Irinotecan in Preoperative Combined-Modality Therapy for Locally Advanced Rectal Cancer
Irinotecan in Preoperative Combined-Modality Therapy for Locally Advanced Rectal Cancer
Since irinotecan (CPT-11, Camptosar) was approved by the US Food and Drug Administration for use in fluorouracil (5-FU)-refractory advanced colorectal cancer, based on its demonstrated antitumor activity, studies have reported the utility of irinotecan in first-line treatment of colorectal cancer.[2-9] In April 2000, irinotecan was approved by the Food and Drug Administration for use as a component of first-line therapy in combination with 5-FU and leucovorin for metastatic colorectal cancer. Additionally, preclinical and clinical studies have suggested the potential effectiveness of irinotecan as a radiosensitizing agent.[10-16]
Combined-modality treatment with chemotherapy and radiation can improve the therapeutic index in rectal carcinoma. Fluorouracil is the most widely used chemotherapeutic agent in the clinical management of patients with rectal cancer. The benefits of combining fluoropyrimidines and radiation are thought to be due to radiosensitization.[18-20] Although postoperative irradiation with systemic chemotherapy is currently considered to be the most effective treatment in the adjuvant setting,[21-23] preoperative irradiation has demonstrated distinct advantages in the treatment of this disease. These include the decrease of tumor seeding while the numbers of oxygenated cells during surgery are increased, and the elimination of postsurgical small bowel fixation in the pelvis. In addition, preoperative radiation therapy allows the surgeon to perform sphincter-sparing, low anterior resection.[25-37] Results of randomized trials also indicate that preoperative irradiation is more effective than postoperative in reducing local failure.[38-40]
Fluorouracil is an analog of uracil and is metabolized to form several nucleotides including fluorodeoxyuridine monophosphate (F-dUMP). This nucleotide inhibits the enzyme thymidylate synthase, thus interfering with the synthesis of new strands of DNA.[41,42] F-dUMP with a folate cofactor binds to thymidylate synthase, leading to depletion of the product deoxythymidine monophosphate (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 synthase inhibition depletes dTTP pools, leading to inhibition of DNA synthesis, DNA fragmentation, G1/S cell-cycle arrest, and ultimately, cell death. Fluorouracil is also incorporated into RNA and DNA, but the inhibition of thymidylate synthase is considered to be its main mechanism of action and ultimately responsible for the DNA-directed effects of the drug.
Radiosensitization is related to thymidylate synthase inhibition and is accompanied by both a decrease in double-stranded breaks[44-46] and sublethal damage repair.[47-49] Fluorouracil radiosensitization is enhanced by leucovorin, presumably by potentiation of thymidylate synthase inhibition.[17,46,48]
Various mechanisms have been proposed to account for fluoropyrimidine-mediated sensitization. These include (1) alteration of nucleotide pools, (2) redistribution of cells to a relatively radiosensitive phase of the cell cycle, and (3) incorporation of fluorodeoxyuridine triphosphate into DNA.
Although each of the proposed mechanisms may play a role in fluoropyrimidine-mediated sensitization, some studies suggest that cytotoxicity may be inconsistent with radiosensitization. The inappropriate progression of cells through the G1/S boundary and into S phase during fluoropyrimidine exposure has also been proposed as a mechanism of radiosensitization.
Preclinical studies have demonstrated synergistic effects and have suggested radiosensitizing activity when the topoisomerase I inhibitor irinotecan is combined with radiation. Irinotecan may potentiate the lethal effects of ionizing radiation by attaching to the DNA-topoisomerase adducts in sites of DNA single-strand breaks. Subsequently, the irinotecan-topoisomerase I-DNA complexes interact with advancing replication forks during the S phase of the cell cycle, converting single-strand breaks into irreversible DNA double-strand breaks, resulting in cell death.
Fractionated irradiation synchronizes and resorbs the tumor cell population, leaving the majority of the cells in the S phase of the cell cycle and thus more sensitive to irinotecan. With potentiating effects more pronounced for chromosome aberrations of the exchange type, it has been suggested that the interaction of unrepaired radiation- and camptothecin-induced lesions during replication may be involved in the observed drug-radiation synergism.
Further studies have demonstrated radiation sensitization with irinotecan in human tumor xenografts. Significant tumor regression was shown when irinotecan was administered 1 hour prior to a single dose of irradiation compared with the response to radiation therapy alone. Other studies have also demonstrated sensitization when the drug is given following irradiation.
In a clinical phase I/II trial in which weekly irinotecan was given with concurrent irradiation of 60 Gy administered in 30 fractions over 6 weeks to patients with non-small-cell lung cancer, the maximum tolerated dose of irinotecan was 60 mg/m2. A total of 24 previously untreated patients with unresectable stage IIIA or IIIB non-small-cell lung cancer received chemoradiation with irinotecan given at a dose of 45 mg/m2. The six planned courses of irinotecan were delivered to 71% of patients; five courses were administered to 21% of patients. External beam irradiation was completed in 88% of patients, with treatment delays in three patients because of fever or fatigue. The overall objective response rate was 76%, with two patients achieving a complete response and 16 a partial response. Dose-limiting toxicities were esophagitis, pneumonitis, and diarrhea. The conclusion of this study was that combined-modality therapy with irinotecan is feasible and active in the treatment of locally advanced non-small-cell lung cancer.
