adjuvant therapy for rectal cancer: results and controversies · radiation: the national surgical...

Adjuvant Therapy for Rectal Cancer: Results and ControversiesPublished on Cancer Network (http://www.cancernetwork.com)

Adjuvant Therapy for Rectal Cancer: Results and ControversiesReview Article [1] | August 01, 1998 | Gastrointestinal Cancer [2], Colorectal Cancer [3]By Bruce D. Minsky, MD [4]

During the past decade, advances have been made in the adjuvant treatment of resectable rectalcancer. Postoperative combined-modality therapy significantly improves local control and survival.Recent Intergroup

Introduction

During the past decade, significant advances have been made in the adjuvant management ofpatients with resectable rectal cancer. In patients with clinically resectable disease, pelvic radiationtherapy decreases local recurrence and, when administered preoperatively, may increase thelikelihood of sphincter preservation. The addition of systemic chemotherapy further enhances localcontrol and improves survival.

This review will examine the results of adjuvant therapy for patients with clinically resectable rectalcancer, as well as selected controversies in adjuvant management. The development and results ofongoing and recently completed randomized trials, as well as the design of innovative phase I/IIprograms, will be discussed. The role of adjuvant therapy in patients with locallyadvanced/unresectable disease[1] and following less radical surgery, such as a local excision,[2] hasbeen reviewed previously and will not be discussed.

Is Adjuvant Therapy Necessary?

Some physicians contend that adjuvant therapy is not necessary in patients with resectable rectalcancer if they undergo more extensive surgery. In one series, total mesorectal excision, whichinvolves sharp dissection around the integral mesentery of the hind gut, decreased the localrecurrence rate to 5%.[3] However, these data must be interpreted with caution, for several reasons.First, mesorectal excision allows for the identification and exclusion of patients with more advanceddisease, as compared with patients treated in the adjuvant trials, in whom more conventionalsurgery is performed. This results in a clear selection bias.

In addition, some patients with T3 and/or N1-2 disease who underwent total mesorectal excisionreceived radiation therapy with or without chemotherapy (ie, 28% in the series of Enker et al[4] and18% in the series of Haas-Kock et al[5]).

Furthermore, total mesorectal excision may be associated with higher complication rates. In theBasingstoke Hospital experience of 219 patients who underwent total mesorectal resection, 11% hadmajor and 6% had minor anastomotic leaks.[6] In the series reported by Aitken, operative deathswere excluded from the analysis.[7]

The Dutch CKVO 95-04 trial is examining the role of intensive, short-course, preoperative radiationtherapy in patients who undergo a total mesorectal excision. Patients are randomized to anintensive, short course of radiation (500 cGy × 5) followed by surgery or to surgery alone.Postoperative radiation is reserved for patients in the surgery-only arm who do not undergo acurative resection. Investigator participation is limited to surgeons who have demonstratedproficiency in performing a total mesorectal excision. This trial is open to patient accrual.

The use of total mesorectal excision has increased awareness that careful surgical techniques arecentral to the successful management of rectal cancer. However, properly performed surgery shouldbe considered a valuable component of treatment, not competitive with adjuvant therapy. Therelative benefits and risks of total mesorectal excision (including effects on local control, survival,sphincter preservation and function, surgical morbidity and mortality, and quality of life) need to be

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documented more carefully.

Postoperative Therapy

The majority of patients with rectal cancer in United States undergo surgery and, if needed, receivepostoperative therapy. The most compelling advantage of this approach is that it allows forpathologic staging. Although advances in preoperative imaging techniques permit more accuratepatient selection, surgery plus postoperative therapy remains the most common approach.

Disadvantages of this approach include an increased amount of small bowel in the radiation field[8]and a potentially hypoxic postsurgical bed. Also, if the patient has undergone an abdominoperinealresection, the radiation field must be extended to include the perineal scar.

Results of Postoperative Therapy

Radiation Therapy Alone--Among patients who received conventional doses of radiation (4,500 to5,500 cGy), nonrandomized data have shown a decrease in the local failure rate to 4% to 31% inpatients with stage T3-4 N0 M0 disease and to 8% to 53% in those with stage T3-4 N1-2 M0disease.[9-11] Five randomized trials have examined the use of adjuvant postoperative radiationtherapy alone in stages T3 and/or N1-2 rectal cancer.[12-18] None of these trials showed animprovement in overall survival. Two trials revealed a decrease in local failure rate with postperativeradiation: the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01 trial (16% vs 25%with surgery alone; P = .06)[12] and the Medical Research Council trial (21% vs 34%;P = .001).[17]Of the 5 trials, NSABP R-01 is the only one in which the radiation was delivered with a continuouscourse, at full dose, and with modern techniques.

