The Pharmaceutical Journal
Vol 272 No 7304 p772-773
19 June 2004

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American Society of Clinical Oncology

Weekly Taxol effective in breast cancer

In patients with metastatic breast cancer a weekly regimen of paclitaxel (Taxol) is superior to the standard three-weekly regimen, according to data presented at the meeting.

Patients were randomised to receive either weekly paclitaxel 80mg/m² via a one-hour infusion or standard three-weekly paclitaxel 175mg/m² via a three-hour infusion. During the course of the study it became the standard of care to administer trastuzumab (Herceptin) along with paclitaxel in patients with human epidermal growth factor-2 (HER2)-positive metastatic breast cancer. HER2 status was therefore assessed and patients who were found to be HER2-positive received trastuzumab; patients found to be HER2-negative were randomised to receive trastuzumab or placebo. In addition, 158 patients treated with standard paclitaxel in a previous study (Winer et al, Journal of Clinical Oncology 2004;22:2061–8) contributed data to the final analysis.

Forty per cent of patients in the weekly paclitaxel group (n=350) responded to treatment compared with 28 per cent of patients in the standard paclitaxel group (n=230) (P=0.017). The addition of trastuzumab in HER2-negative patients did not improve the response rate. Time to progression was nine months in the weekly paclitaxel group and five months in the standard group (P=0.0008) and, again, addition of trastuzumab in HER2-negative patients did not prolong time to progression. No significant survival advantage was shown in patients receiving weekly paclitaxel with or without trastuzumab.

It was noted that weekly paclitaxel resulted in less myelosuppression but more neurosensory and neuromotor toxicity than three-weekly paclitaxel.

Andrew Seidman, Memorial Sloan-Kettering Cancer Centre, New York, and lead investigator, said: “When considered together with the results of [Dr Winer’s study], where an increase in paclitaxel dose did not improve outcome, the present results are consistent with the concept that the frequency of drug administration, or density, may account for the improved efficacy that was observed.”

Participants at the conference raised the question of whether it was statistically valid to “borrow” data from patients in Dr Winer’s study and incorporate them into a randomised controlled trial, particularly as the results of Dr Winer’s study were already known.

Dr Seidman replied that without the extra patients the study was underpowered but the results still point in the same direction.

Raloxifene continues to prevent breast cancer

Analysis of data collected from 3,510 post-menopausal women receiving treatment with raloxifene (Evista) for osteoporosis shows that the risk of invasive breast cancer continues to be substantially reduced after eight years of therapy.

Previous data have shown a reduced incidence after four years and these data indicate that this reduction extends to eight years, with a 66 per cent reduction in incidence of invasive breast cancer in the raloxifene group compared with the placebo group.

Silvana Martino, of the Cancer Institute Medical Group, Santa Monica, California, who presented the data, noted that there was a two-fold increase in the risk of venous thromboembolism in the raloxifene compared with placebo group but said that it was still a rare event and prophylaxis should not be necessary.

She also commented that before the drug could be used routinely to reduce the risk of breast cancer, Food and Drug Administration approval and more data are needed.

Survival benefit with gemcitabine/paclitaxel

Gemcitabine (Gemzar) is a new standard of care for first-line treatment of women with metastatic breast cancer, said Kathy Albain, professor of medicine, Loyola University Chicago, Illinois, who presented the interim analysis of a phase III trial.

The study involved 529 women with metastatic breast cancer whose disease had advanced despite previous anthracycline therapy. The women had not received additional therapy for their disease. They were randomised to receive gemcitabine plus paclitaxel (Taxol) or paclitaxel alone in three-weekly cycles and follow-up was for a median of 15.6 months.

Median overall survival was 18.5 months for women in the gemcitabine/paclitaxel group and 15.8 months for women in the paclitaxel-only group. Those in the gemcitabine/paclitaxel group had a 22.5 per cent reduction in risk of death (P=0.018).

An increase in median time to progression and a better response rate in women taking the combination therapy has previously been reported (see PJ, 14 June 2003, p818) and these improvements were strengthened by the results of this interim analysis.

Professor Albain said that the combination therapy was well tolerated. However, women in the gemcitabine/paclitaxel group did experience higher rates of hair loss, neutropenia and fatigue than those in the paclitaxel-only group. Therapy ended due to adverse events in 6.7 per cent of women in the gemcitabine/paclitaxel group and 5.0 per cent of women in the paclitaxel-only group.

Quality of life was a secondary endpoint and measurements of QoL in women in the gemcitabine/paclitaxel group were significantly better than in those receiving paclitaxel alone.

More data for lung cancer adjuvant therapy

Data presented from two studies support the use of adjuvant chemotherapy in patients with lung cancer.

The first study involved 482 patients with completely resected early stage non-small cell lung cancer who received cisplatin and vinorelbine (Navelbine) in combination over 16 weeks or observation alone. The second study involved 344 similar patients who received a combination of paclitaxel and carboplatin for 12 weeks or observation alone.

A significant improvement in survival was seen after five and four years, respectively.

Bortezomib better than dexamethasone in myeloma

Results from a phase III randomised controlled trial suggest that bortezomib (Velcade) is superior to the current standard of care, dexamethasone, in treating patients with relapsed multiple myeloma.

