the role of adjuvant radiation therapy in the treatment of colorectal cancer

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THE ROLE OF ADJUVANT RADIATION THERAPY IN THE

TREATMENT OF COLORECTAL CANCER

Bruce D. Minsky, MD

Radiation therapy is an effective but local modality in the treatment of colorectal cancer. In general, its use in the adjuvant setting should be limited to those clinical presentations in which the risk of local failure is sufficiently high (at least 10%) to justify its use, and an adequate dose can be delivered to the site at the highest risk for failure. In patients with stages T3 or N + rectal cancer or both, radiation therapy is recommended because the risk of local failure, depending on the stage, is 15% to 67?'0,3~,

and an adequate dose to control microscopic disease (at least 45 Gy) can be delivered safely to the pelvis.66

In contrast to rectal cancer, the role of adjuvant radiation therapy in colon cancer is less well defined. This is due to differences in the natural history of colon cancer as compared with rectal cancer. The most common failure site following potentially curative surgery in colon cancer is within the abdominal cavity rather than local.32, 87 Further- more, because most local failures in colon cancer are extrapelvic, local failure usually does not result in the same degree of debilitating pain as that seen in rectal cancer.

For unsubstantiated reasons, some investigators consider colorectal adenocarcinomas to be "radioresistant." This assumption has been based on the observation that these tumors do not respond as rapidly to

From the Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center; and the Department of Radiation Oncology, Cornell University Medical College, New York, New York

HEMATOLOGY /ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 11 * NUMBER 4 - AUGUST 1997 679

680 MINSKY

radiation as do those with other histologies. This theory was disproved in 1965 by Suit et al?9 who showed that the rapidity of response of tumors to radiation is not an accurate ieflection of their curability. Furthermore, Brierley et a17 reported that of 66 patients with rectal cancer who achieved a complete response to radiation therapy, only 60% had achieved the complete response by 4 months.

Because the natural history, therapeutic approaches, and results of treatment of colon cancer differ from those of rectal cancer, they are discussed separately. In this review, colon cancer is defined as those tumors above the peritoneal reflection, whereas rectal cancer is defined as those tumors at or below the peritoneal reflection. This definition is used to determine eligibility in the Intergroup trials. The discussion will be limited to patients treated in the adjuvant setting. The role of radiation therapy in patients with locally advanced/unresectable disease," as well as following less radical surgery such as a local excision,- has been previously reviewed and is not discussed.

COLONCANCER

The standard adjuvant therapy for node-positive (T14N1-2h/IO) or high-risk T,NoMo colon cancer is postoperative 5-fluorouracil (5-FU)- based chemotherapy.34, 63* 65, 90 Postoperative irradiation has been used with or without chemotherapy in selected patients. This discussion fo- cuses on the rationale and results of radiation therapy as an adjuvant therapy in colon cancer.

Results of Local/Regional Radiation Therapy

Although all the series are retrospective, the most comprehensive series examining the role of local/regional radiation in colon cancer is from Willett et alS6 (Table 1). Eligibility included patients with the following stages: T4N,Mo regardless of anatomic site, T,N,,Mo excluding mid sigmoid and transverse colon, and selected high-risk T,NoMo tumors with close margins. Patients received 45 Gy followed by a shrinking field technique to 50.4-55 Gy depending on the volume of small bowel that could be excluded from the high-dose field. Of the 203 patients, 173 were treated in the adjuvant setting and 30 were treated after a subtotal resection. Sixty-three received bolus 5-FU with a variety of doses and schedules.

