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MINI SYMPOSIUM: LUNG CANCER - GUEST EDITORIAL
Year : 2012  |  Volume : 49  |  Issue : 2  |  Page : 199-201
 

Low-dose gemcitabine in long infusion: When less is more


Institute of Oncology, Ljubljana, Slovenia and Medical School, University of Maribor, Maribor, Slovenia

Date of Web Publication25-Oct-2012

Correspondence Address:
M Zwitter
Institute of Oncology, Ljubljana, Slovenia and Medical School, University of Maribor, Zaloska 2, 1000 Ljubljana
Slovenia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.102860

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How to cite this article:
Zwitter M. Low-dose gemcitabine in long infusion: When less is more. Indian J Cancer 2012;49:199-201

How to cite this URL:
Zwitter M. Low-dose gemcitabine in long infusion: When less is more. Indian J Cancer [serial online] 2012 [cited 2019 Nov 18];49:199-201. Available from: http://www.indianjcancer.com/text.asp?2012/49/2/199/102860


This issue of the Journal brings a small but important report on a clinical trial comparing gemcitabine in low dose in long infusion to standard brief infusion of a much higher dose of gemcitabine, in both arms combined with carboplatin, for advanced non-small cell lung cancer (NSCLC). [1] It is clear that the trial was not powered to confirm significant differences in efficacy between the two treatment arms. Nevertheless, we can agree with the authors that treatment with low-dose gemcitabine in long infusion is effective for advanced NSCLC, has low toxicity, and is especially attractive for deprivileged patients for whom the costs of anti-cancer drugs present an important, and often unsurmountable barrier to treatment.

I would like to stress that treatment with low-dose gemcitabine in long infusion is much more than a simple reduction of costs for cytotoxic drugs. Gemcitabine in long infusion appears to be a different drug, when compared to standard gemcitabine in brief infusion. Long infusion leads to a much higher proportion of conversion of the drug into the active metabolite. As a consequence, maximal tolerated dose (MTD) for gemcitabine which is 1500mg/m 2 or even higher for a brief 20-30 min infusion falls with the duration of infusion. With infusions lasting for 3, 6 or 24hrs, MTD falls to 450mg/m 2 , 250mg/m 2 , and 180mg/m 2 , respectively. [2],[3],[4],[5] In addition to lower MTD, long infusion of gemcitabine has a different toxicity profile. Our randomized trial on 249 patients with advanced NSCLC and treated with standard brief application or low-dose prolonged infusion of gemcitabine revealed significantly less neutropenias and thrombocytopenias for the prolonged-infusion arm; on the other hand, most of these patients developed alopecia, a side effect which is rare with standard brief infusion of gemcitabine.

The most important aspect of treatment with low-dose gemcitabine in prolonged infusion is its efficacy against a variety of tumors. According to reports from other centers, gemcitabine in prolonged infusion alone or in combination with other drugs is an active treatment for advanced cancers of the breast, [3],[6] lung, [7],[8],[9],[10] refractory Hodgkin's disease, [11] sarcomas, [12] cancer of pancreas, gallbladder and biliary tract, [13],[14],[15],[16] and bladder cancer. [17]

At the Institute of Oncology in Ljubljana, Slovenia, we have probably the largest experience on this treatment. Over the past 10 years, a total of 547 patients with NSCLC, with mesothelioma, and a few with other refractory cancers were enrolled in six prospective clinical trials and treated with low dose gemcitabine in prolonged infusion. [18],[19],[20],[21] Our experience can be summarized in the following points:

  • Treatment with gemcitabine at 250mg/m 2 in 6hrs infusion and cisplatin (75mg/m 2 ) leads to remarkable remissions in lung cancer and in mesothelioma [Figure 1] and [Figure 2]. The efficacy of this treatment is at least as good as, and possibly superior to standard brief infusion of gemcitabine. Superiority of the low-dose prolonged-infusion schedule is especially clear for patients with squamous-cell NSCLC (survival advantage two months, when compared to brief high-dose infusion) [19] and for mesothelioma (17 months as median survival for unselected group of patients, including patients in poor performance status). [21] In addition, partial remissions were seen in patients with pre-treated metastatic cervical cancer and head and neck cancer (unpublished observations).
  • For the low-dose gemicitabine in long infusion, no clear dose-response relation is apparent. In our first trial with escalating doses of gemcitabine, we saw a complete response in one of six patients treated at the lowest level of 130mg/m 2 /6hrs. [18]
  • Apart from alopecia, toxicity is very mild. Gemcitabine at 150-200mg/m 2 /6hrs, alone or in combination with cisplatin or carboplatin is a suitable treatment for patients in poor performance status. [20]
Figure 1: Epitheloid mesothelioma of the left pleura, T3 N2 M0, prior to treatment

