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Gemcitabine

A Review of its Pharmacology and Clinical Potential in Non-Small Cell Lung Cancer and Pancreatic Cancer

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Summary

Synopsis

Gemcitabine [2′- deoxy- 2′,2′- difluorocytidine monohydrochloride (β isomer); dFdC] is a novel deoxycytidine analogue which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy.

Gemcitabine monotherapy produced an objective tumour response in 18 to 26% of patients with advanced non-small cell lung cancer (NSCLC) and appears to have similar efficacy to cisplatin plus etoposide. Objective response rates ranging from 26 to 54% were recorded when gemcitabine was combined with cisplatin, and 1- year survival duration after such treatment ranged from 35 to 61 %. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clinical trials.

Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addition, direct costs associated with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options, according to retrospective cost-minimisation analyses. The combination of gemcitabine plus cisplatin was associated with a lower cost per tumour response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness analysis.

In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clinical status. It also showed modest antitumour and palliative efficacy in patients refractory to fluorouracil.

Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The available data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerabilty profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study.

Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity associated with many other chemotherapy regimens. More detailed characterisation of its risk-benefit profile compared with those of current and developing regimens for NSCLC should be possible once results from several ongoing studies are available. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and aalliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognised.

Pharmacodynamic Properties

Gemcitabine [2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β isomer); dFdC] is a novel analogue of deoxycytidine which inhibits DNA synthesis. After cellular uptake, gemcitabine is phosphorylated to gemcitabine di- and triphosphate, the active metabolites. Gemcitabine triphosphate competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death. Its effects in this respect are enhanced by a number of unique self-potentiating pharmacological activities of gemcitabine di- and triphosphate. These effects maintain high intracellular concentrations of gemcitabine metabolites and reduce levels of deoxycytidine triphosphate (with which gemcitabine triphosphate competes for incorporation into DNA).

Gemcitabine has shown cytotoxic effects against a range of cancer cell lines invitroand had antitumour activity in a broad spectrum of animal models, including xenografts from patients with non-small cell lung cancer (NSCLC) or pancreatic cancer. Its effects invivowere schedule-rather than dose-dependent. At the maximum tolerated dose in murine models, gemcitabine inhibited the growth of human NSCLC xenografts by 45 to 76% compared with untreated control animals. It also inhibited growth of 3 of 4 human pancreatic cancer xenografts in mice by 69 to 73% at the maximum tolerated dose.

Pharmacokinetic Properties

Peak plasma concentrations of gemcitabine are reached 15 to 30 minutes after the start of a 30-minute intravenous infusion and typically range from 10 to 40 mg/L. Steady-state gemcitabine concentrations showed a linear relationship to dose over the dose range 53 to 1000 mg/m in one study in patients with a range of malignancies. Intracellular concentrations of gemcitabine triphosphate in peripheral blood mononuclear cells from these patients peaked within 30 minutes of starting the infusion and increased in proportion to dose up to gemcitabine 350 mg/m2. Increasing the dose beyond this level had no significant effect on the area under the intracellular concentration-time curve for gemcitabine triphosphate, indicating intracellular saturation.

Plasma binding of gemcitabine is minimal and the drug is not extensively distributed to tissues after short infusions. Gemcitabine is rapidly metabolised intracellularly, with a median elimination half-life of 8 minutes reported in one study in patients with cancer. Less than 10% of a radiolabelled gemcitabine dose is excreted unchanged in urine (significant amounts of the inactive metabolite 2′-deoxy-2′,2′-difluorouridine are detected in urine). Urinary excretion accounted for 30 to 96% (median 77%) of the administered dose in one small study.

Clinical Potential

Monotherapy with gemcitabine produced objective responses in 18 to 26% of patients with advanced NSCLC. Median response duration ranged from 3.3 to 12.7 months and overall median survival duration was 6.2 to 12.3 months. 22% of patients had an objective response in the largest trial of gemcitabine monotherapy (n=151); overall median survival duration was 9.4 months. Objective response rates for gemcitabine monotherapy and cisplatin plus etoposide were similar in 2 comparative trials (18 vs15% and 19 vs21%), as was median survival duration (6.6 vs7.6 months and 9.3 vs12 months). Gemcitabine in combination with cisplatin produced better results than gemcitabine monotherapy in patients with NSCLC: objective response rates ranged from 26 to 54% and overall median survival duration ranged from 10.4 to 15.4 months in 3 trials. Furthermore, estimated 1-year survival after treatment with gemcitabine plus cisplatin ranged from 35 to 61% in several studies. Improvements in pain were experienced by 31 to 52% of patients with NSCLC who received gemcitabine ± cisplatin in 3 non-comparative studies. Primary disease symptoms (cough, dyspnoea, haemoptysis and pleural effusion) improved in 42 to 89% of patients in one study and in 22 to 68% of patients in another; haemoptysis improved in about two-thirds of patients in both trials.