In a study by Minsky and colleagues at Memorial Sloan-Kettering Cancer Center, a divided dose bolus schedule of escalating doses of irinotecan (Monday through Friday) was administered on weeks 1, 2, 4, and 5 during a standard 6-week radiation therapy cycle (50.4 Gy) for preoperative treatment of locally advanced unresectable rectal cancer. The maximum tolerated dose was 10 mg/m2/d. Because complete responses were fewer than anticipated, this regimen was abandoned.
How then might irinotecan be more effectively incorporated into a combined-modality regimen in the treatment of rectal cancer? Our group at the Kimmel Cancer Center of Thomas Jefferson University is currently conducting a phase I study with protracted continuous infusion of 5-FU given with weekly irinotecan after 4 consecutive weeks and concurrent external beam irradiation (total of 45.0 Gy in 1.8-Gy fractions) given daily. The objective was to determine the maximum tolerated dose of weekly irinotecan combined with 5-FU and concomitant irradiation given preoperatively in previously untreated patients with primary or recurrent clinical stage T3/T4 adenocarcinoma of the rectum.
The treatment regimen was as follows: escalating doses of irinotecan 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/day initially and subsequently reduced to 225 mg/m2 on days 1 through 5 weekly during radiation therapy. Surgery was performed 8 to 10 weeks following completion of therapy. At the time of this preliminary report, a total of 38 patients were enrolled in the study. One patient was removed from the study for noncompliance and one due to early surgical intervention. All are evaluable for toxicity. The incidence of grade 3/4 toxicities at each dose level is outlined in Table 1.
Hematologic toxicities were mild. The major dose-limiting toxicities were diarrhea, intravenous catheter infections, and thrombi. Of 34 patients who have undergone surgery, 10 complete pathologic remissions and 6 patients with minimal residual disease were observed; 4 patients are awaiting surgery. The conclusion was that the combination of irinotecan, 5-FU, and concomitant radiation therapy given preoperatively in this patient population was well tolerated. The maximum tolderated dose had not been achieved in this ongoing investigation.
The radiosensitizing properties of 5-FU have been well delineated. Clinical studies evaluating the potential of irinotecan are underway. Preclinical evidence from a murine model suggests effectiveness. The ability to administer full doses of irinotecan and 5-FU allows the potential of double radio enhancement. Further studies will determine the effectiveness of this combination in the management of patients with adenocarcinoma of the rectum.
1. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irinotecan (CPT-11) therapy for patients with previously treated metastatic colorectal cancer (CRC): Overall results of FDA-reviewed pivotal US clinical trials. Proc Am Soc Clin Oncol 16:228a, 1997.
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000.
3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment 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 of irinotecan 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 of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997.
6. Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 11:909-913, 1993.
7. Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997.
8. Cunningham D, Pyrhönen S, James RD, et al: Randomized trial of iriniotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998.
9. Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998.
10. Tamura K, Takada M, Kawase I, et al: Enhancement of tumor radio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res 88:218-223, 1997.
11. Zanier R, de Salvia R, Fiore M, et al: Topoisomerase I activity and cellular response to radiation in Chinese hamster cells. Int J Radiat Biol 70:251-259, 1996.
12. Hennequin C, Giocanti N, Balossa J, et al: Interaction of ionizing radiation with the topoisomerase I poison camptothecin in growing V-79 and He La cells. Cancer Res 54:1720-1728, 1994.
13. Del Bino G, Bruno S, Yi PN, et al: Apoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation. Cell Prolif 25:537-548, 1992.
14. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human 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 of weekly irinotecan (CPT-11) and simultaneous thoracic radiotherapy (TRT) for unresectable locally advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin 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 Am Soc Clin Oncol 16:447a, 1997.
17. Sobat H, Juretic A, Sanija M: Combined-modality therapy of rectal cancers. Ann Oncol 10(suppl 6):99-103, 1999.
18. Byfield JE: Useful interactions between 5-fluorouracil and radiation 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 radiation sensitizers. Semin Radiat Oncol 3:20-28, 1993.
20. McGinn CJ, Kinsella TJ: The clinical rationale for S-phase radiosensitization in human tumors. Curr Prob Cancer 17:275-321, 1993.
21. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472, 1985.
22. Douglas HO Jr, Moertel CG, Mayer RJ, et al: Survival after postoperative combination treatment of rectal cancer. N Engl J Med 315:1294-1295, 1986.
23. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991.
24. Minsky BD, Cohen AM, Kemeny N, et al: Combined modality therapy of rectal cancer: Decreased acute toxicity with the preoperative approach. J Clin Oncol 10:1218-1224, 1992.
