Irinotecan in Preoperative Combined-Modality Therapy for Locally Advanced Rectal Cancer

Oncology, ONCOLOGY Vol 14 No 12, Volume 14, Issue 12

Irinotecan (CPT-11, Camptosar) is a semisynthetic water-soluble derivative of the plant alkaloid camptothecin. This review will focus on the potential use of irinotecan in combination with fluorouracil (5-FU) in the preoperative combined-modality treatment of advanced rectal cancer.

ABSTRACT: Irinotecan (CPT-11, Camptosar) is a semisynthetic water-soluble derivative ofthe plant alkaloid camptothecin. This review will focus on the potential use ofirinotecan in combination with fluorouracil (5-FU) in the preoperativecombined-modality treatment of advanced rectal cancer. The laboratory studiesthat define the mechanism of fluoropyrimidine- and camptothecin-mediatedradiosensitization are discussed, and the rationale for combined-modalitytherapy using radiation with 5-FU and irinotecan is presented. [ONCOLOGY14(Suppl 14):56-59, 2000]


Since irinotecan (CPT-11, Camptosar) was approved by the USFood and Drug Administration for use in fluorouracil (5-FU)-refractory advancedcolorectal cancer, based on its demonstrated antitumor activity,[1] studies havereported the utility of irinotecan in first-line treatment of colorectalcancer.[2-9] In April 2000, irinotecan was approved by the Food and DrugAdministration for use as a component of first-line therapy in combination with5-FU and leucovorin for metastatic colorectal cancer. Additionally, preclinicaland clinical studies have suggested the potential effectiveness of irinotecan asa radiosensitizing agent.[10-16]

Combined-modality treatment with chemotherapy and radiation canimprove the therapeutic index in rectal carcinoma.[17] Fluorouracil is the mostwidely used chemotherapeutic agent in the clinical management of patients withrectal cancer. The benefits of combining fluoropyrimidines and radiation arethought to be due to radiosensitization.[18-20] Although postoperativeirradiation with systemic chemotherapy is currently considered to be the mosteffective treatment in the adjuvant setting,[21-23] preoperative irradiation hasdemonstrated distinct advantages in the treatment of this disease.[24] Theseinclude the decrease of tumor seeding while the numbers of oxygenated cellsduring surgery are increased, and the elimination of postsurgical small bowelfixation in the pelvis. In addition, preoperative radiation therapy allows thesurgeon to perform sphincter-sparing, low anterior resection.[25-37] Results ofrandomized trials also indicate that preoperative irradiation is more effectivethan postoperative in reducing local failure.[38-40]

Fluoropyrimidine Cytotoxicity

Fluorouracil is an analog of uracil and is metabolized to formseveral nucleotides including fluorodeoxyuridine monophosphate (F-dUMP). Thisnucleotide inhibits the enzyme thymidylate synthase, thus interfering with thesynthesis of new strands of DNA.[41,42] F-dUMP with a folate cofactor binds tothymidylate synthase, leading to depletion of the product deoxythymidinemonophosphate (dTMP) and, ultimately, of deoxythymidine triphosphate (dTTP).This results in accumulation of the substrate dUMP and deoxyuridine triphosphate(dUTP), so that dUTP is misincorporated into DNA. Prolonged thymidylate synthaseinhibition depletes dTTP pools, leading to inhibition of DNA synthesis, DNAfragmentation, G1/S cell-cycle arrest, and ultimately, cell death. Fluorouracilis also incorporated into RNA and DNA, but the inhibition of thymidylatesynthase is considered to be its main mechanism of action and ultimatelyresponsible for the DNA-directed effects of the drug.[43]

Fluoropyrimidine Radiation Interactions

Radiosensitization is related to thymidylate synthase inhibitionand is accompanied by both a decrease in double-stranded breaks[44-46] andsublethal damage repair.[47-49] Fluorouracil radiosensitization is enhanced byleucovorin, presumably by potentiation of thymidylate synthaseinhibition.[17,46,48]