Combined-Modality Therapy--Following the publication of randomized trials conducted by theGastrointestinal Tumor Study Group (GITSG)[19] and the Mayo/North Central Cancer TreatmentGroup (NCCTG) trial 79-47-51,[20] which revealed a significant improvement in local control(Mayo/NCCTG) and survival (GITSG and Mayo/NCCTG) with postoperative radiation plus bolusfluorouracil (5-FU) and semustine (methyl-CCNU [MeCCNU]), the National Cancer Institute (NCI)Consensus Conference concluded in 1990 that combined-modality therapy is the standardpostoperative adjuvant treatment for patients with T3 and/or N+ disease.[21]

Most combined-modality therapy regimens include six cycles of 5-FU-based chemotherapy plusconcurrent pelvic radiation. Six cycles of chemotherapy are thought to be necessary to treatsystemic disease. In a randomized trial from Norway, 144 patients were randomized to postoperativeradiation plus bolus 5-FU (500 to 750 mg/m² limited to days 1 and 2 of weeks 1, 2, and 3 ofradiation) vs surgery alone.[22] Despite the use of 5-FU as a radiosensitizer rather than as systemictherapy, this combined-modality therapy regimen significantly decreased local recurrence (12% vs30% with surgery alone; P = .01) and improved 5-year survival (64% vs 50%; P = .05).

Although these results with limited-dose 5-FU are encouraging, additional experience with thisapproach is needed before modifying the standard recommendation of six cycles of systemicchemotherapy.

Recent and Ongoing Intergroup Trials

Since the 1990 NCI Consensus Conference, the intergroup postoperative trials have focused on theidentification of the optimal chemotherapeutic agents and their method of administration. As afollow-up to trial 79-47-51, the Mayo/NCCTG designed a four-arm trial (86-47-51) to determinewhether methyl-CCNU is necessary, as well as to compare the relative effectiveness of bolus vscontinuous-infusion 5-FU. Since methyl-CCNU did not improve either local control or survival, it is nolonger recommended for the adjuvant treatment of rectal cancer.[23]

Compared with patients given bolus 5-FU with or without methyl-CCNU, patients who receivedcontinuous-infusion 5-FU had a significant decrease in the overall rate of tumor relapse (37% vs47%; P = .01) and distant metastasis (31% vs 40%; P = .03), as well as an improvement in 4-year

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survival rate (70% vs 60%; P = .005). These data suggest that when 5-FU is used as a single agentwith radiation therapy, it is more effective as a continuous infusion than as a bolus.

There were also differences in the individual acute toxicities of the continuous-infusion and bolus5-FU regimens. For example, during the combined-modality segment, the incidence of grade 3+diarrhea was significantly higher in patients who received continuous-infusion 5-FU than in thosegiven bolus 5-FU (24% vs 14%; P < .01), whereas the incidence of grade 3+ leukopenia wassignificantly lower (2% vs 11%; P < .01).

Building on the positive results of continuous-infusion 5-FU reported in the Mayo/NCCTG 86-47-51trial, the replacement postoperative intergroup trial INT 0144 was designed to determine whetherthere is a benefit of continuous-infusion 5-FU throughout the entire chemotherapy course (sixcycles), as compared with continuous infusion only during the combined-modality segment (twocycles) and bolus 5-FU during the remaining four cycles. The control arm is arm 4 of INT 0114 (bolus5-FU plus leucovorin plus levamisole [Ergamisol]). This trial opened in 1993 and is actively accruingpatients.

The NSABP R-01 three-arm trial of postoperative MOF (methyl CCNU, Oncovin, and 5-FU) vs radiationtherapy vs surgery alone revealed that postoperative MOF chemotherapy significantly improved5-year disease free survival (42% vs 30%; P = .006) and overall survival (53% vs 43%; P = .05)compared with surgery.[12] The overall survival advantage afforded by chemotherapy was mostevident in males as a group (60% vs 37%) and in males under 65 years of age (44% vs 26%). Incontrast, females who received chemotherapy experienced a lower survival (37% vs 54%).

As follow-up to the R-01 trial, the NSABP designed the R-02 four-arm trial, in which patients wererandomized, depending on gender, to either MOF ± radiation or 5-FU/leucovorin ± radiation. Apreliminary analysis revealed a significant decrease in local failure in the two combined-modalitytherapy arms compared with the two that arms did not include radiation therapy (7% vs 11%; P =.045).[24] Other results of this trial are pending.

The most recent Intergroup postoperative trial to report results is INT 0114.[25] In this four-arm trial,all patients received six cycles of postoperative chemotherapy plus concurrent radiation therapyduring cycles 3 and 4. The goal of this trial was to determine whether combinations of 5-FU-basedchemotherapy (5-FU/low-dose leucovorin vs 5-FU/levamisole vs 5-FU/leucovorin/levamisole) weresuperior to single-agent 5-FU.

