Combined-Modality Therapy for Rectal Cancer Using Irinotecan

ABSTRACT: Preoperative or postoperative pelvic radiation plus concurrent fluorouracil-based chemotherapy is standard adjuvant treatment for patients with T3 and/or N1/2 rectal cancer. Newer chemotherapeutic regimens have been developed for the treatment of patients with metastatic disease. Irinotecan (CPT-11, Camptosar)-based regimens have improved survival in patients with metastatic disease and are being actively investigated in combination with pelvic radiation therapy for patients with rectal cancer. [ONCOLOGY 16(Suppl5):35-38, 2002]

The standard adjuvant treatment for patients with T3and/or N1/2 rectal cancer is pelvic radiation plus concurrent fluorouracil(5-FU)-based chemotherapy. Several newer chemotherapeutic regimens have beendeveloped for the treatment of patients with metastatic disease and are nowbeing combined with pelvic radiation therapy. This review will focus on theresults of irinotecan (CPT-11, Camptosar)-based regimens in combination withradiation therapy in patients with rectal cancer.

Adjuvant Therapy With 5-FU-Based Regimens: Postoperative Therapy

Published results of randomized trials from the Gastrointestinal Tumor StudyGroup (GITSG)[1,2] and the Mayo/NCCTG (North Central Cancer Treatment Group,trial 79-47-51)[3] revealed significant improvements in local control and/orsurvival with postoperative radiation plus bolus 5-FU with or without semustine(methyl-CCNU) in patients with rectal cancer. Based on these findings, theNational Cancer Institute Consensus Conference concluded in 1990 thatcombined-modality therapy with 5-FU-based regimens was the standardpostoperative adjuvant treatment for patients with T3 and/or N1/2 rectalcancer.[4] While radiation therapy decreases local recurrence rates by half, theaddition of 5-FU-based chemotherapy further decreases local recurrence ratesto approximately 10% to 12%, and is responsible for increasing overall 5-year survival rates by approximately 10% to 15% above those achieved withsurgery alone. Data from the National Surgical Adjuvant Breast and Bowel Project(NSABP) R-02 randomized trial revealed that, although postoperative 5-FU-basedchemotherapy alone decreased the local recurrence rate to 13%, the combinationof chemotherapy plus radiation significantly decreased the local recurrence rateto 8%.[5]

Based on the positive results reported in the Mayo/NCCTG 86-47-51 trial thatused continuous infusion 5-FU, the postoperative Intergroup trial INT 0144 wasdesigned. The primary end point of this trial was to determine whether there wasa benefit of continuous infusion 5-FU throughout the entire chemotherapy course(six cycles) as compared with continuous infusion only during thecombined-modality segment (two cycles) and bolus 5-FU during the remaining fourcycles. The control arm was bolus 5-FU/leucovorin/levamisole (Ergamisol). Thetrial closed to accrual in 2000 and the results are pending.

Until the results of INT 0144 are available, the choice of a postoperativeadjuvant regimen in the nonprotocol setting remains controversial. If 5-FU aloneis used, then it is probably best administered by continuous infusion.Otherwise, published data on 5-FU-based regimens indicate that they areprobably equally effective; the choice of a regimen should be based on factorssuch as acute toxicity profiles and patient compliance.

Adjuvant Therapy With 5-FU-Based Regimens: Preoperative Therapy

Given the advantage of chemotherapy in the postoperative setting, severalphase I/II preoperative combined-modality treatment programs have beendeveloped. Most have used 5-FU-based chemotherapy. Retrospective data suggestthat preoperative combined-modality therapy increases pathologic down-stagingcompared with preoperative radiation alone[6] and is associated with a lowerincidence of acute toxicity compared with postoperative combined-modalitytherapy.[7]

Preoperative therapy may also increase sphincter preservation. Seven seriesexamining this issue have been reported. The studies were carried out inpatients with clinically resectable rectal cancer whose surgeons had determinedprospectively (based on a clinical office exam before beginning preoperativetherapy) that they required abdominoperineal resection. All of the studiedregimens used conventional radiation doses and techniques—three with radiationtherapy alone[8-10] and four as combined-modality therapy.[11-14]

Results showed that the incidence of sphincter preservation afterpreoperative therapy was only 23% in the NSABP R-03 series[11] and 44% in theLyon series[10]; however, approximately 70% of patients in the remaining fiveseries had sphincter preservation. In the four series reporting functionaloutcome, the majority of patients (approximately 75%) had good to excellentsphincter outcome.