The results were compared with a historical control group of 395 patients who underwent surgery only. Three patient groups appeared to benefit from postoperative radiation therapy. First, there was a significant improvement in local control and disease-free survival for patients with stages T4NoMo or T4N,,M0 disease. Second, patients with stage T4NO disease with a perforation or fistula had improved local control and disease-free survival. Third, radiation therapy salvaged

ADJUVANT RADIATION THERAPY IN TREATMENT OF COLORECTAL CANCER 681

Table 1. LOCAL ADJUVANT RADIATION THERAPY IN COLON CANCER

5-Year Disease-Free LocallRegional Failure Survival

Patient Group Stage Surgery Surgery + RT Surgery Surgery + RT ~~ ~

Adjuvant TSNo 163 10% 23 9%* 70% 72% T.& 83 31% 54 7% 63% 79% T3Nj-Z 100 35% 55 30% 44% 47% T4Nj-Z 49 53% 39 28% 37% 53%

37% Residual disease All -

Perforation/fistula T4N, 21 48% 23 6% 43% 91%

- - 30 47%

*Actuarial component of total failure RT = Radiation therapy Data from Willett CG, Fung CY, Kaufman DS, et al: Postoperative radiation therapy for high-risk

colon cancer. J Clin Oncol 11 :1112, 1993

some patients with residual disease following subtotal resection (37% 5- year disease-free survival). There was no benefit in local control or disease-free survival in patients with stage T, or N + disease; however, it must be emphasized that the results in this subgroup of patients may be biased against radiation therapy because many were high-risk patients referred because of concerns about margins.

Building on these encouraging data, a phase I11 Intergroup study (INT #130) has been developed. In this trial, high-risk patients (stages T4N1-*M0, and selected T3Nl,M, lesions with gross tumor penetration into the retroperitoneum) receive 12 cycles of 5-FU/levamisole and are randomized to receive 45 Gy local/regional radiation therapy during cycle two of chemotherapy.

Whole Abdominal Radiation Therapy for Resectable Colon Cancer

Based on the high incidence of abdominal failure, a number of phase I1 trials were designed to examine the efficacy of adjuvant whole abdominal radiation therapy (Table 2).6,20,48,91 The use of whole abdomen radiation is limited by dose considerations. To treat the volume at risk with a potentially curative dose of radiation required for microscopic disease, the whole abdomen would need to receive 45 Gy. Although limited portions of the abdomen can tolerate this dose, the tolerance of the whole abdomen with conventional fractionation is 30 Gy.

In general, patients received 20 to 30 Gy to. the whole abdomen with or without a boost to the primary tumor bed. In three of the series, 5-FU was delivered with a variety of doses and schedules. The combined results revealed an in-field (abdominal) failure rate of 12% to 50%. Significant toxicity varied from 5% to 38%. Although the initial phase I1

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ADJWANT RADIATION THERAPY IN TREATMENT OF COLORECTAL CANCER 683

results appeared promising, three of the series (Brenner et a1,6 Wong et a1,9l and Meek et a148) have not been updated.

The most encouraging data have been reported by Fabian et alZ0 from the Southwest Oncology Group (SWOG 8572). In this phase I1 adjuvant pilot trial, 41 patients with T,Nl-zM, disease received whole abdominal radiation therapy plus continuous-infusion 5-FU followed by nine monthly cycles of maintenance continuous-infusion 5-FU. Owing to unacceptable toxicity in the first six patients, the protocol was modi- fied so that the 5-FU was started day 1 and radiation therapy began concurrently on day 8, and a l-week treatment break from both the 5- FU and radiation was required at day 42. The tumor bed boost (1.6 Gy x 10) was delivered first followed by whole abdominal radiation therapy (1.0 Gy/day x 30) for a total dose of 30 Gy to the whole abdomen and 46 Gy to the tumor bed.

With a median follow-up of 5 years, the 5-year disease-free and overall survival were 58% and 67%, respectively. Limiting the analysis to the 20 patients with more than four positive nodes, the 5-year disease- free and overall survival were 55% and 74%, respectively. For the total patient group, the patterns of failure included 12% local, 22% liver, and 15% peritoneal and other abdominal. In contrast to the other whole abdomen radiation therapy trials, toxicity during the combined modality segment was tolerable (17%: grade 3, 7%: grade 4). The toxicity during the maintenance chemotherapy was also acceptable (25%: grade 3, and 3%: grade 4). The results are encouraging but need further follow-up.