With a median follow-up of 4 years, there have been no significant differences among the four armswith respect to local control or survival (Table 1). Although the total incidence of acute grade 3+toxicity was similar in the four arms, there were individual differences among the regimens. Forexample, the 5-FU-alone arm had a higher incidence of hematologic toxicity, whereas the leucovorincontaining arms had a higher incidence of diarrhea.[25] A subset analysis revealed that in all fourarms, women had a significantly greater incidence of acute grade 3+ toxicity than men. The reasonfor this gender-related difference in toxicity is uncertain.

Recommendations for Nonprotocol Therapy

The choice of which postoperative adjuvant regimen to recommend in the nonprotocol settingremains unclear. Given that (1) the Mayo/NCCTG 86-47-51 trial revealed that continuous-infusion5-FU is more effective than bolus 5-FU, and (2) the INT 0114 trial showed that modulation withleucovorin and/or levamisole does not improve the results of bolus 5-FU alone, one could argue thatcontinuous-infusion 5-FU is the regimen of choice.The ongoing trial, INT 0144, comparescontinuous-infusion 5-FU with bolus 5-FU/leu-covorin/levamisole. However, the results of this trial arenot yet available.

At present, therefore, acceptable regimens for patients not enrolled in a clinical trial include eithercontinuous- infusion 5-FU or bolus 5-FU plus modulation with leucovorin and/or levamisole. Sincethese regimens may be equally effective, the choice among them should be based on such factors asacute toxicity profiles and patient compliance.

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Functional Results with Postoperative Therapy

The effect on sphincter function is most likely related to the cumulative impact of all threecomponents of therapy (surgery, radiation, and chemotherapy). Not only have no prospective,randomized trials examined functional results, but also most series evaluating this end point haveused subjective assessment tools, such as telephone and mail surveys.

In a series from the Mayo Clinic, Kollmorgen et al compared bowel function in patients whounderwent postoperative combined-modality therapy with that in a matched group of patients whounderwent surgery alone.[26] Bowel function was assessed via a nonrandomized, nonblinded,retrospective telephone survey. Compared with patients who underwent surgery alone, patients whoreceived combined-modality therapy reported a significant increase in the number of bowelmovements, clustering of bowel movements, nighttime bowel movements, occasional incontinence,and urgency; they also wore pads more often.

Retrospective survey data from Memorial Sloan-Kettering Cancer Center (MSKCC) also suggestedthat postoperative radiation therapy (with or without chemotherapy) can have a negative impact onsphincter function in patients who undergo a coloanal anastomosis.[27]

In summary, the limited available data suggest that postoperative combined-modality therapy mayadversely affect sphincter function. This potential morbidity needs to be weighed against thebenefits of improved local control and survival achieved with adjuvant therapy. Postoperativecombined-modality therapy is the most commonly used adjuvant therapy for rectal cancer andremains the benchmark against which other approaches need to be compared.

Preoperative Therapy

Preoperative therapy (most commonly, radiation therapy combined with systemic chemotherapy)has been gaining acceptance as a standard adjuvant therapy for rectal cancer. The potentialadvantages of delivering adjuvant therapy in the preoperative setting include decreased tumorseeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhancedsphincter preservation.[28-33]

The primary disadvantage of preoperative radiation therapy is the possibility of overtreating patientswith early-stage or metastatic disease. However, imaging techniques, such as computed tomography(CT),[34] magnetic resonance imaging (MRI) with a phased array[35] or an endorectal coil,[36]endorectal ultrasound,[37] ultrasound-guided pararectal lymph node biopsy,[38] and positronemission tomography (PET),[39] allow for more accurate patient selection, thereby decreasing thenumber of patients receiving unnecessary treatment.

The accuracy of endorectal ultrasound in predicting T-stage preoperatively is as high as 90%.However, endorectal ultrasound is less accurate when performed following preoperative radiationtherapy.[40]

Predictors of Response

It would be helpful to identify clinicopathologic features that could predict which tumors will respondfavorably to preoperative therapy. Based on the data that rapidly dividing cells are more sensitive toradiation, Willett et al analyzed the proliferative index of tumors in patients with locallyadvanced/unresectable disease who underwent preoperative radiation therapy with or without5-FU.[41] Tumors with a higher proliferative index had a higher response rate to preoperativetherapy, and, following radiation, there was a corresponding reduction in the proliferative index.[42]

Desai and colleagues reported a higher incidence of recurrence in PCNA-positive rectal cancers butnoted a decreased likelihood of downstaging of these cancers.[43] Using multivariate analysis,Neoptolemos and associates showed that the proliferative index did not add to the prognostic valueof the Dukes� staging system.[44]

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The proliferative index may be useful in predicting response to preoperative therapy. However,additional experience is needed to determine whether or not this is the case.

