Gemcitabine by Ray Sahelian, M.D.

Gemcitabine belongs to the group of medicines called antimetabolites. Gemcitabine is a prescription medication used to treat cancer of the breast, pancreas. biliary tract, and lung. Gemcitabine may also be used to treat other kinds of cancer, such as nasiophayngioma.

Gemcitabine for Lung Cancer
Gemcitabine is one of the newer antineoplastic agents, showing significant synergism with cisplatin. Recent studies indicate that chemotherapy, when performed appropriately, extends life and provides symptom relief for patients with advanced non-small cell lung cancer (NSCLC) and other types of cancer. In NSCLC, maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin may produce longer survival compared to best supportive care alone.

Gemcitabine Side Effects
Gemcitabine should be administered with caution in patients with underlying cardiac disease. The most common toxic side effects with the combination gemcitrabine and cisplatin are leukopenia, anemia, thrombocytopenia, and vomiting.

Gemcitabine Research
Gemcitabine - Cisplatin Chemotherapy Before Lung Resection: A Case-Matched Analysis of Early Outcome.
Ann Thorac Surg. 2006 Jun;81(6):1963-1968. Unit of Thoracic Surgery, "Umberto I" Regional Hospital, Ancona, Italy.
The objective of the present study was to assess whether neoadjuvant chemotherapy with gemcitabine and cisplatin was associated with an increased incidence of morbidity and mortality after major lung resection for lung cancer. METHODS: We analyzed 570 patients who underwent lobectomy or pneumonectomy for nonsmall-cell lung cancer at our institution from January 2000 through June 2005. Of these, 70 patients underwent three cycles of gemcitabine - cisplatin chemotherapy before operation for locally advanced disease. Propensity scores were constructed to match those patients undergoing neoadjuvant chemotherapy and lung resection with those undergoing surgery alone. The propensity score analysis yielded two groups of 70 well-matched pairs that were compared in terms of baseline characteristics and early outcome (morbidity, mortality, length of postoperative stay, intensive care unit admission). RESULTS: The two case-matched groups had similar morbidity, mortality, perioperative blood transfusions and intensive care unit admission rates. Likewise, the length of postoperative stay did not differ between the groups. CONCLUSIONS: Gemcitabin - cisplatin neoadjuvant chemotherapy appears to be safe before major lung resection. This finding warrants its use for efficacy studies of locally advanced and even early-stage lung cancer.

Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer.
J Gastroenterol Hepatol. 2006 Jun;21(6):999-1003. Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
The aim of this phase II study was to determine the efficacy of gemcitabine plus cisplatin chemotherapy in patients with advanced biliary tract cancer. Results: Twenty-seven patients were enrolled in the study and a total of 120 cycles of chemotherapy were administrated. Objective partial response was observed in nine (33.3%) patients, while stable disease was found in seven (25.9%) patients. The median survival time was 10.0 months and the 1-year survival rate was 36%. Median time to disease progression was 5.6 months. The most common grade 3-4 toxicities were leukopenia (25.9%), anemia (29.6%), thrombocytopenia (22.2%), and vomiting (18.5%). Only one patient was hospitalized for chemotherapy-related complications. Conclusion: Gemcitabine and cisplatin combination chemotherapy is an effective, safe, and well-tolerated regimen for the treatment of advanced biliary tract cancer.

Induction chemotherapy with cisplatin and gemcitabine followed by accelerated radiotherapy and concurrent cisplatin in patients with stage IV(A-B) nasopharyngeal carcinoma.
Head Neck. 2006 May 23; Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong.
The purpose of this study was to evaluate the efficacy and toxicity of cisplatin plus gemcitabine as induction chemotherapy in advanced nasopharyngeal carcinoma (NPC). METHODS.: Thirty-seven patients with stage IV(A-B) NPC were treated with 3 cycles of cisplatin plus gemcitabine (cisplatin 80 mg/m(2) on day 1; gemcitabine 1250 mg/m(2) on days 1 and 8) 3-weekly as induction chemotherapy, followed by another 3 cycles of concurrent cisplatin (100 mg/m(2) on day 1) 3-weekly with accelerated radiotherapy (RT) at 70 Gy in 2-Gy fractions, 6 daily fractions per week. RESULTS.: The overall response rate to induction chemotherapy was > 90%, and side effects other than uncomplicated hematologic toxicities were uncommon. All patients completed RT, with 92% receiving >/= 5 cycles of chemotherapy. At a median follow-up of 2.9 years, the 3-year overall survival (OS) and disease-free survival (DFS) rates were 76% and 63%, respectively. CONCLUSIONS.: Cisplatin plus gemcitabine is a well-tolerated, effective, and convenient induction chemotherapy regimen and warrants further studies to confirm its benefit in advanced NPC.