RECTALCANCER

Adjuvant Therapy of Resectable Rectal Cancer

In the adjuvant setting, combined modality therapy is an integral component in the management of rectal cancer. There are two compo- nents of adjuvant therapy: pelvic irradiation and 5-FU-based chemotherapy. In patients with clinically resectable disease, the role of radiation therapy is to decrease local recurrence and increase the possibility of sphincter preservation. In patients with locally advanced/unresectable disease, radiation therapy has the added role of increasing the resectability rate. The role of chemotherapy, regardless of the resectability status, is to enhance the benefits of irradiation (radiosensitization), as well as improve survival by decreasing the incidence of distant metastasis.

Postoperative Therapy

The advantages of the postoperative approach include (1) the stage is already known (thereby sparing the 10% to 15% of patients with stages T,-zN,M, disease treatment) and (2) more accurate definition of the tumor bed for radiation planning is obtained by the placement of

684 MINSKY

clips at the time of surgery. Disadvantages include (1) an increased amount of small bowel in the radiation (2) a potentially hypoxic postsurgical radiation field, and (3) in the case of an abdominoperineal resection, the field must be extended inferior to include the perineal scar.

Some physicians contend that adjuvant therapy is not necessary if patients receive ”adequate” surgery. In one series, total mesorectal excision, which involves sharp dissection around the integral mesentery of the hind gut, decreased the local recurrence rate to 5%.& These data must be interpreted with caution, because this extensive surgery allows the identification and exclusion of patients with more advanced disease as compared with patients treated in the adjuvant trials, in which more conventional surgery is performed. In addition, a number of patients with T3 or N + disease or both received radiation therapy k chemotherapy (ie, 28% in the series from Enker et all9). Furthermore, total mesorectal excision may also be associated with higher complication rates. In the Basingstoke Hospital experience of 219 patients who underwent a low anterior resection with a total mesorectal resection, 11% had major and 6% had minor anastomotic

Radiation Therapy

In patients who received conventional doses of radiation (45 to 55 Gy), nonrandomized data reveal a local recurrence rate of 4% to 31% in those with stage T,N,M, disease and 8% to 53% in those with stage T,N,,M, disease.”, 84, 88 When local recurrence does occur, it is severely debilitating and salvage has been of limited success. Therefore, even though it does not influence survival, the ability of radiation therapy to decrease local recurrence is, by itself, an important quality of life endpoint.

There are three randomized series examining the use of adjuvant postoperative radiation therapy as a single modality in stages T3 or NIa rectal cancer or both.‘, 23, 25, 26 The only randomized trial that confirms an advantage in local control (with borderline significance) is the National Surgical Adjuvant Breast and Bowel Project (NSABP) RO-1. Patients who received adjuvant radiation in the NSABP RO-1 trial had a borderline significant decrease in local recurrence as compared with surgery alone (16% versus 25%, P = 0.06).23 Of the three trials, the NSABP is the only one in which the radiation was delivered with a continuous course, full doses, and modern techniques.

Combined Modatity Therapy

There are three major randomized trials of postoperative combined modality therapy. The Gastrointestinal Tumor Study Group (GITSG) randomized 202 patients to postoperative radiation therapy, 5-FU/ Methyl CCNU, radiation + 5-FU/MeCCNU (combined modality therapy), or surgery alone.25, 26 There was a significant increase in survival in those patients who received combined modality therapy as compared with the surgery control arm (54% versus 27%, P = 0.005). There was no


significant difference in survival in the radiation only or chemotherapy only arms compared with the surgery control arm.

In the Mayo/North Central Cancer Treatment Group (NCCTG) #79- 47-51 trial, 204 patients were randomized to either postoperative radiation therapy or postoperative radiation therapy + 5-FU/MeCCNU.40 There was no surgery-only control arm. Patients who received combined modality therapy had a significant decrease in local recurrence (14% versus 25%, P = 0.036) and distant failure (29% versus 469'0, P = 0.011) and an increase in 5-year disease-free survival (63% versus 42%, P = 0.0016) and overall survival (57% versus 48%, P = 0.025) as compared with the radiation therapy control arm.

