Improving Adjuvant Therapy for Rectal Cancer by Combining Protracted-Infusion Fluorouracil with Radiation Therapy after Curative Surgery
Michael J. O'Connell, James A. Martenson, Harry S. Wieand, James E. Krook, John S. Macdonald, Daniel G. Haller, Robert J. Mayer, Leonard L. Gunderson, and Tyvin A. Rich
Background The combination of radiation therapy and chemotherapywith fluorouracil plus semustine after surgery has been establishedas an effective approach to decreasing the risk of tumor relapseand improving survival in patients with rectal cancer who areat high risk for relapse or death. We sought to determine whetherthe efficacy of chemotherapy could be improved by administeringfluorouracil by protracted infusion throughout the durationof radiation therapy and whether the omission of semustine wouldreduce the toxicity and delayed complications of chemotherapywithout decreasing its antitumor efficacy.
Methods Six hundred sixty patients with TNM stage II or IIIrectal cancer received intermittent bolus injections or protractedvenous infusions of fluorouracil during postoperative radiationto the pelvis. They also received systemic chemotherapy withsemustine plus fluorouracil or with fluorouracil alone in ahigher dose, both before and after the pelvic irradiation.
Results With a median follow-up of 46 months among survivingpatients, patients who received a protracted infusion of fluorouracilhad a significantly increased time to relapse (P = 0.01) andimproved survival (P = 0.005). There was no evidence of a beneficialeffect in the patients who received semustine plus fluorouracil.
Conclusions A protracted infusion of fluorouracil during pelvicirradiation improved the effect of combined-treatment postoperativeadjuvant therapy in patients with high-risk rectal cancer. Semustineplus fluorouracil was not more effective than a higher doseof systemic fluorouracil given alone.
Rectal cancer is a common malignant disease in the United States,with an estimated 43,000 new cases in 19931. This tumor is frequentlydiagnosed at a stage when complete resection is possible. However,because of local recurrence of tumor in the pelvis or distantmetastasis, only half the patients who undergo surgery willbe cured. The risk of relapse and death is increased if thecarcinoma has penetrated through the rectal wall (TNM stageII) or has spread to regional lymph nodes (TNM stage III).
After studies conducted by the Gastrointestinal Tumor StudyGroup2,3 and the North Central Cancer Treatment Group,4 a NationalInstitutes of Health Consensus Development Conference concludedthat the combination of postoperative chemotherapy and radiationimproved local tumor control and survival in stage II and IIIrectal cancer; it was recommended that this approach be followedin clinical practice5.
The current study was initiated in 1986 with the goal of developingmore effective and less toxic chemotherapy to be used in conjunctionwith radiation after surgery for high-risk rectal cancer. Anew approach that we tested was the protracted venous infusionof fluorouracil throughout the irradiation of the pelvis, whichRich et al. had shown to be tolerable6. We wished to determinewhether this method of delivering fluorouracil during radiationtherapy would have a better outcome than conventional2,3,4 bolusadministration of fluorouracil. Continuous infusion was intendedto prolong the exposure of noncycling tumor cells to fluorouracil;in vitro studies indicated that the cytotoxicity of radiationand fluorouracil given in combination was maximized by the constantexposure of tumor cells to fluorouracil for 24 to 48 hours afterirradiation7.
Methods
Patients
All patients participating in this trial had histologicallyconfirmed adenocarcinoma of the rectum. They had undergone apotentially curative resection, with neither gross nor microscopicalevidence of residual disease, and were entered in the study21 to 70 days after the operation. Patients were eligible ifpathological examination demonstrated that the tumor had penetratedthe rectal wall and involved perirectal fat or adjacent organsby direct extension (stage II) or had metastasized to regionallymph nodes (stage III). The inferior edge of the primary tumorhad to be at or below the sacral promontory or within 12 cmof the anal verge. Patients were excluded if they had a historyof invasive tumor within the previous five years, if their pretreatmentwhite-cell count was less than 4000 per cubic millimeter, iftheir platelet count was less than 130,000 per cubic millimeter,if they had previously received chemotherapy or radiation tothe pelvis, if they had any evidence of distant metastasis orregional metastasis that could not be resected en bloc withthe primary lesion, if they had severe coexistent disease, orif their tumor extended to or below the dentate line. Patientswho also had extrapelvic primary colon cancer could not enterthe study unless the extrapelvic tumor was in stage I and wascompletely resected. Pregnant or lactating women were also excluded.