Other tumor markers have been examined for their ability to predict downstaging. In a study of 50patients treated with preoperative combined-modality therapy, Rich et al reported that tumors with alow spontaneous apoptosis index and positive BCL-2 staining had lower rates of downstaging. In 167patients treated with preoperative radiation, a significant increase in downstaging was noted inthose with well-differentiated cancers.[45] When residual tumor cell density rather than stage wasused as a measure, this difference did not reach statistical significance. By univariate analysis,patients with a pathologic complete response had a nonsignificant improvement in survival. Bergerand associates found that well-differentiated tumors had a greater degree of downstaging than didmoderately or poorly differentiated tumors.[46]

In summary, although some biologic or genetic markers may be more predictive than others, thedecision to use preoperative therapy should not be based solely on their presence or absence. Thedevelopment of predictive markers remains an active area of investigation.

Results of Preoperative Therapy

Nonrandomized trials of preoperative radiation therapy with or without chemotherapy have reportedimproved local control and, possibly, better survival.[47-50] Some trials included patients withearly-stage (T1-2 N0) or metastatic disease. Since these patients are excluded from thepostoperative adjuvant therapy trials, a randomized trial is necessary to accurately compare theresults of preoperative and postoperative therapy.

In a trial from Uppsala, 471 patients were randomized to receive either preoperative radiation (2,550cGy in 1 week) or postoperative radiation (6,000 cGy, split course).[51,52] Patients with stage T1-2N0 disease who were randomized to the postoperative arm did not receive radiation and, instead,were observed.

Preoperative radiation significantly decreased the rate of local failure compared with postoperativeradiation (13% vs 22%; P = .02). However, there was no difference between the two arms withregard to 5-year survival rate (42% vs 38%). Although postoperative mortality was no higher in thepreoperative group compared with the postoperative group, the rate of perineal wound sepsis wassignificantly greater (33% vs 18%; P < .01).

Despite the increased incidence of acute toxicity with preoperative radiation therapy, long-termtoxicity was decreased. The incidence of small bowel obstruction was 5% in the preoperative groupvs 11% in the postoperative group (P = .01), and the incidence of total grade 3+ toxicity was 20% vs41%.

Combined-Modality Therapy--The first randomized trial of preoperative combined-modalitytherapy was conducted by the European Organization for the Research and Treatment of Cancer(EORTC).[53] Patients received preoperative radiation plus 5-FU (375-mg/m² bolus on days 1 through4) or radiation alone. Overall, combined-modality therapy had a negative impact on survival (46% vs59% with radiation alone; P = .06). Since 5-FU was not employed as a systemic therapy with monthlycycles and the radiation techniques were unconventional, it is difficult to interpret the results of thistrial.

Given the advantage of chemotherapy in the postoperative setting, various phase I/II preoperativecombined-modality treatment programs have been developed. Retrospective analysis indicates thatpreoperative combinedmodality therapy increases pathologic downstaging, compared withpreoperative radiation therapy,[54] and is associated with a lower incidence of acute toxicity,compared with postoperative combined-modality therapy.[28]

Whether preoperative combined-modality therapy is more effective than preoperative radiationtherapy is being addressed in an ongoing randomized EORTC trial. This trial will determine whetherthe addition of preoperative and/or postoperative 5-FU/leucovorin to radiation therapy is superior topreoperative radiation therapy alone.

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Table 2 summarizes the results of selected trials of preoperative combined-modality therapy that arelimited to patients with clinically resectable disease. Chari et al[55] and Grann et al[31] employedbolus 5-FU-based chemother-apy, whereas Stryker et al[56] and Rich et al[57,58] usedcontinuous-infusion 5-FU-based chemotherapy.

Combining the four series, the incidence of grade 3+ toxicity during the combined-modality segmentwas 21% to 25%, pathologic complete response rates were 9% to 29%, and the incidence of localfailure was 0% to 5%. These limited data do not permit a valid comparison of bolus vscontinuous-infusion 5-FU.

Randomized Trials of Radiation Alone--There are 11 modern randomized trials of preoperativeradiation therapy (without chemotherapy) for resectable rectal cancer.[53,59-70] All used low tomoderate doses of radiation. The second Medical Research Trial, which revealed a significantimprovement in local control, distant control, and disease-free survival, is excluded from thisanalysis since patients had fixed or partially fixed tumors.[18]

Some of the trials showed a decrease in local recurrence, and, in six trials, this difference reachedstatistical significance. A retrospective analysis of the trials reported prior to 1988 suggested thatthere may be a dose-response effect favoring preoperative over postoperative radiation.[71]Although, in some trials, a subset analysis revealed a significant improvement in survival,[53,60,66]until recently none had reported a survival advantage for the total treatment group.