Gemcitabine was considered highly cost effective in comparison with best supportive care for NSCLC, according to a retrospective pharmacoeconomic analysis. It provided 1 additional life-year saved at a cost of $Can3193 (1993 Canadian dollars). Sensitivity analysis indicated that gemcitabine was still cost effective when the acquisition cost was increased by 80% and the assumed survival advantage over best supportive care was reduced by half. The cost per tumour response of gemcitabine plus cisplatin was 39, 35 or 8% lower than that of etoposide plus cisplatin, vinorelbine plus cisplatin or mitomycin plus ifosfamide plus cisplatin, respectively, according to another retrospective cost-effectiveness analysis (detailed statistical analysis not provided).

Results from a number of retrospective cost-minimisation analyses (which excluded primary drug costs) suggest that direct costs associated with administration of gemcitabine are lower than those for other NSCLC chemotherapy options. This was primarily because of the reduced cost of managing adverse events during gemcitabine therapy and the ability to administer the drug on an outpatient basis.

Gemcitabine was significantly more effective than fluorouracil with respect to both survival and palliative efficacy in a single comparative study in patients with advanced pancreatic cancer. Patients receiving gemcitabine had a 1.6-, 4.8- or 9-fold higher chance of surviving to 6, 9 or 12 months, respectively, than fluorouracil recipients (median survival difference between gemcitabine and fluorouracil recipients was 1.5 months). Furthermore, 5 times as many patients were considered to have derived clinical benefit from gemcitabine as from fluorouracil, based on assessment of pain, analgesic use, performance status and body weight.

Tolerability

Myelosuppression, transient elevation of hepatic enzymes and nausea and vomiting were the most common WHO grade 3 or 4 adverse events in 979 patients who received gemcitabine monotherapy at a starting dose of 800 to 1250 mg/m during clinical trials. However, fewer than 1% of patients withdrew from treatment for each of these reasons. Myelosuppression was the primary dose-limiting toxicity, with grade 3 or 4 neutropenia occurring in 25% of patients. Nausea and vomiting was common (69% at any grade) but occurred predominantly at grade 1 or 2. Transient elevations in hepatic enzymes occurred in about two-thirds of gemcitabine recipients, but were not associated with dose or treatment duration. Overall, about 10% of gemcitabine recipients stopped receiving treatment because of adverse effects (no single effect predominated).

The combination of gemcitabine with cisplatin was considered well tolerated in several small noncomparative trials in patients with NSCLC; grade 3 or 4 neutropenia and nausea and vomiting both occurred in ≈50% of patients in the largest available study (n=55); however, toxicity was considered to be easily managed overall.

Data from 2 comparative studies in patients with NSCLC indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide, although statistical analysis was not provided for either study.

Grade 3 or 4 adverse effects were more common in patients receiving gemcitabine than in those receiving fluorouracil in a randomised study in 126 patients with pancreatic cancer. Treatment withdrawal as a result of adverse effects was about 3 times more common among gemcitabine recipients (14.3%) than among patients receiving fluorouracil (4.8%). However, gemcitabine was generally well tolerated: the most common grade 3 event was neutropenia (19% of patients) and the incidence of individual grade 4 adverse effects was ≤7%. Grade 3 or 4 neutropenia was noted in 26% of patients receiving gemcitabine, compared with 5% of those treated with fluorouracil (p<001), but there was no significant difference between groups for grade 4 neutropenia (6.9 vs3.3%).

Dosage and Administration

The recommended dose for gemcitabine is 1000 mg/m2 as a 30-minute intravenous infusion administered once weekly (dose can be escalated to 1250 or 1500 mg/m2 in the absence of significant toxicity). Patients with NSCLC should be treated using a repeated 4-week cycle (3 weeks on, 1 week off), whereas those with pancreatic cancer receive the drug on an initial 8-week cycle (7 weeks on, 1 week off) followed by the 4-week cycle thereafter. Patients receiving gemcitabine should be monitored regularly for myelosuppression and periodically for renal and hepatic dysfunction.

