Three Adjuvant 5-FU/RT Regimens Are Equally Effective

ATLANTA-In a phase III trialof patients who had undergone surgeryfor rectal cancer, three regimens offluorouracil (5-FU)-based chemotherapyand radiation therapy achieved similarrates of relapse-free and overall survival,although the three regimens hadsomewhat differing toxicity profiles.Lead author Stephen R. Smalley, MD,a radiation oncologist at the Olathe RegionalOncology Center, Olathe, Kansas,reported the results at the 46th AnnualMeeting of the American Societyfor Therapeutic Radiology and Oncology(abstract 14).Recent trials have found that aftersurgery for rectal cancer, protractedvenous infusion (PVI) of 5-FU duringradiation therapy improves outcomesrelative to bolus infusion (Intergroup864751), and outcomes are similar witha variety of different biochemically modulatedbolus regimens of 5-FU (Intergroup0114), Dr. Smalley said.The new trial (Intergroup 0144),therefore, sought to answer three questions,he said: "Number one, would aprotracted course of 5-FU (prior to andfollowing protracted 5-FU and radiation)lead to further improvement inoutcome? Number two, could a biochemicallymodulated 5-FU programwithout central venous catheters produceoutcomes similar to those of theprotracted venous infusion arm? Andnumber three, how would pelvic controlbe affected, especially in those groupsthat were most rationally treated withinitial surgery?"The investigators enrolled patientswho had undergone complete resectionof locally advanced but nonmetastaticrectal adenocarcinoma (T3-4, N0, M0or T1-4, N1-2, M0) in the prior 20 to 70days; dentate involvement was allowed.Patients were required to have adequateorgan function and no prior chemotherapyor radiation therapy.The patients were stratified by typeof resection (abdominoperineal vs lowanterior), T stage, N stage, and timefrom surgery. They were then assignedto three treatment arms:

• Arm 1: Bolus 5-FU before andafter radiation therapy, with 5-FU byPVI during radiation therapy
• Arm 2: 5-FU by PVI before, during,and after radiation therapy
• Arm 3: Bolus 5-FU, leucovorin,and levamisole before and after radiationtherapy, plus bolus 5-FU and leucovorinduring radiation therapy

In all, 1,917 patients were enrolledin the trial, and living patients had amedian follow-up of 6.1 years, makingthe data mature, Dr. Smalley noted.

Study Results

The three treatment arms had statisticallyindistinguishable rates ofoverall survival (81% to 83%) andrelapse-free survival (67% to 69%) at3 years follow-up, Dr. Smalley said.For both endpoints, the findings werethe same in analyses comparing arm 1with arm 2, and arm 1 plus arm 2 witharm 3. (See Table 1 for 5-year survivalrates.)"It's important to evaluate pelviccontrol, especially for those patientswho are initially appropriately managedby surgery," Dr. Smalley said,noting that some trials have foundbetter pelvic control with preoperativeradiation therapy, with or withoutchemotherapy. "However, preoperativeradiotherapy does produce anincreased clinically meaningful toxicity,both gastrointestinal and sexual in nature, and it is obviously desirable toavoid these side effects in those whoare unlikely to benefit from radiationtherapy. This would certainly includepatients who are candidates for sphincter-sparing surgery when they present,as well as patients who do not havefixed primary rectal lesions."With the 6.1-year median followup,the rate of pelvic failure was similarlylow across treatment arms in theentire study population (5% to 7%)and in the subgroup of patients whowere appropriately managed with initialsurgery, namely those with non-T4b disease who underwent low anteriorsurgical resection (3% to 6%).

Toxicity

Patients in arms 1, 2, and 3 hadsimilar rates of treatment-related death(approximately 1%) and gastrointestinaltoxicity of grade 3 or higher (42%to 46%), Dr. Smalley said.In contrast, rates of grade 3 or higherhematologic toxicity differed, with thiscomplication occurring in about halfof the patients in arms 1 and 3 (50% to56%) but in few patients in arm 2(4%). "However this was primarily alaboratory change because the PVI arm[arm 2] had a 6% grade 3-5 infectionrate vs 10% to 11% in the two bolus5-FU arms," Dr. Smalley noted. Asexpected, catheter-related toxicity washigher in arms 1 and 2 (2% to 3%)than in arm 3 (less than 0.5%), headded.

'Similar Outcomes'

"We conclude that all three doseschedules lead to similar outcomes followingresection," Dr. Smalley commented."Hematologic toxicity wasdefinitely decreased with protractedvenous infusion, but it must be balancedagainst the cost, inconvenience,and risk of catheter-related toxicitieswith PVI."He told

ONI

that although otherrecent trials have found PVI to besuperior to bolus therapy, "our trial isby far the biggest and most satisfactorilypowered study, and really suggeststhat any 5-FU regimen plus radiationproduces similar survival outcomes."

Less Extensive Treatment

The findings further suggest thatless extensive treatment is safe in somepatients, Dr. Smalley pointed out. "Initialsurgical management of nonfixedlesions that are amenable to sphincter-preserving surgery at presentationis entirely justified," he said. "Thosepatients who are at low risk of pelvicrecurrence following surgery-certainlythis would include T1-2, N0patients, potentially even selected T3,N0 patients-can avoid the toxicity ofradiation."