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]
Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin [CPT-11, Camptosar]) is a camptothecin analog.[6] 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.[7] Irinotecan(Drug information on 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,[12] non-small-cell lung cancer,[13] uterine cervix cancer,[14] and epithelial ovarian cancer.[15]
Preclinical data evaluating the combination of irinotecan and gemcitabine(Drug information on gemcitabine) are limited. Kanazawa et al,[16] 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.[17] 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 2 µM gemcitabine and 20 µM irinotecan), was seen in MCF7 breast cancer cells (unpublished data).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 [21] 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.
Patients and Methods
Patient Selection
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 informed consent.
Treatment Plan
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