Various mechanisms have been proposed to account forfluoropyrimidine-mediated sensitization. These include (1) alteration ofnucleotide pools, (2) redistribution of cells to a relatively radiosensitivephase of the cell cycle, and (3) incorporation of fluorodeoxyuridinetriphosphate into DNA.[17]

Although each of the proposed mechanisms may play a role influoropyrimidine-mediated sensitization, some studies suggest that cytotoxicitymay be inconsistent with radiosensitization.[19] The inappropriate progressionof cells through the G1/S boundary and into S phase during fluoropyrimidineexposure has also been proposed as a mechanism of radiosensitization.[50]

Radiation SensitizationWith Irinotecan

Preclinical studies have demonstrated synergistic effects andhave suggested radiosensitizing activity when the topoisomerase I inhibitoririnotecan is combined with radiation. Irinotecan may potentiate the lethaleffects of ionizing radiation by attaching to the DNA-topoisomerase adducts insites of DNA single-strand breaks. Subsequently, the irinotecan-topoisomeraseI-DNA complexes interact with advancing replication forks during the S phaseof the cell cycle, converting single-strand breaks into irreversible DNAdouble-strand breaks, resulting in cell death.

Fractionated irradiation synchronizes and resorbs the tumor cellpopulation, leaving the majority of the cells in the S phase of the cell cycleand thus more sensitive to irinotecan.[51] With potentiating effects morepronounced for chromosome aberrations of the exchange type, it has beensuggested that the interaction of unrepaired radiation- and camptothecin-inducedlesions during replication may be involved in the observed drug-radiationsynergism.[11]

Further studies have demonstrated radiation sensitization withirinotecan in human tumor xenografts. Significant tumor regression was shownwhen irinotecan was administered 1 hour prior to a single dose of irradiationcompared with the response to radiation therapy alone.[10] Other studies havealso demonstrated sensitization when the drug is given followingirradiation.[14]

Irinotecan in Combined-Modality Therapy

In a clinical phase I/II trial in which weekly irinotecan wasgiven with concurrent irradiation of 60 Gy administered in 30 fractions over 6weeks to patients with non-small-cell lung cancer, the maximum tolerated doseof irinotecan was 60 mg/m2.[15] A total of 24 previously untreated patientswith unresectable stage IIIA or IIIB non-small-cell lung cancer receivedchemoradiation with irinotecan given at a dose of 45 mg/m2. The six plannedcourses of irinotecan were delivered to 71% of patients; five courses wereadministered to 21% of patients. External beam irradiation was completed in 88%of patients, with treatment delays in three patients because of fever orfatigue. The overall objective response rate was 76%, with two patientsachieving a complete response and 16 a partial response. Dose-limitingtoxicities were esophagitis, pneumonitis, and diarrhea. The conclusion of thisstudy was that combined-modality therapy with irinotecan is feasible and activein the treatment of locally advanced non-small-cell lung cancer.

In a study by Minsky and colleagues at Memorial Sloan-KetteringCancer Center, a divided dose bolus schedule of escalating doses of irinotecan(Monday through Friday) was administered on weeks 1, 2, 4, and 5 during astandard 6-week radiation therapy cycle (50.4 Gy) for preoperative treatment oflocally advanced unresectable rectal cancer. The maximum tolerated dose was 10mg/m2/d. Because complete responses were fewer than anticipated, this regimenwas abandoned.[52]

How then might irinotecan be more effectively incorporated intoa combined-modality regimen in the treatment of rectal cancer? Our group at theKimmel Cancer Center of Thomas Jefferson University is currently conducting aphase I study with protracted continuous infusion of 5-FU given with weeklyirinotecan after 4 consecutive weeks and concurrent external beam irradiation(total of 45.0 Gy in 1.8-Gy fractions) given daily. The objective was todetermine the maximum tolerated dose of weekly irinotecan combined with 5-FU andconcomitant irradiation given preoperatively in previously untreated patientswith primary or recurrent clinical stage T3/T4 adenocarcinoma of the rectum.