The 657 patients evaluated in the trial had previously received one to three lines of chemotherapy. Patients in the bortezomib group showed a reduced time to disease progression compared with the dexamethasone group (5.7 months and 3.6 months, respectively). At eight-month follow-up there were 48 deaths in the bortezomib group and 81 deaths in the dexamethasone group (P<0.01). In addition, there was a trend towards a lower incidence of serious infections in patients in the bortezomib group compared with those in the dexamethasone group (7 and 11 per cent, respectively).

The trial was stopped early and patients in the dexamethasone group whose disease had progressed could cross over to the bortezomib group. The improvement in survival continued when 50 per cent of patients in the dexamethasone group crossed over to receive bortezomib.

Paul Richardson, Dana-Farber Cancer Institute, Boston, Massachusetts, and lead author, said that the results are encouraging and will likely lead to the earlier use of bortezomib in patients with relapsed multiple myeloma.

As a secondary endpoint the researchers also looked at the gene characteristics of patients’ tumours to try to define what determines whether a patient benefits from a therapy.

Oral fluoropyrimidines as good as standard IV 5-fluorouracil/folinic acid in colon cancer

In patients with metastatic colorectal cancer giving capecitabine (Xeloda) orally as an adjunct to surgery is as effective as giving IV bolus 5-fluorouracil/folinic acid, the results of a phase III randomised controlled trial (X-ACT) demonstrate.

The aim of the study was to determine whether capecitabine is at least equivalent to 5-FU/FA with respect to disease-free survival. Follow up was for a median of 3.8 years.

The researchers found an increase in relapse-free survival in the capecitabine group over three years (hazard ratio=0.86 [95 per cent confidence interval 0.74–0.99]; P=0.041). They also noted a trend towards an increase in disease-free survival (P=0.0528) and improved overall survival (P=0.0706).

Capecitabine had an improved safety profile compared with 5-FU/FA, however, an increase in hand-foot syndrome was observed.

Jim Cassidy, Cancer Research UK professor of oncology, Glasgow University, who presented the data, said: “In my opinion capecitabine should replace 5-FU/FA in Dukes C colon cancer.”

Commenting on this along with another study presented at the meeting, Eric Van Cutsem, Digestive Oncology Unit, Leuven, Belgium, said: “X-ACT is an excellent equivalence trial ... in my opinion oral fluoropyrimidines are to be preferred to bolus IV 5-FU/FA in adjuvant treatment based on these two pivotal studies.”

The National Institute for Clinical Excellence recommended last year that capecitabine should be available as an option for treatment of metastatic colon cancer (see PJ, 31 May 2003, p741).

Data support CHOP-rituximab as standard

In younger patients with diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) adding rituximab (MabThera) to their standard CHOP-like chemotherapy improves overall survival, new data from a phase III trial suggest. The value of rituximab (a monoclonal antibody that binds to the CD20 antigen often found on lymphoma cells) in older patients with DLBCL has already been shown.

The trial recruited 824 patients aged between 18 and 60 years with “good prognosis” DLBCL who had not previously received chemotherapy. Patients were randomised to receive six cycles of a “CHOP-like” regimen (cyclophosphamide, vincristine, prednisolone, doxorubicin and etoposide) plus or minus rituximab 375mg/m² on days 1, 22, 43, 64, 85 and 106.

Interim analysis of 326 patients after a median of 24 months revealed that time to treatment failure was longer in the rituximab group than in the chemotherapy only group (81 per cent vs 58 per cent; P<0.000005) and the trial was stopped early. Overall survival at this time was 95 per cent in the CHOP-R group and 85 per cent in the CHOP group (P=0.0026). Commenting on the trial results, Richard Fischer, University of Rochester School of Medicine, Minnesota, said: “I think the time has come to call this the standard [treatment].”

The National Institute for Clinical Excellence has recommended that rituximab is used as first-line therapy for DLBCL in combination with CHOP (see PJ, 27 September 2003, p397).

Letrozole improves survival

Data from a phase III randomised controlled trial show a decrease in mortality in postmenopausal women with early stage breast cancer who take letrozole (Femara) after five years of tamoxifen therapy. The trial involved 5,187 patients and an improvement in disease-free survival in the letrozole group was seen regardless of nodal status.

Prostate cancer survival benefit

Docetaxel/estramustine is better than mitoxantrone/prednisolone in men with androgen-independent prostate cancer, according to phase III trial data. A 23 per cent improvement in survival was seen in the docetaxel/estramustine group. Time to progression was prolonged and response rate was higher. However, toxicity was also increased in this group.

Gefitinib most effective in women

A phase II trial of gefitinib (Iressa) in patients with advanced bronchioloalveolar carcinoma has shown differences in outcomes based on gender, smoking status and rash development. Females survived longer than males, non-smokers survived longer than smokers and patients who developed a rash survived longer than those who did not.

Rituximab maintenance therapy

Maintenance therapy with rituximab in patients with advanced slow growing non-Hodgkin’s lymphoma delays time to progression, trial data show. Giving rituximab after disease progression or as maintenance therapy are both valid options until survival benefit can be shown, commented Richard Fischer, University of Rochester School of Medicine, Minnesota.