Randomization
Informed consent was obtained from all patients before randomization.Randomization was carried out centrally at the Operations Officeof the North Central Cancer Treatment Group; treatments werebalanced across strata according to the sequential-treatment-assignmentmethod described by Pocock and Simon8. The four stratificationfactors were the type of resection (abdominoperineal or anterior),the degree of invasion of perirectal fat or adjacent organsby direct extension of the tumor (no invasion, microscopic invasion,gross invasion confirmed microscopically, or adherence to orinvasion of surrounding structures or organs), the number ofregional lymph nodes involved (0, 1 to 4, or >4), and theorganization enrolling patients in the study (25 organizations).
Patients were assigned to one of the following treatments: (1)systemic chemotherapy with fluorouracil and semustine, plusradiation therapy and concomitant bolus injection of fluorouracil;(2) systemic chemotherapy with fluorouracil and semustine, plusradiation therapy and concomitant protracted venous infusionof fluorouracil; (3) systemic chemotherapy with fluorouracil,plus radiation therapy and concomitant bolus injection of fluorouracil;or (4) systemic chemotherapy with fluorouracil, plus radiationtherapy and concomitant protracted venous infusion of fluorouracil.
Treatment
All patients received an initial nine-week cycle of systemicchemotherapy, followed by radiation therapy and concomitantfluorouracil treatment, followed in turn by a second cycle ofsystemic chemotherapy according to the schedule shown in Figure 1.Patients assigned to treatment with fluorouracil plus semustinereceived 130 mg of semustine per square meter of body-surfacearea on day 1 and 100 mg per square meter on day 134. The fluorouracilwas administered by rapid intravenous injection at a dose of350 mg per square meter on days 1 to 5; 400 mg per square meteron days 36 to 40; 300 mg per square meter on days 134 to 138;and 350 mg per square meter on days 169 to 173.
Figure 1. Schedule of Chemotherapy and Radiation Therapy for Rectal Cancer.
Bolus denotes the administration of fluorouracil by rapid intravenous injection, and PVI its administration by protracted venous infusion. Fluorouracil was given in a dose of 500 mg per square meter of body-surface area on days 1 to 5 and days 36 to 40 and 450 mg per square meter on days 134 to 138 and days 169 to 173. Semustine was given in a dose of 130 mg per square meter on day 1 and 100 mg per square meter on day 134. Radiation therapy began on day 64; the total dose was 4500 cGy. For other details of therapy, see the Methods section.
Patients assigned to treatment with fluorouracil as a singleagent during the systemic-chemotherapy phase of the treatmentreceived fluorouracil by rapid intravenous injection at a doseof 500 mg per square meter on days 1 to 5 and days 36 to 40,and 450 mg per square meter on days 134 to 138 and days 169to 173. The total dose of fluorouracil per 10-week course oftherapy was higher when the drug was given as a single agentthan when it was given in combination with semustine.
All patients received radiation therapy beginning on day 64;radiation was delivered by a linear accelerator with a minimalphoton energy of 4 MV. Multiple-field techniques9,10 were usedto include the tumor bed and nodal groups (anteroposterior-posteroanteriorplus lateral fields; the use of anteroposterior-posteroanteriorfields only was not allowed). The superior border of the radiationfield was at least 1.5 cm above the level of the sacral promontory.In patients who had undergone anterior resection, the inferiorfield margin was 3 to 5 cm below the anastomosis. The lateralborders of the anterior-posterior radiation field were at least1.5 cm lateral to the widest bony margin of the true pelvicsidewalls. In patients who had undergone abdominoperineal resection,the inferior and posterior border of the radiation fields includedthe perineal scar. Paired lateral fields were used in combinationwith anteroposterior-posteroanterior fields, to decrease thedose of radiation to anteriorly located small-bowel tissue9.Techniques that displaced the small bowel out of the pelviswere also encouraged. Simulation and treatment in the proneposition were recommended. A total of 4500 cGy in 180-cGy fractionsgiven over a five-week period was directed at the initial pelvicfield. All patients received a minimal boost dose of 540 cGyto the entire tumor bed, the immediately adjacent lymph nodes,and the 2 cm of adjacent tissue (in patients with abdominoperinealresection, the perineum was excluded after it had received 4500cGy). A second boost dose of 360 cGy was allowed to a smallerfield in patients with good to excellent displacement of thesmall bowel out of the field.