The treatment regimen was as follows: escalating doses ofirinotecan at 30 to 50 mg/m2 over 90 minutes on days 1, 8, 15, and 22.Fluorouracil was given as a protracted venous infusion at 300 mg/m2/dayinitially and subsequently reduced to 225 mg/m2 on days 1 through 5 weeklyduring radiation therapy. Surgery was performed 8 to 10 weeks followingcompletion of therapy. At the time of this preliminary report, a total of 38patients were enrolled in the study. One patient was removed from the study fornoncompliance and one due to early surgical intervention. All are evaluable fortoxicity. The incidence of grade 3/4 toxicities at each dose level is outlinedin Table 1.

Hematologic toxicities were mild. The major dose-limitingtoxicities were diarrhea, intravenous catheter infections, and thrombi. Of 34patients who have undergone surgery, 10 complete pathologic remissions and 6patients with minimal residual disease were observed; 4 patients are awaitingsurgery. The conclusion was that the combination of irinotecan, 5-FU, andconcomitant radiation therapy given preoperatively in this patient populationwas well tolerated. The maximum tolderated dose had not been achieved in thisongoing investigation.[53]


The radiosensitizing properties of 5-FU have been welldelineated. Clinical studies evaluating the potential of irinotecan areunderway. Preclinical evidence from a murine model suggests effectiveness. Theability to administer full doses of irinotecan and 5-FU allows the potential ofdouble radio enhancement. Further studies will determine the effectiveness ofthis combination in the management of patients with adenocarcinoma of therectum.


1. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irinotecan(CPT-11) therapy for patients with previously treated metastatic colorectalcancer (CRC): Overall results of FDA-reviewed pivotal US clinical trials. ProcAm Soc Clin Oncol 16:228a, 1997.

2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plusfluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan StudyGroup. N Engl J Med 343:905-914, 2000.

3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecancombined with fluorouracil compared with fluorouracil alone as first-linetreatment for metastatic colorectal cancer: A multicentre randomised trial.Lancet 355:1041-1047, 2000.

4. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial ofirinotecan in patients with progresssive or rapidly recurrent colorectal cancer.J Clin Oncol 14:1128-1135, 1996.

5. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial ofirinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol15:2910-2919, 1997.

6. Shimada Y, Yoshino M, Wakui A, et al: Phase II study ofCPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J ClinOncol 11:909-913, 1993.

7. Rougier P, Bugat R, Douillard JY, et al: Phase II study ofirinotecan in the treatment of advanced colorectal cancer in chemotherapy-naivepatients and patients pretreated with fluorouracil-based chemotherapy. J ClinOncol 15:251-260, 1997.

8. Cunningham D, Pyrhönen S, James RD, et al: Randomized trialof iriniotecan plus supportive care versus supportive care alone afterfluorouracil failure for patients with metastatic colorectal cancer. Lancet352:1413-1418, 1998.

9. Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trialof irinotecan versus fluorouracil by continuous infusion after fluorouracilfailure in patients with metastatic colorectal cancer. Lancet 352:1407-1412,1998.

10. Tamura K, Takada M, Kawase I, et al: Enhancement of tumorradio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res88:218-223, 1997.

11. Zanier R, de Salvia R, Fiore M, et al: Topoisomerase Iactivity and cellular response to radiation in Chinese hamster cells. Int JRadiat Biol 70:251-259, 1996.

12. Hennequin C, Giocanti N, Balossa J, et al: Interaction ofionizing radiation with the topoisomerase I poison camptothecin in growing V-79and He La cells. Cancer Res 54:1720-1728, 1994.

13. Del Bino G, Bruno S, Yi PN, et al: Apoptotic cell deathtriggered by camptothecin or teniposide. The cell cycle specificity and effectsof ionizing radiation. Cell Prolif 25:537-548, 1992.

14. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of thecamptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation inhuman colon adenocarcinoma cells grown as spheroids. Radiother Oncol 43:197-201,1997.

