Advances in Chemotherapeutic Treatments: Prospects with Paclitaxel

Cancers are a major contributor to the leading causes of death around the world, with many millions of cases diagnosed each year. Treatment options include surgery, radiotherapy, chemotherapy, or a combination of the tree. Paclitaxel (anzatax) belongs to a group of antineoplastic medications, also known as the taxoid drugs or taxanes, acting to inhibit the mitotic process central to a range of cancers. This chemotherapeutic agent has shown promising results and is now used in the primary treatment of ovarian cancer, metastatic ovarian cancer and metastatic breast cancer; and in the adjuvant treatment of node positive breast cancer, non small cell lung cancers, and some head and neck cancers. Multiple studies have demonstrated the improvement paclitaxel offers in patient morbidity and mortality.

Paclitaxel was initially listed on the PBS in 1994 as an authority benefit for treating advanced metastatic ovarian carcinoma after standard treatment failure. Two years later, the authority listing was extended to include the treatment of advanced metastatic breast cancer after standard therapy failure, and also, in combination with a platinum compound, for the primary treatment of ovarian cancer. In 2000 paclitaxel was approved for the adjuvant treatment of node-positive, oestrogen receptor-negative breast cancer, administered sequentially with doxorubicin and cyclophosphamide.¹Breast CancerAdjuvant treatmentThere have been multiple clinical trials investigating the effects of adjuvant taxoid drugs due to their high levels of activity and survival benefits in metastatic disease, and also to their potential effects against anthracycline-resistant disease. Numerous major randomized studies involving sequential paclitaxel have been conducted. A trial known as the CALGB (Cancer and Leukaemia Group B) 9344 was conducted in 3170 women with node-positive primary breast cancer. The study group included both oestrogen receptor-positive and receptor-negative cancer patients. The trial evaluated 4 cycles of escalating doses of doxorubicin combined with a fixed dose of cyclophosphamide, with or without 4 cycles of sequential paclitaxel. After 52 months there were significant changes, compared with results at 21 and 30 months. Patients who received sequential paclitaxel to cyclophosphamide had a statistically significant improved disease-free survival rate, but not overall survival rate. At 48 months follow-up, the disease-free survival rate for patients treated with sequential paclitaxel was 73%, versus 70% for those treated with cyclophosphamide alone. The study also showed that adjuvant paclitaxel has the greatest benefit on disease-free survival in patients with oestrogen receptor-negative tumours.³Anthracycline-Taxane CombinationsMany randomised trials have investigated the use of taxanes in the treatment of metastatic breast cancer. Often, taxanes were combined or sequentially used with an anthracycline where anthracycline preparations alone failed to manage metastatic disease. Paclitaxel has been studied as a second line single agent in several randomised phase II trials, and as therapy following failure of doxorubicin in phase III trials. Response rates ranging from 16% to 32% have been obtained.⁵Neoadjuvant TherapyNeoadjuvant chemotherapy has significantly improved clinical response rates and opportunities for breast conservation. Neoadjuvant taxane therapy has been used in different clinical settings, both as a single therapy and in combination with other agents.Paclitaxel has been used as a single neoadjuvant agent in phase III trials. One trial investigated 350 patients whose primary breast tumours were resected. They were randomised to either eight cycles of adjuvant FAC (5-fluorouracil, Adriamycin, and cyclophosphamide) or four cycles of paclitaxel followed by four cycles of FAC. After four years there was no statistically significant difference between the two groups, but there was a 24% reduction in the risk of recurrence with the paclitaxel-FAC combination.⁸Paclitaxel versus DocetaxelA recent trial conducted by the North American Breast Cancer Intergroup E1199 compared the two primary taxane medications, paclitaxel and docetaxel. Between 1999 and 2002, 4,988 women with lymph node-positive or high-risk node-negative breast cancer were involved in the study. All patients received 12 weeks of doxorubicin and cyclophosphamide. Following this, patients were divided into four groups to receive specific doeses of either paclitaxel weekly, paclitaxel 3-weekly, docetaxel weekly, or docetaxel 3-weekly.Results of the study were in keeping with previous conclusions that taxanes are beneficial in prolonging survival. There were no significant differences between paclitaxel and docetaxel in terms of survival rates, but docetaxel was associated with more potentially dangerous side-effects.