-containing regimens can be used in the preoperativetreatment of other platinum-sensitive tumors.
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