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References

  1. Guchelaar H-J, Richel DJ, van Knapen A. Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat Rev 1996 Jan; 22: 15–31

    PubMed  CAS  Google Scholar 

  2. Lund B, Kristjansen PEG, Hansen HH. Clinical and preclinical activity of 2′,2′-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 1993 Jan; 19: 45–55

    PubMed  CAS  Google Scholar 

  3. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer Drugs 1995 Dec; 6 Suppl. 6: 7–13

    PubMed  CAS  Google Scholar 

  4. Plunkett W, Huang P, Xu Y-Z, et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 1995 Aug; 22 Suppl.. 11: 3–10

    PubMed  CAS  Google Scholar 

  5. Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol 1996 Oct; 23 Suppl. 10: 3–15

    PubMed  CAS  Google Scholar 

  6. Heinemann V, Hertel LW, Grindey GB, et al. Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-gb-D-arabinofuranosylcytosine. Cancer Res 1988 Jul 15; 48: 4024–31

    PubMed  CAS  Google Scholar 

  7. Gandhi V, Huang R Xu Y-Z, et al. Metabolism and action of 2′,2′-difluorodeoxycytidine: self-potentiation of cytotoxicity. Adv Exp Med Biol 1991; 309: 125–30. Harkness RA, et al., editors. Purine and pyrimidine metabolism in man VII, Part A. New York: Plenum Press, 1991

    Google Scholar 

  8. Heinemann V, Xu Y-Z, Chubb S, et al. Cellular elimination of 2′,2′-difluorodeoxycytidine 5′-triphosphate: a mechanism of self-potentiation. Cancer Res 1992 Feb 1; 52: 533–9

    PubMed  CAS  Google Scholar 

  9. Huang P, Chubb S, Hertel LW, et al. Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991 Nov 15; 51: 6110–7

    PubMed  CAS  Google Scholar 

  10. Huang P, Plunkett W. Fludarabine- and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 1995 Jul; 36: 181–8

    PubMed  CAS  Google Scholar 

  11. Ruiz van Haperen VWT, Veerman G, Vermorken JB, et al. 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 1993 Aug 17; 46: 762–6

    PubMed  CAS  Google Scholar 

  12. Santini V, Bernabei PA, Gozzini A, et al. Apoptotic and antiproloferative effects of gemcitabine and gemcitabine plus ara-c on blast cells from patients with blast crisis chronic myeloproliferative disorders. Haematologica 1997; 82: 11–5

    PubMed  CAS  Google Scholar 

  13. Bouffard DY, Momparler LF, Momparler RL. Comparison of antineoplastic activity of 2′,2′-difluorodeoxycytidine and cytosine arabinoside against human myeloid and lymphoid leukemic cells. Anticancer Drugs 1991 Feb; 2: 49–55

    PubMed  CAS  Google Scholar 

  14. Ruiz van Haperen VWT, Veerman G, Noordhuis P, et al. Concentration and time dependent growth inhibition and metabolism in vitro by 2′,2′-difluoro-deoxycytidine (gemcitabine). Adv Exp Med Biol 1991; 309: 57–60. Harkness RA, et al., editors. Purine and pyrimidine metabolism in man VII, Part A. New York: Plenum Press, 1991

    Google Scholar 

  15. Hanauske A-R, Degen D, Marshall MH, et al. Activity of 2′,2′-difluorodeoxycytidine (gemcitabine) against human tumor colony forming units. Anticancer Drugs 1992 Apr; 3: 143–6

    PubMed  CAS  Google Scholar 

  16. Cory AH, Hertel LW, Kroin JS, et al. Effects of 2′,2′-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells. Oncol Res 1993; 5(2): 59–63

    PubMed  CAS  Google Scholar 

  17. Ruiz van Haperen VWT, Veerman G, Boven E, et al. Schedule dependence of sensitivity to 2′,2′-difluorodeoxycytidine (gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumour cell lines and solid tumours. Biochem Pharmacol 1994 Oct 7; 48: 1327–39

    PubMed  CAS  Google Scholar 

  18. Csoka K, Liliemark J, Larsson R, et al. Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol 1995 Aug; 22 Suppl. 11: 47–53

    PubMed  CAS  Google Scholar 

  19. Tsai C-M, Chang K-T, Chen J-Y, et al. Cytotoxic effects of gemcitabine-containing regimens against human non-small cell lung cancer cell lines which express different levels of pl85neul. Cancer Res 1996 Feb 15; 56: 794–801

    PubMed  CAS  Google Scholar 

  20. Santini V, D’Ippolito G, Bernabei PA, et al. Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: direct comparison of cytotoxicity and cellular Ara-C uptake enhancement. Leuk Res 1996 Jan; 20: 37–45

    PubMed  CAS  Google Scholar 

  21. Cronauer MV, Klocker H, Talasz H, et al. Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells. Prostate 1996 Mar; 28: 172–81

