Gemcitabine Hydrochloride

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2′-Deoxy-2′,2′-difluoro-cytidine monohydrochloride
Molecular Formula: C₉H₁₁F₂N₃O₄•ClH
CAS Number: 122111-03-9
Brands: Gemzar

Introduction

Antimetabolite antineoplastic agent; a synthetic pyrimidine nucleoside.^{1 2 4}

Uses for Gemcitabine Hydrochloride

Breast Cancer

Used in combination with paclitaxel as first-line therapy for metastatic breast cancer in patients who did not respond to previous anthracycline-containing chemotherapy or in whom such chemotherapy was contraindicated.^a

Non-small Cell Lung Cancer

Used for initial treatment in patients with inoperable, locally advanced (stage IIIA or IIIB) or metastatic (stage IV) non-small cell lung cancer in combination with cisplatin.^{1 5 27 28 54 58 68}

Used as monotherapy† for advanced non-small cell lung cancer^{36 37 38 49 50 51 54} in patients with relapsed or refractory advanced non-small cell lung cancer who previously were treated with platinum-containing chemotherapy regimens⁴¹ or in those who have not received prior chemotherapy.^{36 37 38 50 51}

Use of chemotherapy generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond.⁵² Individualize decision to use chemotherapy according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.^{52 54 55}

Pancreatic Cancer

Used as first-line therapy^{1 10 57} for the palliative treatment of locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas.^{1 5}

Also used as second-line therapy in patients previously treated with fluorouracil.^{1 11}

Bladder Cancer

Used alone^{22 23 24} or in combination therapy⁵ (i.e., cisplatin)^{59 59 60} for the treatment of advanced or metastatic bladder cancer†.

Objective responses to gemcitabine have been observed in patients with metastatic bladder cancer that did not respond to previous treatment with cisplatin-based regimens, including some patients with hepatic metastases.^{24 25}

Ovarian Cancer

Currently being investigated for use in the treatment of advanced epithelial ovarian cancer†.^{5 62 63 64 65 66}

Gemcitabine Hydrochloride Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Perform CBC, including differential and platelets, prior to each dose of gemcitabine.¹ Modify or temporarily withhold dosage if myelosuppression is detected, according to the degree of hematologic toxicity.¹ When used in combination with other antineoplastic agents, dosage modification of the concomitant agent also may be required for hematologic and/or nonhematologic toxicity.

  
  

Administration

IV Administration

Administer by IV infusion.^{1 11 57}

The drug is for IV use only.^a

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vials containing 200 mg or 1 g of gemcitabine by adding 5 or 25 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide a solution containing 38 mg/mL (accounts for the displacement volume of lyophilized powder).^{1 3 21} Shake to dissolve.¹

Total volume upon reconstitution for vials labeled as containing 200 mg or 1 g is about 5.26 or 26.3 mL, respectively.^{1 3}

Smaller volumes should not be used for reconstitution; concentrations >38 mg/mL may exceed the solubility of the drug and result in incomplete dissolution.^{1 3}

Discard any unused portion after preparation of the appropriate dose.¹

Dilution

Reconstituted solutions can be infused IV without further dilution or as solutions that have been further diluted in 0.9% sodium chloride injection to concentrations as low as 0.1 mg/mL.¹

Rate of Administration

Infuse over a period of 30 minutes.¹

Prolonged IV infusion (>60 minutes) is associated with a prolonged half-life and increased toxicity, including clinically important myelosuppression.^{1 15} (See Elimination under Pharmacokinetics.) Infusion time should not exceed 60 minutes.¹

Dosage

Available as gemcitabine hydrochloride; dosage expressed in terms of gemcitabine.¹

Individualize dosage based on body surface area and patient tolerance and response.¹

Adults

Breast Cancer

IV

1250 mg/m² given on days 1 and 8 of a 21-day cycle; administer in combination with paclitaxel 175 mg/m², given on day 1, as a 3-hour infusion before administration of gemcitabine.^a

Patients should have an absolute granulocyte count of ≥1500/mm³ and platelet count of ≥100,000/mm³ prior to each cycle.^a Adjust dosage according to granulocyte and platelet counts obtained on day 8 of therapy (see Table 1).^a

Table 1. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Paclitaxel in Breast Cancer