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Figure 2: Complete remission three months after treatment with gemcitabine (130 mg/m2/6 hours on days 1 and 8) and cisplatin (75 mg/m2 on day 2)

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On the basis of current experience with low-dose gemcitabine in long infusion, we can say that this treatment is effective and safe. Future development will probably lead in two directions. The first one is based on low costs of this particular treatment. The second one is clinical research on potential superiority of this treatment against standard treatment for a variety of advanced cancers.

Low costs of anti-cancer drugs are an important parameter in clinical decisions, especially in economically deprivileged patients. Reduction of gemcitabine to 25% of the standard dose presents important savings. In addition, four hours infusion of gemcitabine, followed by carboplatin can be completed in a single day and is a suitable regime for out-patient treatment. This may be an important advantage of the schedule used by Beniwal SK et al., [1] when compared to our schedule which is divided between two days: six hours infusion of gemcitabine on day one, followed by cisplatin on day two. However, apart from reduction of costs, other advantages of the 4hrs infusion of gemcitabine over standard brief infusions are uncertain.

Research on new indications and on potential superiority of low-dose gemcitabine in long infusion is a challenge for future clinical trials. Candidates for clinical trials are patients with NSCLC (especially squamous type), mesothelioma, pancreatic carcinoma, breast cancer, advanced cancer of head and neck, esophageal cancer, and cervical cancer. When it comes to clinical trials, we should explore the optimal schedule of application, rather than a compromise made due to easier logistics. On the basis of all existing experience, I strongly believe that the advantage of low-dose gemcitabine can be expected only with infusion duration of at least 6hrs [Table 1]. Use of infusion pumps is mandatory to control the duration of the infusion. The optimal dose of gemcitabine is less clear. For a 6hrs infusion, the dose should not exceed 250mg/m 2 but lower doses of 150-200mg/m 2 may be equally effective, as seen in our Phase 1-2 clinical trial of escalating doses of gemcitabine for NSCLC and in our trial for mesothelioma. [21] Finally, aiming at optimal results, the doublet should include cisplatin, rather than carboplatin. As explained, the doublet of gemcitabine in 6hrs infusion and cisplatin with appropriate antiemetics and hydration is usually divided between two days. While this involves some logistics and costs for additional transport or hospitalization, I believe that the effort is justified if superiority of this treatment is to be confirmed.
Table 1: Comparison of different schedules of gemcitabine

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Design, organization and performance of clinical research which is not commercially interesting is a challenge which invites brave, dedicated and enthusiastic physicians. From the experience of our team in Ljubljana, I can testify that even without commercial sponsorship, the task is feasible and scientifically and personally rewarding. Less is more-a new challenge for Indian oncologists.

 
  References Top

1.Beniwal SK, Patel KM, Shukla S, Parikh BJ, Shah S, Patel A. Gemcitabine in brief versus prolonged low dose infusion, both combined with carboplatin for advanced non-small cell lung cancer. Indian J Cancer 2012; 49:204-10.  Back to cited text no. 1
    
2.Anderson H, Thatcher N, Walling J, Hansen H. 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: 460-62   Back to cited text no. 2
    
3.Akrivakis K, Schmid P, Flath B, Schweigert M, Sezer O, Mergenthaler HG, et al. Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study. Anticancer Drugs 1999; 10: 525-31   Back to cited text no. 3
    
4.Maurel J, Zorrilla M, Puertolas T, Anton A, Herrero A, Artal A, et al. Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors. Anticancer Drugs 2001; 12: 713-17   Back to cited text no. 4
    
5.Pollera CF, Ceribelli A, Crecco M, Oliva C, Calabresi F. Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drugs 1997; 15: 115-21  Back to cited text no. 5
    