    PubMed  CAS  Google Scholar 

  22. Bergman AM, Ruiz van Haperen VWT, Veerman G, et al. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996 Mar; 2: 521–30

    PubMed  CAS  Google Scholar 

  23. Von Hoff DD, San Antonio Drug Development Team. Activity of gemcitabine in a human tumor cloning assay as a basis for clinical trials with gemcitabine. Invest New Drugs 1996; 14(3): 265–70

    Google Scholar 

  24. Peters GJ, Smitskamp-Wilms E, Veerman G, et al. Three-dimensional cell cultures as a model system to evaluate the biological activity of gemcitabine (2′,2′-difluoro-2′deoxycytidine). Nucleosides Nucleotides 1995; 14(3-5): 661–4

    CAS  Google Scholar 

  25. Gruber J, Geisen F, Sgonc R, et al. 2′,2′-Difluorodeoxycytidine (gemcitabine) induces apoptosis in myeloma cell lines resistant to steroids and 2-chlorodeoxyadenosine (2-CdA). Stem Cells 1996 May; 14: 351–62

    PubMed  CAS  Google Scholar 

  26. Nakamura H, Yamaji Y, Fujita T, et al. Synergistic growth inhibition of gemcitabine/cisplatin, and gemcitabine/etoposide on a human lung cancer cell line, RERF-LC-OK [abstract]. 86th Annu Meet Am Assoc Cancer Res 1995 Mar; 36: 407

    Google Scholar 

  27. van Moorsel CJA, Veerman G, Bergman AM, et al. Combination chemotherapy studies with gemcitabine. Semin Oncol 1997 Apr; 24(2) Suppl. 7: S17–23

    Google Scholar 

  28. Peters GJ, Bergman AM, Ruiz van Haperen VWT, et al. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995 Aug; 22 Suppl. 11: 72–9

    PubMed  CAS  Google Scholar 

  29. Shewach DS, Lawrence TS. Radiosensitization of human tumor cells by gemcitabine in vitro. Semin Oncol 1995 Aug; 22 Suppl. 11: 68–71

    PubMed  CAS  Google Scholar 

  30. Shewach DS, Lawrence TS. Gemcitabine and radiosensitization in human tumor cells. Invest New Drugs 1996; 14(3): 257–63

    PubMed  CAS  Google Scholar 

  31. Shewach DS, Lawrence TS. Radiosensitization of human solid tumor cell lines with gemcitabine. Semin Oncol 1996 Oct; 23 Suppl. 10: 65–71

    PubMed  CAS  Google Scholar 

  32. Lawrence TS, Chang EY, Hahn TM, et al. Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys 1996 Mar 1; 34: 867–72

    PubMed  CAS  Google Scholar 

  33. Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 1990 Jul 15; 50: 4417–22

    PubMed  CAS  Google Scholar 

  34. Veerman G, Ruiz van Haperen VWT, Vermorken JB, et al. Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors. Cancer Chemother Pharmacol 1996 Aug; 38: 335–42

    PubMed  CAS  Google Scholar 

  35. Schultz RM, Merriman RL, Toth JE, et al. Evaluation of new anticancer agents against the MIA paCa-2 and PANC-1 human pancreatic carcinoma xenografts. Oncol Res 1993; 5(6–7): 223–8

    PubMed  CAS  Google Scholar 

  36. Merriman RL, Hertel LW, Schultz RM, et al. Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Invest New Drugs 1996; 14(3): 243–7

    PubMed  CAS  Google Scholar 

  37. Braakhuis BJM, Ruiz van Haperen VWT, Welters MJP, et al. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur J Cancer A 1995; 31A(13-14): 2335–40

    PubMed  CAS  Google Scholar 

  38. Braakhuis BJM, Ruiz van Haperen VWT, Boven E, et al. Schedule-dependent antitumor effect of gemcitabine in in vivo model systems. Semin Oncol 1995 Aug; 22 Suppl. 11: 42–6

    PubMed  CAS  Google Scholar 

  39. Braakhuis BJM, van Dongen GAMS, Vermorken JB, et al. Preclinical in Vivo activity of 2′,2′-difluorodeoxycytidine (Gemcitabine) against human head and neck cancer. Cancer Res 1991 Jan 1; 51: 211–4

    PubMed  CAS  Google Scholar 

  40. Boven E, Schipper H, Erkelens CAM, et al. The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer. Br J Cancer 1993 Jul; 68: 52–6