In a follow-up study, the Mayo/NCCTG designed a four-arm trial (#86-47-51) to determine if MeCCNU is necessary and to compare the relative effectiveness of bolus versus continuous-infusion 5-FU. All patients received postoperative radiation therapy and were randomized to receive concurrent bolus 5-FU f MeCCNU versus continuous-infusion 5-FU f MeCCNU. MeCCNU did not improve either local control or survival. Therefore, it is no longer used in the adjuvant treatment of rectal cancer.66

Compared with bolus 5-FU (with or without MeCCNU), continuous-infusion 5-FU offers a significant decrease in the overall rate of tumor relapse (37% versus 47%, P = O.Ol), distant metastasis (31% versus 40%, P = 0.03), and improvement in 4-year survival (70% versus 6O%, P = 0.005); however, there were no significant differences in the incidence of local failure as the first site of failure.

The toxicities of continuous-infusion and bolus 5-FU were different. During the combined modality segment, patients who received continuous-infusion 5-FU had a significant increase in grade 3 + diarrhea (24% versus 14%, P < 0.01), whereas they had a significant decrease in grade 3+ leukopenia (2% versus 11%, P < 0.01) as compared with bolus 5- FU. Therefore, if 5-FU is used as a single agent with radiation therapy, the data suggest that it is more effective as a continuous infusion as compared with a bolus.

In the NSABP RO-1 trial, 528 patients were randomized to postoperative MOF chemotherapy, radiation therapy, or surgery alone.= For the total patient group, there was a significant increase in 5-year disease- free survival (42% versus 30%, P = 0.006) and overall survival (53% versus 43%, P = 0.05) in patients who received chemotherapy as compared with surgery. There was no significant difference in disease-free or overall survival in patients who received radiation therapy compared with surgery.

There are some concerns with the interpretation of the NSABP RO- 1 data. First is that the patterns of failure did not correlate with the differences in survival. For example, despite the advantage in disease- free and overall survival in the chemotherapy versus surgery arm, there were no differences in either local/regional failure (21% versus 25%) or distant failure (24% versus 26%). In fact, the only impact on local/

686 MINSKY

regional failure as compared with surgery was seen in the irradiation arm (16% versus 25%, P = 0.06).

The second concern is the conflicting results of the subset analysis. In a logistic regression analysis, the advantage in overall survival in patients who received chemotherapy versus surgery was limited to node-negative patients (80% versus 57%). There was no difference in node-positive patients (37% versus 35%). Furthermore, the advantage in overall survival of the chemotherapy arm was limited to men (60% versus 37%) and men under 65 years (44% versus 26%). The opposite results were seen in women. Women who received chemotherapy had a lower survival (37% versus 54%) as compared with surgery alone. Other series have not reported these differences by gender and nodal status.

Based on these findings, the NSABP designed RO-2 in which patients, depending on gender, were randomized to either MOF ? radiation or 5-FU/leucovorin k radiation. Men were randomized to all four arms, whereas women were randomized to only the 5-FU/leucovorin ? radiation arms. A preliminary analysis of the NSABP RO-2 trial revealed a significant decrease in local recurrence in the two arms that included combined modality therapy versus the two that received chemotherapy alone (7% versus 119'0, P = 0.045).74 Other results are pending.

The most recent trial to complete accrual was the Intergroup Adjuvant Trial INT #0114. This was a four-arm trial in which all patients received six cycles of postoperative chemotherapy and concurrent radiation therapy during cycles three and four. The goal of this trial was to determine if combinations of 5-FU-based chemotherapy (5-FU/leucovorin (low dose) versus 5-FU/levamisole versus 5-FU/leucovorin/levamisole) were superior to 5-FU. The trial exceeded its accrual goals and closed in late 1992. Preliminary results presented at ASCO 1996 suggest that arm four is not superior to arms one to three.83

Building on the positive results of continuous-infusion 5-FU reported in the Mayo/NCCTG #86-47-51 trial, the replacement postoperative adjuvant intergroup rectal trial (Intergroup INT 0144, SWOG 9304) tests whether there is a benefit of continuous-infusion 5-FU throughout the entire chemotherapy course (six cycles) as compared with continuous infusion only during the combined modality segment (two cycles) and bolus 5-FU during the remaining four cycles. The control arm is arm four (bolus 5-FU/LV/levamisole) of Intergroup #0114.