All patients received fluorouracil during pelvic irradiationtherapy. Those randomly assigned to bolus fluorouracil administrationreceived 500 mg per square meter by rapid intravenous injectionfor three consecutive days during weeks 1 and 5 of radiationtherapy. In patients randomly assigned to protracted venousinfusion of fluorouracil, access to the central venous circulationwas established by means of an implanted catheter, an externalcatheter in a subcutaneous tunnel, or a peripheral long-linecatheter. Fluorouracil was infused at a rate of 225 mg per squaremeter per day by an ambulatory infusion pump during the entireperiod of radiation therapy or until severe chemotherapy-relatedtoxicity occurred.
Quality Control of Radiation Therapy
Radiation oncologists were required to submit simulation filmsfor central review by a radiation-oncology coordinator beforethey began radiation therapy. They were notified of any neededmodification of treatment. Quality-control procedures have beendescribed in detail elsewhere11.
There were minor deviations or no deviations from protocol specificationsin the treatment of 87 percent of the patients who receivedradiation therapy. Radiation therapy was incomplete or not administeredaccording to protocol because of noncompliance or an interveningcondition in 2 percent of patients, and the results of treatmentcould not be evaluated in 2 percent. There were major deviationsfrom the protocol in 8 percent.
Follow-up
During adjuvant therapy patients were monitored for signs oftoxicity, with appropriate adjustments of their chemotherapyand radiation therapy. Complete blood counts were performedweekly to detect myelosuppression. Patients were also evaluatedby means of history taking and physical examination, blood-chemistry-paneltesting, and chest radiography before each five-day course ofchemotherapy and before radiation therapy. They were evaluatedfor tumor relapse and delayed toxic reactions every 3 monthsfor the first 18 months after the completion of adjuvant treatmentand then every 6 months, for a total of 5 years. It was recommendedthat patients with anterior resections undergo proctoscopicexamination every six months for two years and then annually.Radiography of the colon was performed at one, three, and fiveyears. It was also recommended that computed tomography of theabdomen and pelvis be performed during the six-month evaluationand at the time of tumor relapse. A clear demonstration of pulmonaryor osseous metastases or demonstration of an enlarging pelvicmass by computed tomography was accepted as evidence of tumorrelapse, without a biopsy. Histologic confirmation was encouragedwhenever possible.
Statistical Analysis
The end points of this study were the length of time to initialtumor relapse (local recurrence or distant metastasis), ratesof local recurrence and distant metastasis, and survival. Afactorial (two-by-two) design was used for analysis. One primaryanalysis compared the combined data on the two groups of patientsreceiving protracted venous infusion with the combined dataon the two groups receiving bolus doses, and the other analysiscompared the combined data on the two groups receiving semustineplus fluorouracil with the combined data on the two groups receivingfluorouracil alone. Sample-size estimates and power calculationswere based on projected rates of relapse three years after entry.
After 445 eligible patients had been entered, a planned interimanalysis indicated that semustine treatment did not result inan improvement in relapse-free or overall survival, and thelast 215 patients entered all received fluorouracil alone assystemic therapy. These 215 patients were randomly assignedto protracted venous infusion or bolus administration of fluorouracilduring radiation therapy. When the rates of relapse, survival,or toxic reactions among the patients receiving semustine werecompared with those among patients not receiving semustine,the analysis included only the 445 patients who were equallylikely to be entered in one of the four groups (Table 1).
Table 1. Distribution of Patients According to Regimen.
Statistical analyses were carried out according to SAS procedures12.The Kaplan-Meier method was used to construct curves for therelapse-free interval and overall survival13. Data on patientswho died from causes other than cancer were censored in ourcalculations of the relapse-free interval. The log-rank statisticwas used to compare distributions14. The Cox proportional-hazardsmodel was used for all multivariate analyses15. A backward-regressionanalysis was used to identify significant factors; variableswere kept in the model only if the standardized maximum-likelihood-estimatestatistics had a P value below 0.05. To adjust for covariateswhen evaluating treatments, we kept treatment in the model andapplied backward regression to the other covariates. All P valuesare two-sided.