    PubMed  CAS  Google Scholar 

  41. Kristjansen PEG, Quistorff B, Vindel0v LL, et al. 19F-NMR-spectroscopic pharmacokinetic analysis and in vivo activity of difluorodeoxycytidine (dFdC) in two small cell lung cancer (SCLC) xenografts. Preliminary results [abstract no. W3: 9]. Ann Oncol 1990; 1 Suppl.: 88

    Google Scholar 

  42. Eli Lilly and Company. Summary of product characteristics: gemcitabine. UK prescribing information. Eli Lilly, 1997

  43. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991 Mar; 9: 491–8

    PubMed  CAS  Google Scholar 

  44. Grunewald R, Abbruzzese JL, Tarassoff P, et al. Saturation of 2′,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991 Jan; 27: 258–62

    PubMed  CAS  Google Scholar 

  45. Eli Lilly and Company. Gemzar® (gemcitabine HCl) for injection. US prescribing information. Eli Lilly and Company (Indianapolis)

  46. Peters GJ, Schornagel JH, Milano GA. Clinical pharmacokinetics of anti-metabolites. Cancer Surv 1993; 17: 123–56

    PubMed  CAS  Google Scholar 

  47. van Moorsel CJA, Veerman G, Ruiz van Haperen VWT, et al. Differential effects of gemcitabine on nucleotide pools in 19 solid tumor cell lines. Adv Exp Biol Med. Griesmacher A, Chiba P, Muller MM, editors. Purine and pyrimidine metabolism in man IX. New York: Plenum Publishing Corporation. In press

  48. Esumi Y, Mitsugi K, Seki H, et al. Placental transfer, lacteal transfer and plasma protein binding of gemcitabine. Xenobiotica 1994 Oct; 24: 957–64

    PubMed  CAS  Google Scholar 

  49. Abratt RP, Bezwoda WR, Falkson G, et al. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 1994 Aug; 12: 1535–40

    PubMed  CAS  Google Scholar 

  50. Anderson H, Lund B, Bach F, et al. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994 Sep; 12: 1821–6

    PubMed  CAS  Google Scholar 

  51. Begbie SD, Hui R, Levi JA, et al. Initial experience with gemcitabine for non-small cell lung cancer in Australia [abstract]. Proc Am Soc Clin Oncol 1995 Mar; 14: 378

    Google Scholar 

  52. Crino L, Mosconi AM, Scagliotti G, et al. Salvage therapy with gemcitabine (GEM) in pretreated, advanced non-small cell lung cancer (NSCLC) [abstract no. *1603]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 446a

    Google Scholar 

  53. Fossella FV, Lippman SM, Shin DM, et al. Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer. J Clin Oncol 1997 Jan; 15(1): 310–6

    PubMed  CAS  Google Scholar 

  54. Fukuoka M, Negoro S, Kudo S, et al. A late phase II study of gemcitabine (LY188011) against non-small cell lung cancer [in Japanese]. Jpn J Cancer Chemother 1996; 23(13): 1825–32

    CAS  Google Scholar 

  55. Gatzemeier U, Shepherd FA, Le Chevalier T, et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer A 1996 Feb; 32A: 243–8

    PubMed  CAS  Google Scholar 

  56. Lund B, Ryberg M, Petersen PM, et al. Phase II study of gemcitabine (2′,2′-difluorodeoxycytidine) given as a twice weekly schedule to previously untreated patients with non-small cell lung cancer. Ann Oncol 1994 Nov; 5: 852–3

    PubMed  CAS  Google Scholar 

  57. Malayeri R, Ulsperger E, Baumgartner G, et al. Gemcitabine in the treatment of non-small-cell lung cancer [abstract no. 460P]. Ann Oncol 1996; 7 Suppl. 5

  58. Yokoyama A, Nakai Y, Yoneda S, et al. A late phase II study of gemcitabine (LY 188011) against non-small cell lung cancer [in Japanese]. Jpn J Cancer Chemother 1996; 23(12): 1681–8

    CAS  Google Scholar 

  59. Manegold C, Stahel R, Ricci S, et al. Randomized phase II study of gemcitabine (GEM) monotherapy versus cisplatin plus etoposide (C/E) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) [abstract no. * 1651]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 460A

    Google Scholar 

  60. Perng R-P, Chen Y-M, Ming-Liu J, et al. Gemcitabine versus the combination of cisplatin and etoposide in patients with inoperable non-small-cell lung cancer in a phase II randomized study. J Clin Oncol 1997 May; 15(5): 2097–102

    PubMed  CAS  Google Scholar 

  61. Abratt RP, Bezwoda WR, Goedhals L, et al. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 1997 Feb; 15(2): 744–9