Postoperative radiation therapy can affect sphincter function. Koll- morgen et a139 examined the impact of postoperative combined modality therapy on bowel function and compared it with a matched group of patients who underwent surgery alone. It should be emphasized that this was a nonrandomized, nonblinded, telephone survey. Patients who received combined modality therapy had a significant increase in the number of bowel movements, clustering of bowel movements, nighttime bowel movements, occasional incontinence, and urgency, and they wore pads more often. Data from Memorial Sloan-Kettering Cancer Center (MSKCC) also suggest that postoperative radiation therapy can have a


negative impact on sphincter function (increased stool frequency and difficulty with evacuation) in patients who undergo a coloanal anasto- m ~ s i s . ~ ~

Preoperative Therapy

Preoperative Radiation Therapy

There are a variety of advantages of preoperative radiation therapy. These include biologic (decreased tumor seeding at the time of surgery and increased radiosensitivity owing to more oxygenated cells), physical (no postsurgical small bowel fixation in the pelvis), and functional (ability to change the operation from an abdominoperineal resection to a sphincter-sparing low anterior resection (LAR) /coloanal anastomo- s ~ s ) . ~ ~ , sf 77 An additional benefit in patients with locally advanced/ unresectable disease is the ability to increase the resectability rate.55

The major potential disadvantage of preoperative radiation therapy is possibly overtreating patients (ie, those patients with stages T,,N,M, or metastatic disease). With the use of CT and MR imaging,38, 46 which increase the detection of unsuspected liver metastasis, transrectal ultra- son0graphy,3~ which increases the detection of transmural tumor penetration, and positron emission tomography?l the true incidence of patients overtreated may be less.

Randomized Trials. There are 11 modem randomized trials of preoperative radiation therapy for resectable rectal cancer.5, *, 9, 17, 27, 29, 36,

69, 73* 76, 81 All use low to moderate doses of radiation. Some show a decrease in local recurrence, and in five of the series (Stockholm I,9 Stockholm 11: Swedish Rectal Cancer Trial:' European Organization for the Research and Treatment of Cancer [EORTC]?7 and the Imperial Cancer Research Fundz9) this difference reached statistical significance. The Stockholm I trial (Stockholm-Malmo)9 showed a significant advantage in disease-free survival, and the EORTC combined modality therapy trial5 revealed a borderline advantage in survival (P = 0.06). The Stock- holm I1 trial revealed an advantage in survival in some subsets of patients.* The most impressive results were reported from Sao Paulo Catholic University; however, a statistical analysis was not p e r f ~ r m e d . ~ ~ Although in some trials a subset analysis has revealed a significant improvement in local control or survival or both, none of the trials report a survival advantage for the total treatment group.

There are design flaws in all of these randomized trials. First, none use standard radiation doses (at least 45 Gy). Second, the interval be- tween the completion of radiation therapy and surgery is inadequate. An interval of 4 to 6 weeks is recommended to allow maximum tumor downstaging and the recovery of normal tissues in the radiation field. Third, the radiation techniques employed were suboptimal and are known to be associated with an increased incidence of complications. For example, simple anterior/posterior rather than multiple field techniques

688 MINSKY

were commonly used, and no attempt was made to limit the dose to the small bowel. The superior border in most series was extended to L2 (rather than the more standard L5/S1), thereby further increasing the volume of small bowel in the radiation field. The fraction sizes were unconventional and were as high as 5.1 Gy per day. These inferior radiation techniques contributed to the significant increase in complications, most notably in the EORTCZ7 and the Stockholm I9 series.

The Swedish Rectal Cancer Trial reported a significant increase in postoperative mortality in patients who received radiation with an anterior/posterior as compared with a three- or four-field technique (10Y0 versus 4%, P < 0.001).81 The postoperative mortality with surgery alone was 2% ( P = NS). The postoperative morbidity for the total group of patients receiving radiation (regardless of the technique) was still significantly higher when compared with the surgery control arm (44% versus 34%, P = 0.001).