Absolute Granulocyte Count (per mm3)		Platelets (per mm3)	Gemcitabine Dosage in Next Cycle (expressed as % of full dose)
≥1200	and	>75,000	100%
1000–1199	or	50,000–75,000	75%
700–999	and	≥50,000	50%
<700	or	<50,000	Withhold dose

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, acccording to clinician’s judgment.^a

Non-small Cell Lung Cancer

Combination Therapy with Cisplatin

Optimum dosage regimen has not been established.¹

IV

1000 mg/m² administered on days 1, 8, and 15 of each 28-day cycle (4-week schedule) or 1250 mg/m² administered on days 1 and 8 of each 21-day cycle (3-week schedule).^{1 27 28} Administer cisplatin 100 mg/m² on day 1 following completion of the gemcitabine infusion.¹

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.^a

See Table 2 for gemcitabine dosage modification for hematologic toxicity.

Table 2. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Cisplatin in Non-small Cell Lung Cancer

Absolute Granulocyte Count (per mm3)		Platelets (per mm3)	Gemcitabine Dose Modification (expressed as % of full dose)
≥1000	and	≥100,000	100%1
500–999	or	50,000–99,000	75%1 3
<500	or	<50,000	Withhold dose until counts exceed these levels

Monotherapy

IV

1000 or 1250 mg/m² once weekly for 3 weeks followed by 1 week of rest.^{36 37 38 41 42 44 50 51}

Pancreatic Cancer

Initial Dosing Cycle

IV

1 g/m² once weekly;^{1 11 57} repeat at weekly intervals as tolerated for up to 7 weeks, followed by a week of rest from treatment.¹ If necessary, reduce or withhold dosage according to the degree of hematologic toxicity. (See Table 3 for dosage modification for hematologic toxicity.)¹

Table 3. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Cisplatin in Non-small Cell Lung Cancer

Absolute granulocyte count (per mm3)		Platelets (per mm3)	Gemcitabine Dose Modification (expressed as % of full dose)
≥1000	and	≥100,000	100%1
500–999	or	50,000–99,000	75%1 3
<500	or	<50,000	Withhold dose until counts exceed these levels

Subsequent Dosing Cycles

IV

1 g/m² once weekly for 3 consecutive weeks, followed by a week of rest from treatment.¹

Dosage may be increased to 1.25 g/m² weekly for 3 consecutive weeks, followed by a week of rest, in patients who successfully complete the initial 7-week or subsequent 3-week cycle of therapy at the full weekly dosage, provided nadirs of the absolute granulocyte and platelet counts are >1500 and 100,000/mm³, respectively, and WHO nonhematologic toxicity > grade 1 is not present.^{1 11} Dosage can be further increased to 1.5 g/m² weekly given in 3-week cycles if previous 3-week course is tolerated (i.e., hematologic parameters are met and no evidence of WHO nonhematologic toxicity >1).¹

If necessary, reduce or withhold dosage according to the degree of hematologic toxicity.¹ (See Table 3.)

In clinical trials, patients received an average of 3 cycles of therapy.³

Prescribing Limits

Do not administer more frequently than once weekly, since risk of toxicity is increased with such dosing.^{1 16} Infusion time should not exceed 60 minutes.¹ (See Rate of Administration under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.¹

Renal Impairment

No specific recommendations for dosage adjustment; use with caution.¹

Geriatric Patients

Decreased clearance.¹ No dosage adjustments in patients >65 years of age except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).¹

Female Patients

Decreased clearance.¹ No dosage adjustments except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).¹

Cautions for Gemcitabine Hydrochloride

Contraindications

• 
  

  Known hypersensitivity to gemcitabine or any ingredient in the formulation.^a

  
  

Warnings/Precautions

Warnings

IV Administration

IV infusion over >60 minutes and administration more frequent than once weekly may be associated with increased toxicity (e.g., myelosuppression).¹ (See Rate of Administration under Dosage and Administration.)