    PubMed  CAS  Google Scholar 

  62. Anton A, Artal A, Carrato A, et al. Gemcitabine plus cisplatin in advanced NSCLC: final phase II results [abstract no. 1656]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 461a

    Google Scholar 

  63. 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 1997; 15: 297–303

    PubMed  Google Scholar 

  64. Gonzalez-Baron M, Ordonez A, Gracia M, et al. Gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC): results from a phase II study [abstract no. 1687]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 469a

    Google Scholar 

  65. Sandler AB, Ansari R, McClean J, et al. A Hoosier Oncology Group phase II study of gemcitabine plus cisplatin in non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol 1995 Mar; 14: 357

    Google Scholar 

  66. Shepherd FA, Cormier Y, Burkes R, et al. Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer.Semin Oncol 1997 Jun; 24(3) Suppl. 8: S27–30

    Google Scholar 

  67. Steward WP, Dunlop DJ, Cameron C, et al. Phase I/II study of cisplatin in combination with gemcitabine in non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol 1995 Mar; 14:351

    Google Scholar 

  68. Cardenal F, Rosell R, Anton A, et al. Gemcitabine + cisplatin versus etoposide + cisplatin in advanced non-small cell lung cancer patients: preliminary randomized phase III results [abstract no. *1648]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 458a

    Google Scholar 

  69. Eli Lilly and Company (Indianapolis), 1997. Data on file

  70. Gatzemeier U, Manegold C, Eberhard W, et al. A phase II trial of gemcitabine and ifosfamide in non-small cell lung cancer. Semin Oncol 1997; 24(3) Suppl. 8: S8-36–S8-38

    Google Scholar 

  71. Cornelia P, Panza N, Frasci G, et al. Gemcitabine (GEM)-cisplatin (CDDP)-vinorelbine (VNR) combination in advanced non-small cell lung cancer (NSCLC): a phase II randomized study [abstract no. *1615]. Thirty-Third Annual Meeting, American Society of Clinical Oncologists; 1997 May 17–20; Denver, Vol. 16, 449a

    Google Scholar 

  72. Copley-Merriman C, Martin C, Johnson N, et al. Economic value of gemcitabine in non-small cell lung cancer. Semin Oncol 1996 Oct; 23 Suppl. 10: 90–8

    PubMed  CAS  Google Scholar 

  73. Copley-Merriman C, Corral J, King K, et al. Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer. Lung Cancer 1996 Feb; 14: 45–61

    PubMed  CAS  Google Scholar 

  74. Koch P, Johnson N, van Schaik J, et al. Gemcitabine: clinical and economic impact in inoperable non-small cell lung cancer. Anticancer Drugs 1995 Dec; 6 Suppl. 6: 49–54

    PubMed  CAS  Google Scholar 

  75. Ragnarson Tenvall G, Fernberg J-O, Grupper M, et al. Chemotherapy treatment in stage IIIB and IV NSCLC — a health economic evaluation of gemcitabine Vs standard treatment [abstract no. 467P]. Ann Oncol 1995; 7 Suppl. 5

  76. Evans WK. An estimate of the cost effectiveness of gemcitabine in stage IV non-small cell lung cancer. Semin Oncol 1996 Oct; 23 Suppl. 10: 82–9

    PubMed  CAS  Google Scholar 

  77. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: report of a Canadian multicentre randomized trial. J Clin Oncol 1988 Apr; 6(4): 633–41

    PubMed  CAS  Google Scholar 

  78. Palmer AJ, Brandt A. The cost-effectiveness of four cisplatincontaining chemotherapy regimens in the treatment of stages III B and IV non-small cell lung cancer: an Italian perspective. Monaldi Arch Chest Dis 1996; 51(4): 279–88

    PubMed  CAS  Google Scholar 

  79. Will BP, Evans WK, Berthelot J-M, et al. A Canadian economic analysis of chemotherapeutic agents versus best supportive care in the treatment of advanced lung cancer [abstract]. Thirteenth Annual Meeting, International Society Technology Assessment Health Care; 1997 May 25–28; Barcelona, 77

  80. Gralla RJ, Grusenmeyer PA, Brooks BJ. Evaluating the costs and cost-effectiveness of new regimens for non-small cell lung cancer (NSCLC) [abstract no. *1501]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 420a

    Google Scholar 

  81. Carmichael J, Fink U, Russell RCG, et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 1996 Jan; 73: 101–5

    PubMed  CAS  Google Scholar 

  82. Casper ES, Green MR, Kelsen DP, et al. Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994; 12(1): 29–34

    PubMed  CAS  Google Scholar 

  83. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996; 7: 347–53

    PubMed  CAS  Google Scholar 

  84. Storniolo AM, Enas NH, Brown CA, et al. Treatment investigational new drug program for Gemzar (gemcitabine HC1) in patients with pancreas cancer (PaCa) [abstract no. 1088]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 306a