15. Kudoh S, Kurihara N, Okishio K, et al: A phase I-II study ofweekly irinotecan (CPT-11) and simultaneous thoracic radiotherapy (TRT) forunresectable locally advanced non-small cell lung cancer (NSCLC). Proc Am SocClin Oncol 15:372, 1996.

16. Saka H, Shimokata K, Yoshida S, et al: Irinotecan (CPT-11)and concurrent radiotherapy in locally advanced non-small cell clung cancer(NSCLC): A phase II study of Japan Clinical Oncology Group (JCOG9504). Proc AmSoc Clin Oncol 16:447a, 1997.

17. Sobat H, Juretic A, Sanija M: Combined-modality therapy ofrectal cancers. Ann Oncol 10(suppl 6):99-103, 1999.

18. Byfield JE: Useful interactions between 5-fluorouracil andradiation in man: 5-fluorouracil as a radiosensitizer, in Hill BT and Bellamy AS(eds): Antitumor Drug Radiation Interactions pp. 87-105. Boca Raton, Florida,CRC Press, 1990.

19. Lawrence TS, Maybaum J: Fluoropyrimidines as radiationsensitizers. Semin Radiat Oncol 3:20-28, 1993.

20. McGinn CJ, Kinsella TJ: The clinical rationale for S-phaseradiosensitization in human tumors. Curr Prob Cancer 17:275-321, 1993.

21. Gastrointestinal Tumor Study Group: Prolongation of thedisease-free interval in surgically treated rectal carcinoma. N Engl J Med312:1465-1472, 1985.

22. Douglas HO Jr, Moertel CG, Mayer RJ, et al: Survival afterpostoperative combination treatment of rectal cancer. N Engl J Med315:1294-1295, 1986.

23. Krook JE, Moertel CG, Gunderson LL, et al: Effectivesurgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med324:709-715, 1991.

24. Minsky BD, Cohen AM, Kemeny N, et al: Combined modalitytherapy of rectal cancer: Decreased acute toxicity with the preoperativeapproach. J Clin Oncol 10:1218-1224, 1992.

25. Minsky BD, Kemeny N, Cohen AM, et al: Preoperative high-doseleucovorin/5-fluorouracil and radiation therapy for unresectable rectal cancer.Cancer 67:2859-2866, 1991.

26. Brierley JD, Cummings BJ, Wong CS, et al: Adenocarcinoma ofthe rectum treated by radical external radiation therapy. Int J Radiat OncolBiol Phys 31:255-259, 1995.

27. Emami B, Pilepich M, Willett C, et al: Effect ofpreoperative irradiation on resectability of colorectal carcinomas. Int J RadiatOncol Biol Phys 8:1295-1299, 1982.

28. Dosoretz DE, Gunderson LL, Hedberg S, et al: Preoperativeirradiation for unresectable rectal and rectosigmoid carcinomas. Cancer52:814-818, 1983.

29. Chan A, Wong A, Langevin J, et al: Preoperative concurrent5-fluorouracil infusion, mitomycin C and pelvic radiation therapy in tetheredand fixed rectal carcinoma. Int J Radiat Oncol Biol Phys 25:791-799, 1993.

30. Minsky BD, Cohen AM, Kemeny N, et al: Pre-operative combined5-FU, low dose leucovorin, and sequential radiation therapy for unresectablerectal cancer. Int J Radiat Oncol Biol Phys 25:821-827, 1993.

31. Minsky B, Cohen A, Enker W, et al: Preoperative5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectalcancer. Cancer 73:273-278, 1994.

32. Gérard A, Buyse M, Nordlinger B, et al: Preoperativeradiotherapy as adjuvant treatment in rectal cancer. Ann Surg 208:606-614, 1988.

33. Rich TA, Skibber JM, Ajani JA, et al: Preoperativeinfusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat OncolBio Phys 32:1025-1029, 1995.

34. Chen ET, Mohiuddin M, Brodovsky H, et al: Downstaging ofadvanced rectal cancer following combined preoperative chemotherapy and highdose radiation. Int J Radiat Oncol Bio Phys 30:169-175, 1994.