Results
Enrollment and Follow-up
Six hundred eighty patients were entered in the study betweenJune 1986 and August 1990. Twenty patients (3 percent) werefound to be ineligible; the other 660 patients (97 percent)were included in the statistical analyses. Ninety percent ofexpected tumor relapses and 75 percent of expected deaths fromcancer have been observed. The median length of follow-up ofthe 431 patients currently alive is 46 months, and all patientshave been followed-up for at least 2 years.
Characteristics of the Patients
Selected characteristics of the treatment groups are shown inTable 2. There were no significant differences in the distributionsof these characteristics among the groups.
Evaluation of the Method of Fluorouracil Administration during Radiation Therapy
Among the 328 patients who received a protracted venous infusionof fluorouracil, there was a significant decrease in the overallrate of tumor relapse (from 47 to 37 percent, P = 0.01) anddistant metastasis (from 40 to 31 percent, P = 0.03), as comparedwith the 332 patients who received bolus injections of fluorouracilduring radiation therapy. Among the 434 patients who did notreceive semustine, there was also a significant decrease inthe overall rate of tumor relapse and distant metastasis amongpatients who received a protracted infusion of fluorouracil.Individual sites of distant metastases were documented at thetime of initial tumor relapse in the following numbers of patients:the liver in 105 patients, the lungs in 104, the lymph nodesin 34, the peritoneum in 19, and other sites in 30. Protractedvenous infusion of fluorouracil was not associated with a significantdecrease in local recurrence (P = 0.11).
The curves for relapse-free interval and overall survival areshown in Figure 2. Patients who received a protracted infusionof fluorouracil had a significant improvement in the time torelapse (P = 0.01) and survival (P = 0.005), as compared withthose who received a bolus injection of fluorouracil; theirtumor-relapse rate was decreased by 27 percent, and their deathrate by 31 percent. When these improvements were expressed interms of four-year rates, the time to relapse was increasedfrom 53 percent to 63 percent and survival from 60 percent to70 percent among patients who received a protracted venous infusionof fluorouracil.
Figure 2. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil by Protracted Venous Infusion (PVI) or Bolus Injection during Radiation.
Multivariate analyses showed that increased age, greater lymph-nodeinvolvement, a greater depth of tumor invasion, and a highertumor grade were independent factors indicating a poor prognosiswith respect to the time to relapse and survival. After adjustmentfor these significant prognostic variables, the method of fluorouraciladministration remained significantly associated with the timeto relapse (P = 0.02) and survival (P = 0.01).
Severe or life-threatening toxic reactions associated with thetwo forms of adjuvant fluorouracil therapy are summarized inTable 3. Diarrhea and leukopenia were the most frequently encounteredreactions during and four weeks after combined pelvic irradiationand fluorouracil therapy. The incidence of severe diarrhea wassignificantly higher among patients who received fluorouracilby protracted infusion, and that of severe leukopenia was significantlyhigher among those who received the drug by bolus injection.There was no significant difference between these two groupsin the number of patients who began the full course of pelvicradiation therapy but did not complete it (protracted venousinfusion, 10 patients; bolus injection, 7 patients). The averagedoses of fluorouracil administered were 6546 and 2499 mg persquare meter when given by protracted infusion and bolus injection,respectively, during the radiation phase of the study. Small-bowelobstruction requiring surgical intervention after pelvic irradiationoccurred in 10 patients who received fluorouracil by protractedvenous infusion (3 percent) and 7 who received it by bolus injection(2 percent). There was a single treatment-related death duringthe study, due to sepsis after surgery for bowel obstruction.
Table 3. Incidence of Severe or Life-Threatening Toxic Reactions to Treatment.
Evaluation of Semustine as a Component of Systemic Chemotherapy
No significant difference was found between the rate of localtumor recurrence among the 226 patients who received systemicchemotherapy with fluorouracil plus semustine and the rate amongthe 219 concurrently randomized patients who received fluorouracilalone (9 vs. 11 percent). The curves for relapse-free intervaland overall survival are shown in Figure 3. After adjustmentfor the independent prognostic factors described above, therewas no significant difference between the group who receivedboth semustine and fluorouracil and the group who received semustinealone in relapse-free interval (P = 0.33) and overall survival(P = 0.61).
Figure 3. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil with or without Semustine as Systemic Chemotherapy.