Hematologic Effects

Myelosuppression, including leukopenia, anemia, and thrombocytopenia, (usually dose-limiting) may require blood transfusions.^a Perform a CBC, including differential and platelets, prior to each dose; modify dosage accordingly.¹

Pulmonary Effects

Severe adverse pulmonary effects, sometimes fatal (e.g., pulmonary edema, interstitial pneumonitis, pulmonary fibrosis, ARDS), have been reported.^{1 70 71} Onset of pulmonary symptoms has occurred up to 2 weeks following administration of the last dose; rarely, respiratory failure and death have occurred despite discontinuance of therapy.¹

Dyspnea, occasionally accompanied by bronchospasm, has been reported.¹ Possible dose-limiting pulmonary toxicity (e.g., esophagitis, pulmonary fibrosis, and pneumonitis) in patients receiving concurrent thoracic radiation therapy for non-small cell lung cancer.⁷²

Discontinue therapy immediately and institute appropriate supportive care (e.g., diuretics, corticosteroids) promptly in patients who develop severe adverse pulmonary effects.^{1 70 71}

Renal Effects

Risk of hemolytic-uremic syndrome and/or renal failure; rarely fatal or requires dialysis despite discontinuance of therapy.¹ Discontinue therapy immediately and consider a diagnosis of hemolytic-uremic syndrome in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, reticulocytosis, and/or severe thrombocytopenia with or without evidence of renal failure (e.g., elevation of S_cr or BUN).^{1 70}

Hepatic Effects

Severe hepatotoxicity, including hepatic failure and death, has been reported rarely.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;^a embryotoxic and fetotoxic in animals.^a If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.^a

Sensitivity Reactions

Anaphylactoid reactions reported rarely.^a

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under close supervision of qualified clinician experienced in cancer chemotherapy.^a Adverse effects generally are reversible and do not require discontinuance of therapy; however, dosage adjustments may be required.^a

Assess renal and hepatic function prior to and periodically during therapy.^a

Specific Populations

Pregnancy

Category D.^a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether gemcitabine is distributed into human milk.^a Discontinue nursing because of potential risk to nursing infants.^a

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 3}

Geriatric Use

Decreased clearance and increased half life.^{1 a} Possible increased incidence of severe (grade 3/4) thrombocytopenia.^a

Hepatic Impairment

Use with caution; assess hepatic function prior to and periodically during therapy.^a

Renal Impairment

Use with caution; assess renal function prior to and periodically during therapy.^a

Women

Decreased clearance.¹ Women tolerate the drug more poorly than men, are less likely to progress to subsequent cycles, and are more likely to experience hematologic toxicity (i.e., neutropenia, thrombocytopenia).^{1 3}

Common Adverse Effects

Myelosuppression, transient elevations of serum AST and ALT, proteinuria, hematuria, nausea, vomiting, pain, fever, fatigue, rash, dyspnea, diarrhea, edema, flu-like symptoms, infection, alopecia, stomatitis, somnolence, paresthesias, and injection site reactions.^a

Gemcitabine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained up to 30 minutes after discontinuance of the infusion.^a

Distribution

Extent

Volume of distribution increases with length of infusion.^a Not extensively distributed into tissues following IV infusion over <70 minutes (volume of distribution 50 L/m²).^a Following long infusion times, volume of distribution is 370 L/m², indicating slow equilibration into tissues.^a

Plasma Protein Binding

Negligible.^a

Special Populations

Volume of distribution is affected by gender.^a

Elimination

Metabolism

Converted intracellularly to active metabolites (gemcitabine diphosphate and gemcitabine triphosphate).^{1 2 4 19 58}

Elimination Route

Excreted principally in urine as unchanged drug (<10%) and as inactive metabolite.^a

Half-life

Increases with age.^a

42, 48, 61, and 79 minutes for men 29, 45, 65, and 79 years of age, respectively.^a

49, 57, 73, and 94 minutes for women 29, 45, 65, and 79 years of age, respectively.^a

32–94 minutes following short infusions; 245–638 minutes following long infusions.^a

Special Populations

Clearance is reduced and half-life increased in women and geriatric patients.¹

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C); do not refrigerate since crystallization may occur.^a

