Gemcitabine (2¢,2¢-difluorodeoxycytidine [dFdC,
Gemzar]) is a pyrimidine analog antimetabolite with single-agent activity in a
variety of solid tumors.[1-3] It is activated by intracellular phosphorylation
and has multiple mechanisms of cytotoxicity. The predominant intracellular
moiety, difluorodeoxycytidine triphosphate (dFdCTP), is incorporated as a
substrate during DNA synthesis causing inhibition of DNA elongation and chain
termination after the addition of another base or another molecule of dFdCTP.[2,4,5]
carbonyloxycamptothecin [CPT-11, Camptosar]) is a camptothecin analog. Its
active metabolite, SN-38, inhibits topoisomerase I activity by stabilizing the
topoisomerase I-DNA cleavable complex formed during enzymatic relaxation of
DNA tortional strain. Irinotecan has demonstrated broad activity against
human tumors in vitro and in vivo.[8,9] Significant single-agent activity has
been reported in colorectal cancer,[10,11] small-cell lung cancer, non-small-cell
lung cancer, uterine cervix cancer, and epithelial ovarian cancer.
Preclinical data evaluating the combination of irinotecan and gemcitabine are
limited. Kanazawa et al, evaluating the combination effects of anti-cancer
drugs, suggested dose-dependent interactions between gemcitabine and irinotecan.
Moreover, our recent laboratory data suggest antagonism at low concentrations,
but synergism at concentrations of gemcitabine above 0.1 µM and irinotecan above
3.2 µM in the SCOG small-cell lung cancer cell line. Absolute, marked
synergism was evident in the HL-60 acute myeloid leukemia cell line. Synergism
at concentrations of 0.1-2 µM gemcitabine and 0.2-10 µM irinotecan, but
antagonism at high concentrations (ie, concentrations > 2 µM gemcitabine and
20 µM irinotecan), was seen in MCF7 breast cancer cells (unpublished data). In
addition, preclinical data also suggest synergy with concurrent administration
of cytosine arabinoside (a gemcitabine analog) and irinotecan or SN-38.[18-20]
In this phase I trial, initially reported by our group in 1999  and
updated here, the dose of gemcitabine was fixed at 1,000 mg/m² and irinotecan
doses were escalated until a maximum tolerated dose for the combination was
defined. Because other studies of gemcitabine combinations using a day 1, 8, and
15 schedule had shown substantial day 15 marrow toxicity, we chose to administer
both drugs on days 1 and 8 of a 21-day treatment cycle.
Adult patients with pathologically confirmed solid tumors refractory to
standard therapy were eligible if they had adequate organ function (granulocyte
count of at least 1,500/µL, platelet count of at least 100,000/µL, serum
creatinine less than 2.1 mg/dL, and serum bilirubin less than 2.1 mg/dL), and
performance status of 0 to 2. Patients were ineligible if they had bone marrow
metastases, New York Heart Association class III or IV heart disease or
myocardial infarction within 6 months, uncontrolled infection, whole pelvic
radiation, prior gemcitabine and irinotecan, or a psychiatric condition.
Measurable or evaluable disease was not required. All patients gave written
1. Heinemann V, Hertel LW, Grindey GB, et al: Comparison of the cellular
pharmacokinetics and toxicity of 2¢,2¢-difluorodeoxycytidine and
1-b-D-arabinofuranosylcytosine. Cancer Res 48:4024-4031, 1988.
2. Lund B, Kristjansen PEG, Hansen HH: Clinical and preclinical activity of
2¢,2¢-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 19:45-55, 1993.
3. Hertel LW, Boder GB, Kroin JS, et al: Evaluation of the antitumor activity
of gemcitabine (2¢,2¢-difluoro-2¢-deoxycytidine). Cancer Res 50:4417-4422,
4. Plunkett W, Chubb S, Nowak B. Increased Cytotoxicity and therapeutic
activity of 2¢,2¢-difluorodeoxycytidine (dFdC) over cytosine arabinoside
(ara-C) in L1210 leukemia (abstract 1402). Proc Am Assoc Cancer Res 29:352,
5. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical
Pharmacology and mechanism of action. Semin Oncol 23(suppl 10):3-15, 1996.
6. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of
7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel
water-soluble derivative of camptothecin, against murine tumors. Cancer Res
7. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, a
metabolite of the camptothecin derivative CPT-11, in the antitumor effect of
CPT-11. Cancer Res 51:4187-4191, 1991.
8. Shimada Y, Rothemberg ML, Hilsenbeck SG, et al: Activity of CPT-11
(irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumor
colony-forming units. Anticancer Drugs 5:202-206, 1994.
9. Kawato Y, Furuta T, Aonuma M et al: Antitumor activity of a camptothecin
derivative, CPT-11, against human tumor xenografts in nude mice. Cancer
Chemother Pharmacol 28:192-198, 1991.
10. 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. Rothenberg M, Eckardt J, Kuhn J, et al: Phase II trial of irinotecan in
patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol
12. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative of
camptothecin for the treatment of refractory or relapsed small-cell lung cancer.
J Clin Oncol 10:1225-1229, 1992.
13. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study of CPT-11, a new
derivative of camptothecin, for previously untreated non-small-cell lung cancer.
J Clin Oncol 10:16-20, 1992.