35. Myerson RJ, Michalski JM, King ML, et al: Adjuvant radiationtherapy for rectal carcinoma: Predictors of outcome. Int J Radiat Oncol Bio Phys32:41-50, 1995.

36. Swedish Rectal Cancer Trial: Improved survival withpreoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987,1997.

37. Frykholm G, Glimelius B, Påhlman L: Preoperativeirradiation with and without chemotherapy (MFL) in the treatment of primarilynon-resectable adenocarcinoma of the rectum. Results from two consecutivestudies. Eur J Cancer Clin Oncol 11:1535-1541, 1989.

38. Påhlman L, Glimelius B: Pre- or postoperative radiotherapyin rectal and rectosigmoid carcinoma: Report from a randomized multicentertrial. Ann Surg 211:187-195, 1990.

39. Glimelius B, Isacsson U, Jung B, et al: Radiotherapy inaddition to radical surgery in rectal cancer: Evidence for a dose-responseeffect favoring preoperative treatment. Int J Radiat Oncol Bio Phys 37:281-287,1997.

40. Frykholm GJ, Glimelius B, Påhlman L: Preoperative orpostoperative irradiation in adenocarcinoma of the rectum: Final treatmentresults of a randomized trial and an evaluation of late secondary effects. DisColon Rectum 36:564-572, 1993.

41. Chabner BA: Pyrimidine antagonists, in Chabner B (ed):Pharmacologic Principles of Cancer Treatment, pp 183-212. Philadelphia, WBSaunders, 1982.

42. Valeriote F, Santelli G: 5-fluorouracil (FUra). PharmacolTher 24:107-132, 1984.

43. Pinedo HM, Peters GFJ: Fluorouracil: Biochemistry andpharmacology. J Clin Oncol 6:1653-1664, 1988.

44. Pu AT, Robertson JM, Lawrence TS: Current status ofradiation sensitization by fluoropyrimidines. Oncology 9:707-714, 1995.

45. Bruso CE, Shewach DS, Lawrence TS:Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA doublestrand break repair in human colon cancer cells. J Radiat Oncol Biol Phys19:1411-1417, 1990.

46. Miller EM, Kinsella TJ: Radiosensitization byfluorodeoxyuridine: Effects of thymidylate synthase inhibition and cellsynchronization. Cancer Res 52:1687-1694, 1992.

47. Heimburger DK, Shewach DS, Lawrence TS: The effect offluorodeoxyuridine on sublethal damage repair in human colon cancer cells. Int JRadiat Oncol Biol Phys 21:983-987, 1991.

48. Lawrence TS, Davis MA, Maybaum J: Dependence of5-fluorouracil-mediated radiosensitization on DNA-directed effects. Int J RadiatOncol Biol Phys 29:519-523, 1994.

49. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologicrequirements for obtaining sensitization of human tumor cells in vitro tocombined 5-fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys8:1923-1933, 1982.

50. Davis MA, Tang HY, Maybaum J, et al: Dependence offluorodeoxyuridine-mediated radiosensitization on S phase progression. Int JRadiat Oncol Biol 67:509-517, 1995.

51. Szumiel I, Buraczewska I, Gradzka I, et al: Effects oftopoisomerase I-targeted drugs on radiation response of L5178Y sublinesdifferentially radiation and drug sensitive. Int J Radiat Biol 67:441-448, 1995.

52. Minsky BD, O’Reilly E, Wong D, et al: Daily low-doseirinotecan (CPT-11) plus pelvic irradiation as preoperative treatment of locallyadvanced rectal cancer. Proc Am Soc Clin Oncol 18:266a, 1999.

53. Anne P, Mitchell EP, Ahmad N, et al: Radiosensitization inlocally advanced adenocarcinoma of the rectum using combined modality therapywith CPT-11, 5-FU concomitant irradiation (abstract 970). Proc Am Soc Clin Oncol19:250a, 2000.