Solutions are stable for 24 hours at 20–25°C.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Amifostine
Amikacin sulfate
Aminophylline
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Aztreonam
Bleomycin sulfate
Bumetanide
Buprenorphine HCl
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Cefazolin sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Chlorpromazine HCl
Cimetidine HCl
Ciprofloxacin
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dactinomycin
Daunorubicin HCl
Dexamethasone sodium phosphate
Dexrazoxane
Diphenhydramine HCl
Dobutamine HCl
Docetaxel
Dopamine HCl
Doxorubicin HCl
Doxycycline hyclate
Droperidol
Enalaprilat
Etoposide
Etoposide phosphate
Famotidine
Floxuridine
Fluconazole
Fludarabine phosphate
Fluorouracil
Gentamicin sulfate
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Hydroxyzine HCl
Idarubicin HCl
Ifosfamide
Leucovorin calcium
Linezolid
Lorazepam
Mannitol
Meperidine HCl
Mesna
Metoclopramide HCl
Metronidazole
Mitoxantrone HCl
Morphine sulfate
Nalbuphine HCl
Ofloxacin
Ondansetron HCl
Oxaliplatin
Paclitaxel
Potassium chloride
Promethazine HCl
Ranitidine HCl
Sodium bicarbonate
Streptozocin
Teniposide
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Topotecan HCl
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Acyclovir sodium
Amphotericin B
Cefotaxime sodium
Furosemide
Ganciclovir sodium
Imipenem–cilastatin sodium
Irinotecan HCI
Lansoprazole
Methotrexate sodium
Methylprednisolone sodium succinate
Mitomycin
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Prochlorperazine edisylate

ActionsActions

• 
  

  Cell-cycle specific, acting principally in the S phase of the cell cycle; the drug also may cause cellular arrest at the G₁—S border.¹

  
  


• 
  

  Combined actions of diphosphate and triphosphate metabolites lead to inhibition of DNA synthesis.^{1 2 4 19 20 58}

  
  


• 
  

  Gemcitabine diphosphate interferes with subsequent de novo nucleotide production^{1 2 4 58} by inhibiting ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis.^{1 2 4 58}

  
  


• 
  

  Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA.^{1 2 4 58} Following incorporation of gemcitabine triphosphate into the DNA chain, a single additional nucleotide, a normal base pair, is added and DNA synthesis is terminated, resulting in apoptosis (programmed cell death).^{1 2 4 58}

  
  


• 
  

  DNA polymerase ε is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand,^{1 2 3 4 58} which results in a prolonged intracellular half-life of gemcitabine compared with other nucleoside analogs such as cytarabine and is thought to contribute to gemcitabine’s expanded spectrum of antineoplastic activity relative to such agents.^{4 58}

  
  

Advice to Patients

• 
  

  Risk of myelosuppresion.^a

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^a

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information.^a (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Gemcitabine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	200 mg (of gemcitabine)	Gemzar (with mannitol)	Lilly
		1 g (of gemcitabine)	Gemzar (with mannitol)	Lilly

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gemzar 1GM Solution (LILLY): 1/$850.02 or 3/$2395.88

Gemzar 200MG Solution (LILLY): 1/$170.43 or 3/$503.19

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Eli Lilly and Company. Gemzar (gemcitabine) prescribing information. Indianapolis, IN: 2003 Jan 6.

2. Eli Lilly and Company. Treatment IND of Gemzar (gemcitabine) for patients with pancreatic cancer. Protocol No. B9E-MC-JHEW (c). Indianapolis, IN: Eli Lilly and Company; 1995 Feb 2.

3. Eli Lilly and Company, Indianapolis, IN: Personal communication.

4. Eli Lilly and Company. Gemzar (gemcitabine hydrochloride) product information. Indianapolis, IN: 1995 Apr 27.

5. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

6. Pancreatic cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jul 3.

7. Brennan MF, Kinsella TJ, Casper ES. Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:849-82.

8. Weiss GR, Burris HA III, Eckardt JR et al. New anticancer agents. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:132-67.

9. Vaughn DJ, Treat J. Cancers of the large bowel and hepatobiliary tract. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:495-10.

10. Carmichael J, Fink U, Russell RC et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996; 73:101-5. [PubMed 8554969]

11. 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 8805925]

12. Moore M, Andersen J, Burris H et al. A randomized trial of gemcitabine (GEM) versus 5FU as first-line therapy in advanced pancreatic cancer. Proc Annu Meet Soc Clin Oncol. 1995; 14:A473.

13. Andersen JS, Burris HA, Casper E et al. Development of a new system for assessing clinical benefit for patients with advanced pancreatic cancer. Proc Annu Meet Am Soc Clin Oncol. 1994; 13:A1600.