Phase II study of gemcitabine plus cisplatin in metastatic breast cancer.
Anticancer Drugs. 2006 Jun;17(5):565-570. Tijuana, Mexico bINCan, Mexico City, Mexico cHospital Gral. De Occidente, Guadalaraja, Mexico dIMSS, Chihuahua, Mexico eISSSTE, Hermosillo, Mexico fCentro Medico del Potosi, San Luis Potosi, Mexico gISSSTE, Ensenada, Mexico hEli Lilly de Mexico, Mexico City, Mexico iEli Lilly and Company, Indianapolis, Indiana, USA.
Our objectives were to assess the efficacy and toxicity of gemcitabine plus cisplatin as first-line therapy in metastatic breast cancer (MBC). Patients with stage IV MBC and no prior chemotherapy for metastatic disease were treated with gemcitabine 1200 mg/m on days 1 and 8, and cisplatin 75 mg/m on day 1 every 21 days. Up to 6 cycles were given. A total of 46 patients with a median age of 49 years (range 24-77) and Karnofsky performance status of 80 or above were enrolled. In total, 238 cycles were administered. We conclude that gemcitabine plus cisplatin is a highly effective and safe first-line treatment for patients with MBC. The time to progression of 14.9 months compares favorably with other standard treatments (anthracyclines, taxanes). A randomized study is required to further investigate the role of this combination as first-line treatment for MBC.

Cisplatin plus gemcitabine on days 1 and 4 every 21 days for solid tumors: Result of a dose-intensity study.
Invest New Drugs. 2006 May 11; Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni, 56 Rozzano-Milan, Rozzano, Italy,
Three and 4-week cisplatin - gemcitabine schedules have shown similar dose-intensity (DI) and activity in non-small-cell lung cancer (NSCLC). The 3-week schedule is generally preferred because it enables better treatment compliance. To improve DI and compliance further, we delivered gemcitabine plus cisplatin over 4 days every 21 days. Patients with any stage NSCLC or epithelial neoplasms and an ECOG PS </=2 were given gemcitabine 1000 mg/m(2) on days 1 and 4 plus cisplatin 70 mg/m(2) on day 2 of a 21-day cycle. Minimax design was used and a received DI for gemcitabine of >/=580 mg/m(2)/wk was considered successful. Results: Thirty-nine patients (34 NSCLC, 5 epithelial neoplasias) were enrolled. SWOG grade 3-4 neutropenia and thrombocytopenia were observed in 17% and 12% of patients, respectively. Nonhematological toxicity was minimal. Twenty-eight (18%) of 158 cycles required dose modifications and/or delays. Twenty-five patients received a gemcitabine dose intensity of >/=580 mg/m(2)/wk. The received DIs were 601.8 mg/m(2)/wk for gemcitabine and 21.0 for cisplatin, with a relative DIs of 90.3% and 90.1%, respectively. The response rate of 27 evaluable patients with NSCLC was 44%.Conclusions: The shorter schedule of gemcitabine on days 1 and 4 plus cisplatin on day 2 produces an effective DI and a toxicity profile comparable to that of weekly regimens.

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial.
Lung Cancer. 2006 May;52(2):155-63. Central European Cooperative Oncology Group CECOG. Medical University Hospital, Vienna, Austria.
The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months. Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms. The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone.

Optimizing chemotherapy and targeted agent combinations in NSCLC.
Lung Cancer. 2005 Dec;50 Suppl 2:S25-32. Lynch T Jr, Kim E. Massachusetts General Hospital, Boston, MA
Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. Investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.

Adding aprinocarsen to gemcitabine and cisplatin regimen does not enhance survival and other efficacy measures in patients with advanced NSCLC.

Randomized phase II study of gemcitabine plus cisplatin versus etoposide plus cisplatin for the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience.
Lung Cancer. 2006 Apr;52(1):75-81. Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul, South Korea.
Several randomized trials have demonstrated superior response rates and survivals for new agent platinum doublets than for older platinum doublets in advanced non-small cell lung cancer (NSCLC), however, few trials have been performed in Asian populations. Thus, we conducted a randomized study to compare gemcitabine - cisplatin with etoposide-cisplatin (EP) in Korean patients with advanced NSCLC. CONCLUSION: Gemcitabine - cisplatin provided a significantly higher response rate and a longer time to progression than EP and should be considered a standard treatment in advanced NSCLC in Korean population.

Gemcitabine and Breast Cancer
Gemcitabine adds efficacy to vinorelbine without undue toxicity compared with vinorelbine alone in patients with metastatic breast cancer who have already undergone anthracycline chemotherapy.

Gemcitabine and Ovarian Cancer

The U.S. Food and Drug Administration approved the drug Gemzar ( gemcitabine ) for treating recurrent ovarian cancer, ignoring the advice given by an FDA panel. The FDA approved use of Gemzar in combination with carboplatin, a widely used chemotherapy, for women with advanced ovarian cancer that has relapsed at least six months after initial therapy. The FDA usually follows the advice of its advisory panel. Gemcitabine is already approved in the United States for lung, pancreatic and breast cancers and is approved outside the United States for ovarian cancer. In March 2006, the FDA advisory panel voted 9-2 against recommending approval of gemcitabine for ovarian cancer, questioning Lilly's trial data and the way the company conducted the 356-person clinical study. Panel members were concerned that patients in the trial did not survive longer than those taking carboplatin alone. One course of treatment with Gemzar costs about $12,600.
Although women with recurrent ovarian cancer don't live longer on gemcitabine.