6.Schmid P, Krocker J, Jehn C, Michniewicz K, Lehenbauer-Dehm S, Eggemann H, et al. Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial. Ann Oncol. 2005;16:1624-31  Back to cited text no. 6
    
7.Cappuzzo F, Novello S, De Marinis F, Selvaggi G, Scagliotti GV, Barbieri F, et al. A randomized phase II trial evaluating standard (50 mg/min) versus low (10 mg/min) infusion duration of gemcitabine as first-line treatment in advanced non-small cell lung cancer patients who are not eligible for platinum-based chemotherapy. Lung Cancer 2006;52:319 -325.  Back to cited text no. 7
[PUBMED]    
8.Anderson H, Thatcher N, Walling J, Hansen H. 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: 460-62  Back to cited text no. 8
    
9.Parikh PM, Narayanan P, Mistry RC, Agarwal JP, Pai VR, Nair R, et al. Treatment of advanced NSCLC (Stage IIIB and IV) with low dose Gemcitabine and Carboplatin. J Clin Oncol - 2005 ASCO Annual Meeting Proceedings, Vol 23, No. 16S, Part I of II (June 1 Supplement): 7306  Back to cited text no. 9
    
10.Xiong JP, Zhang L, Zhong LX, Qiu F, Guo YL, Lian HY, Luo H. Phase II trial of prolonged infusion of low-dose gemcitabine in advanced non-small cell lung cancer treatment. Ai Zheng. 2006;25:995-8  Back to cited text no. 10
    
11.Sezer O, Eucker J, Jakob C, Kaufmann O, Schmid P, Possinger K. Achievement of complete remission in refractory Hodgkin's disease with prolonged infusion of gemcitabine. Invest New Drugs 2001;19:101-4  Back to cited text no. 11
    
12.Spath-Schwalbe E, Genvresse I, Koschuth A, Dietzmann A, Grunewald R, Possinger K. Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs. 2000;11:325-9.  Back to cited text no. 12
    
13.Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs. 1997;15:331-41  Back to cited text no. 13
    
14.Eckel F, Schmelz R, Erdmann J, Mayr M, Lersch C. Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma. Cancer Invest. 2003;21:690-4.  Back to cited text no. 14
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15.von Delius S, Lersch C, Schulte-Frohlinde E, Mayr M, Schmid RM, Eckel F. Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma. BMC Cancer. 2005;5:61  Back to cited text no. 15
    
16.Kornek GV, Potter R, Selzer E, Schratter A, Ulrich-Pur H, Rogy M, Kraus G, Scheithauer W. Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine. Int J Radiat Oncol Biol Phys. 2001;49:665-71  Back to cited text no. 16
    
17.Khaled H, Emara ME, Gaafar RM, Mansour O, Abdel Warith A, Zaghloul MS, et al. Primary chemotherapy with low-dose prolonged infusion gemcitabine and cisplatin in patients with bladder cancer: a Phase II trial. Urol Oncol 2008; 26:133-136.  Back to cited text no. 17
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18.Zwitter M, Kovac V, Smrdel U, Kocijancic I, Segedin B, Vrankar M. Phase I-II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer. Anticancer Drugs 2005;16:1129-34.  Back to cited text no. 18
[PUBMED]    
19.Zwitter M, Kovac V, Smrdel U, Vrankar M, Zadnik V. Gemcitabine in brief versus prolonged low-dose infusion, both combined with cisplatin, for advanced non-small cell lung cancer: a randomized phase II clinical trial. J Thorac Oncol 2009;4:1148-55.  Back to cited text no. 19
[PUBMED]    
20.Zwitter M, Kovac V, Rajer M, Vrankar M, Smrdel U. Two schedules of chemotherapy for patients with non-small cell lung cancer in poor performance status: a phase II randomized trial. Anticancer Drugs 2010;21:662-8.  Back to cited text no. 20
[PUBMED]    
21.Kovac V, Zwitter M, Rajer M, Marin A, Debeljak A, Smrdel U, Vrankar M. A phase II trial of low-dose gemcitabine in prolonged infusion and cisplatin for malignant pleural mesothelioma. Anticancer Drugs 2012; 23:230-8  Back to cited text no. 21
    


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