    Google Scholar 

  85. Burris III HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer: a randomized trial. J Clin Oncol 1997 Jun; 15(6): 2403–13

    PubMed  CAS  Google Scholar 

  86. Niyikiza C, Anderson JS, Tarassoff PG, et al. Prognostic factors in a randomized trial of gemcitabine (GEM) versus 5-FU as first-line therapy in advanced pancreatic cancer and in pancreatic cancer patients failing 5-FU who receive gemcitabine (GEM) as a palliative therapy [abstract no. 1624]. Thirty-Second Annual Meeting, American Society of Clinical Oncology; 1996 May 18–21; Philadelphia, Vol. 15, 506

    Google Scholar 

  87. Green MR. Gemcitabine safety overview. Semin Oncol 1996 Oct; 23 Suppl. 10: 32–5

    PubMed  CAS  Google Scholar 

  88. Tonato M, Mosconi AM, Martin C. Safety profile of gemcitabine. Anticancer Drugs 1995 Dec; 6 Suppl. 6: 27–32

    PubMed  CAS  Google Scholar 

  89. Martin C, Pollera CF. Gemcitabine: safety profile unaffected by starting dose. Int J Clin Pharmacol Res 1996; 16(1): 9–18

    PubMed  CAS  Google Scholar 

  90. Martin C, Lund B, Anderson H, et al. Gemcitabine: once-weekly schedule active and better tolerated than twice-weekly schedule. Anticancer Drugs 1996 May; 7: 351–7

    PubMed  CAS  Google Scholar 

  91. Eli Lilly and Company. Gemzar labelling outside the United States. Eli Lilly and Company, 1997. Data on file

  92. American Cancer Society. Lung cancer. In: Cancer Facts and Figures — 1997 [online]. American Cancer Society; 1997. Available from: URL: http://www.cancer.org/971ung.html [Accessed 1997 Mar 24]

  93. Kelly P, Clancy L. Is the use of chemotherapy justified in non-small-cell lung cancer? Drugs Aging 1994 Jan; 4: 1–8

    PubMed  CAS  Google Scholar 

  94. Carbone DP, Minna JD. Chemotherapy for non-small cell lung cancer: a meta-analysis suggests that the benefits are small. BMJ 1995 Oct 7; 311: 889–90

    PubMed  CAS  Google Scholar 

  95. Abang AM. Chemotherapy versus best supportive care for advanced non-small-cell lung cancer. Am J Health System Pharm 1996 Dec 15; 53: 2980–4

    CAS  Google Scholar 

  96. Thatcher N, Niven RM, Anderson H. Aggressive vs nonaggressive therapy for metastatic NSCLC. Chest 1996 May; 109 Suppl.: 87S–92S

    PubMed  CAS  Google Scholar 

  97. Raby B, Pater J, Mackillop W. A survey of Canadian physician’s beliefs about the use of radiation and chemotherapy in non-small cell lung cancer [abstract no. * 1079]. 30th Annual Meeting, American Society of Clinical Oncology; 1994 May 14–17; Vol. 13,327

    Google Scholar 

  98. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899–909

    Google Scholar 

  99. Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993 July 3; 342: 19–21

    PubMed  CAS  Google Scholar 

  100. Thatcher N, Anderson H, Betticher DC, et al. Symptomatic benefit from gemcitabine and other chemotherapy in advanced non-small cell lung cancer: changes in performance status and tumour-related symptoms. Anticancer Drugs 1995 Dec; 6 Suppl. 6: 39–48

    PubMed  CAS  Google Scholar 

  101. Hansen HH, Sorensen JB. Efficacy of single-agent gemcitabine in advanced non-small cell lung cancer: a review. Semin Oncol 1997 Apr; 24 (2 Suppl. 7): S38–41

    Google Scholar 

  102. Comis RL, Friedland DM. New chemotherapy agents in the treatment of advanced non-small cell lung cancer: an update including data from the Seventh World Conference on Lung Cancer. Lung Cancer 1995 Jun; 12 Suppl. 2: S63–99

    PubMed  Google Scholar 

  103. Steward WP, Dunlop DJ. New drugs in the treatment of non-small cell lung cancer. Ann Oncol 1995; 6 Suppl. 1: S49–54

    Google Scholar 

  104. van Zandwijk N, Giaccone G. Treatment of metastatic non-small cell lung cancer. Curr Opin Oncol 1996 Mar; 8: 120–5