14. Takeuchi S, Noda K, Yakushiji M, et al: Late phase II study of CPT-11,
topoisomerase I inhibitor, in advanced cervical carcinoma (abstract 708). Proc
Am Soc Clin Oncol 11:224, 1992.
15. Takeushi S, Dobashi K, Fujimoto S, et al: A late phase II study of
CPT-11, on uterine cervical cancer and ovarian cancer. Jpn J Cancer Chemother
16. Kanzawa F, Saijo N: In vitro interaction between gemcitabine and other
anticancer drugs using a novel three-dimensional model. Semin Oncol 24(suppl
17. Bahadori HR, Ogretmen B, Rocha Lima CM, et al: Evaluation of irinotecan
(CPT-11) and gemcitabine as single agents and in combination in small-cell lung
cancer cells (abstract 1837). Proc Am Soc Clin Oncol 17:477, 1998.
18. Kano Y, Suzuki K, Akutsu M, et al: Effects of CPT-11 in combination with
other anti-cancer agents in culture. Int J Cancer 50:604-610, 1992.
19. Furuta T, Yokokura T: Combination therapy of CPT-11, a camptothecin
derivative with various antitumor drugs against L 1210 leukemia. Jpn J Cancer
Chemother 18:393-402, 1991.
20. Akutsu M, Suzuki K, Tsunoda S, et al: Effects of SN-38 in combination
with other anticancer agents against Dauji cells. Jpn J Cancer Chemother
21. Rocha-Lima CS, Leong SS, Sherman CA, et al: Phase I study of CPT-11 and
gemcitabine in patients with solid tumors. Cancer Ther 2:58-66, 1999.
22. Sheperd FA, Burkes R, Cormier Y, et al: Phase I dose escalation trial of
gemcitabine and cisplatin for advanced non-small-cell lung cancer: Usefulness of
mathematic modeling to determine maximum-tolerable dose. J Clin Oncol
23. Crinò L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine
combination in advanced non-small-cell lung cancer: A phase II study. J Clin
Oncol 15:297-303, 1997.
24. Sandler A, Ansari R, McClean J, et al: Gemcitabine plus cisplatin in
non-small cell lung cancer: A phase II study. Sixth International Congress.
Anti-Cancer Treatment 78:1997.
25. Stadler WM, Murphy B, Kaufman D et al: Phase II trial of gemcitabine plus
cisplatin in metastatic urothelial cancer (abstract 1152). Proc Am Soc Clin
Oncol 16:323, 1997.
26. Maase H, Andersen L, Crino L, et al: A phase II study of gemcitabine and
cisplatin in patients with transitional cell carcinoma of the urothelium
(abstract 1155). Proc Am Soc Clin Oncol 16:324, 1997.
27. Rodier JM, Chouaki N, Schlumberger M, et al: Gemcitabine and vinorelbine
in solid tumors. Preliminary results of a phase I study (abstract 881). Proc Am
Soc Clin Oncol 16:249, 1997.
28. Panza N, Frasci G, Commela P, et al: Gemcitabine in addition to cisplatin
and vinorelbine in locally advanced or metastatic non-small-cell lung cancer
(NSCLC). A phase I study. Ann Oncol 8:1045-1048, 1997.
29. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous
infusions of CPT-11, a new derivative of camptothecin, in the treatment of
non-small-cell lung cancer. J Natl Cancer Inst 83:1164-1168, 1991.
30. de Forni M, Bugat R, Chabot GG, et al: Phase I and pharmacokinetic study
of the camptothecin derivative irinotecan, administered on a weekly schedule in
cancer patients. Cancer Res 54:4347-4354, 1994.
31. Abigerges D, Chabot GG, Armand J-P, et al: Phase I and pharmacologic
studies of the camptothecin analog irinotecan administered every 3 weeks in
cancer patients. J Clin Oncol 13:210-221, 1995.
32. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and pharmacokinetic
study of the novel topoisomerase I inhibitor
administered as a 90-minute infusion every 3 weeks. Cancer Res 54:427-436, 1994.
33. Rothenberg ML, Kuhn JG, Burris HA, III, et al: Phase I and
pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194-2204, 1993.
34. Ohe Y, Sasaki Y, Shinkai T, et al: Phase I and pharmacokinetic study of
CPT-11 with 5 days continuos infusion. J Natl Cancer Inst 12:972-974, 1992.
35. Merrouche Y, Extra J, Abigerges D et al: High dose-intensity of
irinotecan administered every 3 weeks in advanced cancer patients: A feasibility
study. J Clin Oncol 15:1080-1086, 1997.
36. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and
clinical benefit with gemcitabine as first-line therapy for patients with
advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997.
37. Sakata Y, Shimada Y, Yoshino M, et al: A late phase II study of CPT-11,
irinotecan hydrochloride, in patients with advanced pancreatic cancer. CPT-11
study group on gastrointestinal cancer. Jpn J Cancer Chemother 21:1039-1046,
38. Wagener DJ, Verdonk HE, Dirix LY, et al: Phase II trial of CPT-11 in
patients with advanced pancreatic cancer, an EORTC early clinical trials group
study. Ann Oncol 6:129-132, 1995.
39. Rocha Lima C, Savarese D, Bruckner H, et al: Irinotecan plus gemcitabine
induces both radiographic and CA 19-9 tumor marker responses in patients with
previously untreated advanced pancreatic cancer. J Clin Oncol 20:1182-1191,