14. 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; 34:867-72. [PubMed 8598364]

15. Pollera CF, Ceribelli A, Crecco M et al. Prolonged infusion of gemcitabine: a preliminary report of a Phase I study. Ann Oncol. 1992; 3(Suppl 5):52.

16. Hansen HH, Lund B. Gemcitabine (2,2-difluorodeoxycytidine): a novel antineoplastic agent with activity in both lung and ovarian cancer. Ann Oncol. 1992; 3(Suppl 1):161.

17. Abbruzzese JL, Gravel D, Tarassoff P et al. Pharmacologically directed strategy for dose intensification of gemcitabine: a Phase I trial. Proc Annu Meet Am Assoc Cancer Res. 1993; 34:A2233.

18. Brown T, O’Rourke T, Burris H et al. A phase I trial of gemcitabine (LY188011) administered IV every two weeks. Proc Annu Meet Am Soc Clin Oncol. 1991; 10:A328.

19. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anti-Cancer Drugs. 1995; 6(Suppl 6):7-13. [PubMed 8718419]

20. Plunkett W, Huang P, Yi-Zheng X et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995; 22(Suppl 11):3-10.

21. O’Brien TE. Gemcitabine concentration lower than cited in package insert. Am J Health-Syst Pharm. 1996; 53:2882.

22. De Lena M, Gridelli C, Lorusso V et al. Gemcitabine activity (objective responses and symptom improvement) in resistant stage IV bladder cancer. Proc Am Soc Clin Oncol. 1996; 15:246.

23. Stadler WM, Kuzel T, Roth B et al. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997; 15:3394-8. [IDIS 396655] [PubMed 9363871]

24. Pollera CF, Ceribelli A, Crecco M et al. Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol. 1994; 5:182-4. [PubMed 8186164]

25. Roth BJ. Chemotherapy for advanced bladder cancer. Semin Oncol. 1996; 23:633-44. [PubMed 8893874]

26. Moore MJ, Tannock IF, Ernst DS et al. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol. 1997; 15:3441-5. [IDIS 397896] [PubMed 9396395]

27. Sandler AB, Nemunaitis J, Denham C et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000; 18:122-30. [IDIS 438909] [PubMed 10623702]

28. Cardenal F, Lopez-Cabrerizo MP, Anton A et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999; 17:12-8. [IDIS 419947] [PubMed 10458212]

29. Crino 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. [IDIS 379623] [PubMed 8996156]

30. Anton A, Carrato A, Gonzalez Larriba JL et al. Phase II activity of gemcitabine in combination with cisplatin in advanced non-small cell lung cancer (NSCLC). Ann Oncol. 1996; 7(Suppl 5):A457P.

31. Shepherd F, Cormier Y, Evans W et al. A phase II study of gemcitabine and cisplatin weekly x 3 every 4 weeks in patients with non-small cell lung cancer (NSCLC). Proc Annu Meet Am Soc Clin Oncol. 1996; 15:A1135.

32. 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; 15:744-9. [IDIS 381290] [PubMed 9053500]

33. 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). Proc Annu Meet Am Soc Clin Oncol. 1995; 14:A1089.

34. Steward WP, Dunlop DJ, Dabouis G et al. Phase I/II study of gemcitabine and cisplatin in the treatment of advanced non-small cell lung cancer: preliminary results. Semin Oncol. 1996; 23(5 Suppl 10):43-7. [PubMed 8893881]

35. Weick JK, Crowley J, Natale RB et al. A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1991; 9:1157-62. [PubMed 1646292]

36. 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. 1996; 32A:243-8. [PubMed 8664035]

37. Abratt RP, Bezwoda WR, Folkson G et al. Efficacy and safety profile of gemcitabine in non-small cell lung cancer: a phase II study. J Clin Oncol. 1994; 12:1535-40. [IDIS 334284] [PubMed 8040664]

38. 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; 12:1821-6. [IDIS 335229] [PubMed 8083706]

39. Perng RP, Chen YM, 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; 15:2097-102. [IDIS 387805] [PubMed 9164223]

40. Manegold C, Bergman B, Chemaissani A et al. Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomized phase II study in locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 1997; 8:525-9. [PubMed 9261520]