    PubMed  Google Scholar 

  105. Bergman B, Aaronson NK. Quality-of-life and cost-effectiveness assessment in lung cancer. Curr Opin Oncol 1995; 7: 138–43

    PubMed  CAS  Google Scholar 

  106. Riggs CE, Bennett JP. Clinical pharmacology of individual antineoplastic agents. In: Moosa AR, Schimpff SC, Robson MC, editors. Comprehensive textbook of oncology. 2nd ed. v. 1. Baltimore: Williams & Wilkins, 1991: 537–64

    Google Scholar 

  107. The Pharmaceutical Press, editor. Martindale: the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press, 1993

    Google Scholar 

  108. Natale RB. Overview of current and future chemotherapeutic agents in non-small cell lung cancer. Semin Oncol 1997 Apr; 24(2) Suppl. 7: S7-29–S7-37

    Google Scholar 

  109. Desch CE, Hillner BE, Smith TJ. Economic considerations in the care of lung cancer patients. Curr Opin Oncol 1996 Mar; 8: 126–32

    PubMed  CAS  Google Scholar 

  110. Thatcher N, Hopwood P, Anderson H. Improving quality of life in patients with non-small cell lung cancer: research experience with gemcitabine. Eur J Cancer 1997; 33 Suppl. 1: S8–13

    PubMed  CAS  Google Scholar 

  111. American Cancer Society. Pancreas Cancer. In: Cancer Facts & Figures — 1997 [online]. American Cancer Society; 1997. Available from: URL: http://www.cancer.org/97pancre.html [Accessed 1997 Mar 24]

  112. Schnall SF, Macdonald JS. Chemotherapy of adenocarcinoma of the pancreas. Semin Oncol 1996 Apr; 23: 220–8

    PubMed  CAS  Google Scholar 

  113. National Cancer Institute. Pancreatic cancer for phsicians. In: Clinical cancer information for physicians, WWW CancerNet [online]. National Cancer Institute, Feb 1997. Available from: URL: http://www.arc.com/cgi-bin/Cancernet.sh?eng/physician=Pancreatic_cancer_for_Physicians [Accessed 1997 Feb 26]

  114. Schultz RM. Future directions for the treatment of human pancreatic carcinoma. Expert Opin Invest Drug 1995 Dec; 4: 1273–9

    Google Scholar 

  115. Lionetto R, Pugliese V, Bruzzi P, et al. No standard treatment is available for advanced pancreatic cancer. Eur J Cancer A 1995; 31A(6): 882–7

    PubMed  CAS  Google Scholar 

  116. Blackstock AW, Cox AD, Tepper JE. Treatment of pancreatic cancer: current limitations, future possibilities. Oncology 1996 Mar; 10: 301–7

    PubMed  CAS  Google Scholar 

  117. Ahlgren JD. Chemotherapy for pancreatic carcinoma. Cancer 1996 Aug 1; 78 Suppl.: 654–63

    PubMed  CAS  Google Scholar 

  118. Faggiuolo R, Raucci CA, Roncari A, et al. Phase I study of gemcitabine and continuous infusion of 5-fluorouracil in advanced pancreatic cancer [abstract no. 1023]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 288a

    Google Scholar 

  119. Hidalgo M, Paz-Ares L, Hitt R, et al. Phase I-II study of gemcitabine combined with continuous infusion 5-fluorouracil as first-line chemotherapy in locally advanced and metastatic pancreatic cancer [abstract no. 1030]. Thirty-Third Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, Vol. 16, 290a

    Google Scholar 

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    Stuart Noble & Karen L. Goa

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Various sections of the manuscript reviewed by: R.P. Abratt, Department of Radiation Oncology, University of Cape Town, Cape Town, South Africa; H.Anderson, Chest Clinic, Wythenshawe Hospital, Manchester, England; S. Bank, Division of Gastroenterology, Long Island Jewish Medical Center, New York, New York, USA; A.M. Bergman, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; J.P. Bernard, Centre Hospitalier Lyon Sud, Pierre Benite, France; L. Crinó, Divisione di Oncologia Medica, Policlinico Monteluce, Perugia, Italy; J.M. Kroep, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; G.J. Peters, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; M.L. Rothenberg, Department of Medicine, Division of Medical Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; W.P. Steward, Department of Oncology, Leicester Royal Infirmary, Leicester, England; N. Thatcher, Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, England; C.J.A. van Moorsel, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.

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Noble, S., Goa, K.L. Gemcitabine. Drugs 54, 447–472 (1997). https://doi.org/10.2165/00003495-199754030-00009

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