In summary, even with suboptimal radiation techniques, the more recent randomized trials reveal a significant decrease in local recurrence with preoperative radiation therapy. Although the 1-week course of radiation therapy is commonly used in Europe, it is not favored in North America because (1) it is unlikely that it can be combined with adequate doses of systemic chemotherapy, (2) it is not designed to enhance sphincter preservation, and (3) regardless of the radiation techniques, it is still associated with a significant increase in postoperative morbidity.

Nonrandomized TrialsEphincter Preservation. In patients with clinically resectable disease, the primary rationale for preoperative radiation therapy has been to enhance sphincter preservation. Only two series (Minsky et a153 and Rouanet et aln) have reported results in patients who were prospectively examined by their surgeon prior to radiation therapy and were declared to need an abdominoperineal resection. Nei- ther series used chemotherapy. There is a large experience from Mohiud- din and "; however, the data were not reported in that fashion. In the series from Minsky et al,53 30 patients (T2: 2, T3:28) received 50.4 Gy preoperatively. Of the 29 patients who underwent surgery, 10% had a pathologic complete response and 83% were able to successfully undergo a low anterior resection/coloanal anastomosis. Prospective sphincter function analysis in the 22 eligible patients was good or excellent in 77%.

A similar approach was reported by Rouanet and associate^.^^ A total of 37 patients (T2: 15; T3:12) received 40 Gy preoperatively. Addi- tional treatment was based on the primary tumor response. If 3 weeks following the completion of radiation there was at least a 30% response, an additional 20 Gy was delivered and a low anterior resection/coloanal anastomosis was performed 2 to 4 weeks later. If there was less than a 30% response, patients went directly to surgery. Of the 27 patients who underwent surgery, 17 (63%) had a low anterior resection/coloanal anastomosis, and four (15%) had a transanal local excision, resulting in a total of 78% of patients who were able to undergo sphincter-preserving surgery. Of the 14 patients available for sphincter function analysis, 71%


had "perfect continence," 86% had two or fewer bowel movements per day, and 14% had urgency.

One series has reported that the detrimental effect on sphincter function seen with postoperative radiation therapy39, 67 may not be as problematic with preoperative radiation. Birnbaum and colleagues have prospectively examined the short-term2 and long-term3 impact of preoperative radiation therapy on sphincter function. Patients received conventional doses and techniques of radiation and were assessed objectively by anal manometry with or without transrectal ultrasonography. In the 20 patients assessed for short-term and 10 patients assessed for long-term results, radiation therapy had a "minimal" effect on sphincter function.

In summary, the limited data suggest that preoperative radiation therapy allows sphincter preservation in approximately 80% of patients who were prospectively examined and declared to need an abdominoperineal resection. Of those 8O%, approximately 75% to 80% have good to excellent sphincter function. Additional experience is needed to assess the long-term efficacy and functional results of this approach.

Preoperative Combined Modality Therapy

Although the most common adjuvant approach for patients with clinically resectable T3 or N + disease or both is postoperative combined modality therapy,16, 26, 40 an increasing number of patients are receiving preoperative therapy. A number of trials have used preoperative combined modality therapy. Some have included patients with both resectable and locally advanced/unresectable disease? 33, 41, 47, s ~ , 52, s6, 587 60, 85

and others are limited to unresectable disease.lo, 12, 13, 24, 43, 57 The discussion will focus on the three trials that are limited to patients with clinically resectable disease (T2-3).11, 30, 72 The only phase I11 trial is reported from the EORTC5 With the exception of the phase I dose-escalation trials from Minsky et a15*, 56, s7, 6o and the dose-attenuation trials from Bosset and associates,4 all were phase I1 trials.