41. Crino L, Mosconi AM, Scagliotti GV et al. Gemcitabine as second-line treatment for relapsing or refractory advanced non-small cell lung cancer: a phase II trial. Semin Oncol. 1998; 25(4 Suppl 9):23-6. [PubMed 9728581]

42. Le Chevalier T. Single-agent activity of gemcitabine in advanced non-small cell lung cancer. Semin Oncol. 1996; 23(5 Suppl 10):36-42. [PubMed 8893880]

43. Shepherd F, Iglesias JL. Single agent gemcitabine: a new alternative for the treatment of elderly patients with advanced non-small cell lung cancer (NSCLC). Ann Oncol. 1996; 7(Suppl 5):A201P.

44. 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. Anti-Cancer Drugs. 1995; 6(Suppl 6):39-48. [PubMed 8718424]

45. Hui YF, Reitz J. Gemcitabine: a cytidine analogue active against solid tumors. Am J Health-Syst Pharm. 1996; 54:162-70.

46. 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; 15:310-6. [IDIS 379625] [PubMed 8996158]

47. Kassem B, Miketic LM, Landreneau RJ et al. Phase I study of gemcitabine, given weekly as short infusion. Proc Annu Meet Am Soc Clin Oncol. 1995; 14:A1190.

48. Anderson H, Thatcher N, Walling J et al. A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. Br J Cancer. 1996; 74:460-2. [PubMed 8695365]

49. Ramanathan RK, Belani CP. Chemotherapy for advanced non-small cell lung cancer: past, present, and future. Semin Oncol. 1997; 24:440-54. [PubMed 9280224]

50. Halme M, Jekunen A, Tamminen K et al. Phase II study of weekly gemcitabine in advanced non-small cell lung cancer. Respir Med. 1997; 91:423-6. [PubMed 9327044]

51. Yokoyama A, Nakai Y, Yoneda S et al. Activity of gemcitabine in the treatment of patients with non-small cell lung cancer: a multicenter phase II study. Anticancer Drugs. 1997; 8:574-81. [PubMed 9300571]

52. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol. 1997; 15:2996-3018. [IDIS 391214] [PubMed 9256144]

53. Castellano D, Lianes P, Paz-Ares L et al. A phase II study of a novel gemcitabine plus cisplatin regimen administered every three weeks for advanced non-small-cell lung cancer. Ann Oncol. 1998; 9:457-9. [PubMed 9636840]

54. Non-small cell lung cancer. From CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

55. 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. [PubMed 7580546]

56. Martin C, Ardizzoni A, Rosso R. Gemcitabine: safety profile and efficacy in non-small cell lung cancer unaffected by age. Aging Clin Exp Res. 1997; 9:297-303.

57. Burris III HA, Moore MJ, Anderson 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. 1997; 15:2403-13. [IDIS 388900] [PubMed 9196156]

58. Noble S, Goa KL. Gemcitabine: a review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs. 1997; 54:447-72. [PubMed 9279506]

59. von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000; 18:3068-77. [PubMed 11001674]

60. Reviewers’ comments (personal observations) on bladder cancer.

61. Bladder cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

62. Lund B, Hansen OP, Theilade K et al. Phase II study of gemcitabine (2’,2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst. 1994; 86:1530-3. [IDIS 336649] [PubMed 7932808]

63. Shapiro JD, Millward MJ, Rischin D et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol. 1996; 63:89-93. [PubMed 8898175]

64. Friedlander M, Millward MJ, Bell D et al. A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol. 1998; 9:1343-5. [PubMed 9932166]

65. von Minckwitz G, Bauknecht T, Visseren-Grul CM et al. Phase II study of gemcitabine in ovarian cancer. Ann Oncol. 1999; 10:853-5. [PubMed 10470434]

66. Ovarian epithelial cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jul.

67. Vansteenkiste JF, Bomans P, Verbeken EK et al. Fatal pulmonary veno-occlusive disease possibly related to gemcitabine. Lung Cancer. 2001; 31:85-5.

68. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346:92-8. [IDIS 478960] [PubMed 11784875]

69. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001; 357:1478-84. [IDIS 463814] [PubMed 11377599]

70. Food and Drug Administrati