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▼Gemcitabine for lung cancer
  • Relevant BNF section: 8.1.3

Abstract

The prognosis for most patients with lung cancer is poor. About 75% will have tumours of non-small-cell lung cancer (NSCLC) type and, at diagnosis, 4 out of 5 patients with NSCLC have either locally advanced or metastatic disease. Despite treatment, fewer than 1 in 10 of these people will be alive 5 years later. Gemcitabine (Gemzar - Lilly) has recently been licensed for the palliative treatment of adults with such late-stage cancers. It is promoted as a "new option in the management of NSCLC" with "no trade off between tumour remission and toxicity". What advantages does gemcitabine offer?

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  • Relevant BNF section: 8.1.3

Background

The appropriate treatment for NSCLC, which includes squamous cell carcinoma, adenocarcinoma and large-cell carcinoma, depends on accurate staging of the disease. For early (stage I or II) disease, surgery usually gives the best outcome. For locally advanced (stage III) or metastatic (stage IV) disease, therapy aims principally at palliation. For those at stage III, palliation is provided by various combinations and sequences of radiotherapy, chemotherapy and surgery. For those at stage IV, emphasis turns to symptom relief with, for example, analgesics and psychological support.

It is difficult to evaluate new treatments for patients with advanced NSCLC as there is no standard management, no standard chemotherapy regimen and even controversy about the value of chemotherapy itself.1 However, in a recent meta-analysis including 33 randomised controlled trials in patients with advanced NSCLC, chemotherapy as an adjunct to radiotherapy or supportive care was found to produce a slight increase in the length of survival, compared with radiotherapy or supportive care alone.2 Ifosfamide, cisplatin, mitomycin and vindesine are among the few established single-drug treatments that produce tumour responses in more than 15% of patients. But even these drugs help fewer than one-third of patients treated.3 Combinations of drugs may produce better tumour responses (and better control of disease symptoms) but at the cost of increased unwanted effects.

Pharmacology

Gemcitabine, a fluorinated analogue of cytarabine, is converted to its active diphosphate and triphosphate forms intracellularly.4 Gemcitabine triphosphate halts DNA replication by replacing the natural nucleotide, deoxycitidine triphosphate, in the growing DNA strand. This effect is enhanced by inhibitory effects of gemcitabine metabolites on enzymes involved in DNA synthesis.4 Gemcitabine, which must be given intravenously, is metabolised by an enzyme in tissues including liver, kidney and blood, and metabolites are excreted in the urine.

Clinical studies

Gemcitabine as single-drug chemotherapy has been evaluated in four uncontrolled studies involving 361 patients with advanced NSCLC who had not previously received chemotherapy.58 Two of the studies are published only as abstracts.7,8 Complete response was defined as disappearance of all known disease; partial response as a decrease of at least 50% in total tumour size (as assessed by CT scan or X-ray). Tumour responses were confirmed by independent reviewers.

Effect on tumour size

In three of the studies involving a total of 327 patients, gemcitabine was given at a starting dose of 800-1250mg/m body surface area once a week for 3 weeks followed by a 1-week rest. In an unspecified number of patients, the dose of gemcitabine was increased in subsequent cycles by increments of 20%5 or up to 1850mg/m.6 Tumour response was similar in all three trials. Out of 306 evaluable patients there was a complete response in 0-3% of patients and a partial response in 17-20%.57 In contrast, in a fourth, smaller study involving 34 patients using a starting dose of 800mg/m, there was only 1(3%) partial response.8

Effect on patient survival

In the four trials the overall median survival times for responders and non-responders (7-9 months) were similar.58 These overall median survival times are comparable with those seen with other single-drug or combination chemotherapy (3-9 months), and with best supportive care which sometimes includes palliative radiotherapy (2.1-8.7 months).9

Effect on patient activity

Change in performance score (a measurement of the patient's physical capabilities) was evaluated in one of the open trials: 31% of patients had an improvement in performance score that lasted at least 28 days.5 In a further 67% of patients, scores over this period remained stable and in 2% scores worsened.10 For the other trials details of performance score and symptom control are not published. However, a brief analysis of symptom improvement given in abstract form for 243 patients in two of the open studies suggests that gemcitabine might improve some symptoms.11 Haemoptysis improved in all those with the symptom, cough in 73%, dyspnoea in 51%, anorexia in 38% and chest pain in 37%.11 However, the numbers of patients with each of these symptoms were not given. Symptomatic improvements must be weighed against unwanted effects of treatment and no detailed risk-benefit assessment has yet been published.

Unwanted effects

Data from open studies suggest that gemcitabine is relatively well-tolerated,12 with most patients being able to be treated as out-patients. Nausea and vomiting, needing treatment with a standard anti-emetic such as metoclopramide or prochlorperazine, occurs in 20% of patients. A 5-HT3 antagonist such as ondansetron has not generally been needed. Gemcitabine can cause bone marrow suppression. Patients given the drug should have blood counts measured fortnightly. If these fall below the normal ranges, the dose of gemcitabine should be either reduced, or doses withheld. About two-thirds of patients develop a mild but transient rise in liver transaminases and about half develop mild proteinuria and haematuria. Renal failure of unknown cause has been reported during gemcitabine therapy. Patients with liver or kidney impairment were excluded from the reported trials. The data sheet recommends that gemcitabine be used with caution in those with impaired liver function and those with significant renal impairment and that liver function and serum creatinine be measured periodically in those given gemcitabine. It would seem prudent to monitor liver and kidney function after each cycle of therapy.

About a quarter of patients develop a rash which is typically macular, varies in its location and may not occur with every course of treatment. Some patients develop skin pigmentation at the rash site. Peripheral oedema unrelated to cardiac or renal function occurs in about a third of patients. This resolves when gemcitabine is stopped. Gemcitabine can cause influenza-like symptoms (e.g. fever, headache, chills) which generally respond to paracetamol. Alopecia occurs but is rare.

Interactions

The data sheet warns against using radical radiotherapy (aimed at curing disease) concurrently with gemcitabine (an unlicensed use) because potentially fatal oesophagitis or pneumonitis may result. In animals gemcitabine and cisplatin appear synergistic.13 Gemcitabine's possible synergism with other cytotoxic drugs in patients needs further investigation.

Dose and cost

The data sheet recommends that gemcitabine is given as a 30-minute i.v. infusion at a dose of 1000mg/m body surface area once a week for 3 weeks, followed by a 1-week rest. Repeated cycles may be given. The drug cost of one 3-week cycle is £487 for an average adult (body surface area 1.73m).

Conclusion

Data from non-randomised, uncontrolled studies suggest that gemcitabine is relatively well-tolerated and in about 20% of patients with advanced non-small-cell lung cancer produces a reduction in tumour size of at least 50%. This is similar to the response rates seen with other single-drug regimens. It is not known, however, whether gemcitabine improves symptoms and quality of life better than do supportive care and palliative radiotherapy, or how the drug compares with commonly used chemotherapeutic regimens. Well-controlled clinical trials are needed to define the place of gemcitabine in the management of non-small-cell lung cancer. Until such information is published, the use of gemcitabine remains essentially experimental.

References

[M = meta-analysis; R = randomised controlled trial; S = sponsored symposium]

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