EORTC Randomized Trial. The EORTC randomized 247 patients with clinically resectable rectal cancer to preoperative radiation therapy + 5-FU (375 mg/m2 bolus on days 1 to 4) versus radiation therapy alone? Similar to the other preoperative randomized trials in resectable rectal cancer, the total dose (34.5 Gy), fraction size (2.3 Gy per fraction), field size (extended to the superior border of LZ), and technique of radiation (anterior/posterior), as well as the short radiation-surgery interval (2 weeks), were not conventional. Although there was no difference in local control, patients who received combined modality therapy had a decrease in liver metastasis (8% versus 18%, P = 0.07). Overall, combined modality therapy had a negative impact on survival (46% versus 59%, P = 0.06). Because 5-FU was not employed as a systemic therapy with monthly cycles and the radiation techniques were unconventional, it is not surprising that it was a negative study.

Nonrandomized Trials. Three trials were limited to patients with

690 MINSKY

clinically resectable disease (Table 3). Chari et all1 from Duke University reported the results for 43 patients with transrectal ultrasonography- staged T, or T, rectal cancer. Patients received 45 Gy and, within a week of starting radiation, 5-FU (500 mg/m’) and cisplatin (20 mg/m’) bolus daily X 5 for two cycles. No postoperative chemotherapy was delivered. The incidence of total grade 3+ acute toxicity was 21%. Of the 41 patients who underwent surgery, 27% had a pathologic complete response. With a median follow-up of 25 months, the local recurrence rate was 5% and the 5-year actuarial survival was 93%.

In the series from the M.D. Anderson Hospital reported by Rich and associates, 77 patients received 45 Gy and concurrent continuous- infusion 5-FU (300 mg/m’).” All had T, disease based on clinical exami- nation. Transrectal ultrasonography was performed in 63 of the 77 patients. Of the 63 patients, 58 had T3 and the remaining 5 had TI or T, disease. Postoperative chemotherapy was delivered in 43%. The incidence of total toxicity was not presented; however, individual grade 3 + acute toxicities during the preoperative segment included diarrhea, 1%; nausea, 6%; vomiting, 1%; skin, 5%; mucositis, 6%; hand-foot syndrome, 1%; and hematologic, 4%. The incidence of total toxicity was not presented. All patients underwent surgery, and the pathologic complete response rate was 29%. Sphincter-preserving surgery was possible in 68%. With a median follow-up of 27 months, the local recurrence rate was 4%, and the 3-year actuarial survival was 83%.

Grann et a130 from MSKCC reported the results for 32 patients with transrectal ultrasonography-staged T, rectal cancers who received 50 Gy and two monthly cycles (bolus daily X 5) of concurrent leucovorin (20 mg/m2) and 5-FU (325 mg/m2). Patients underwent surgery 4 to 5 weeks later, and they received a median of two monthly cycles of postoperative LV/5-FU. The incidence of total toxicity during the preoperative segment was 25%, and individual grade 3 + acute toxicities included diarrhea, 16%; bowel movements, 16%; and leukopenia, 12%. The complete response rate was 9% pathologic and 13% clinical for a total of 22%. Of the 25 patients thought to initially require an abdominoperineal resection, 17 (68%) were able to undergo sphincter-preserving surgery. Of the 25 patients, five had involvement of the anal sphincter at initial presentation and preoperative therapy was not performed with the goal of sphincter preservation, because an abdominoperineal resection was planned regardless of the degree of downstaging. Excluding those five patients, the incidence of sphincter preservation would have been 17 of 20 (85%). The outcome analysis was limited to the 15 patients with a minimum follow-up of 1 year or who developed failure prior to 1 year. With a median follow-up of 24 months, there were no local recurrences, the 2-year actuarial disease-free survival was 86%, and the overall 2- year survival was 100%.

The preoperative concurrent low-dose leucovorin regimen from MSKCC30, 52 is the basis of the combined modality segments of two separate randomized trials of preoperative versus postoperative combined modality therapy for clinically resectable T, rectal cancer. Both of

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692 MINSKY

these trials use bolus 5-FU/leucovorin, and the endpoints are patterns of failure, survival, sphincter preservation and function, and quality of life. The first trial Radiation Therapy Oncology Group (RTOG) (94-01, INT 0147) is an Intergroup trial comparing this preoperative regimen to arm two of the postoperative adjuvant Intergroup rectal trial 0114. In this trial, the design of the treatment arms is identical with the exception of the sequencing of the therapy. Unfortunately, due to low accrual, this trial has closed.