Intensive, Short-Course, Preoperative Radiation

The Swedish Rectal Cancer Trial was the first randomized trial of preoperative radiation therapy toshow a significant improvement in survival when the data were analyzed by intent to treat. A total of1,168 patients with clinically resectable rectal cancer were randomized to radiation (2,500 cGy in 1week) followed by surgery 1 week later or to surgery alone.[70] Included in the trial were 316patients enrolled in the Stockholm II trial.[72] With a median follow-up of 75 months, patientsrandomized to preoperative radiation showed a significant decrease in local failure rate, comparedwith those treated with surgery alone (12% vs 27%; P < .001), as well as an improvement in the5-year survival rate (58% vs 48%; P = .004).

The survival benefit is intriguing. Furthermore, compared with postoperative combined-modalitytherapy, intensive, short-course, preoperative radiation therapy offers increased patient convenienceand lower cost. For example, patients receive only 5 fractions of radiation (1 week), as opposed to 28fractions (6 weeks), and do not need 6 months of chemotherapy. If the 1-week course ofpreoperative radiation significantly improves survival, why not adopt it as standard therapy?

First, given that the other 10 randomized trials of preoperative radiation therapy have beennegative, these positive data clearly need to confirmed by additional studies. Second, even if futuretrials confirm this survival advantage, there are other equally important end points in rectal cancerthat need to be addressed. These include acute toxicity, sphincter preservation and function, andquality of life.

Prior trials of intensive, short-course radiation have revealed a significant increase in mortality.[73]However, this was not reported in the Swedish Rectal Cancer Trial, which may have related to theuse of multiple-field radiation techniques in that trial.

Conventional radiation techniques include the use of multiple fields (rather than simpleanterior/posterior fields), computerized treatment planning, and customized blocking. Thesetechniques allow for the delivery of higher doses of radiation while sparing the surrounding normaltissues, such as the small intestine. As previously mentioned in the discussion of the Uppsalatrial,[51,52] the anterior/posterior radiation techniques commonly used with intensive, short-courseradiation are associated with an increase in toxicity.

The absence of an increase in mortality in the Swedish trial may have been due to the fact that 91%of patients received radiation using the more sophisticated multiple-field radiation techniques. As

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has been reported in patients who receive conventional doses and techniques of preoperativecombined-modality therapy,[28] the volume of small bowel in the radiation field may be thedose-limiting organ with intensive, short-course radiation therapy.[74]

In the Swedish trial, patients who received radiation with multiple-field techniques had significantlylower postoperative mortality than those who received treatment with an anterior/posteriortechnique (3% vs 15%; P < .001). Postoperative mortality with surgery alone was 12%. However, theincidence of postoperative morbidity in the total group of patients receiving radiation (regardless oftechnique) was still significantly higher than in the surgical controls (44% vs 34%; P = .001).

It should be emphasized that recent data from two other Scandinavian trials (Stockholm I and IItrials) suggest that, even when multiple-field techniques are used, there is still a significant increasein postoperative mortality in patients receiving intensive, short-course radiation compared withsurgery alone (4% vs 1%).[73] These high complication rates with intensive, short-course radiationhave not been reported in patients who receive conventional doses and techniques of preoperativeradiation.

Sphincter Preservation With Preoperative Radiation

A major goal of preoperative radiation therapy is sphincter preservation. Various treatmentapproaches have been used to achieve this goal, and selecting among them depends on such factorsas tumor histology, size, location, mobility, anatomic constraints, and the technical expertise of thesurgeon and radiation oncologist.

An analysis of 1,316 patients treated in two previously published Scandinavian trials of intensive,short-course preoperative radiation indicated that downstaging is most pronounced when theinterval between the completion of radiation and surgery is at least 10 days.[75] However, none ofthe randomized trials of intensive, short-course radiation has addressed one of the most importantcontroversies regarding preoperative therapy: Is the degree of downstaging adequate to enhancesphincter preservation?

From the viewpoint of sphincter preservation, the advantage of preoperative therapy is to decreasethe 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 procedurethat would not otherwise have been possible. However, patients whose tumors directly invade theanal sphincter are unlikely to undergo sphincter preservation even following a complete response topreoperative radiation.

In general, when sphincter preservation is the goal of therapy, the use of preoperative radiationtherapy should be limited to patients who are unable to undergo a local excision due to tumor sizeand/or anatomic constraints. For example, if the tumor is close to the anal sphincter, a full-thicknesslocal excision with negative margins may require partial removal of the sphincter, resulting incompromised function.