Some investigators have concluded that it is not necessary to addchemotherapy to preoperative radiation therapy. For example, in the SwedishRectal Cancer Trial, patients received an intensive short course of preoperativeradiation (5 Gy × 5) vs surgery alone.[15] Patients randomized to thepreoperative radiation group had a significant decrease in local recurrence rate(12% vs 27%, P < .001) and an improved 5-year survival rate (58% vs 48%, P =.004).

These impressive results should be analyzed in the context of other publishedliterature: First, given that the other 11 randomized trials of preoperativeradiation therapy did not report a survival benefit, these data clearly need tobe confirmed by additional studies.[16] Second, even if future trials confirm asurvival benefit, there are other equally important end points in rectal cancerthat need to be addressed. These include morbidity, mortality, and sphincterpreservation and function, all of which are adversely affected by intensiveshort-course preoperative radiation.[17,18] Lastly, the Dutch CKVO 95-04 trial,in which a total mesorectal excision was mandated and patients underwent thesame intensive short-course preoperative randomization to 5 Gy × 5 vs surgeryalone, reported a significant decrease in local recurrence rate withpreoperative radiation (2% vs 8%); however, the survival advantage reported inthe Swedish Rectal Cancer Trial was not demonstrated.[19]

To address whether chemotherapy (bolus 5-FU/leucovorin) is necessary eitherconcurrently with preoperative radiation and/or postoperatively, the EuropeanOrganization for Research and Treatment of Cancer (EORTC) is conducting thedefinitive randomized trial (EORTC 22921). The results are pending at this time.

When the goal of preoperative therapy is sphincter preservation, conventionaldoses and techniques of radiation are recommended. These include multiple-fieldtechniques to a total dose of 4,500 to 5,040 cGy at 180 cGy/fraction. Surgeryshould be performed a minimum of 4 weeks following completion of radiation.Unlike the intensive short course of radiation, this conventional design allowsfor recovery from acute side effects of radiation and enhances tumordown-staging. Data from the Lyon trial of preoperative radiation suggest that aninterval greater than 2 weeks following completion of radiation increases thechance of downstaging.[10]

Clearly, randomized trials are needed to confirm the suggestion of decreasedacute toxicity and enhanced sphincter preservation with preoperative therapy.Three randomized trials of preoperative vs postoperative combined modalitytherapy for clinically resectable T3 rectal cancer have been developed. Two arefrom the United States (INT 0147, NSABP R-03) and one is from Germany (CAO/ARO/AIO94). The three studies used conventional doses and techniques of radiationtherapy and concurrent 5-FU-based chemotherapy. A preoperative clinicalassessment to determine the type of operation indicated was also required.

Unfortunately, low accrual has resulted in early closure of both the INT 0147and NSABP R-03 trials. The German CAO/ARO/AIO 94 trial completed accrual of morethan 800 patients. It is the only trial that can adequately address the issuesof toxicity, efficacy, and sphincter preservation. A preliminary analysis of theNSABP R-03 trial, albeit underpowered with only 300 of the planned 900 patientsaccrued, revealed that patients who received preoperative therapy had a higherchance of having sphincter-sparing surgery and achieving disease-free status(44% vs 34%); however, this group also had an unexplained increase in grade 4 +toxicity (34% vs 23%).[20]

Preoperative Therapy Using Newer Chemotherapeutic Regimens

Several phase I/II trials of preoperative combined-modality therapy usingnewer chemotherapeutic agents such as raltitrexed (Tomudex),[21] UFT (uracil andtegafur)/leucovorin,[22] irinotecan,[23-27] oxaliplatin,[28] and capecitabine(Xeloda)[29] for patients with both resectable and unresectable disease areunder way. Additional trials are also examining targeted therapies such as C225and SU5416 (Iressa).