The second trial is NSABP R-03. This trial has a similar design to INT 0147; however, patients receive six cycles of weekly 5-FU/high- dose leucovorin followed by a 3-week rest prior to the combined modality therapy. The combined modality segment is identical to the sched- ule in INT 0147. Also, R-03 allows patients to undergo a local excision, whereas INT 0147 requires conventional surgery.

A trial of concurrent preoperative radiation (45 Gy), bolus 5-FU, and low-dose leucovorin similar to that performed at MSKCC was reported by Bossett et a14 from the EORTC. Based on these results, the EORTC is performing a four-arm randomized trial. In some European countries, preoperative radiation therapy is considered the standard therapy for resectable rectal cancer. The trial will determine if 5-FUl leucovorin-preoperatively, postoperatively, or both-is superior to preoperative radiation therapy alone.

Issues with Adjuvant Preoperative Combined Modality Therapy. (1) Acute Toxicity. Chari et all1 and Grann and colleagues30 reported a similar incidence of total grade 3 + acute toxicity (21% and 25%, respectively). Rich et al" reported individual toxicities only rather than total toxicity, thereby making an accurate comparison more difficult. Toxici- ties will also vary according to the method of 5-FU delivery. For example, with bolus 5-FU/leucovorin, Gram et a1 reported a higher incidence of diarrhea and leukopenia, whereas with continuous-infusion 5-FU, Rich et a1 reported a higher incidence of nausea, vomiting, skin, mucositis, and hand-foot syndrome.

(2) Local Recurrence and Survival. The median follow-up for the three series are similar (24 to 27 months), and they report similar local recurrence rates (O0/o to 5%); however, a minimum of 5 years' follow-up is needed to determine local recurrence and survival rates with certainty.

(3) Complete Response Rate. The pathologic complete response rates in the series from Chari et a1 (27°/~)11 and Rich and associates (29?'0)~* were higher than those reported by Grann et a1 (9% pathologic and 13% clinical).30 It must be emphasized that all patients in the trial from Grann et a1 had transrectal ultrasonography-confirmed T3 disease, whereas the other trials included patients with T,, tumors. The differences in the results may also be related to other differences in other clinicopathologic variables.

The impact of a complete response is still unclear. In patients with unresectable disease (T4) who receive preoperative radiation therapy with or without chemotherapy and achieve a pathologic complete response, nonrandomized data suggest an advantage in local control (Min:


sky and colleague^^^) and 5-year disease-free survival (Willett et aP9). In patients with T, disease, Rich et al” reported a higher but nonsignificant survival rate in patients who achieved a complete response (pathologic plus clinical). Local control rates were not presented.

(4) Sphincter Presemation. Although one would predict that it would be easier to perform a sphincter-preserving operation following a complete response, the small number of patients in all of the series have precluded a meaningful analysis of this issue. Likewise, prospective sphincter preservation and function analysis has not been an endpoint of the preoperative combined modality trials. Whether the latter will offer the same level of sphincter preservation as well as sphincter function as reported with preoperative radiation therapy 77 remains to be determined. Prospective functional data are being collected in the INT 0147 and NSABP R-03 rectal trials.

Investigational Radiation Therapy Approaches

A number of investigational radiation therapy approaches have been employed in an attempt to enhance the treatment results in patients with both resectable and unresectable rectal cancers, as well as other pelvic malignancies. These include neutron beam radiation,18 hyperthermia,22, 28 radiosensitizers,42 radio protector^,^^, 78 altered radiation fractionation ~chemes,’~, l5 and three-dimensional treatment planning.82 To date, these approaches remain experimental.

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Bruce D. Minsky, MD Department of Radiation Oncology

Memorial Sloan Kettering Cancer Center 1275 York Ave

New York, NY 10021

the role of adjuvant radiation therapy in the treatment of colorectal cancer

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