Two surgical techniques have been used following preoperative therapy: local excision and a lowanterior resection with or without a coloanal anastomosis. Since local excision has been reserved forpatients who are unable to undergo a conventional operation for medical or technical reasons,[76]this discussion will be limited to patients who undergo a low anterior resection with or without acoloanal anastomosis.

If the goal of preoperative therapy is sphincter preservation, conventional doses and techniques ofradiation are recommended. These include multiple-field techniques to a total dose of 4,500 to 5,040cGy at 180 cGy/fraction. Surgery should be performed 4 to 6 weeks following the completion ofradiation. Unlike the intensive, short course of radiation, this design allows for recovery from theacute side effects of radiation and enhances tumor downstaging.

Prospective Preoperative Clinical Assessment--The most accurate method by which todetermine whether preoperative therapy increases sphincter preservation is to perform aprospective clinical assessment. The operating surgeon examines the patient prior to the start of

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preoperative therapy and declares the type of operation required. It must be emphasized that thisassessment is based on an office examination and may not accurately reflect the assessment whenthe patient is relaxed under general anesthesia. The only way to account for this potential bias is toperform a randomized trial of preoperative vs postoperative therapy. With the randomized design,the accuracy of the assessment is determined since half of the patients are randomized to undergosurgery prior to the initiation of postoperative therapy.

Clinical Experience With Sphincter Preservation--Only five series have reported results inpatients with clinically resectable rectal cancer who underwent a prospective clinical assessment bytheir surgeon prior to the start of preoperative therapy and were declared to need anabdominoperineal resection (Table 3). All used conventional radiation doses and techniques.

Two of the series are from MSKCC. The initial approach to sphincter preservation at MSKCC waspreoperative radiation therapy alone, and the results of this prospective phase I/II trial have beenreported by Wagman et al.[30] The more recent approach at MSKCC has been preoperativecombined-modality therapy and has been reported by Grann and associates.[31]

A trial of preoperative radiation therapy (without chemotherapy) was conducted by Rouanet et alfrom the Montpellier Cancer Institute.[32] The remaining two trials used combined-modality therapy:Hyams and colleagues published an interval analysis of the ongoing NSABP R-03 phase IIIrandomized trial of preoperative vs postoperative combined modality therapy.[33] The other trialwas reported by Maghfoor and colleagues from Ellis Fischel Cancer Center.[29]

There have been other studies in which patients received preoperative radiation therapy followed bysphincter preservation. For example, Papillon and Gerard from the Centre Leon Berard[77] describedtheir results with this approach, and there is a large experience with preoperative radiation therapyfrom the Thomas Jefferson University.[42,49] However, since patients in these trials did not undergoa prospective clinical assessment by their surgeon, the impact of the preoperative radiation therapyon enhancing sphincter preservation cannot be determined.

Preoperative Radiation Therapy--In an update of the MSKCC series by Wagman et al, 36 patientswith clinically resectable disease underwent a prospective clinical assessment by their surgeon andwere declared to require an abdominoperineal resection due to the proximity (but not invasion ) ofthe tumor to the anal sphincter.[30] As determined by transrectal ultrasound, the clinical stage wasT2 in 5 patients and T3 in 31. The median distance of the tumor from the anal verge was 4 cm, andthe median tumor size was 3.8 cm.

Patients received 5,040 cGy followed by surgery 4 to 5 weeks later. Although no chemotherapy wasdelivered concurrently with radiation, patients with pathologically positive pelvic nodes (N = 13) ormetastatic disease (N = 6) received postoperative 5-FU-based chemotherapy. All patients underwenta diverting colostomy, which was closed 2 to 4 months after surgery.

Sphincter function was ascertained using a telephone survey and was rated according to the MSKCCanal sphincter function scale.[78] This scale defines excellent function as one to two bowelmovements per day, with no soilage; good function as three to four bowel movements per day, withor without mild soilage; fair function as more than four episodic bowel movements per day, with orwithout moderate soilage; and poor function as incontinence.

Of the 35 patients who underwent surgery, 27 (77%) of 35 were able to undergo a low anteriorresection/coloanal anastomosis, and the pathologic complete response rate was 14%. With a medianfollow-up of 56 months, cumulative local failure rates as a component of failure were 17% (crude)and 21% (5-year actuarial). The 5-year actuarial disease-free survival rate was 60% and the overallsurvival rate was 64%.

Of the 27 patients eligible for analysis, sphincter function was excellent in 59%, good in 26%, fair in15%, and poor in 0%. Therefore, 85% of patients had good or excellent sphincter function. Themedian number of bowel movements was two per day (range, zero to eight).

