Gemcitabine

Locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium.

Gemcitabine 1000mg/m2 IV day 1, 8, and 15, with cisplatin 70 mg/m2 day 2, each 28 days, receiving a maximum of 6 cycles.1

Without chemotherapy, the prognosis for patients with locally advanced or metastatic TCC of the bladder is limited with a median survival of 4–6 months.2 With chemotherapy, survival and quality of life can be increased. MVAC chemotherapy (methotrexate, vinblastine, doxorubicin [adriamycin], and cisplatin) was defined as the standard of care for the treatment of TCC during the 1980s and 1990s, with reported median survival of over 12 months.3

However this drug regimen is associated with significant toxicity—including severe mucositis, neutropenic sepsis, and treatment-related deaths in up to 4% of patients in early reports.1,3 Research continues to define new treatment regimens that provide greater benefit with increased effectiveness (or similar benefit) with lesser toxicity than those funded at present.

Gemcitabine in combination with cisplatin has been shown in a pivotal phase III study to be equally effective as MVAC in this tumour type but associated with significantly less toxicity.

The median survival of the patients with locally advanced or metastatic TCC of the bladder treated with gemcitabine and cisplatin was equivalent to that of MVAC at 14 months, and 13% of those treated on study were still alive at 5 years.1

The ‘cancer drug basket’ (Part V of Schedule H) was established in October 2001 as a result of a ministerial directive. ‘High cost’ cancer drugs within the basket are funded only for specific indications. Extension of funded treatment indications or addition of a new agent to the basket is considered upon application to PHARMAC.

Pharmaceutical companies submit the majority of applications to PHARMAC, although this facility is also available to individual clinicians. The request for a funded extension to the treatment indications for gemcitabine to include locally advanced or metastatic TCC of the bladder was the first clinician-sponsored application to PHARMAC for funding of an oncology drug, and as such has been watched with interest by the oncology community. This submission was forwarded to PHARMAC January 2004. CaTSOP (Cancer Treatments Sub-committee of PTAC) considered the submission in March 2004.

The committee considered that gemcitabine with a platinum analogue had equal effectiveness with current therapy (MVAC) but with markedly reduced adverse effects. It was noted that number of patients currently treated is low, but that more patients would be suitable for gemcitabine therapy due to the decreased toxicity of treatment. The committee estimated that approximately 70–90 patients would receive treatment per annum.

New Zealand

Gemcitabine was initially licensed in December 1998 by MedSafe for use alone or in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer. In June 1999, gemcitabine was also licensed for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. This was followed in May 2000 with licensing of gemcitabine for the treatment of patients with advanced bladder cancer (TCC).

Although licensed for use in TCC from May 2000, gemcitabine is currently not funded for this indication. Currently gemcitabine is listed in Part V of Section H (July 2005) of the Pharmaceutical Schedule5 for the restricted indications of:

International

By comparison, gemcitabine has been funded for TCC in Australia since August 2001,6 and is used for this indication within the NHS in the United Kingdom.

Gemcitabine for use in TCC can be obtained through prescription at a cost of $1983 per cycle (3 doses calculated at average body surface area of 1.8m2), but is not able to be administered in the public health sector for this indication, although it is commonly used in public hospital oncology units for the above funded indications.

PHARMAC’s cost-utility analysis4 based on the data from the pivotal study calculates a cost of $817,808 per QALY (Quality Adjusted Life Year) gained when using gemcitabine and cisplatin for advanced bladder cancer compared to the historical regimen of MVAC. This figure was generated from an incremental treatment cost calculated for cisplatin and gemcitabine over that of MVAC of $4276.60, and an estimated incremental benefit of 0.00523 QALYs gained.

The calculated incremental cost of treatment is similar to those calculated in other countries of GBP £2976(7) and AUD $5035 (communication Eli Lilly8), however the incremental utility gained was 25 times greater in the UK study at 0.13 QALYs than that proffered by PHARMAC. If the UK utility is used for PHARMAC’s calculations, the cost decreases by the same magnitude to $32,900 per QALY.

There is no accessible site on PHARMAC’s webpage that provides up-to-date information on drug submissions made.9 Recent accessing of the site reported applications that had been made up until July 2005, but does not include the submission for gemcitabine. This site also only lists the drug and the applicant, but not the treatment indication for which the submission has been made.

The first is the time to receive a decision from the process. The application was submitted early 2004, and reviewed by CaTSOP within a few months. Since that time there has been no formal decision notified, and it is unclear where the application is in the PHARMAC process. It is now over 18 months since the submission was made. During this process, gemcitabine is not available for use in advanced TCC bladder, at least not within the public system.

This lack of transparency of the process regarding submissions has also been true of subsequent clinician applications. It is also unclear from PHARMAC’s own website which submissions have been made or are being currently considered. The cited PHARMAC report in this commentary was made available under the Official Information Act and the fate of the gemcitabine application is unknown at present (9 months after the PHARMAC report).

PHARMAC’s pharmacoeconomic analysis is admittedly a preliminary analysis, however these analyses are instrumental in decisions regarding funding of new treatments. It is of concern that there is such a large discrepancy in the utility calculated by PHARMAC and that reported in a peer-reviewed journal, especially as the magnitude of the difference leads to a cost per QALY of $817,808 rather than $32,900.

Decisions to fund or not fund treatments need to be based on robust analysis. Large discrepancies between reports raise the question of the accuracy of the assumptions and calculations made. To gain confidence in the process used there needs to be complete transparency such that the assumptions made are seen to be evidence based, inaccuracies can be challenged, and the resulting calculations or decisions are robust and able to withstand scrutiny.