25. Minsky BD, Kemeny N, Cohen AM, et al: Preoperative high-dose leucovorin/5-fluorouracil and radiation therapy for unresectable rectal cancer. Cancer 67:2859-2866, 1991.
26. Brierley JD, Cummings BJ, Wong CS, et al: Adenocarcinoma of the rectum treated by radical external radiation therapy. Int J Radiat Oncol Biol Phys 31:255-259, 1995.
27. Emami B, Pilepich M, Willett C, et al: Effect of preoperative irradiation on resectability of colorectal carcinomas. Int J Radiat Oncol Biol Phys 8:1295-1299, 1982.
28. Dosoretz DE, Gunderson LL, Hedberg S, et al: Preoperative irradiation for unresectable rectal and rectosigmoid carcinomas. Cancer 52:814-818, 1983.
29. Chan A, Wong A, Langevin J, et al: Preoperative concurrent 5-fluorouracil infusion, mitomycin C and pelvic radiation therapy in tethered and fixed rectal carcinoma. Int J Radiat Oncol Biol Phys 25:791-799, 1993.
30. Minsky BD, Cohen AM, Kemeny N, et al: Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 25:821-827, 1993.
31. Minsky B, Cohen A, Enker W, et al: Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer. Cancer 73:273-278, 1994.
32. Gérard A, Buyse M, Nordlinger B, et al: Preoperative radiotherapy as adjuvant treatment in rectal cancer. Ann Surg 208:606-614, 1988.
33. Rich TA, Skibber JM, Ajani JA, et al: Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Bio Phys 32:1025-1029, 1995.
34. Chen ET, Mohiuddin M, Brodovsky H, et al: Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Bio Phys 30:169-175, 1994.
35. Myerson RJ, Michalski JM, King ML, et al: Adjuvant radiation therapy for rectal carcinoma: Predictors of outcome. Int J Radiat Oncol Bio Phys 32:41-50, 1995.
36. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997.
37. Frykholm G, Glimelius B, Påhlman L: Preoperative irradiation with and without chemotherapy (MFL) in the treatment of primarily non-resectable adenocarcinoma of the rectum. Results from two consecutive studies. Eur J Cancer Clin Oncol 11:1535-1541, 1989.
38. Påhlman L, Glimelius B: Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: Report from a randomized multicenter trial. Ann Surg 211:187-195, 1990.
39. Glimelius B, Isacsson U, Jung B, et al: Radiotherapy in addition to radical surgery in rectal cancer: Evidence for a dose-response effect favoring preoperative treatment. Int J Radiat Oncol Bio Phys 37:281-287, 1997.
40. Frykholm GJ, Glimelius B, Påhlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993.
41. Chabner BA: Pyrimidine antagonists, in Chabner B (ed): Pharmacologic Principles of Cancer Treatment, pp 183-212. Philadelphia, WB Saunders, 1982.
42. Valeriote F, Santelli G: 5-fluorouracil (FUra). Pharmacol Ther 24:107-132, 1984.
43. Pinedo HM, Peters GFJ: Fluorouracil: Biochemistry and pharmacology. J Clin Oncol 6:1653-1664, 1988.
44. Pu AT, Robertson JM, Lawrence TS: Current status of radiation sensitization by fluoropyrimidines. Oncology 9:707-714, 1995.
45. Bruso CE, Shewach DS, Lawrence TS: Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells. J Radiat Oncol Biol Phys 19:1411-1417, 1990.
46. Miller EM, Kinsella TJ: Radiosensitization by fluorodeoxyuridine: Effects of thymidylate synthase inhibition and cell synchronization. Cancer Res 52:1687-1694, 1992.
47. Heimburger DK, Shewach DS, Lawrence TS: The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells. Int J Radiat Oncol Biol Phys 21:983-987, 1991.
48. Lawrence TS, Davis MA, Maybaum J: Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects. Int J Radiat Oncol Biol Phys 29:519-523, 1994.
49. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys 8:1923-1933, 1982.
50. Davis MA, Tang HY, Maybaum J, et al: Dependence of fluorodeoxyuridine-mediated radiosensitization on S phase progression. Int J Radiat Oncol Biol 67:509-517, 1995.
51. Szumiel I, Buraczewska I, Gradzka I, et al: Effects of topoisomerase I-targeted drugs on radiation response of L5178Y sublines differentially radiation and drug sensitive. Int J Radiat Biol 67:441-448, 1995.
52. Minsky BD, O’Reilly E, Wong D, et al: Daily low-dose irinotecan (CPT-11) plus pelvic irradiation as preoperative treatment of locally advanced rectal cancer. Proc Am Soc Clin Oncol 18:266a, 1999.
53. Anne P, Mitchell EP, Ahmad N, et al: Radiosensitization in locally advanced adenocarcinoma of the rectum using combined modality therapy with CPT-11, 5-FU concomitant irradiation (abstract 970). Proc Am Soc Clin Oncol 19:250a, 2000.