Rouanet and associates used a similar approach.[32] They treated a total of 37 patients (15 patients

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with stage T2 disease and 12 with stage T3) with 4,000 cGy of preoperative radiation. Furthertreatment was based on the primary tumor response: If, 3 weeks following the completion ofradiation, a response of ³ 30% was noted, an additional 2,000 cGy was delivered and a low anteriorresection/coloanal anastomosis was performed 2 to 4 weeks later. If there was < 30% response,patients underwent surgery directly.

Of the 27 patients who underwent surgery, 17 (63%) had a low anterior resection/coloanalanastomosis and 4 (15%), a transanal local excision. Thus, overall, a total of 78% of patients wereable to undergo sphincter-preserving surgery. Of the 14 patients available for sphincter functionanalysis, 71% had "perfect" continence, 86% had two or more bowel movements per day, and 14%had urgency.

Preoperative Combined-Modality Therapy--Extrapolating from data showing an improvement inlocal control and survival with combined-modality therapy in the postoperative adjuvant setting,[21]most patients with clinically resectable T3 disease receive preoperative combined-modality therapyrather than radiation therapy alone. Preliminary results of the MSKCC experience with this approachhave been reported by Grann et al.[31] A total of 32 patients with endorectal ultrasound-staged T3rectal cancers received preoperative combined-modality therapy with concurrent 5-FU/low-doseleucovorin. Patients underwent surgery 4 to 5 weeks later and following surgery received a medianof 2 monthly cycles of 5-FU/leucovorin.

All 32 patients underwent surgery, and 24 (75%) were able to have a low anterior resection with orwithout a coloanal anastomosis. Of the 20 patients who, by prospective clinical assessment, weredeclared to require an abdominoperineal resection, 17 (85%) were able to undergosphincter-preserving surgery.

The outcome analysis was limited to the 15 patients who had a minimum follow-up of 1 year or whodeveloped failure prior to 1 year. With a median follow-up of 24 months, there were no localrecurrences, the 2-year actuarial disease-free survival rate was 86%, and the overall 2-year survivalrate was 100%.

Hyams and colleagues have analyzed data from the first 116 patients enrolled in the NSABP R-03randomized trial of preoperative vs postoperative combined-modality therapy.[33] It should be notedthat this is an interim analysis of an ongoing trial, and, therefore, the results should be interpretedwith caution.

Prospective clinical assessment, performed in the 59 patients who received preoperativecombined-modality therapy, identified 22 patients who were judged to require an abdominoperinealresection. Of the 22, 16 actually underwent an abdominoperineal resection. Therefore, preoperativetherapy converted only 27% of patients from an abdominoperineal resection to a low anteriorresection/coloanal anastomosis. The reason for the low rate of sphincter preservation in the NSABPtrial is unclear. Hopefully, future reports will address this issue.

Since half of the patients were randomized to undergo surgery prior to postoperative therapy, theaccuracy of the office assessment in predicting the type of operation required could be determined.Of the 57 of patients randomized to the postoperative combined-modality arm, 26 were declaredclinically to require an abdominoperineal resection, and all 26 patients underwent anabdominoperineal resection. Therefore, these data suggest that the office assessment is an accuratemethod for predicting the type of operation required.

The incidence of postoperative complications was similar in the preoperative and postoperative arms(33% and 30%, respectively). Functional results were not presented.

In the preliminary report from Maghfoor and colleagues, 29 patients (25 with stage T3 disease and 4with stage T4) who were judged clinically to require an abdominoperineal resection receivedcontinuous-infusion 5-FU concurrently with 5,400 cGy of radiation. The pathologic complete responserate was 14%, and 22 patients (76%) were able to undergo sphincter-preserving surgery. With amedian follow-up of 12 months, the disease-free survival rate was 87% and the local failure rate was3%. Sphincter function data were not reported.

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Effects of Preoperative Therapy on Sphincter Function--Sphincter preservation withoutadequate function is meaningless. A well-functioning colostomy may be more desirable than a poorlyfunctioning sphincter. One series has reported that preoperative radiation may have less of adetrimental effect on sphincter function than does postoperative radiation therapy.[26,27]

Birnbaum and colleagues prospectively examined the short-term[79] and long-term[80] impact ofpreoperative radiation therapy on sphincter function. Patients received conventional radiation dosesand techniques and were assessed objectively by anal manometry with or without transrectalultrasound. In the 20 patients assessed for short-term and 10 patients assessed for long-termresults, radiation therapy had a "minimal" effect on sphincter function.

Preoperative vs Postoperative Combined-Modality Therapy--Given the suggestion ofdecreased acute toxicity and enhanced sphincter preservation with preoperative radiation therapy,three randomized trials of preoperative vs postoperative combined-modality therapy for clinicallyresectable, T3 rectal cancer have been developed. Two studies are from the United States (INT 0147,NSABP R-03) and the third is from Germany (CAO/ARO/AIO 94). All three studies are usingconventional doses and techniques of radiation therapy and concurrent 5-FU-based chemotherapy.Both the INT 0147 and the NSABP R-03 trials require a preoperative clinical assessment declaring thetype of operation required. Unfortunately, low accrual has resulted in the closure of the INT 0147trial and may also lead to the early closure of the NSABP R-03 trial.