⁷Head and Neck CancersLocally advanced cases of head and neck cancers have been given new hope, with researchers finding the addition of paclitaxel to the standard chemotherapy regimen able to treat tumours in approximately one third of patients. An improved quality of life, due to the ability to retain functions such as speaking and swallowing, was also demonstrated. 384 patients with locally advanced head and neck cancers were randomised in a phase III study, receiving treatment with either 100 mg/m² of cisplatin on day 1 and a continual infusion of 1 g/m² of 5-Fluorouracil (5-FU) for five days every three weeks; or the same drugs with the addition of 175 mg/m² of paclitaxel on day 1 of each cycle.Tumours resolved in 32% of patients who received the triple therapy incorporating paclitaxel. Chemotherapy with cisplatin and 5-FU was associated with a complete response rate in only 13% of patients. Tumours were reduced in size by half or more in 56% of patients given the paclitaxel combination, compared to 48% of those receiving conventional chemotherapy.Progression of disease was retarded to approximately 23 months in patients receiving the paclitaxel combination, compared to 18 months for patients treated with the conventional drugs. Parts of the oro-digestive tract, including the larynx, pharynx, and tongue, were preserved in 88% of patients who received the paclitaxel combination, compared with 75% of those who were treated with cisplatin and 5-FU alone.⁹Drug eluting StentsCoronary artery disease is a major cause of morbidity and mortality in contemporary society. Drug eluting stents are fast becoming a widely practised and accepted option when choosing the type of stent to treat coronary artery stenosis. A major concern in coronary artery stenting is the risk of in-stent restenosis. Patients at particular risk for this complication include those with diabetes, small vessel diameters, and long, tortuous lesions. Recent randomised controlled trials have demonstrated that drug eluting stents are undeniably associated with a reduced risk of restenosis. Paclitaxel has been commonly applied in drug eluting stents. A review was conducted, involving seven randomised controlled trials, that assessed polymer-based paclitaxel or sirolimus eluting stents versus bare-metal stents in patients with coronary atherosclerosis. Stent thrombosis, myocardial infarction, coronary artery bypass grafting and mortality rates were examined.Results from the review provided strong evidence that drug eluting stents reduce the risk of revascularisation at 12 months in patients with single atherosclerotic lesions by 71-80%, compared with bare metal stents. Results from patients in high risk groups also supported these findings. However, rates of stent thrombosis, mortality, myocardial infarction and bypass grafts did not differ by stent type. There are still issues with drug eluting stents, such as cost and longer term benefits (reductions in overall patient mortality), that need to be addressed with further research.⁴Ovarian cancersOvarian cancers are associated with poor prognoses due to their late presentation and diagnosis. There have been improvements in overall survival rates which can be partly attributed to the advancement of chemotherapy agents and techniques. Many randomised trials have been conducted. The chemotherapeutic efficacy (response rates, progression-free survival rates, overall survival rates) and decreased toxicity of the cisplatin-paclitaxel combination have been shown to be superior to those of the cisplatin-cyclophosphamide combination. Due to the response rate seen with paclitaxel in ovarian cancers, randomised prospective trials have compared a cisplatin-paclitaxel combination with a carboplatin-paclitaxel combination. Although preliminary results suggest that there is no significant difference in outcome between the carboplatin or cisplatin treatment arms, the carboplatin-paclitaxel combination is associated with fewer adverse effects.⁶ Non-Small Cell Lung Cancers (NSCLC)The effectiveness and tolerability of following platinum based chemotherapy with salvage chemotherapy for progressive cases of NSCLC are being further investigated in patient groups. A recent study was conducted on the safety and efficacy of a combination of celecoxib (celebrex) and weekly paclitaxel as a second line treatment for NSCLC. The biomarkers interleukin 6 and vascular endothelial growth factor were used as secondary endpoints. 58 patients diagnosed with platinum refractory NSCLC were enrolled in the study. Weekly doses of paclitaxel in combination with twice daily doses of celecoxib were administered for eight cycles. There was a median progression-free survival period of five months and an overall mean survival period of eleven months, with one year survival rates in 42.5% of the patient group. In summary, the combination of celecoxib and weekly paclitaxel was found to be an effective and relatively safe option in the treatment of progressive NSCLC. However, further clinical trials involving larger patient groups and randomisation of treatment regimes needs to be conducted.²References

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