The severe or life-threatening toxic reactions to systemic chemotherapyare summarized in Table 3. The incidence of severe reactionsto either of the two regimens was low. The incidence of diarrhea,stomatitis, and leukopenia was significantly higher among patientswho received fluorouracil alone, and that of thrombocytopeniawas significantly higher among patients who received semustinein combination with a lower dose of fluorouracil (P<0.01for both comparisons). Acute leukemia developed in a patientwho received fluorouracil alone as systemic chemotherapy. Delayedrenal toxicity was not observed in any patient.
Discussion
We assessed the value of the protracted infusion of fluorouracilthroughout the duration of pelvic irradiation for rectal cancer.Although we documented a decrease in local tumor recurrencewith this treatment, the difference was not statistically significant,given the small number of local recurrences observed. However,the rate of distant metastasis was significantly decreased,suggesting that fluorouracil given by prolonged infusion hasan improved systemic effect on micrometastases.
Theoretically, the prolonged exposure of tumor cells with lowgrowth fractions and long doubling times to a chemotherapeuticagent with cell-cycle specificity and a short plasma half-life,such as fluorouracil, would result in enhanced cytotoxicity16.Alternatively, the beneficial effect of protracted infusionof fluorouracil in this study may simply have been the resultof the much higher total doses of drug that could be safelydelivered by protracted infusion as compared with bolus administration.
Controlled trials of the continuous infusion of fluorouracilin patients with advanced metastatic colorectal cancer haveindicated some improvement in objective tumor-response ratesbut have shown no significant effect on survival17,18,19. Ourstudy, however, suggests that the incorporation of protractedvenous infusion of fluorouracil as a component of postoperativeadjuvant therapy for patients with early-stage malignant diseasecan improve survival. Further follow-up will be required todetermine accurately the magnitude of any long-term survivalbenefit.
The protracted venous infusion of fluorouracil at the dose levelused in this study was generally well tolerated, although itwas associated with a moderate increase in the incidence ofsevere diarrhea. This treatment method also requires centralvenous access and an ambulatory infusion pump, which increasethe complexity and cost of therapy.
Although the incidence of acute side effects of adjuvant radiationcombined with chemotherapy is higher than the incidence of sideeffects of adjuvant radiation without chemotherapy, this hasnot translated into an increase in chronic toxic reactions4.The relative risk of chronic small-bowel problems requiringreoperation does not exceed the risk of 5 to 10 percent associatedwith surgery alone. This is probably related to the use of multiple-fieldradiation that includes lateral fields and the imaging of thesmall bowel9,10,20 to reduce the volume of small-bowel tissueincluded within the isodose curve of 4500 to 5040 cGy.
This study has also demonstrated that semustine does not addto the therapeutic benefit of adjuvant therapy with fluorouraciland pelvic irradiation, confirming the earlier observationsof the Gastrointestinal Tumor Study Group21.
Recent studies have indicated that the outcome of surgery forhigh-risk colon cancer is significantly improved by the useof fluorouracil given by simple bolus injection in combinationwith levamisole22 or leucovorin23,24. The relative efficacyof protracted venous infusion of fluorouracil as compared withbolus administration of fluorouracil modulated by leucovorinor levamisole (or both) remains to be determined in patientswith rectal cancer who are at high risk for relapse or death,as does the value of administering fluorouracil by protractedvenous infusion throughout all phases of adjuvant therapy (notjust during radiation treatment). More effective control ofoccult distant metastasis remains the principal challenge inthe curative treatment of rectal cancer today.
Supported by grants (CA-25224, CA-31224, and CA-06294) fromthe National Cancer Institute.
Source Information
From the Mayo Clinic, Rochester, Minn. (M.J.O., J.A.M., H.S.W., L.L.G.); the Duluth Clinic, Duluth, Minn. (J.E.K.); Temple University School of Medicine (J.S.M.) and the University of Pennsylvania Cancer Center (D.G.H.), Philadelphia; the Dana-Farber Cancer Institute, Boston (R.J.M.); and the M.D. Anderson Cancer Center, Houston (T.A.R.).Coordinated by the North Central Cancer Treatment Group, Rochester, Minn. Other participants include the Southwest Oncology Group, the Eastern Cooperative Oncology Group, Cancer and Acute Leukemia Group B, the Radiation Therapy Oncology Group, and the M.D. Anderson Cancer Center.
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