Although sphincter preservation is an end point of the German CAO/ARO/AIO 94 trial, it does notrequire a preoperative clinical assessment (Figure 1). Therefore, although the German trial willaddress the issue of toxicity and efficacy of preoperative vs postoperative combined-modalitytherapy, it will not clearly answer the question of sphincter preservation.

Investigative Approaches

Although advances in adjuvant therapy have been made, the development of innovative treatmenttechniques needs to continue. Selected approaches include altered radiation fractionation schemesand new chemotherapeutic agents. Some of these techniques have been developed in patients withadvanced disease and have not yet been used in the adjuvant setting.

Altered Radiation Fractionation Schemes

Various fractionation programs have evolved, with the goal of enhancing tumor cell damage byradiation without increasing normal tissue injury.[81] The repair of subcellular injury, regeneration,cell-cycle redistribution, and reoxygenation are all factors at the cellular level that contribute todifferences in how various normal tissues and tumors respond to fractionated radiation.Hyperfractionation and accelerated fractionation schemes take advantage of some of these factors.

A phase I trial of postoperative accelerated hyperfractionation (160 cGy twice daily to 4,800 cGy)from Lausanne reported acceptable acute toxicity.[82] Recent data from this group suggest thattwice-daily radiation is better tolerated when delivered preoperatively than postoperatively.[83]

Although the incidence of late effects with accelerated hyperfractionation should be the same as or,more likely, lower than that with conventional fractionation schemes, the major limitation ofaccelerated schemes is acute normal tissue toxicity.

In a randomized trial of patients receiving radiation therapy for pelvic malignancies,three-dimensional (3D) conformal radiation therapy decreased the volume of normal tissue in thefield but did not decrease acute toxicity.[84] Other techniques, such as hyperthermia,[85,86]radiosensitizers,[87] radioprotectors,[88,89] altered radiation fractionation schemes,[82,83] andproton and 3D treatment planning,[90,91] are encouraging but remain experimental.

New Chemotherapeutic Agents

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Among the new chemotherapeutic agents with activity in colorectal cancer that are either indevelopment or have been approved are irinotecan (CPT-11 [Camptosar]), raltitrexed (Tomudex),trimetrexate (Neutrexin), oxaliplatin, and uracil-ftorafur (UFT).[92-94] Clinical phase I and II trialsexamining the combination of some of these agents with pelvic radiation are underway.

Another new approach under investigation is a chronobiologically shaped infusion of 5-FU. Marsh etal have studied a chronobiologically shaped 5-FU infusion in combination with preoperative radiationtherapy in patients with unresectable disease.[95]

Summary

For patients with clinically resectable rectal cancer, the decision of whether to use preoperative orpostoperative therapy is based on a number of factors. The most important of these is anassessment of the type of surgery required. If the tumor is proximal enough in the rectum so that itcan be removed while preserving the rectum, most physicians would recommend surgery. If a tumorso located is stage T3 and/or N1-3, this would be followed by postoperative combined-modalitytherapy.

If sphincter preservation is not technically possible, the preoperative approach should be used. Thedecision of whether to use preoperative radiation therapy or combined-modality therapy is based onthe results of endorectal ultrasound. If it reveals T2 disease, the patient may have pathologic T2 N0M0 disease. Since the sole reason for using preoperative therapy is sphincter preservation,preoperative radiation therapy alone would be recommended.

If positive mesorectal and/or pelvic lymph nodes are identified at the time of surgery, 6 months ofadjuvant postoperative 5-FU-based chemotherapy would be advised. There are two potentialdisadvantages to this approach. First, ultrasound may understage approximately 10% of patientswho have pathologic stage T3 disease. Second, since preoperative radiation downstages pelviclymph nodes, the true incidence of node-positive disease is unknown. Obviously, thesedisadvantages need to be weighed against the risk of overtreating these patients withcombined-modality therapy.

Patients with transrectal ultrasound stage T3 disease who clinically require an abdominoperinealresection should receive preoperative combined-modality therapy followed by surgery andpostoperative 5-FU-based chemotherapy. This recommendation is based on extrapolation of datashowing a significant improvement in local control and survival in patients with T3 and/or N1-3disease who receive adjuvant postoperative combined-modality therapy. References: 1. Minsky BD: Management of locally advanced/unresectable rectal cancer. Radiat Oncol Invest3:97-107, 1995.

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