The significant survival advantage of irinotecan/5-FU/leucovorin vs5-FU/leucovorin or irinotecan alone in patients with metastatic colorectalcancer has generated considerable interest in integrating irinotecan intopreoperative combined-modality therapy regimens for rectal cancer.[30] Fivephase I or II trials are using combined irinotecan with radiation therapy. Twoof the trials assessed irinotecan as monotherapy[23,24] and three assessedirinotecan combined with 5-FU.[25-27]

Irinotecan Alone in Combined-Modality Therapy

Minsky et al[23] reported results of a phase I trial of escalating doses ofweekly irinotecan (8 to 13 mg/m² daily) administered weeks 1, 2, 4, and 5, plusconcurrent radiation at 50.4 Gy in 28 patients with T3/4 rectal cancer. Among 16patients treated at the recommended dose of 10 mg/m², the pathologic completeresponse rate was 5% and the grade 3 + acute toxicity rate was 29%. Becausethese results were inferior to those achieved previously with 5-FU/leucovorin-basedregimens tested at Memorial Sloan-Kettering Cancer Center,[14] this single-agentirinotecan regimen was not tested in the phase II setting.

Another trial of irinotecan alone with preoperative radiation was reported byVolter and colleagues from Lausanne.[24] A total of 20 patients with T3/4 rectalcancer were entered in this phase I trial. The irinotecan dose was escalatedfrom 30 to 105 mg/m² weekly × 3; hyperfractionated radiation (1.6 Gy bid to atotal dose of 41.6 Gy) began on week 2. There was a high incidence ofanastomotic leak and/or abscess (30%), which may have been partly related to thehyperfractionated radiation. The recommended dose level of irinotecan was 90mg/m².

Irinotecan Combination Regimens in Combined-Modality Therapy

In the remaining three trials of irinotecan in combined-modality therapy,5-FU was added to the preoperative radiation/irinotecan combination. Klautke andassociates from the University of Rostock performed a phase II trial in 26patients with various stages of rectal cancer.[26] Doses were fixed: irinotecan(40 mg/m² weekly), 5-FU (250 mg/m² by continuous infusion), and radiationtherapy (50.4 Gy). Grade 3 + toxicities were hematologic (15%) and diarrhea(35%). The 15 patients who underwent surgery had an impressive complete responserate (26% pathologic and 26% clinical).

Even higher complete response rates were reported in a phase II trial fromMetha and coworkers from Stanford University Medical Center.[25] A total of 22patients with T3 disease received irinotecan (50 mg/m² weekly × 4), 5-FU (200mg/m² by continuous infusion), and radiation at 50.4 Gy. Grade 3 + acutetoxicities were diarrhea (20%) and mucositis (15%). Among 18 patients whounderwent surgery, the complete response rates were 67% pathologic and 17%clinical.

The largest study was reported by Mitchell and colleagues from ThomasJefferson University.[27] In this phase I trial, 46 patients with T3/4 rectalcancer received irinotecan (30 to 60 mg/m² weekly × 4), 5-FU (225 to 300mg/m²by continuous infusion), and radiation therapy (45 to 54 Gy). This trial hadboth escalation and attenuation of the irinotecan, 5-FU, and radiation doses.Overall, there was a 24% pathologic complete response rate and a 15% clinicalcomplete response rate. Interestingly, patients whose tumors had evidence ofmicrosatellite instability had a higher complete response rate compared withthose without microsatellite instability. The recommended dose levels wereirinotecan at 50 mg/m² weekly × 4, 5-FU at 225 mg/m² daily × 5, and radiationtherapy at 54 Gy. This regimen is being compared with a regimen of preoperativecontinuous infusion 5-FU plus radiation bid in the randomized phase II RadiationTherapy Oncology Group (RTOG) protocol R-0012.

Conclusions

In summary, the ideal irinotecan-based preoperative combined-modality regimenhas not been determined. Results from phase I/II trials suggest thatpreoperative irinotecan plus radiation therapy is most effective when used incombination with 5-FU. This is consistent with data from the randomized trialthat revealed a significant survival benefit in patients with advancedcolorectal cancer.[30] While preliminary data reveal encouragingly high completeresponse rates, it should be emphasized that these rates need to be comparedwith those achievable with 5-FU-based therapy in randomized trials.

5-FU-based combined-modality therapy remains the standard of care forpatients with T3/4 rectal cancer. In addition to irinotecan, a number of newerchemotherapeutic agents are available and should be examined in preoperative andpostoperative combined-modality therapy regimens in patients with rectal cancer.

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